ABSTRACT
In the search for versatile and effective weld cladding processes to deposit ultra-wear-resistant Ni-WC MMC (Ni-based tungsten carbide metal matrix composite) overlays for mining applications, there is an increasing interest in exploring advanced low-heat-input cold metal transfer (CMT) method. Depositions of single weld bead tracks of Ni-WC MMCs on steel plates were performed by employing the CMT process; Taguchi's design of experiments was used to plan the experimental investigation. All weld tracks exhibit continuous and uniform bead profile and sound metallurgical bonding to the substrate. Retained WCs are present in the overlay tracks relatively uniformly. The formation of primary WC and secondary carbides is observed depending on the level of dilution. In contrast to standard gas metal arc welding processes, the volume fraction of retained WC, which is negatively correlated with dilution level, is not directly interrelated with heat input for the CMT process and can reach a high level together with improved weld bead appearance at high deposition rate. Deposition rate has a positive correlation with average instantaneous power, which is, in turn, positively correlated with wire feed speed. The addition of oxygen into shielding gas mixtures promotes carbide transfer from cored feed wire to the weld track and increases the volume fraction of retained WC. Analysis of signal-to-noise ratios shows that it is difficult to find a single set of optimized processing parameters, and trade-offs are needed in engineering practice. The present investigation demonstrates that the Taguchi method is a powerful tool in process improvement for weld cladding of Ni-WC MMC overlays.
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Novel N-benzylarylamide saderivatives were designed and synthesized, and their antiproliferative activities were explored. Some of 51 target compounds exhibited potent inhibitory activities against MGC-803, HCT-116 and KYSE450 cells with IC50 values in two-digit nanomolar. Compound I-33 (MY-875) displayed the most potent antiproliferative activities against MGC-803, HCT-116 and KYSE450 cells (IC50 = 0.027, 0.055 and 0.067 µM, respectively) and possessed IC50 values ranging from 0.025 to 0.094 µM against other 11 cancer cell lines. Further mechanism studies indicated that compound I-33 (MY-875) inhibited tubulin polymerization (IC50 = 0.92 µM) by targeting the colchicine bingding site of tubulin. Compound I-33 (MY-875) disrupted the construction of the microtubule networks and affected the mitosis in MGC-803 and SGC-7901 cells. In addition, although it acted as a colchicine binding site inhibitor, compound I-33 (MY-875) also activated the Hippo pathway to promote the phosphorylation status of MST and LATS, resulting in the YAP degradation in MGC-803 and SGC-7901 cells. Due to the degradation of YAP, the expression levels of TAZ and Axl decreased. Because of the dual actions on colchicine binding site and Hippo pathway, compound I-33 (MY-875) dose-dependently inhibited cell colony formatting ability, arrested cells at the G2/M phase and induced cells apoptosis in MGC-803 and SGC-7901 cells. Moreover, compound I-33 (MY-875) could regulate the levels of cell cycle and apoptosis regulatory proteins in MGC-803 and SGC-7901 cells. Furthermore, molecular docking analysis suggested that the hydrogen bond and hydrophobic interactions made compound I-33 (MY-875) well bind into the colchicine binding site of tubulin. Collectively, compound I-33 (MY-875) is a novel anti-gastric cancer agent and deserves to be further investigated for cancer therapy by targeting the colchicine binding site of tubulin and activating the Hippo pathway.
Subject(s)
Antineoplastic Agents , Tubulin Modulators , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Colchicine/pharmacology , Drug Screening Assays, Antitumor , Hippo Signaling Pathway , Molecular Docking Simulation , Polymerization , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
Purpose: Idiopathic rapid eye movement Sleep Behavior Disorder (iRBD) is considered as a prodromal and most valuable warning symptom for Parkinson's disease (PD). Although iRBD and PD without RBD (nRBD-PD) are both α-synucleinopathies, whether they share the same neurodegeneration process is not clear enough. In this study, the pattern and extent of neurodegeneration were investigated and compared between early-stage nRBD-PD and iRBD from the perspective of whole-brain functional network changes. Methods: Twenty-one patients with iRBD, 23 patients with early-stage nRBD-PD, and 22 matched healthy controls (HCs) were enrolled. Functional networks were constructed using resting-state functional MRI (fMRI) data. Network topological properties were analyzed and compared among groups by graph theory approaches. Correlation analyses were performed between network topological properties and cognition in the iRBD and nRBD-PD groups. Results: Both patients with iRBD and patients with early-stage nRBD-PD had attention, executive function, and some memory deficits. On global topological organization, iRBD and nRBD-PD groups still presented small-worldness, but both groups exhibited decreased global/local efficiency and increased characteristic path length. On regional topological organization, compared with HC, nRBD-PD presented decreased nodal efficiency, decreased degree centrality, and increased nodal shortest path length, while iRBD presented decreased nodal efficiency and nodal shortest path. For iRBD, brain regions with decreased nodal efficiency were included in the corresponding regions of nRBD-PD. Nodal shortest path changes were significantly different in terms of brain regions and directions between nRBD-PD and iRBD. Attention deficits were correlated with local topological properties of the occipital lobe in both iRBD and nRBD-PD groups. Conclusion: Both global and local efficiency of functional networks declined in nRBD-PD and iRBD groups. The overlaps and differences in local topological properties between nRBD-PD and iRBD indicate that iRBD not only shares functional changes of PD but also presents distinct features.
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To ensure safety and prevent failure of engineering equipment throughout its lifespan, the concept of 'Safety Design' is proposed, which covers all the cradle-to-grave phases of engineering equipment, considers at least ten essential factors of failure causes, and conducts root cause analysis at three different scales, in order to proactively control the safety risks before the occurrence of failure rather than passively conduct the remedial measures after failure. Herein, in order to demonstrate how to implement this effective and efficient concept in engineering practice, a case study of failure analysis and prevention is addressed on the extraction column in the production line for methyl methacrylate. Based on the analysis results, the causes were finally determined to be all derived from the stages before operation, including inappropriate design, limited quality inspection of fabrication and installation. Pertinent countermeasures were then proposed from the 'Safety Design' point of view, which would not only solve the failure problem for this sole equipment but also contribute to safety risk control of other engineering equipment before operation.
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INTRODUCTION: The structural and functional damages of the striatum were evident in idiopathic REM sleep behavior disorder (iRBD). With the research on iRBD deepens, cognitive impairment in iRBD is getting increasing attention. However, the mechanism of cognitive impairment in iRBD was poorly understood. METHODS: Neuropsychological assessment was carried out in 21 polysomnographies (PSGs) confirmed iRBD patients and 22 normal controls. Both regional homogeneity (ReHo) and seed-based functional connectivity (FC) rs-fMRI analyses were applied to explore the FC abnormalities and its association with cognition in iRBD patients. Positive ReHo clusters were set as seeds for further FC analysis. RESULTS: Idiopathic REM sleep behavior disorder patients presented cognitive deficits in attention/working memory, executive function, immediate memory, and visuo-spatial ability. ReHo analysis revealed abnormal spontaneous brain activities in the striatum (right caudate, left pallidum and bilateral putamen) in iRBD. FC analysis showed decreased striatum-related FCs in the frontal, temporal, occipital lobes, thalamus, anterior cingulate gyrus, as well as decreased intrinsic FCs between bilateral putamen and between caudate and pallidum. Deficits in attention/working memory, executive function, and immediate memory were associated with abnormal striatal-cortical FCs including frontal, temporal, and anterior cingulate cortices. CONCLUSION: Functional changes of striatum and cognitive impairment in iRBD were reconfirmed in the present study. Abnormal striatal-cortical networks, especially the striatal-frontal network, contribute to the working memory/executive function deficits in iRBDs. These findings supported the role of striatum not only in motor but also in cognition impairment in iRBD.
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OBJECTIVE: The present aimed to evaluate the efficacy and safety of fluconazole for prophylactic use in preterm infants with very low birth weight (VLBW) by using an evidence-based methodology. METHODS: A computerized literature search was conducted in PubMed, the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, the ISI Web of Knowledge databases, the Chinese Biomedical (CBM) database, China National Knowledge Infrastructure, the WanFang database, and the VIP Chinese science and technology journal database to find all the randomized controlled trials conducted between January 2000 and December 2019 that studied the prevention of invasive fungal infection (IFI) by fluconazole in preterm infants with VLBW. A meta-analysis was conducted using the RevMan 5.3 and GRADEprofiler 3.2.2 software. RESULTS: A total of 14 studies (including 1,930 preterm infants with VLBW) were included. The meta-analysis found that the prophylactic use of fluconazole significantly reduced the incidence of IFI (RR = 0.39; 95% CI: 0.24-0.64, P < 0.05), overall mortality (RR = 0.77; 95% CI: 0.61-0.97, P < 0.05), and fungal colonization rate (RR = 0.32; 95% CI: 0.25-0.41, P < 0.05) in preterm infants with VLBW. There was no significant effect on some common complications and neurological development in preterm infants. The application of fluconazole would not lead to the development of fungal resistance in the short term and would have no significant adverse effects. CONCLUSION: The prophylactic use of fluconazole significantly reduced the incidence of IFI, overall mortality, and fungal colonization in preterm infants; however, the impact of prophylactic use of fluconazole on preterm infants needs to be evaluated in a large number of clinical studies because of the limited data.
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A series of novel indole derivatives were synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (MGC803, EC-109 and PC-3). Among these analogues, 2-(5-methoxy-1H-indol-1-yl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (V7) showed the best inhibitory activity against MGC803 cells with an IC50 value of 1.59 µM. Cellular mechanisms elucidated that V7 inhibited colony formation, induced apoptosis and arrested cell cycle at G2/M phase. Importantly, indole analogue V7 inhibited NEDDylation pathway and MAPK pathway against MGC803 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Indoles/chemistry , Signal Transduction/drug effects , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Damage/drug effects , Drug Design , Drug Evaluation, Preclinical , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Indoles/pharmacology , Mitogen-Activated Protein Kinases/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Structure-Activity Relationship , Ubiquitin-Conjugating Enzymes/metabolismABSTRACT
Tubulin, an important target in tumor therapy, is one of the hotspots in the field of antineoplastic drugs in recent years, and it is of great significance to design and screen new inhibitors for this target. Natural products and chemical synthetic drugs are the main sources of tubulin inhibitors. However, due to the variety of compound structure types, it has always been difficult for researchers to screen out polymerization inhibitors with simple operation, high efficiency and low cost. A large number of articles have reported the screening methods of tubulin inhibitors and their biological activity. In this article, the biological activity detection methods of tubulin polymerization inhibitors are reviewed. Thus, it provides a theoretical basis for the further study of tubulin polymerization inhibitors and the selection of methods for tubulin inhibitors.
Subject(s)
Tubulin Modulators/pharmacology , Tubulin/metabolism , Humans , Polymerization/drug effects , Tubulin Modulators/chemistryABSTRACT
Pesticide residues have become a healthy threaten of human beings. Among the pesticides, many of them have neurotoxicity. Extracellular Regulated Protein Kinases (ERK) pathway is an important signaling pathway that regulates a variety of downstream progress. In this work, peach (PRUNUS persica) and cherry (PRUNUS cerasus) were sampled from over 300 plantations in China and assessed for the residue risk. In mechanism studies, high-risk pesticide Avermectin showed a high activity inhibiting three neurotoxicity models, SH-SY5Y, PC-12 and SK-N-SH cells. At protein levels, ERK pathway proteins and their downstream proteins were obviously down-regulated. Moreover, the effects of low-dose Avermectin can be accumulated at protein levels in the low-dose long-term chronic toxicology detection.
Subject(s)
Pesticide Residues , raf Kinases , China , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Ivermectin/analogs & derivatives , MAP Kinase Kinase Kinases , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase Kinases/metabolism , raf Kinases/metabolismABSTRACT
Chalcone is a common scaffold found in many biologically active compounds. The chalcone scaffold was also frequently utilized to design novel anticancer agents with potent biological efficacy. Aiming to continue the research of effective chalcone derivatives to treat cancers with potent anticancer activity, fourteen amino chalcone derivatives were designed and synthesized. The antiproliferative activity of amino chalcone derivatives was studied in vitro and 5-Fu as a control group. Some of the compounds showed moderate to good activity against three human cancer cells (MGC-803, HCT-116 and MCF-7 cells) and compound 13e displayed the best antiproliferative activity against MGC-803 cells, HCT-116 cells and MCF-7 cells with IC50 values of 1.52 µM (MGC-803), 1.83 µM (HCT-116) and 2.54 µM (MCF-7), respectively which was more potent than the positive control (5-Fu). Further mechanism studies were explored. The results of cell colony formatting assay suggested compound 10e inhibited the colony formation of MGC-803 cells. DAPI fluorescent staining and flow cytometry assay showed compound 13e induced MGC-803 cells apoptosis. Western blotting experiment indicated compound 13e induced cell apoptosis via the extrinsic/intrinsic apoptosis pathway in MGC-803 cells. Therefore, compound 13e might be a valuable lead compound as antiproliferative agents and amino chalcone derivatives worth further effort to improve amino chalcone derivatives' potency.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Chalcone/chemical synthesis , Chalcone/pharmacology , Chemistry Techniques, Synthetic , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chalcone/analogs & derivatives , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
On the basis and continuation of our previous studies on anti-tubulin and anti-gastric cancer agents, novel tertiary amide derivatives incorporating benzothiazole moiety were synthesized and the antiproliferative activity was studied in vitro. Preliminary structure activity relationships (SARs) were explored according to the in vitro antiproliferative activity results. Some of compounds could significantly inhibit the proliferation of three cancer cells (HCT-116, MGC-803 and PC-3 cells) and compound F10 exhibited excellent antiproliferative activity against HCT-116 cells (IC50 = 0.182 µM), MGC-803 cells (IC50 = 0.035 µM), PC-3 cells(IC50 = 2.11 µM) and SGC-7901 cells (IC50 = 0.049 µM). Compound F10 effectively inhibited tubulin polymerization (IC50 = 1.9 µM) and bound to colchicine binding site of tubulin. Molecular docking results suggested compound F10 could bind tightly into the colchicine binding site of ß-tubulin. Moreover, compound F10 could regulate the Hippo/YAP signaling pathway. Compound F10 activated Hippo signaling pathway from its very beginning MST1/2, as the result of Hippo cascade activation YAP were inhibited. And then it led to a decrease of c-Myc and Bcl-2 expression. Further molecular experiments showed that compound F10 arrested at G2/M phase, inhibited cell colony formatting and induced extrinsic and intrinsic apoptosis in MGC-803 and SGC-7901 cells. Collectively, compound F10 was the first to be reported as a new anticancer agent in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.
Subject(s)
Amides/chemistry , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/drug effects , Stomach Neoplasms/pathology , Tubulin/chemistry , Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Drug Design , G2 Phase Cell Cycle Checkpoints/drug effects , Hippo Signaling Pathway , Humans , M Phase Cell Cycle Checkpoints/drug effects , Protein Multimerization/drug effects , Protein Structure, Quaternary , Transcription Factors/metabolism , YAP-Signaling ProteinsABSTRACT
NEDDylation pathway regulates multiple physiological process, unlike inhibitors, NEDDylation activators are rarely studied. Novel amide derivatives were synthesized and evaluated for antiproliferative activity against MGC803, MCF-7 and PC-3 cells. Among them, â ¦-31 displayed the most potent activity with an IC50 value of 94 nmol/L against MGC803 cells. Cellular mechanisms elucidated that â ¦-31 inhibited the cell viability, arrested cell cycle at G2/M phase and induced apoptosis via intrinsic and extrinsic pathways against MGC803 cells. In addition, â ¦-31 activated NAE1-Ubc12-Cullin1 NEDDylation via interacting with NAE1 directly. Furthermore, the activation of NEDDylation resulted in the degradation of inhibitor of apoptosis proteins (IAPs). Importantly, â ¦-31 inhibited tumor growth in xenograft models in vivo without the apparent toxicity. In summary, it is the first time to reveal that â ¦-31 deserves consideration for cancer therapy as a NEDDylation activator.
Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Drug Discovery , NEDD8 Protein/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Neddylation modification is often over-expressed in a variety of human tumor cells. Therefore, targeting neddylation pathway may represent a potential approach to the treatment of human tumors. Herein, we describe the discovery of a hit scaffold from our in-house library and further structure-based optimizations. In this work, compound V11 could block the neddylation and inhibit the activity of NAE (with an EC50 value of 3.56⯵M), and a dose-dependent reduction of the Ubc12-NEDD8 conjugations was also observed. Molecular docking results suggest compound V11 could bind tightly to NAE via hydrogen bonds and hydrophobic interactions. Compound V11 showed the best antiproliferative ability with an IC50 value of 8.22⯵M against gastric cancer MGC-803 cells. Further anticancer activity studies suggested that compound V11 inhibited MGC-803 cell growth, caused a cell cycle arrestment at G2/M phase and induced apoptosis via extrinsic and intrinsic apoptosis pathways. All the findings suggest that 1,2,4-triazine scaffold might provide a novel scaffold for the further development of neddylation inhibitors and compound V11 might be a potential neddylation inhibitor with anticancer activity.
Subject(s)
Antineoplastic Agents/chemistry , Triazines/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Molecular Docking Simulation , NEDD8 Protein/metabolism , Protein Processing, Post-Translational/drug effects , Protein Structure, Tertiary , Stomach Neoplasms , Structure-Activity Relationship , Triazines/pharmacology , Ubiquitin-Conjugating Enzymes/metabolismABSTRACT
The effect of dietary conjugated linoleic acid (CLA) supplementation on lipid metabolism in laying hens was investigated. A total of 360 eighteen-wk-old Hy-Line Brown layers were randomly divided into 4 groups that consisted of 6 replicates with 15 birds each. Birds were fed basal diets with 0, 1%, 2%, and 4% CLA addition. The experiment lasted for 56 D after a 7-D adaptation period. Results showed that dietary CLA addition linearly reduced (P < 0.05) abdominal fat percentage but linearly increased (P < 0.05) relative liver weight of layers on day 56. A linear reduction (P < 0.05) in serum low-density lipoprotein cholesterol (LDL-C) level and a linear elevation (P < 0.05) in the ratio of serum high-density lipoprotein cholesterol level to LDL-C level of layers on both days 28 and 56 were observed with dietary CLA addition, which also linearly decreased (P < 0.05) cholesterol content in the liver of layers on day 56 as well as in eggs on both days 28 and 56. Besides, there were linear reductions (P < 0.05) in the gene expression and contents of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and cholesterol 7 alpha hydroxylase 1 (CYP7A1), along with a linear increase (P < 0.05) in the gene expression and content of hepatic low-density lipoprotein receptor (LDLR) in layers responded to dietary CLA addition. In conclusion, dietary CLA supplementation decreased the accumulation of lipids including abdominal fat and cholesterol in the liver and egg of laying hens, probably by upregulating hepatic LDLR expression and downregulating hepatic HMGR and CYP7A1 expression.
Subject(s)
Chickens/genetics , Cholesterol 7-alpha-Hydroxylase/genetics , Gene Expression , Hydroxymethylglutaryl CoA Reductases/genetics , Linoleic Acids, Conjugated/metabolism , Lipid Metabolism , Receptors, LDL/genetics , Animal Feed/analysis , Animals , Avian Proteins/genetics , Avian Proteins/metabolism , Chickens/metabolism , Cholesterol 7-alpha-Hydroxylase/metabolism , Diet/veterinary , Dietary Supplements/analysis , Female , Hydroxymethylglutaryl CoA Reductases/metabolism , Linoleic Acids, Conjugated/administration & dosage , Liver/metabolism , Receptors, LDL/metabolismABSTRACT
OBJECTIVE: To systematically evaluate the efficacy and safety of probiotic supplementation for preventing necrotizing enterocolitis (NEC) and reducing mortality in preterm very low birth weight (VLBW) infants. METHODS: The randomized controlled trials (RCTs) about probiotics for preventing NEC in preterm neonates were searched in PubMed, EMbase, Cochrane Central Register of Controlled Trials (CENTRAL), the ISI Web of Knowledge databases, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Weipu and Wanfang Data from their establishment to March 2014. The Cochrane Collaboration's RevMan 5.1 Software was used for a Meta analysis. RESULTS: A total of 21 RCTs involving 4 607 preterm VLBW infants were eligible for inclusion in the Meta analysis. The Meta analysis showed that probiotic supplement was associated with a significantly decreased risk of NEC in preterm VLBW infants (RR=0.47; 95%CI: 0.35-0.62; P<0.001). Risk of mortality was also significantly reduced in the probiotic group (RR=0.63; 95%CI: 0.51-0.78; P<0.01). Probiotic supplement did not decrease the risk for sepsis (RR=0.87; 95%CI: 0.72-1.06; P=0.17) and NEC related mortality (RR=0.68; 95%CI: 0.31-1.48, P=0.33). CONCLUSIONS: The results confirm that probiotic supplement can reduce risk of NEC and mortality in preterm VLBW infants. However, the long-term effects and safety of probiotics need to be assessed in large trials.
Subject(s)
Enterocolitis, Necrotizing/prevention & control , Infant, Very Low Birth Weight , Probiotics/therapeutic use , Enterocolitis, Necrotizing/mortality , Humans , Infant, Newborn , Probiotics/adverse effects , Sepsis/prevention & controlSubject(s)
Communication , Internet , Physician-Patient Relations , Humans , Patient Education as TopicABSTRACT
Use of social media by doctors and medical students is common and growing. Although professional standards and codes of ethics that govern the behaviour of medical practitioners in Australia and New Zealand do not currently encompass social media, these codes need to evolve, because professional standards continue to apply in this setting. Inappropriate use of social media can result in harm to patients and the profession, including breaches of confidentiality, defamation of colleagues or employers, and violation of doctor-patient boundaries. The professional integrity of doctors and medical students can also be damaged through problematic interprofessional online relationships, and unintended exposure of personal information to the public, employers or universities. Doctors need to exercise extreme care in their use of social media to ensure they maintain professional standards.
Subject(s)
Internet/ethics , Physicians/standards , Confidentiality , Ethics, Medical , Humans , Physician-Patient Relations , Physicians/ethics , Students, MedicalABSTRACT
Sepsis occurs frequently in the intensive care unit (ICU) and is a leading cause of admission, mortality, and cost. Treatment guidelines recommend early intervention, however positive blood culture results may take up to 48 h. Insulin sensitivity (S(I)) is known to decrease with worsening condition and could thus be used to aid diagnosis. Some glycemic control protocols are able to accurately identify insulin sensitivity in real-time. Hourly model-based insulin sensitivity S(I) values were calculated from glycemic control data of 36 patients with sepsis. The hourly S(I) is compared to the hourly sepsis score (ss) for these patients (ss=0-4 for increasing severity). A multivariate clinical biomarker was also developed to maximize the discrimination between different ss groups. Receiver operator characteristic (ROC) curves for severe sepsis (ss ≥ 2) are created for both S(I) and the multivariate clinical biomarker. Insulin sensitivity as a sepsis biomarker for diagnosis of severe sepsis achieves a 50% sensitivity, 76% specificity, 4.8% positive predictive value (PPV), and 98.3% negative predictive value (NPV) at an S(I) cut-off value of 0.00013 L/mU/min. Multivariate clinical biomarker combining S(I), temperature, heart rate, respiratory rate, blood pressure, and their respective hourly rates of change achieves 73% sensitivity, 80% specificity, 8.4% PPV, and 99.2% NPV. Thus, the multivariate clinical biomarker provides an effective real-time negative predictive diagnostic for severe sepsis. Examination of both inter- and intra-patient statistical distribution of this biomarker and sepsis score shows potential avenues to improve the positive predictive value.
Subject(s)
Computer Simulation , Models, Biological , Sepsis/diagnosis , Biomarkers/blood , Blood Glucose/metabolism , Critical Illness , Diagnosis, Computer-Assisted , Humans , Insulin Resistance , Multivariate Analysis , Predictive Value of Tests , ROC Curve , Sepsis/blood , Sepsis/physiopathologyABSTRACT
BACKGROUND: Timely diagnosis and treatment of sepsis in critical care require significant clinical effort, experience, and resources. Insulin sensitivity is known to decrease with worsening condition and could thus be used to aid diagnosis. Some glycemic control protocols are able to identify insulin sensitivity in real time. METHODS: Receiver operating characteristic curves and cutoff insulin sensitivity values for diagnosing sepsis were calculated for model-based insulin sensitivity (S(I)) and a simpler metric (SS(I)) that was estimated from glycemic control data of 30 patients with sepsis and can be calculated in real time without use of a computer. Results were compared to the insulin sensitivity profiles of a general intensive care unit population of 113 patients without sepsis and 30 patients with sepsis, comprising a total of 26,453 patient hours. Patients with sepsis were identified as having sepsis based on a sepsis score (ss) of 3 or higher (ss = 0 - 4 for increasing severity). Patients with type I or type II diabetes were excluded. Ethics approval for this study was granted by the South Island Regional Ethics Committee. RESULTS: Receiver operating characteristic cutoff values of S(I) = 8 x 10-5 liter mU(-1) min(-1) and SS(I) = 2.8 x 10-4 liter mU(-1) min(-1) were determined for ss > or = 3. The model-based S(I) fell below this value in 15% of all patient hours. The S(I) test had a negative predictive value of 99.8%. The test sensitivity was 78% and specificity was 82%. However, the positive predictor value was 2.8%. Slightly lower sensitivity (68.8%) and specificity (81.7%), but equally good negative prediction (99.7%), were obtained for the estimated SS(I). CONCLUSIONS: Insulin sensitivity provides a negative predictive diagnostic for sepsis. High insulin sensitivity rules out sepsis for the majority of patient hours and may be determined noninvasively in real time from glycemic control protocol data. Low insulin sensitivity is not an effective diagnostic, as it can equally mark the presence of sepsis or other conditions.
ABSTRACT
Batch-scale experiments were done to quantitatively study the effect of inorganic chemical parameters on iron release in drinking water distribution systems. The parameters include acid-base condition, oxidation-reduction condition, and neutral ion condition. It was found that the iron release rate decreased with pH, alkalinity, the concentration of dissolved oxygen increasing, and the iron release rate increased with the concentration of chloride increasing. The theoretical critical formula of iron release rate was elucidated. According to the formula, the necessary condition for controlling iron release is that pH is above 7.6, the concentration of alkalinity and dissolved oxygen is more than 150 mg/L and 2 mg/L, and the concentration of chloride is less than 150 mg/L of distributed water.