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In this work, a new method is proposed to meet the challenge of preparing new catalysts with cascade/non-cascade switching catalytic property. Inspired from “soft” characteristics and divisional isolation function in natural biological systems, this objective was accomplished by developing a new class of hydrogels made of two unique functional layers with different temperature responses where each may self-govern coupled processes at a specific temperature. This hydrogel polymer reactor exhibited almost no catalytic activity at low-temperature range (50 °C), the hydrogel catalytic polymer reactor further exhibited significant efficiency towards the hydrolysis reaction of NPA as well as the reduction of the intermediate product p-nitrophenol (NP). This mainly resulted from the opening of both the weak polymer complexes and the stronger polymer complexes hydrogel layers, allowing entrance to both the acidic catalytic active center and the metal nanoparticles active center. As a result, the novel hydrogel polymer reactor could be used to control cascade/non-cascade catalysis reactions. This new protocol enables efficient control of switchable tandem reactions, inspiring for difficulty to control tandem catalytic reactors

Background: Air pollution is one of the greatest public health concerns worldwide. In order to understand its mechanism of harm, we investigated the effects of diesel exhaust particles (DEPs), one of the major constituents of ambient air pollutants, on reactive cell viability, oxygen stress, autophagy, and apoptosis. Materials and Methods: In in vitro human umbilical vein endothelial cell (HUVEC) model, cells were exposed to freshly dispersed DEP preparations at 0, 12.5, 25, 50, 100, or 200 µg/mL for 24 h or at 50 µg/mL DEP for 1, 3, 6, 12, or 24 h. Cell survival and oxidative stress were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), and generation of reactive oxygen species (ROS). Protein expressions of autophagy (Beclin-1, p62, and light chain 3 [LC3]-II) and apoptosis (Bcl2 and Bax) were assayed by Western blotting. Results: DEP induced a significant dose-dependent and temporal decrease in cell viability and increase in ROS generation and NOX activity, in association with decreased or increased protein levels of p62 or Beclin-1, as well as conversion of the LC3 in a dose-dependent manner. DEP increased pro-apoptotic protein Bax and decreased anti-apoptotic protein Bcl2. Conclusions: These results demonstrated that DEP exposure induced cytotoxicity, oxidative stress, autophagy, and apoptosis in HUVECs. Novel insight into the mechanisms of cardiovascular diseases caused by air pollution may be provided through these findings.

OBJECTIVE Studies have identified longitudinally that there exists an association between depression, cerebral blood flow (CBF), and white matter hyperintensities that are thought to be due to vascular pathologies in the brain. However, the changes in CBF, a measure that reflects cerebrovascular integrity, following pharmacotherapy are not well understood. In this study, we investigated the dynamic CBF changes over the course of antidepressant treatment and the association of these changes with depressive symptoms. METHODS We used pseudocontinuous arterial spin labeling to investigate CBF changes in a sample of older patients (≥ 50 years of age; N = 46; 29 female) with a DSM-IV diagnosis of major depressive disorder. Participants had 5 magnetic resonance imaging scans (at baseline, the day after receiving a placebo, the day after receiving a first dose of venlafaxine, a week after starting venlafaxine treatment, and at the end of trial [12 weeks]). Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate depression severity and treatment outcome. We investigated the association between changes in depression severity with changes in voxel-wise CBF while adjusting for potential confounding factors. RESULTS Increased CBF in the middle and posterior cingulate between baseline and end of treatment was significantly associated with percent decrease in MADRS score, independent of sex and Mini-Mental State Examination score (5,000 permutations, cluster forming threshold P < .005, family-wise error P < .05). No significant effects were detected between baseline and other scans (ie, placebo, acute [single dose], or subacute [after a week]). CONCLUSIONS Regional CBF increases were associated with decreases in depressive symptoms. This observation is consistent with the vascular depression hypothesis in late-life depression. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00892047 and NCT01124188.

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems are prokaryotic adaptive immune systems against invading nucleic acids. CRISPR locus variability has been exploited in evolutionary and epidemiological studies of Mycobacterium tuberculosis, the causative agent of tuberculosis, for over 20 yr, yet the biological function of this type III-A system is largely unexplored. Here, using cell biology and biochemical, mutagenic, and RNA-seq approaches, we show it is active in invader defense and has features atypical of type III-A systems: mature CRISPR RNA (crRNA) in its crRNA-CRISPR/Cas protein complex are of uniform length (∼71 nt) and appear not to be subject to 3'-end processing after Cas6 cleavage of repeat RNA 8 nt from its 3' end. crRNAs generated resemble mature crRNA in type I systems, having both 5' (8 nt) and 3' (28 nt) repeat tags. Cas6 cleavage of repeat RNA is ion dependent, and accurate cleavage depends on the presence of a 3' hairpin in the repeat RNA and the sequence of its stem base nucleotides. This study unveils further diversity among CRISPR/Cas systems and provides insight into the crRNA recognition mechanism in M. tuberculosis, providing a foundation for investigating the potential of a type III-A-based genome editing system.-Wei, W., Zhang, S., Fleming, J., Chen, Y., Li, Z., Fan, S., Liu, Y., Wang, W., Wang, T., Liu, Y., Ren, B., Wang, M., Jiao, J., Chen, Y., Zhou, Y., Zhou, Y., Gu, S., Zhang, X., Wan, L., Chen, T., Zhou, L., Chen, Y., Zhang, X.-E., Li, C., Zhang, H., Bi, L. Mycobacterium tuberculosis type III-A CRISPR/Cas system crRNA and its maturation have atypical features.

An approach presented in our previous work showed that sequential minimal optimization (SMO) algorithms could be executed in parallel. However, its convergence was not guaranteed in some cases. To solve the problem, we propose two novel algorithms in this paper. The first one is to add a condition to decide whether a single violating pair or multiple pairs should be chosen. Thus, the objective function decreases strictly in each iteration, and the algorithm is convergent. The second one aims at choosing better working set in each iteration to reduce the number of entire iterations. Due to the violating pairs chosen in each parallel way are violating at the updating moment, the convergence can be guaranteed. The results of our experiments show the two proposed algorithms can be executed successfully and their convergences are guaranteed totally.

To explore the potential role of the methylidyne radical (CH) in the transformation of 2,3,7,8-tetrachlorodibenzofuran (TCDF), in this study, the detailed reaction mechanisms between TCDF and CH radical have been systematically investigated employing the B3LYP method of density functional theory (DFT) in combination with the atoms in molecules (AIM) theory and ab initio molecular dynamics. It was found that the title reaction is a multi-channel reaction, i.e., the CH radical can attack the C–X (X = C, Cl, H, O) bonds of TCDF via the insertion modes, resulting in the formation of 13 products. Thermodynamically, the whole reaction processes are exothermic and spontaneous since all the enthalpy and Gibbs free energy changes are negative values in the formation processes. Moreover, the thermodynamic stability of the products is controlled by the distribution of the single unpaired electron. Kinetically, the most favorable reaction channel is the insertion of the CH radical into the C–C bond except for the C atoms attached to the chlorine atom. Moreover, the dominant products have been further confirmed by the molecular dynamics. Meanwhile, the IR spectra and hyperfine coupling constants of the dominant products have been investigated to provide helpful information for their identification experimentally. In addition, the reactivity of the CH radical toward the F- and Br-substituted TCDFs has also been investigated. Expectedly, the present findings can enable us to better understand the reactivity of the CH radical toward organic pollutants analogous to TCDF in the atmosphere.

Damage to pancreatic β‑cells is closely associated with diabetes. However, the mechanism underlying injury to pancreatic β‑cells remains unclear, although hypoxia is considered as one of the leading causes. Appoptosin is a mitochondrial protein that promotes neuronal apoptosis. Studies conducted on appoptosin thus far have primarily focused on Alzheimer's disease, and have demonstrated that the expression of appoptosin is significantly increased in ischemic‑reperfused rat brains, which indicates its close association with hypoxia. However, the role of appoptosin in pancreatic β‑cells, which are sensitive to hypoxia, remains unknown. Therefore, the current study aimed to investigate the function of appoptosin in pancreatic β‑cells in a hypoxic environment. Cobalt chloride (CoCl2) was used to mimic the hypoxic status of the cells. The results of a terminal deoxynucleotidyl transferase dUTP nick‑end labeling assay demonstrated that CoCl2 promoted apoptosis in MIN6 mouse insulinoma cells, and western blotting and reverse transcription‑quantitative polymerase chain reaction results demonstrated that the activation of appoptosin was induced, promoting mitochondrial damage and caspase 3 activation. Silencing of appoptosin using short hairpin RNA significantly reduced CoCl2‑induced apoptosis in MIN6 cells. In conclusion, CoCl2 increased the expression of appoptosin, which aggravated mitochondrial damage in MIN6 cells. Therefore, inhibiting the expression of appoptosin may benefit pancreatic β-cells survival during islet transplantation.

Type 1 diabetes is caused by destruction of the pancreatic β‑cells and, to date, no cure has been developed. Promoting the survival of pancreatic β‑cells may be beneficial for patients with type 1 diabetes. Puerarin is an estrogen analogue that been demonstrated in previous studies to be able to decreased blood glucose in patients with type 1 diabetes. Similar results were demonstrated in previous studies which additionally demonstrated that puerarin was able to decreased blood glucose in type 1 diabetic mice by protecting pancreatic β‑cells. However, the mechanism underlying the function of puerarin in pancreatic β‑cells remains unclear. Therefore, the present study sought to investigate the detailed function of puerarin in pancreatic β‑cells. In the present study, H2O2 was used to induce apoptosis. It was observed that puerarin significantly decreased H2O2‑induced apoptosis in mouse insulinoma MIN6 cells. It was additionally observed that puerarin decreased the levels of intracellular reactive oxygen species and mitochondrial superoxide in MIN6 cells. The protective effect of puerarin was markedly decreased by 6‑aminonicotinamide, an inhibitor of glucose‑6‑phosphate dehydrogenase (G6PD). In conclusion, the results of the present study suggested that puerarin may increase the activity of G6PD, decreased the level of oxidative stress in MIN6 cells, protect mitochondria and promote MIN6 cell survival. Investigating the mechanism underlying the effect of puerarin in MIN6 cells may provide a novel approach for development of a cure for type 1 diabetes.

Background Patients reporting penicillin allergy often receive unnecessary and costly broad-spectrum alternatives such as aztreonam with negative consequences. Penicillin allergy testing improves antimicrobial therapy but is not broadly used in hospitals due to insufficient testing resources and short-term expenses. We describe a clinical decision support (CDS) tool promoting pharmacist-administered penicillin allergy testing in patients receiving aztreonam and its benefits toward antimicrobial stewardship and costs. Methods A CDS tool was incorporated into the electronic medical record, directing providers to order penicillin allergy testing for patients receiving aztreonam. An allergy-trained pharmacist reviewed orders placed through this new guideline and performed skin testing and oral challenges to determine whether these patients could safely take penicillin. Data on tests performed, antibiotic utilization, and cost-savings were compared with patients tested outside the new guideline as part of our institution’s standard stewardship program. Results The guideline significantly increased penicillin allergy testing among patients receiving aztreonam from 24% to 85% (P < .001) while reducing the median delay between admission and testing completion from 3.31 to 1.05 days (P = 0.008). Patients tested under the guideline saw a 58% increase in penicillin exposure (P = .046). Institutional aztreonam administration declined from 2.54 to 1.47 administrations per 1000 patient-days (P = .016). Average antibiotic costs per patient tested before and after CDS decreased from $1265.81 to $592.08 USD, a 53% savings. Conclusions Targeting penicillin allergy testing to patients on aztreonam yields therapeutic and economic benefits during a single admission. This provides a cost-effective model for inpatient testing.

The problem of short-term travel time estimation has been intensively investigated recently. However, accurate travel time predicting is still a challenge due to dynamic changes of the traffic and the difficulty of extracting urban traffic data features. In this paper, we mainly focus on time shifting feature of urban roads, which represents the impact of the upstream sections that will be conveyed to the downstream sections after a certain period of time \(\varDelta {t}\). Firstly, we obtain the spatial relationships of the traffic time with Kullback-Leibler divergence (KL-divergence) and urban road networks. Then a Convolutional Neural Network (CNN) module is adopted to extract the spatial-temporal and time shifting information of the target road. Finally, a novel deep architecture combined CNN and Long-short Term Memory Recurrent Neural Network (LSTM) is utilized to predict the short-term travel time. The experimental result on the real data set shows that the proposed model is more effective than other existing approaches.

Background Over 2 million people in the United States are diagnosed with antibiotic-resistant infections annually. The Infectious Diseases Society of America (IDSA) recommends cascade reporting of antibiotic susceptibility data by the clinical microbiology laboratory as an intervention to decrease resistance, though this is based on low-quality evidence. Methods We conducted a retrospective study to assess the effect of cascade susceptibility reporting on prescribing practices and patient outcomes. A cascaded testing algorithm was executed wherein susceptibility data for piperacillin–tazobactam (PT) was suppressed from the susceptibility report if an organism was susceptible to ceftriaxone. Patients with positive monomicrobial blood cultures with non-ESBL Escherichia coli (E. coli) or Klebsiella isolates in blood cultures and receiving empiric PT were included. Data were collected one year prior and one year after cascading protocol implementation, and included patient demographics, length of stay (LOS), duration of antibiotics, time to de-escalation, and adverse events including acute kidney injury (AKI) and Clostridioides difficile infection (CDI). Results 212 patients (108 pre-intervention and 104 post-intervention) were included. 87% of patients were de-escalated from PT pre-intervention, while 90% were deescalated post-intervention. Mean time to deescalation decreased from 30 hours before to 17 hours after cascade implementation (P = 0.02) (Figure 1). Median LOS decreased from 15 to 10 days following the intervention (P = 0.12). While the rate of AKI increased from 14 to 19% post-intervention (P = 0.89), the rate of CDI (2 vs. 2 patients) was comparable among both cohorts (P = 0.97) (Figure 2). Conclusion While cascade susceptibility reporting is recommended by the IDSA as a tool for antimicrobial stewardship, this recommendation has weak support due to paucity of data. In this study, we found that selective susceptibility reporting has the potential to decrease the use of PT and to reduce LOS in patients with E. coli and Klebsiella bacteremia. Further research to better identify patient populations most impacted by a cascade algorithm and its overall effectiveness as a stewardship tool is needed. Disclosures All authors: No reported disclosures.

High extracellular potassium could induce depression-like depolarizations, elevations of extracellular glutamate and even neuronal death in brain. To investigate the contribution of high potassium in vivo , microelectrode arrays (MEAs) probe were fabricated and implanted in a rat brain for simultaneous record of striatal local field potential (LFP) and glutamate concentration. During these multi-modal recordings, the rat brain was exposed to a high potassium solution. It was observed that high potassium elevated extracellular glutamate while suppressing the LFP irreversibly. This is one of the first studies in which a dual-mode MEA probes is applied in vivo for neuronal death. It is concluded that the MEA probes are capable of examining specific spatiotemporal relationships between electrical and chemical signaling in the brain.

Supported ionic liquids/polyurethane (PU) membranes were prepared by immobilizing ionic liquids on a porous anodic aluminum oxide membrane (AAOM) support that was coated on one side with polyurethane (PU). The microstructure of all membranes was characterized using scanning electron microscopy (SEM). The pervaporation separation performance of the supported ionic liquids/polyurethane membranes was investigated for benzene/cyclohexane (Bz/Cy) mixtures. The SEM results demonstrated that the porous surface of the AAOM support was sealed by the dense polyurethane membrane and the pores of the AAOM support were impregnate with ionic liquids. The ionic liquids filling in the AAOM support enhanced the separation selectivity of Bz/Cy. The separation factor of Bz to Cy increased from 5 to 34.4 and the largest PSI of AAOM-[C4mim]PF6/PU membrane reached 452.54 g m−2 h−1 at 55 °C for a 50 wt.% Bz/Cy mixture. Because the polyurethane prevented the leakage of ionic liquids filled in the AAOM support, the supported ionic liquids/polyurethane membranes exhibited excellent stability.

This study was aimed at addressing the present challenge in tandem catalysts, as to how to furnish catalysts with tandem catalytic-ability without involving the precise control and man-made isolation of different types of catalytic sites. This objective was realized by constructing an enzyme-like imprinted-polymer reactor made of a unique polymer composite inspired from the compartmentalization of cells, a composite of a reactive imprinted polymer (containing acidic catalytic sites), and encapsulated metal nanoparticles (acting as catalytic reduction sites). The compilation of two types of catalytic sites with admissible access allowed this reactor to behave like compartments of cells for enzymatic reactions and hence catalytically constituted two quantum interaction-segregated domains, which led to the occurrence of catalytic tandem processes. Unlike the reported functional reactors that run tandem catalysis by largely depending on the precise control and man-made isolation of different types of catalytic sites, tandem catalysis in this reactor run naturally with segregated quantum confinements, which does not involve the precise control and isolation of different types of catalytic sites. This protocol presents new opportunities for the development of functional catalysts for complicated chemical processes.

Background: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. Methods: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. Results: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval −5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p = 0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR) = 1.2; 95% CI, 0.3–4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR) = 5.4; 95% CI, 1.1–26.8). Conclusion: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections. Keywords: Nafcillin, Cefazolin, Methicillin-susceptible Staphylococcus aureus, MSSA, Bacteremia

Criegee intermediates (CIs) play a key role in controlling the atmospheric budget of hydroxyl radical, organic acids, and secondary organic aerosols. In this study, the detailed reaction mechanisms of the simplest Criegee intermediate CH

The nano-structure TiN was modified on the laboratory self-made planar microelectrode array pMEA by magnetron sputtering method. The performance of modified pMEA was investigated. The research on neuroelectrical and neurochemical recording was studied in vitro. The impedance of the modified pMEA was decreased almost one order of magnitude, and the background noise level was reduced to ±6 μV. In the same testing environment, the signal-to-noise ratio (SNR) of modified electrodes was 1.7 times of bare electrodes. The SNR of neuroelectrical recording on the brain slice of SD rats reached 10:1, and the weak signal such as ±12 μV was separated easily. For neuroelectrical recordings, the detection limit of dopamine (DA) solution reached 50 nM with the 2:1 SNR. In the concentration range of 0.05–100 μM, the linearly dependent coefficient of the DA oxidation currents was 0.998. The modification of nano-structure TiN on pMEA reduced pMEA impedance and background noise level, meanwhile the SNR was increased. The weak signals of neuroelectrical and neurochemical recording were successfully recorded.

Neural probes based on graphene field-effect transistors have been demonstrated. Yet, the minimum detectable signal of graphene transistor-based probes is inversely proportional to the square root of the active graphene area. This fundamentally limits the scaling of graphene transistor-based neural probes for improved spatial resolution in brain activity recording. Here, we address this challenge using highly crumpled all-carbon transistors formed by compressing down to 16% of its initial area. All-carbon transistors, chemically synthesized by seamless integration of graphene channels and hybrid graphene/carbon nanotube electrodes, maintained structural integrity and stable electronic properties under large mechanical deformation, whereas stress-induced cracking and junction failure occurred in conventional graphene/metal transistors. Flexible, highly crumpled all-carbon transistors were further verified for in vivo recording of brain activity in rats. These results highlight the importance of advanced material and device design concepts to make improvements in neuroelectronics.

Background Fluoroquinolones (FQ) are the leading class of antibiotics prescribed during adult ambulatory care visits, resulting in over 20 million outpatient prescriptions annually. Overuse of this class of antibiotics has contributed to increased antibiotic resistance and risk for Clostridioides difficile infection. In 2016, the Food and Drug Administration (FDA) updated the Boxed Warnings advising against FQ use for patients with uncomplicated sinusitis, bronchitis, or cystitis as the risk for potential serious side effects outweighs the benefit. Methods The antimicrobial stewardship team at Parkland Health and Hospital System undertook a multi-interventional approach to decrease outpatient FQ usage (Figure 1). First, the FDA warning was added to all oral FQ orders in the electronic medical record and education regarding risk and appropriate use of FQ was given to providers in the primary care clinics and emergency department. Secondly, ciprofloxacin susceptibilities were suppressed by the laboratory when organisms were susceptible to third-generation cephalosporins. To assess the impact of these interventions, FQ utilization was compared across the same time period, each one year apart. Pre-education was assessed from November 2015 to February 2016, post-education from November 2016 to February 2017, and post-education plus susceptibility suppression from November 2017 to February 2018. Results Comparative utilization data by site was collected (Figure 2) with all sites demonstrating a decrease in FQ utilization and one site showing an 85% decrease. We observed an overall 19% decrease in outpatient FQ prescribing after education alone and 14% decrease after susceptibility suppression plus continuing education. Compared with pre-intervention baseline, there was a total 30% decrease in FQ utilization after both interventions were implemented, corresponding to approximately 150 fewer prescriptions per month (Figure 3). Conclusion Educational efforts alone proved effective in decreasing outpatient FQ usage. Additional improvement was observed when change was implemented at a system level via susceptibility suppression. Further decrease in FQ utilization is expected with ongoing education and additional system changes. Disclosures All authors: No reported disclosures.

Capreomycin (CAP), a cyclic peptide antibiotic, is considered to be an ideal second-line drug for tuberculosis (TB). However, in the past few years, the emergence of more CAP-resistant (CAPr) TB patients has limited its use. Although it has been reported that CAP resistance to Mycobacterium tuberculosis (Mtb) is associated with rrs or tlyA mutation, the exact mechanism of CAPr Mtb strains, especially the mechanism associated with tlyA deficient or mutation, is not fully understood. Herein, we utilized a multi-omics (genome, proteome, and metabolome) approach to assess CAP resistance on tlyA deficient CAPr Mtb strains (CAPr1) and tlyA point mutation CAPr Mtb strains (CAPr2) that we established for the first time in vitro to investigate the CAP-resistant mechanism. Our results showed that the CAPr1 strains (> 40 μg/ml) was more resistant to CAP than the CAPr2 strains (G695A, 10 μg/ml). Furthermore, multi-omics analysis indicated that the CAPr1 strains exhibited greater drug tolerance than the CAPr2 strains may be associated with the weakening of S-adenosyl-L-methionine-dependent methyltransferase (AdoMet-MT) activity and abnormal membrane lipid metabolism such as suppression of fatty acid metabolism, promotion of glycolipid phospholipid and glycerolipid metabolism. As a result, these studies reveal a new mechanism for CAP resistance to tlyA deficient or mutation Mtb strains, and may be helpful in developing new therapeutic approaches to prevent Mtb resistance to CAP.

In this paper, a new type of resonant cavity sensor based on diamond is proposed. Using the single straight-racetrack structure, the effective refractive index of the core layer is changed by the external factors, which can change the optical signal intensity of the output spectrum. According to the variation of the output spectrum with the different effective refractive index, the COMSOL and MATLAB software are used to simulate the amplitude attenuation factor and the transmission coefficient of the resonator. When the attenuation factor is 0.981 and the transmission coefficient is 0.99, the simulation results reveal that the effective refractive index change is Δneff ≈ 1.1 × 10−4, the normalized output light intensity change is ΔI0≈0.87 and the sensitivity of the optimized racetrack resonant cavity sensor is 7909.09dB/RIU. In the detection system with the signal-to-noise ratio of 30 dB, the detection limit of the sensor is 3.79 × 10−7 RIU, and the quality factor Q can reach 105, improving the characteristics of the single straight-racetrack resonant cavity sensor. Finally, the interface bonding and preparation method of the diamond core layer and substrate are described.

Background The Infectious Diseases Society of America guidelines for the treatment of acute uncomplicated pyelonephritis (AUP) recommend oral fluoroquinolones (FQs) as a first-line agent in patients not requiring hospitalization. However, with increasing rates of FQ and trimethoprim/sulfamethoxazole resistance, oral β-lactams are attractive agents due to improved empiric susceptibility patterns at our institution. The current guideline advises caution when using oral β-lactams due to concern for inferior efficacy, but studies specifically evaluating the efficacy of oral cephalosporins (CPHs) in AUP are limited. The purpose of this study was to provide additional evidence for the safe and effective use of oral CPHs for empiric treatment of AUP. Methods Retrospective chart review was performed on all patients prescribed oral CPHs or FQs for AUP from the Emergency Department (ED) at Parkland Memorial Hospital between September 2017 and July 2018. The primary endpoint was treatment failure within 30 days, defined as ED return due to any cause or modification to an alternative antibiotic. Secondary endpoints included ED return within 30 days due to continued symptoms of AUP, documented adverse drug reactions (ADRs), and C. difficile infection (CDI) within 30 days. Results Of the 333 patients included in the study, treatment failure occurred in 72 (21.6%) patients and was similar between oral FQs and CPHs (21.4% vs. 21.7%). A higher rate of treatment failure was observed for first-generation (1GC) CPHs compared with second-generation (2GC) or third-generation (3GC) CPHs (19/51 [43.1%] vs. 18/107 [16.8%] vs. 9/68 [13.2%]). The primary reason for treatment failure was modification to an alternative antibiotic, and was highest for oral 1GC, followed by FQs, then 2GC and 3GC (19/51 [37.3%] vs. 14/107 [13.1%] vs. 11/107 [10.3%] vs. 4/68 [5.9%]). Rates of return to the ED for continued symptoms of AUP were found to be lower for oral CPHs (8/226 [3.5%]) vs. FQs (9/107 [8.4%]). Documented ADRs were low (5/333 [1.5%]) and none developed CDI. Conclusion Oral CPHs appear to be as safe and effective as FQs for the empiric treatment of AUP. In concordance with the susceptibility data of our institutional antibiogram, 2GC and 3GC were observed to have a lower rate of treatment failure compared with 1GC and FQs. Disclosures All authors: No reported disclosures.

DNA polymerase III (DNA pol III) is a multi-subunit replication machine responsible for the accurate and rapid replication of bacterial genomes, however, how it functions in Mycobacterium tuberculosis (Mtb) requires further investigation. We have reconstituted the leading-strand replication process of the Mtb DNA pol III holoenzyme in vitro and investigated the physical and functional relationships between its key components. We verify the presence of an αβ2ε polymerase-clamp-exonuclease replicase complex by biochemical methods and protein-protein interaction assays in vitro and in vivo and confirm that, in addition to the polymerase activity of its α subunit, Mtb DNA pol III has two potential proofreading subunits; the α and ε subunits. During DNA replication, the presence of the β2 clamp strongly promotes the polymerization of the αβ2ε replicase and reduces its exonuclease activity. Our work provides a foundation for further research on the mechanism by which the replication machinery switches between replication and proofreading and provides an experimental platform for the selection of antimicrobials targeting DNA replication in Mtb.

Background In the wake of Hurricane Maria, hospitals nationwide have faced a shortage of IV fluids sourced from Puerto Rico. Out of necessity to conserve IV fluids, Parkland Memorial Hospital shifted IV antibiotic administration from traditional fluid suspension via pump/gravity to “IV push” administration. The safety and potential cost savings of short infusion administration of antibiotics have been previously described; however, implementation of IV push administration among patients receiving long-term IV antibiotics has yet to be described. Methods Starting November 2017, patients requiring long-term IV antimicrobial treatment with were transitioned to receive IV push administration from infusion. Per the Parkland self-administered Outpatient Parenteral Antimicrobial Therapy (S-OPAT), patients were screened and trained to self-administer IV antibiotics prior to hospital discharge and followed in the Parkland OPAT clinic. Results Since implementation November 2017, 200 patients completed antimicrobial therapy with IV push method with 100% success rate and no reported complications. The following supplies were estimated to be saved: 3,000 less IV fluid bags, 1,000 IV tubing, and 50% fewer gloves and alcohol swabs, amounting to approximately $22,000 of cost savings for a patient going home on once a day antibiotic therapy. Teaching time for the nursing team was reduced on average by 50% per patient. Preliminary patient satisfaction surveys indicate greater satisfaction due to decreased infusion time from an average of 45 minutes to 3–5 minutes with the IV push method. Patient’s reported satisfaction with the new IV Push method due to greater convenience for both storing the medication and a faster preparation time. Conclusion Parkland Memorial Hospital was able to implement IV push as a safe and cost-effective alternative to traditional IV antibiotic administration in fluid suspension. Use of IV push antibiotics resulted in $22,000 of cost savings and reduced utilization of a critical resource currently facing a nationwide shortage. Though implemented at our institution in response to a national crisis, IV push is a favorable alternative to administration via a pump or gravity due to time savings, cost reduction, and convenience. Disclosures All authors: No reported disclosures.

Background Appropriate conversions from intravenous (IV) to oral (PO) therapy early in the hospital stay can promote patient comfort and satisfaction while decreasing unnecessary costs and adverse events related to IV catheters. Although IV to PO conversion as a stewardship intervention is considered “low hanging fruit,” the time spent on review can be extensive and reporting can be challenging. Utilization of an automated decision support system allows for easy monitoring of IV to PO switches as well as identification of ways to enhance the efficiency and effectiveness of the program. The primary objective was improving IV to PO conversions through an automated system and measuring outcomes electronically without manual chart review. Desired metrics were percentage of eligible antimicrobials ordered as PO, number of conversions, and cost avoidance. Methods A protocol was approved by the Pharmacy and Therapeutics committee allowing pharmacists to auto-convert medications from IV to PO when meeting prespecified criteria. These identification criteria were implemented electronically using a traffic light decision support system to prioritize eligible patients (Figure 1). Education was provided both in person and as pocket cards with guidance on eligible antimicrobials for IV to PO conversions. Metrics were based on monthly antimicrobial utilization data and displayed as a dashboard (Figure 2). Results Monthly metrics provided the stewardship team feedback on the effectiveness of the IV to PO program and identified areas for improvement. From January 2017 to January 2018, cost avoidance from ordering PO as opposed to IV agents was $524,788 with 1,843 IV to PO conversions performed by both providers and pharmacists. A total of 65% of the eligible antimicrobials were ordered via the PO route. Based on these findings, a multifaceted approach to further expand the initiative was undertaken. Conclusion The IV to PO decision support system improves the efficiency of IV to PO review process and reduces time spent reviewing charts of patients who do not meet criteria for conversion. The development of automated monthly metrics is an efficient method to assess the effectiveness of the program as well as identify key areas for future development. Figure 1. Automated Decision Support System Figure 2. Dashboard Disclosures All authors: No reported disclosures.

Cubic BaCo0.7Fe0.3−xYxO3−δ (BCFY, x = 0.08−0.2) was prepared by the conventional solid state reaction route as oxygen permeation membranes. The effects of Y-doping on the crystal structure, electrical conductivity, and oxygen permeability are investigated, and the factors influencing the activation energy of oxygen migration are discussed from the viewpoints of metal−oxygen bonding energy and geometric lattice structure. Y-substitution decreases the electrical conductivity but increases the oxygen vacancy concentration of BCFY samples. Nevertheless, the oxygen permeability decreases with increasing Y-doping level. Both the strong Y−O bonding energy and the decreased critical radius (rC) with Y-doping should be responsible for the increased activation energy. First principle calculation reveals that Y-doping results in the nonequivalent positions of the mobile oxygen ions and thus limits the oxygen ion diffusion passages. BaCo0.7Fe0.22Y0.08O3−δ membrane exhibits a high oxygen permeability of 1.73 mL min−1 ...

Critical radius ( r C ) for cubic perovskite structure is an important factor affecting the migration energy of oxygen ions. The monotonic dependence of the critical radius on the ionic radii of A- and B- site cations in cubic perovskite AB O 3 structure was systematically investigated by strict mathematical derivation. When the tolerance factor ( t ) A -site cation ( r A ) and B -site cation ( r B ), respectively. For the case of t > 1, there is a reverse dependence of r C on r A and r B . With respect to the case of t = 1, r C displays a decreasing function with respect to both r A and r B .

L-glutamate, the most common excitatory neurotransmitter in the mammalian central nervous system (CNS), is associated with a wide range of neurological diseases. Because neurons in CNS communicate with each other both electrically and chemically, dual-mode (electric and chemical) analytical techniques with high spatiotemporal resolution are required to better understand glutamate function in vivo. In the present study, a silicon-based implantable microelectrode array (MEA) composed of both platinum electrochemical and electrophysiological microelectrodes was fabricated using micro-electromechanical system. In the MEA probe, the electrophysiological electrodes have a low impedance of 0.018 MΩ at 1 kHz, and the electrochemical electrodes show a sensitivity of 56 pA µM−1 to glutamate and have a detection limit of 0.5 µM. The MEA probe was used to monitor extracellular glutamate levels, spikes and local field potentials (LFPs) in the striatum of anaesthetised rats. To explore the potential of the MEA probe, the rats were administered to KCl via intraperitoneal injection. K+ significantly increases extracellular glutamate levels, LFP low-beta range (12–18 Hz) power and spike firing rates with a similar temporal profile, indicating that the MEA probe is capable of detecting dual-mode neuronal signals. It was concluded that the MEA probe can help reveal mechanisms of neural physiology and pathology in vivo. Abnormal transmission of L-glutamate can cause neurological disorders such as Parkinson's disease, stroke and epilepsy. In their search for effective treatments, researchers are deploying extensive efforts to understand this key neurotransmitter, which regulates receptors located at chemical synapses. However, their attempts often fail to analyze the syntrophic complexity of biochemical and electrical events occurring in neurons. Now, Xinxia Cai and co-workers from the Institute of Electronics, Chinese Academy of Sciences, Beijing, China, have developed a silicon-based probe that simultaneously measures L-glutamate levels and electrical activity at various locations in the brain with high spatial and temporal resolution. The implantable array combines electrochemical and electrophysiological microelectrodes created through MEMS and nanotechnology. The team expects it to provide insight into physiological and pathological pathways in live brain tissue, paving the way to new diagnostic and therapeutic approaches.

Consensus on the optimal treatment of Clostridium difficile infection (CDI) is rapidly changing. Treatment with metronidazole has been associated with increased clinical failure rates; however, the reasons for this are unclear. The purpose of this study was to assess age-related treatment response rates in hospitalized patients with CDI treated with metronidazole. This was a retrospective, multicenter cohort study of hospitalized patients with CDI. Patients were assessed for refractory CDI, defined as persistent diarrhea after 7 days of metronidazole therapy, and stratified by age and clinical characteristics. A total of 242 individuals, aged 60 ± 18 years (Charlson comorbidity index, 3.8 ± 2.4; Horn's index, 1.7 ± 1.0) were included. One hundred twenty-eight patients (53%) had severe CDI. Seventy patients (29%) had refractory CDI, a percentage that increased from 22% to 28% and to 37% for patients aged less than 50 years, for patients from 50 to 70 years, and for patients aged >70 years, respectively ( P = 0.05). In multivariate analysis, Horn's index (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.50 to 2.77; P < 0.001), severe CDI (OR, 2.25; 95% CI, 1.15 to 4.41; P = 0.018), and continued use of antibiotics (OR, 2.65; 95% CI, 1.30 to 5.39; P = 0.0072) were identified as significant predictors of refractory CDI. Age was not identified as an independent risk factor for refractory CDI. Therefore, hospitalized elderly patients with CDI treated with metronidazole had increased refractory CDI rates likely due to increased underlying severity of illness, severity of CDI, and concomitant antibiotic use. These results may help identify patients that may benefit from alternative C. difficile treatments other than metronidazole.

For the measurement of events of dopamine (DA) release as well as the coordinating neurotransmission in the nerve system, a neural microelectrode array (nMEA) electrodeposited directionally with polypyrrole graphene (PG) nanocomposites was fabricated. The deposited graphene significantly increased the surface area of working electrode, which led to the nMEA (with diameter of 20 μm) with excellent selectivity and sensitivity to DA. Furthermore, PG film modification exhibited low detection limit (4 nM, S/N = 3.21), high sensitivity, and good linearity in the presence of ascorbic acid (e.g., 13933.12 μA mM(-1) cm(-2) in the range of 0.8-10 μM). In particular, the nMEA combined with the patch-clamp system was used to detect quantized DA release from pheochromocytoma cells under 100 mM K(+) stimulation. The nMEA that integrates 60 microelectrodes is novel for detecting a large number of samples simultaneously, which has potential for neural communication research.

Analysis of the basic situation of water resources in china. The development and utilization of water resources and the protection countermeasures, in order to promote the sustainable development and utilization of water resources.

Lysine acetylation is an important post-translational modification and is known to regulate many eukaryotic cellular processes. Little, however, is known about acetylated proteins in prokaryotes. Here, using immunoblotting, mass spectrometry and mutagenesis studies, we investigate the acetylation dynamics of the DNA repair protein Ku and its relationship with the deacetylase protein Sir2 and the non-homologous end joining (NHEJ) pathway in Mycobacterium smegmatis. We report that acetylation of Ku increases with growth, while NHEJ activity decreases, providing support for the hypothesis that acetylation of Ku may be involved in the DNA damage response in bacteria. Ku has multiple lysine sites. Our results indicate that K29 is an important acetylation site and that deficiency of Sir2 or mutation of K29 affects the quantity of Ku and its acetylation dynamics. Our findings expand knowledge of acetylation targets in prokaryotes and indicate a new direction for further research on bacterial DNA repair mechanisms.

The mammalian central nervous system (CNS) relies on a constant supply of external glucose for its undisturbed operation. This article presents an implantable Multi-Electrode Array (MEA) probe for brain glucose measurement. The MEA was implemented on Silicon-On-Insulator (SOI) wafer using Micro-Electro-Mechanical-Systems (MEMS) methods. There were 16 platinum recording sites on the probe and enzyme glucose oxidase (GOx) was immobilized on them. The glucose sensitivity of the MEA probe was as high as 489 µA mM(-1) cm(-2). 1,3-Phenylenediamine (mPD) was electropolymerized onto the Pt recording surfaces to prevent larger molecules such as ascorbic acid (AA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and dopamine (DA) from reaching the recording sites surface. The MEA probe was implanted in the anesthetized rat striatum and responded to glucose levels which were altered by intraperitoneal injection of glucose and insulin. After the in vivo experiment, the MEA probe still kept sensitivity to glucose, these suggested that the MEA probe was reliable for glucose monitoring in brain extracellular fluid (ECF).

Tuberculosis (TB) remains a significant human health issue. More effective biomarkers for use in tuberculosis prevention, diagnosis, and treatment, including markers that can discriminate between healthy individuals and those with latent infection, are urgently needed. To identify a set of such markers, we used Solexa sequencing to examine microRNA expression in the serum of patients with active disease, healthy individuals with latent TB, and those with or without prior BCG inoculation. We identified 24 microRNAs that are up-regulated (2.85–1285.93 fold) and 6 microRNAs that are down-regulated (0.003–0.11 fold) (P

Glucose is the main substrate for neurons in the central nervous system. In order to efficiently characterize the brain glucose mechanism, it is desirable to determine the extracellular glucose dynamics as well as the corresponding neuroelectrical activity in vivo. In the present study, we fabricated an implantable microelectrode array (MEA) probe composed of platinum electrochemical and electrophysiology microelectrodes by standard micro electromechanical system (MEMS) processes. The MEA probe was modified with nano-materials and implanted in a urethane-anesthetized rat for simultaneous recording of striatal extracellular glucose, local field potential (LFP) and spike on the same spatiotemporal scale when the rat was in normoglycemia, hypoglycemia and hyperglycemia. During these dual-mode recordings, we observed that increase of extracellular glucose enhanced the LFP power and spike firing rate, while decrease of glucose had an opposite effect. This dual mode MEA probe is capable of examining specific spatiotemporal relationships between electrical and chemical signaling in the brain, which will contribute significantly to improve our understanding of the neuron physiology.