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Three experiments are reported that used a new test of spatial memory in rats. The apparatus used was dual eight-arm radial mazes that were connected at one arm of each maze, with a start arm and doors to each maze. Rats could be forced to go to one maze or the other or could make a free choice between mazes. In Experiment 1, rats formed reference memory for the arm containing food on one maze but had food randomly placed on different arms over trials on the other maze. In Experiment 2, rats formed working memory for the arm containing food on one maze but not the other. In Experiment 3, food location changed randomly among trials on both mazes, but one maze contained a cue for the location of food. Rats used reference and working memory to go directly to the food arm on one maze but found food only after searching several arms on the other maze. Most importantly, when given free-choice trials rats developed a significant preference for the maze where they knew the location of food reward or found the cue indicating the location of reward. We suggest these findings may be best interpreted by rats applying two successive rules: (1) choose the maze that leads to the most immediate reward, and (2) use extramaze or intramaze cues to find reward location on the maze.

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High redox potential, two-electron organic catholytes for nonaqueous redox flow batteries were developed by appending diaminocyclopropenium (DAC) substituents to phenazine and phenothiazine cores. The parent heterocycles exhibit two partially reversible oxidations at moderate potentials [both at lower than 0.7 V vs ferrocene/ferrocenium (Fc/Fc+)]. The incorporation of DAC substituents has a dual effect on these systems. The DAC groups increase the redox potential of both couples by ∼300 mV while simultaneously rendering the second oxidation (which occurs at 1.20 V vs Fc/Fc+ in the phenothiazine derivative) reversible. The electron-withdrawing nature of the DAC unit is responsible for the increase in redox potential, while the DAC substituents stabilize oxidized forms of the molecules through resonance delocalization of charge and unpaired spin density. These new catholytes were deployed in two-electron redox flow batteries that exhibit voltages of up to 2.0 V and no detectable crossover over 250 cycles.

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Characterizing community mental health (CMH) treatment duration and discharge is an important step toward understanding how to better meet client needs. This report describes patterns of treatment duration and discharge among clinicians participating in a state-funded evidence-based treatment (EBT) training initiative. After training and consultation, clinicians (N = 376) reported on treatment duration and discharge for their "most complete case." On average, clinicians delivered 12.4 sessions (SD = 5.1) of the treatment. After completing treatment, half of clinicians (58.7%) continued with regularly scheduled therapy, either using EBT elements or switching to supportive therapy. Clinicians who continued with regularly scheduled therapy delivered treatment in approximately the same number of sessions. Results revealed that CMH clinicians often do not discontinue therapy after completing a treatment protocol. These findings suggest it may be essential to better understand clinician decision-making around applying EBTs to their caseloads.

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Background: Most evidence-based treatments (EBTs) for posttraumatic stress disorder (PTSD) and anxiety disorders include exposure; however, in community settings, the implementation of exposure lags behind other EBT components. Clinician-level determinants have been consistently implicated as barriers to exposure implementation, but few organizational determinants have been studied. The current study examines an organization-level determinant, implementation climate, and clinician-level determinants, clinician demographic and background factors, as predictors of attitudes toward exposure and changes in attitudes following training. Method: Clinicians (n = 197) completed a 3-day training with 6 months of twice-monthly consultation. Clinicians were trained in cognitive behavioral therapy (CBT) for anxiety, depression, behavior problems, and trauma-focused CBT (TF-CBT). Demographic and background information, implementation climate, and attitudes toward exposure were assessed in a pre-training survey; attitudes were reassessed at post-consultation. Implementation climate was measured at the aggregated/group-level and clinician-level. Results: Attitudes toward exposure significantly improved from pre-training to post-consultation (t(193) = 9.9, p < .001; d = 0.71). Clinician-level implementation climate scores did not predict more positive attitudes at pre-training (p > .05) but did predict more positive attitudes at post-consultation (ß = -2.46; p < .05) and greater changes in those attitudes (ß = 2.28; p < .05). Group-level implementation climate scores did not predict attitudes at pre-training, post-consultation, or changes in attitudes (all ps > .05). Higher frequency of self-reported CBT use was associated with more positive attitudes at pre-training (ß = -0.81; p < .05), but no other clinician demographic or background determinants were associated with attitudes at post-consultation (all p > .05) or with changes in attitudes (all p > .05). Conclusions: Clinician perceptions of implementation climate predicted greater improvement of attitudes toward exposure following EBT training and consultation. Findings suggest that organizational determinants outside of training impact changes in clinicians' attitudes. Training in four EBTs, only two of which include exposure as a component, resulted in positive changes in clinicians' attitudes toward exposure, which suggests non-specialty trainings can be effective at changing attitudes, which may enable scale-up.

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Ti(salen) complexes catalyze the asymmetric [3 + 2] cycloaddition of cyclopropyl ketones with alkenes. While high enantioselectivities are achieved with electron-rich alkenes, electron-deficient alkenes are less selective. Herein, we describe mechanistic studies to understand the origins of catalyst and substrate trends in an effort to identify a more general catalyst. Density functional theory (DFT) calculations of the selectivity determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst, which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building blocks.

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The development of an electrochemically driven, ruthenium-catalyzed C-H hydroxylation reaction of amine-derived substrates bearing tertiary C-H bonds is described. The reaction is performed under constant current electrolysis in a divided cell to afford alcohol products in yields comparable to those of our previously reported process, which requires the use of stoichiometric H5IO6 for catalytic turnover. With aqueous acid as solvent, the cathodic electrode reaction simply involves the reduction of protons to evolve hydrogen gas. The optimized protocol offers a convenient, efficient, and atom-economical method for sp3-C-H bond oxidation.

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Medicinal chemistry campaigns set the foundation for streamlined molecular design strategies through the development of quantitative structure-activity models. Our group's enduring underlying interest in reaction mechanism propelled our adaption of a similar strategy to unite mechanistic interrogation and catalyst optimization by relating reaction outputs to molecular descriptors. Through collaborative opportunities, we have recently expanded these predictive statistical modeling tools to electrocatalysis and the design of redox-active organic molecules for application as electrolytes in nonaqueous redox flow batteries. Utilizing small, strategically designed data sets for a given core structure, we develop predictive statistical models that enable rapid virtual screening campaigns to identify analogues with enhanced properties. This process relates structural parameters to the output of interest, providing insight into the structural features that influence the output under study. Furthermore, the weighting of the coefficients for each parameter in the model can furnish mechanistic insight. Such a synergistic implementation of experimental and computational tools for mechanistic insight provides a means of forecasting properties of analogues without necessitating the synthesis and analysis of each molecule of interest. Through collaborative efforts, we have demonstrated the effectiveness of these tools for predicting diverse outputs such as stability, redox potential, and nonaqueous solubility. In this Account, we outline our entry into the field of organic electrochemistry and the implementation of statistical modeling tools for designing organic electrolytes. Through these projects we were exposed to the power of electrochemical techniques as a mechanistic tool, which has provided access to critical information that would otherwise be difficult to obtain. Utilizing electroanalytical techniques, we have quantified the rates of disproportionation of a variety of cobalt complexes and developed statistical models that provide critical insight into understanding of fundamental processes involved in the disproportionation of organometallic complexes. Electroanalytical tools have also been effective in elucidating the active catalyst oxidation state in different catalytic organometallic systems for C-H functionalization. Thus, our foray into electrolyte design and electrocatalysis, in which the statistical modeling tools developed for mechanistic insight were applied in a new context, came full circle to the core foundation of our group: mechanistic understanding.

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Nonaqueous redox flow batteries (RFBs) represent a promising technology for grid-scale energy storage. A key challenge for the field is identifying molecules that undergo reversible redox reactions at the extreme potentials required to leverage the large potential window of organic solvents. In this Article, we use a combination of computations, chemical synthesis, and mechanistic analysis to develop thioether-substituted cyclopropenium derivatives as high potential electrolytes for nonaqueous RFBs. These molecules exhibit redox potentials that are 470-500 mV higher than those of known electrolytes. Strategic variation of the alkyl substituent on sulfur afforded a derivative that undergoes charge-discharge cycling at +1.33 V vs ferrocene/ferrocenium in acetonitrile/tetrabutylammonium hexafluorophosphate. This electrolyte was paired with a phthalimide derivative to achieve a proof-of-principle 3.2 V all-organic RFB.

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BACKGROUND: Point prevalence studies identify that pneumonia is the most common healthcare associated infection. However, non-ventilator associated healthcare associated pneumonia (NV-HAP) is both underreported and understudied. Most research conducted to date, focuses on ventilator associated pneumonia. We conducted a systematic review, to provide the latest evidence for strategies to reduce NV-HAP and describe the methodological approaches used. METHODS: We performed a systematic search to identify research exploring and evaluating NV-HAP preventive measures in hospitals and aged-care facilities. The electronic database Medline was searched, for peer-reviewed articles published between 1st January 1998 and 31st August 2018. An assessment of the study quality and risk of bias of included articles was conducted using the Newcastle-Ottawa Scale. RESULTS: The literature search yielded 1551 articles, with 15 articles meeting the inclusion criteria. The majority of strategies for NV-HAP prevention focussed on oral care (n = 9). Three studies evaluated a form of physical activity, such as passive movements, two studies used dysphagia screening and management; and another study evaluated prophylactic antibiotics. Most studies (n = 12) were conducted in a hospital setting. Six of the fifteen studies were randomised controlled trials. CONCLUSION: There was considerable heterogeneity in the included studies, including the type of intervention, study design, methods and definitions used to diagnose the NV-HAP. To date, interventions to reduce NV-HAP appear to be based broadly on the themes of improving oral care, increased mobility or movement and dysphagia management.

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The implementation of redox active organics in nonaqueous redox flow batteries requires the design of molecules that exhibit high solubility (>1 M) in all battery-relevant redox states. Methods for forecasting nonaqueous solubility would be valuable for streamlining the identification of promising structures. Herein we report the development of a workflow to parametrize and predict the solubility of conformationally flexible tris(dialkylamino)cyclopropenium (CP) radical dications. A statistical model is developed through training on monomer species. Ultimately, this model is used to predict new monomeric and dimeric CP derivatives with solubilities of >1 M in acetonitrile in all oxidation states. The most soluble CP monomer exhibits high stability to electrochemical cycling at 1 M in acetonitrile without a supporting electrolyte in a symmetrical flow cell.

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We have recently disclosed [(dtbpy)2RuCl2] as an effective precatalyst for chemoselective C-H hydroxylation of C(sp3)-H bonds and have noted a marked disparity in reaction performance between 4,4'-di- tert-butyl-2,2'-bipyridine (dtbpy)- and 2,2'-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been unveiled through evaluation of ligand structure-activity relationships, electrochemical and kinetic studies, and pressurized sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is dependent on the identity of bipyridyl 4,4'-substituent groups. Dissociated bipyridyl ligand is oxidized to mono- and bis- N-oxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a catalytically inactive tris-ligated [Ru(dtbpy)2(dtbpy N-oxide)]2+ complex. Insights gained through this work highlight the power of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, next-generation catalyst systems for C-H hydroxylation.

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Nonaqueous redox flow batteries (NRFBs) represent an attractive technology for energy storage from intermittent renewable sources. In these batteries, electrical energy is stored in and extracted from electrolyte solutions of redox-active molecules (termed catholytes and anolytes) that are passed through an electrochemical flow cell. To avoid battery self-discharge, the anolyte and catholyte solutions must be separated by a membrane in the flow cell. This membrane prevents crossover of the redox active molecules, while simultaneously allowing facile transport of charge-balancing ions. A key unmet challenge for the field is the design of redox-active molecule/membrane pairs that enable effective electrolyte separation while maintaining optimal battery properties. Herein, we demonstrate the development of oligomeric catholytes based on tris(dialkylamino)cyclopropenium (CP) salts that are specifically tailored for pairing with size-exclusion membranes composed of polymers of intrinsic microporosity (PIMs). Systematic studies were conducted to evaluate the impact of oligomer size/structure on properties that are crucial for flow battery performance, including cycling stability, charge capacity, solubility, electron transfer kinetics, and crossover rates. These studies have led to the identification of a CP-derived tetramer in which these properties are all comparable, or significantly improved, relative to the monomeric counterpart. Finally, a proof-of-concept flow battery is demonstrated by pairing this tetrameric catholyte with a PIM membrane. After 6 days of cycling, no crossover is detected, demonstrating the promise of this approach. These studies provide a template for the future design of other redox-active oligomers for this application.

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The deployment of nonaqueous redox flow batteries for grid-scale energy storage has been impeded by a lack of electrolytes that undergo redox events at as low (anolyte) or high (catholyte) potentials as possible while exhibiting the stability and cycling lifetimes necessary for a battery device. Herein, we report a new approach to electrolyte design that uses physical organic tools for the predictive targeting of electrolytes that possess this combination of properties. We apply this approach to the identification of a new pyridinium-based anolyte that undergoes 1e- electrochemical charge-discharge cycling at low potential (-1.21 V vs Fc/Fc+) to a 95% state-of-charge without detectable capacity loss after 200 cycles.

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The binding of drugs to metalloenzymes is an intricate process that involves several interactions, including binding of the drug to the enzyme active site metal, as well as multiple interactions between the drug and the enzyme residues. In order to determine the free energy contribution of Zn(2+) binding by known metalloenzyme inhibitors without the other interactions, valid active site zinc structural mimetics must be formed and binding studies need to be performed in biologically relevant conditions. The potential of each of five ligands to form a structural mimetic with Zn(2+) was investigated in buffer using Isothermal Titration Calorimetry (ITC). All five ligands formed strong 1 : 1 (ligand : Zn(2+)) binary complexes. The complexes were used in further ITC experiments to study their interaction with 8-hydroxyquinoline (8-HQ) and/or acetohydroxamic acid (AHA), two bidentate anionic zinc-chelating enzyme inhibitors. It was found that tetradentate ligands were not suitable for creating zinc structural mimetics for inhibitor binding in solution due to insufficient coordination sites remaining on Zn(2+). A stable binary complex, [Zn(BPA)](2+), which was formed by a tridentate ligand, bis(2-pyridylmethyl)amine (BPA), was found to bind one AHA in buffer or a methanol : buffer mixture (60 : 40 by volume) at pH 7.25 or one 8-HQ in the methanol : buffer mixture at pH 6.80, making it an effective structural mimetic for the active site of zinc metalloenzymes. These results are consistent with the observation that metalloenzyme active site zinc ions have three residues coordinated to them, leaving one or two sites open for inhibitors to bind. Our findings indicate that Zn(BPA)X2 can be used as an active site structural mimetic for zinc metalloenzymes for estimating the free energy contribution of zinc binding to the overall inhibitor active site interactions. Such use will help aid in the rational design of inhibitors to a variety of zinc metalloenzymes.

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