Achieving Ultra-Broadband Sunlight-Like Emission in Single-Phase Phosphors: The Interplay of Structure and Luminescence.

The quest for artificial light sources that mimic sunlight's spectral characteristics has been a long-standing endeavor, particularly for applications in anticounterfeiting, agriculture, and color hue detection. Conventional sunlight simulators, such as xenon lamps, are often cost-prohibitive and bulky, limiting their adoption. In this regard, the development of a series of single-phase phosphors Ca9LiMg1-xAl2x/3(PO4)7:0.1Eu2+ (x = 0-0.75) with sunlight-like emission described in this work holds immense promise as a compact and economical light source alternative. The phosphors have been obtained by an original heterovalent substitution method and emit a broad spectrum that encompasses the entire visible region, spanning from violet to deep red. Notably, the phosphor with x = 0.5 exhibits an impressive full width at half maximum of 330 nm. A synergistic interplay of experimental investigations and density-functional theory calculations unveils the underlying mechanism behind sunlight-like emission. It is attributed to the local structural perturbations introduced by the heterovalent substitution of Al3+ for Mg2+, leading to a varied distribution of Eu2+ within the lattice. Subsequent characterization of a series of organic dyes combining absorption spectroscopy with convolutional neural network analysis convincingly demonstrates the potential of this phosphor in portable photodetection devices. Broad-spectrum light source testing empowers our model to precisely differentiate dye patterns. This points to the phosphor being ideal for mimicking sunlight. And beyond this demonstrated application, we envision the phosphor's utility in other relevant domains, including visible light communication and smart agriculture. These findings not only enrich our understanding of luminescent materials design but also pave the way for advancements in various application areas. This article is protected by copyright. All rights reserved.

Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment Against Cholinergic-Induced Status Epilepticus in Rats.

Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.

Evaluation of Midazolam-Ketamine-Allopregnanolone Combination Therapy against Cholinergic-Induced Status Epilepticus in Rats.

Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABAA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABAA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.

Changes in arbuscular mycorrhizal fungal communities, mycorrhizal soil infectivity, and phosphorus availability under Chromolaena odorata (Asteraceae) invasions in a West-African forest-savanna ecotone.

Substantial areas of agricultural lands in Sub-Saharan Africa have been invaded by Chromolaena odorata (Asteraceae), but the consequences for arbuscular mycorrhiza fungi (AMF) remains poorly understood. This study explores changes in diverse AMF community attributes and soil available phosphorus following C. odorata invasion in forest and savanna fragments in Côte d'Ivoire (West Africa). Invaded-forest (COF) and savanna (COS) sites were compared to adjacent natural forest (FOR) and savanna (SAV) fragments, respectively. Physico-chemical variables and AMF spore density parameters were determined for soil samples from 0-20 cm depth. An 18S ribosomal RNA metabarcoding analysis of AMF communities was conducted. In addition, cowpea (Vigna unguiculata) was grown on soils collected from these sites under greenhouse conditions for determination of soil mycorrhizal infectivity. Noticeable changes in the composition of AMF communities in C. odorata relative to nearby forest and savanna non-invaded sites were observed. AMF-specific richness in COS (47 species) was lower than that in SAV (57 species) while it was higher in COF (68 species) than in FOR (63 species). COF and COS differed in AMF specific composition (Dissimilarity index = 50.6%). Chromolaena odorata invasions resulted in increased relative abundances of the genera Claroideoglomus and Glomus in COF, a decreased relative abundance of Paraglomus in COS and decreased relative abundances of Ambispora in both COF and COS. Total and healthy spore densities, cowpea root colonization intensity and soil available P were all higher in invaded sites than in natural ecosystems. Remarkably, although these values were different in FOR and SAV, they turned out to be similar in COF and COS (4.6 and 4.2 total spores g-1 soil, 2.3 and 2.0 healthy spores g-1 soil, and 52.6 and 51.6% root colonization, respectively) suggesting a C. odorata-specific effect. These findings indicate that soil mycorrhizal potential and phosphorus availability have improved following C. odorata invasion.

The last days: The medical response of United States and allied military teams during the Afghanistan Exodus.

OBJECTIVES: The objective of this study is to describe the United States and allied military medical response during the withdrawal from Afghanistan. BACKGROUND: The military withdrawal from Afghanistan concluded with severe hostilities resulting in numerous civilian and military casualties. The clinical care provided by coalition forces capitalized on decades of lessons learned and enabled unprecedented accomplishments. METHODS: In this retrospective, observational analysis, casualty numbers, and operative information was collected and reported from military medical assets in Kabul, Afghanistan. The continuum of medical care and the trauma system, from the point of injury back to the United States was captured and described. RESULTS: Prior to a large suicide bombing resulting in a mass casualty event, the international medical teams managed distinct 45 trauma incidents involving nearly 200 combat and non-combat civilian and military patients over the preceding 3 months. Military medical personnel treated 63 casualties from the Kabul airport suicide attack and performed 15 trauma operations. US air transport teams evacuated 37 patients within 15 hours of the attack. CONCLUSION: Lessons learned from the last 20 years of combat casualty care were successfully implemented during the culmination of the Afghanistan conflict. Ultimately, the effort, teamwork, and system adaptability exemplify not only the attitudes and character of service members who provide modern combat casualty care but also the paramount importance of the battlefield learning health care system. A continued posture to maintain military surgical preparedness in unique environments remain crucial as the US military prepares for the future.Retrospective observational analysis. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level V.

Interictal aggression in rats with chronic seizures after an early life episode of status epilepticus.

OBJECTIVE: In spite of anecdotal reports describing an association between chronic epilepsy and interictal aggressiveness, and of a few studies suggesting that such an association is common in temporal lobe epilepsy, this concept has not been generally accepted by epileptologists. In the course of studies of the long-term consequences of limbic status epilepticus (SE) in juvenile rats, we noticed that experimental animals, unlike littermate controls, could not be housed together because of severe fighting. We now report a study of interictal aggression in those rats. METHODS: Long-term behavioral consequences of lithium/pilocarpine SE were studied 3 months after SE had been induced with lithium and pilocarpine in male Wistar rats at age 28 days. Chronic spontaneous seizures developed in 100% of animals. We tested rats for territorial aggression under the resident-intruder paradigm. We measured the number of episodes of dominance (mounting and pinning), and agonistic behavior (attacks, boxing, and biting). RESULTS: Untreated lithium/pilocarpine SE induced a large increase in aggressive behavior, which involved all aspects of aggression in the resident-intruder paradigm when tested 3 months after SE. The experimental rats were dominant toward the controls, as residents or as intruders, and showed episodes of biting and boxing rarely displayed by controls. They also displayed increased aggressiveness compared with controls when tested against each other. SIGNIFICANCE: This robust model offers an opportunity to better understand the complex relationship between seizures, epilepsy, and aggression, and the role of age, SE vs. recurrent spontaneous seizures, and focal neuronal injury in the long-term behavioral effects of SE.

Enhancing control systems of higher plant culture chambers via multilevel structural mechanistic modelling.

Modelling higher plant growth is of strategic interest for modern agriculture as well as for the development of bioregenerative life support systems for space applications, where crop growth is expected to play an essential role. The capability of constraint-based metabolic models to cope the diel dynamics of plants growth is integrated into a multilevel modelling approach including mass and energy transfer and enzyme kinetics. Lactuca sativa is used as an exemplary crop to validate, with experimental data, the approach presented as well as to design a novel model-based predictive control strategy embedding metabolic information. The proposed modelling strategy predicts with high accuracy the dynamics of gas exchange and the distribution of fluxes in the metabolic network whereas the control architecture presented can be useful to manage higher plants chambers and open new ways of merging metabolome and control algorithms.

Structure, reactivity and luminescence studies of triphenylsiloxide complexes of tetravalent lanthanides.

Among the 14 lanthanide elements (Ce-Lu), until recently, the tetravalent oxidation state was readily accessible in solution only for cerium while Pr(iv), Nd(iv), Dy(iv) and Tb(iv) had only been detected in the solid state. The triphenylsiloxide ligand recently allowed the isolation of molecular complexes of Tb(iv) and Pr(iv) providing an unique opportunity of investigating the luminescent properties of Ln(iv) ions. Here we have expanded the coordination studies of the triphenylsiloxide ligand with Ln(iii) and Ln(iv) ions and we report the first observed luminescence emission spectra of Pr(iv) complexes which are assigned to a ligand-based emission on the basis of the measured lifetime and computational studies. Binding of the ligand to the Pr(iv) ion leads to an unprecedented large shift of the ligand triplet state which is relevant for future applications in materials science.

Pure Superior Wall Acetabular Fracture: A Rare Posterior Wall Variant.

CASE: We present a case of a pure superior wall acetabular fracture in an US soldier, caused by a collapsing wall. Although Letournel and Judet classified this pattern as a rare variant of a posterior-superior wall acetabular fracture, it shares features of several patterns and the treatment more closely follows that of the anterior-based elementary patterns. CONCLUSION: The mechanism, incidence, and long-term outcomes of this fracture remain unknown, but improved recognition and proper classification may help to guide treatment. This case highlights 1 patient with this unique pattern and outlines its management and short- to mid-term outcome.

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats.

OBJECTIVE: Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABAA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABAA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. METHODS: We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. RESULTS: The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity. SIGNIFICANCE: Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.

Lanthanide-tetrapyrrole complexes: synthesis, redox chemistry, photophysical properties, and photonic applications.

Tetrapyrrole derivatives such as porphyrins, phthalocyanines, naphthalocyanines, and porpholactones, are highly stable macrocyclic compounds that play important roles in many phenomena linked to the development of life. Their complexes with lanthanides are known for more than 60 years and present breath-taking properties such as a range of easily accessible redox states leading to photo- and electro-chromism, paramagnetism, large non-linear optical parameters, and remarkable light emission in the visible and near-infrared (NIR) ranges. They are at the centre of many applications with an increasing focus on their ability to generate singlet oxygen for photodynamic therapy coupled with bioimaging and biosensing properties. This review first describes the synthetic paths leading to lanthanide-tetrapyrrole complexes together with their structures. The initial synthetic protocols were plagued by low yields and long reaction times; they have now been replaced with much more efficient and faster routes, thanks to the stunning advances in synthetic organic chemistry, so that quite complex multinuclear edifices are presently routinely obtained. Aspects such as redox properties, sensitization of NIR-emitting lanthanide ions, and non-linear optical properties are then presented. The spectacular improvements in the quantum yield and brightness of YbIII-containing tetrapyrrole complexes achieved in the past five years are representative of the vitality of the field and open welcome opportunities for the bio-applications described in the last section. Perspectives for the field are vast and exciting as new derivatizations of the macrocycles may lead to sensitization of other LnIII NIR-emitting ions with luminescence in the NIR-II and NIR-III biological windows, while conjugation with peptides and aptamers opens the way for lanthanide-tetrapyrrole theranostics.

Identifying lifetime as one of the key parameters responsible for the low brightness of lanthanide-based OLEDs.

OLEDs based on lanthanide complexes have decisive optical advantages but are hampered by low brightness. Despite the efforts to optimize several parameters such as quantum yield and charge carrier mobility, there seems to be another key parameter that hinders their performances. Experimental data are therefore collected for mixed-ligand europium complexes with bathophenanthroline and different classes of anionic ligands and screened to identify the key parameter responsible for this situation, which turns out to be the long lifetime of their excited states. A broad literature search supports this conclusion, showing that lanthanide complexes are inferior to other classes of OLED emitters often because of their long lifetimes; furthermore, among a series of lanthanide complexes, the best results are achieved for those with the shortest lifetimes, even though they suffer from low quantum yields.

Lanthanide-Based Peptide-Directed Visible/Near-Infrared Imaging and Inhibition of LMP1.

A lanthanide-based peptide-directed bioprobe LnP19 (Ln = Eu or Yb) is designed as an impressive example of a small molecule-based dual-functional probe for the EBV oncoprotein LMP1. The peptide P19 (Pra-KAhx-K-LDLALK-FWLY-K-IVMSDKW-K-RrRK) is designed to selectively bind to LMP1 by mimicking its TM1 region during oligomerization in lipid rafts while signal transduction is significantly suppressed. Immunofluorescence imaging and Western blotting results reveal that P19 can effectively inactivate the oncogenic cellular pathway nuclear factor κB (NF-κB) and contribute to a selective cytotoxic effect on LMP1-positive cells. By conjugation with cyclen-based europium(III) and ytterbium(III) complexes, EuP19 and YbP19 were constructed to offer visible and near-infrared LMP1-targeted imaging and cancer monitoring. In addition to the ability to target and inhibit LMP1 and to selective inhibit LMP1-positive cells, selective growth inhibition toward the LMP1-positive tumor by LnP19 is also demonstrated.

A hybrid erbium(III)-bacteriochlorin near-infrared probe for multiplexed biomedical imaging.

Spectrally distinct fluorophores are desired for multiplexed bioimaging. In particular, monitoring biological processes in living mammals needs fluorophores that operate in the 'tissue-transparent' near-infrared (NIR) window, that is, between 700 and 1,700 nm. Here we report a fluorophore system based on molecular erbium(III)-bacteriochlorin complexes with large Stokes shift (>750 nm) and narrowband NIR-to-NIR downconversion spectra (full-width at half-maximum ≤ 32 nm). We have found that the fast (2 × 109 s-¹) and near-unity energy transfer from bacteriochlorin triplets to the erbium(III) 4I13/2 level overcomes the notorious vibrational overtones quenching, resulting in bright and long-lived (1.73 µs) 1,530 nm luminescence in water. We demonstrate the excitation/emission-multiplexed capability of the complexes in the visualization of dynamic circulatory and metabolic processes in living mice, and through skull tracking of cancer cell metastases in mouse brain. This hybrid probe system facilitates robust multiplexed NIR imaging with high contrast and spatial resolution for applications ranging from fluorescence-guided surgery, diagnostics and intravital microscopy.

Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study.

Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N = 65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.

A Novel Proteomics-Based Strategy for the Investigation of Peptide Sequences in Extraterrestrial Samples.

Method development is one of the objectives of the astrophysical community for characterizing the organic matter in objects of the solar system. In this context, we report on the development of an enzyme-catalyzed stereoselective hydrolysis, inspired by the proteomics discipline, which has enabled the indirect detection of peptide sequences in extraterrestrial samples. A proof of concept has been performed on a Murchison extract. We show that our approach can successfully highlight l- and d-amino acids involved in peptide bonds. While we show that some d-amino acids must have been involved in peptide bonds, we cannot at this stage conclude on the indigenous or exogenous nature of these biopolymers. However, our strategy constitutes the first step toward direct UPLC-MS evidence of peptide sequences in extraterrestrial samples. It should thus contribute to deepening knowledge on the molecules available in the solar system, hence providing new clues about their chemical history, especially on Earth.

The management of embedded metal fragment patients and the role of chelation Therapy: A workshop of the Department of Veterans Affairs-Walter Reed National Medical Center.

Exposure to retained metal fragments from war-related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short-term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.

Clinical placement anxiety in undergraduate nursing students: A concept analysis.

OBJECTIVE: The primary aim of this review was to complete an in-depth analysis of clinical placement anxiety in undergraduate nursing students. Our overall goal was to establish a strong foundation for clinical education strategies and future research on clinical placement anxiety in nursing education. DESIGN & METHODS: We utilized Walker and Avant's systematic 8-step approach to concept analysis as a framework to develop a comprehensive understanding of clinical placement anxiety in undergraduate students. DATA SOURCES: A review of existing literature on clinical placement anxiety was conducted using the electronic databases of PubMed, CINAHL, and PsychInfo, as well as a grey literature and snowball search. Search terms included clinical placement, clinical experience, nursing students, undergraduate nursing students, and anxiety. RESULTS: The literature search resulted in 81 articles that met the inclusion criteria. Five defining attributes were identified: a vague or unknown threat, psychological-emotional responses, psychological-cognitive responses, physiological responses, and unfamiliar environments or situations. Antecedents, consequences, and empirical referents of the concept were also highlighted. CONCLUSIONS: Insights gleaned from this concept analysis may enhance the ability of clinical nursing educators to effectively prevent and manage student anxiety in the clinical setting. By contextualizing anxiety, we have also validated the importance of further exploration of the anxiety experienced by undergraduate nursing students during their clinical experiences. Thus, this concept analysis establishes the foundation for educational strategies, as well as future research in nursing education.

Rational polytherapy in the treatment of cholinergic seizures.

The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.