Greater mechanistic understanding of the cutaneous pathogenesis of Stevens-Johnson syndrome/toxic epidermal necrolysis can shed light on novel therapeutic strategies: a comprehensive review.

PURPOSE OF REVIEW: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions (SCARs) characterized by widespread epithelial detachment and blistering, which affects the skin and mucocutaneous membranes. To date, therapeutic interventions for SJS/TEN have focused on systematic suppression of the inflammatory response using high-dose corticosteroids or intravenous immunoglobulin G (IgG), for example. No targeted therapies for SJS/TEN currently exist. RECENT FINDINGS: Though our understanding of the pathogenesis of SJS/TEN has advanced from both an immunological and dermatological perspective, this knowledge is yet to translate into the development of new targeted therapies. SUMMARY: Greater mechanistic insight into SJS/TEN would potentially unlock new opportunities for identifying or repurposing targeted therapies to limit or even prevent epidermal injury and blistering.

Glycolysis: An early marker for vancomycin-specific T-cell activation.

BACKGROUND: Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients. METHODS: CD4+ and CD8+ vancomycin-responsive TCCs were generated by serial dilution. The Seahorse XFe96 Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T-cell proliferation and cytokine release (IFN-γ) assay were utilised to correlate the bioenergetic characteristics of T-cell activation with in vitro assays. RESULTS: Model T-cell stimulants induced non-specific T-cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose-dependent and drug-specific glycolytic shift when vancomycin-reactive TCCs were exposed to the drug. Vancomycin-reactive TCCs did not exhibit T-cell cross-reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross-reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction. CONCLUSION: These studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T-cell activation is located upstream of metabolic signalling.

Exposure of human immune cells, to the antiretrovirals efavirenz and lopinavir, leads to lower glucose uptake and altered bioenergetic cell profiles through interactions with SLC2A1.

SLC2A1 mediates glucose cellular uptake; key to appropriate immune function. Our previous work has shown efavirenz and lopinavir exposure inhibits T cell and macrophage responses, to known agonists, likely via interactions with glucose transporters. Using human cell lines as a model, we assessed glucose uptake and subsequent bioenergetic profiles, linked to immunological responses. Glucose uptake was measured using 2-deoxyglucose as a surrogate for endogenous glucose, using commercially available reagents. mRNA expression of SLC transporters was investigated using qPCR TaqMan™ gene expression assay. Bioenergetic assessment, on THP-1 cells, utilised the Agilent Seahorse XF Mito Stress test. In silico analysis of potential interactions between SLC2A1 and antiretrovirals was investigated using bioinformatic techniques. Efavirenz and lopinavir exposure was associated with significantly lower glucose accumulation, most notably in THP-1 cells (up to 90% lower and 70% lower with efavirenz and lopinavir, respectively). Bioenergetic assessment showed differences in the rate of ATP production (JATP); efavirenz (4 µg/mL), was shown to reduce JATP by 87% whereas lopinavir (10 µg/mL), was shown to increase the overall JATP by 77%. Putative in silico analysis indicated the antiretrovirals, apart from efavirenz, associated with the binding site of highest binding affinity to SLC2A1, similar to that of glucose. Our data suggest a role for efavirenz and lopinavir in the alteration of glucose accumulation with subsequent alteration of bioenergetic profiles, supporting our hypothesis for their inhibitory effect on immune cell activation. Clarification of the implications of this data, for in vivo immunological responses, is now warranted to define possible consequences for these, and similar, therapeutics.

Acclimation to warmer temperature reversibly improves high-temperature hypoxia tolerance in both diploid and triploid brook charr, Salvelinus fontinalis.

Rising temperature leads to reduced oxygen solubility and therefore increases the risk of exposure to harmful hypoxic condition for fish in their natural aquatic environments and in aquaculture. The goal of this study was to determine whether acclimation to warmer temperature can improve high-temperature hypoxia tolerance in fish, using sibling diploid and triploid brook charr as the experimental model. Triploid fish are used for aquaculture and fisheries management because they are sterile, but they are known to have reduced thermal and hypoxia tolerance compared to conventional diploids. Fish were pre-acclimated to either 15 °C (optimum temperature for diploids) or 18 °C and then assessed for high-temperature hypoxia tolerance by rapidly increasing temperature to pre-determined levels (up to 30 °C), holding fish at these temperatures for one hour, and then using compressed nitrogen to drive oxygen out of the water. Hypoxia tolerance was expressed as both the oxygen tension at loss of equilibrium and the time taken to reach this endpoint following the start of the trial. Acclimation to 18 °C improved hypoxia tolerance at high temperatures but this advantage was lost after reacclimation to 15 °C. Although 18 °C acclimation improved the hypoxia tolerance of triploids, it remained inferior to that of diploids under identical test conditions. Somatic energy reserves (estimated as condition factor and hepatosomatic index), cardiac output (relative ventricular mass) and oxygen carrying capacity of the blood (hemoglobin concentration and hematocrit) did not markedly affect high-temperature hypoxia tolerance.

The Metacognitive Processes of Decentering Scale: Development and initial validation of trait and state versions.

The ability to decenter from internal experiences is important for mental health. Consequently, improving decentering is a common therapeutic target, particularly for mindfulness-based interventions. However, extant decentering measures are limited as they fail to directly assess all 3 metacognitive processes recently theorized to subserve decentering. We thus conducted 4 studies to develop and test the Metacognitive Processes of Decentering-Trait (MPoD-t) and State (MPoD-s) scales. Consistent with the metacognitive processes model, exploratory factor analysis (N = 355) and then bifactor exploratory structural equation modeling (N = 275) indicated the MPoD-t was composed of three independent yet interrelated lower-order factors, metaawareness, (dis)identification with internal experience, and (non)reactivity to internal experience, which subserved an emergent, higher-order, decentering factor. We next found evidence of the MPoD-t's convergent validity; as well as known-groups criterion validity, wherein mindfulness practitioners reported higher MPoD-t scores than nonpractitioners. Item response theory analyses were then used to identify a subset of 3 MPoD-t items for the MPoD-s. Finally, we found evidence that the MPoD-s was sensitive to changes in state decentering following a brief mindfulness induction relative to an active control condition; and that MPoD-s changes mediated the effect of mindfulness on levels of pain and related outcomes among a sample of preoperative surgery patients (N = 82). These studies indicate the trait and state versions of the MPoD may prove useful for the study of decentering and its constituent metacognitive processes. As such, the MPoD may help advance our understanding of how the metacognitive processes of decentering support mental health and well-being. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Safety perspectives on presently considered drugs for the treatment of COVID-19.

Intense efforts are underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm-benefit ratios that may be encountered when treating COVID-19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life-threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID-19.

The mitochondrial paradox.

A structural motif that is found in two cancer drugs may be responsible for their ability to tackle cancers and for the side-effects caused by the drugs.

A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy.

BACKGROUND: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. METHODS: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors. RESULTS: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and PI3K appeared as a significant factor in controlling tumour proliferation. CONCLUSIONS: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

Avatars in nursing: an integrative review.

This integrative review explored the use of avatars and virtual worlds in education, synthesizing the articles and findings and presenting implications for nurse educators. Evaluation of available publications concluded that avatars allow students to practice in a safe environment, enhancing learning. The need now is for faculty who use avatars and virtual worlds in their teaching to plan more robust outcomes assessment that evaluates if the acquired knowledge of students, met program objectives, and achieved improved patient outcomes.

Clinical reasoning during simulation: comparison of student and faculty ratings.

A recently developed tool, the Lasater Clinical Judgment Rubric (LCJR), was used to evaluate nursing students' clinical reasoning during simulated patient care scenarios. For two semesters, students and nursing faculty completed the clinical reasoning tool after participating in and observing students' reactions to simulated emergent patient simulations. Scores were compared between nursing students and faculty and between programs, associate (AS) and baccalaureate of science (BS). Students' scores differed statistically based on program, BS means greater than AS, but student and faculty ratings were rarely significantly different. Additional research across multiple programs for a larger sample size and additional testing of the clinical reasoning tool are needed. To promote more realistic self-appraisals, students may need more opportunities to self-assess clinical reasoning behaviors in conjunction with feedback on performance from faculty throughout the nursing program.

Effective panchromatic sensitization of electrochemical solar cells: strategy and organizational rules for spatial separation of complementary light harvesters on high-area photoelectrodes.

Dye-sensitized solar cells, especially those comprising molecular chromophores and inorganic titania, have shown promise as an alternative to silicon for photovoltaic light-to-electrical energy conversion. Co-sensitization (the use of two or more chromophores having complementary absorption spectra) has attracted attention as a method for harvesting photons over a broad spectral range. If implemented successfully, then cosensitization can substantially enhance photocurrent densities and light-to-electrical energy conversion efficiencies. In only a few cases, however, have significant overall improvements been obtained. In most other cases, inefficiencies arise due to unconstructive energy or charge transfer between chromophores or, as we show here, because of modulation of charge-recombination behavior. Spatial isolation of differing chromophores offers a solution. We report a new and versatile method for fabricating two-color photoanodes featuring spatially isolated chromophore types that are selectively positioned in desired zones. Exploiting this methodology, we find that photocurrent densities depend on both the relative and absolute positions of chromophores and on "local" effective electron collection lengths. One version of the two-color photoanode, based on an organic push-pull dye together with a porphyrin dye, yielded high photocurrent densities (J(SC) = 14.6 mA cm(-2)) and double the efficiency of randomly mixed dyes, once the dyes were optimally positioned with respect to each other. We believe that the organizational rules and fabrication strategy will prove transferrable, thereby advancing understanding of panchromatic sensitization as well as yielding higher efficiency devices.

Dye-sensitized solar cells: sensitizer-dependent injection into ZnO nanotube electrodes.

Two porphyrin-based dyes with carboxylic acid tethers of differing acidity in both protonated and deprotonated forms were examined on ZnO nanotube electrodes. All of the dyes have similar surface coverage, but only the more acidic dye in the acid form injects electrons well; this dye is the only one that corrodes the ZnO. In control experiments on TiO(2) nanoparticle electrodes, both dyes load and inject in protonated and deprotonated forms. These results are consistent with a requirement that the dye must partially corrode the ZnO surface in order for efficient injection to occur. Alternatively, it may possibly point to a coupling of electron injection to proton uptake.

Three technological enhancements in nursing education: informatics instruction, personal response systems, and human patient simulation.

With the healthcare system in a state of flux, nursing education faces many challenges. Nursing faculty must design a dynamic curriculum that deals with the explosion of information, the complexity of the healthcare system, and optimal patient outcomes while addressing the diverse expectations of learners. Inclusion of information management and interactive technology facilitates learner engagement promoting critical thinking and improving clinical judgment. This paper details the faculty's vision for an ubiquitous information technology curricula, highlighting an undergraduate informatics course, use of a personal response system, and integration of human patient simulations.

Fast energy transfer within a self-assembled cyclic porphyrin tetramer.

The structure of a cyclic self-assembled tetramer of an asymmetric meso-ethynylpyridyl-functionalized Zn(II)-porphyrin was established by solution-phase X-ray scattering and diffraction; femtosecond transient absorption and anisotropy spectroscopies were used to (a) observe rapid energy transfer (3.8 ps(-1)) between porphyrin subunits and (b) establish that the transfer occurs between adjacent units.

Single nanoparticle based optical pH probe.

This paper describes the development of a nanoscale optical pH probe based upon the surface-enhanced Raman scattering (SERS) properties of silica-gold core-shell nanoparticles. In this approach, a thin layer of gold is deposited onto a core of silica to form a metallic nanoshell with surface plasmon modes in the red-to-near-infrared spectral region. The surface of the nanoshell is functionalized with a pH-sensitive SERS reporter molecule, 4-mercaptopyridine (4-MPy). The SERS spectra of 4-MPy is shown to be sensitive to the pH of the surrounding media within the range of 3 to 7. In addition, it is shown that individual silica-gold core-shell nanoparticles yield more reliable SERS spectra than aggregates of core-shell nanoparticles.

Re-examining the origins of spectral blinking in single-molecule and single-nanoparticle SERS.

Single metal nanoparticles and nanoaggregates are known to emit intense bursts of surface-enhanced Raman scattering (SERS) in an intermittent on and off fashion. The characteristic "blinking" timescales range from milliseconds to seconds. Here we report detailed temperature dependence (both heating and cooling) and light-intensity studies to further examine the origins of this intriguing phenomenon. The results indicate that blinking SERS contains both a thermo-activated component and a light-induced component. Several lines of evidence suggest that the observed fluctuations are caused by thermally activated diffusion of individual molecules on the particle surface, coupled with photo-induced electron transfer and structural relaxation of surface active sites or atomic-scale roughness features.

Cation-cation interactions between uranyl cations in a polar open-framework uranyl periodate.

Novel open-framework alkali metal uranyl periodates, having the formula A[(UO2)3(HIO6)(OH)(O)(H2O)].1.5H2O (A = Li, Na, K, Rb, Cs), have been prepared through mild hydrothermal synthesis. These isostructural compounds contain distorted UO7 pentagonal bipyramids that are linked through a uranyl (UO22+) to uranyl cation-cation interaction. This interaction arises from a single axial uranyl oxygen coordinating at an equatorial site of an adjacent uranyl unit. These uranium oxide polyhedra are further bound by IO6 distorted octahedra creating an open-framework structure whose channels contain the alkali metal cations.