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.

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.

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.

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.