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bioRxiv2020

Adaptive current-flow models of ECT: Explaining individual static impedance, dynamic impedance, and brain current delivery

BackgroundImprovements in electroconvulsive therapy (ECT) outcomes have followed refinement in device electrical output and electrode montage. The physical properties of the ECT stimulus, together with those of the patients head, determine the impedances measured by the device and govern current delivery to the brain and ECT outcomes. ObjectiveHowever, the precise relations among physical properties of the stimulus, patient head anatomy, and patient-specific impedance to the passage of current are long-standing questions in ECT research and practice. MethodsWe developed anatomical MRI-derived models of transcranial electrical stimulation (tES) that included changes in tissue conductivity due to local electrical current flow. These "adaptive" models simulate ECT both during therapeutic stimulation using high (~1 A) current and when dynamic impedance is measured, as well as prior to stimulation when low (~1 mA) current is used to measure static impedance. We modeled two scalp layers: a superficial scalp layer with adaptive conductivity that increases with electric field up to a subject specific maximum [Formula], and a deep scalp layer with a subject-specific fixed conductivity ({sigma}DS). ResultsWe demonstrate that variation in these scalp parameters explain clinical data on subject-specific static impedance and dynamic impedance, their imperfect correlation across subjects, their relationships to seizure threshold, and the role of head anatomy. Adaptive tES models demonstrate that current flow changes local tissue conductivity which in turn shapes current delivery to the brain in a manner not accounted for in fixed tissue conductivity models. ConclusionsOur predictions that variation in individual skin properties, rather than other aspects of anatomy, largely govern the relationship between static impedance, dynamic impedance, and current delivery to the brain, are themselves subject to assumptions about tissue properties. Broadly, our novel pipeline for tES models is important in ongoing efforts to optimize devices, personalize interventions, and explain clinical findings.

bioengineering↗

bioRxiv2020

Candida auris phenotypic heterogeneity determines pathogenicity in vitro

Candida auris is an enigmatic yeast that provides substantial global risk in healthcare facilities and intensive care units. A unique phenotype exhibited by certain isolates of C. auris is their ability to form small clusters of cells known as aggregates, which have been to a limited extent described in the context of pathogenic traits. In this study, we screened several non-aggregative and aggregative C. auris isolates for biofilm formation, where we observed a level of heterogeneity amongst the different phenotypes. Next, we utilised an RNA-sequencing approach to investigate the transcriptional responses during biofilm formation of a non-aggregative and aggregative isolate of the initial pool. Observations from these analyses indicate unique transcriptional profiles in the two isolates, with several genes identified relating to proteins involved in adhesion and invasion of the host in other fungal species. From these findings we investigated for the first time the fungal recognition and inflammatory responses of a three-dimensional skin epithelial model to these isolates. In these models, a wound was induced to mimic a portal of entry for C. auris. We show both phenotypes elicited minimal response in the model minus induction of the wound, yet in the wounded tissue both phenotypes induced a greater response, with the aggregative isolate more pro-inflammatory. This capacity of aggregative C. auris biofilms to generate such responses in the wounded skin highlights how this opportunistic yeast is a high risk within the intensive care environment where susceptible patients have multiple indwelling lines. ImportanceCandida auris has recently emerged as an important cause of concern within healthcare environments due to its ability to persist and tolerate commonly used antiseptics and disinfectants, particularly when surface attached (biofilms). This yeast is able to colonise and subsequently infect patients, particularly those that are critically ill or immunosuppressed, which may result in death. We have undertaken analysis on two different types of this yeast, using molecular and immunological tools to determine whether either of these has a greater ability to cause serious infections. We describe that both isolates exhibit largely different transcriptional profiles during biofilm development. Finally, we show that the inability to form small aggregates (or clusters) of cells has an adverse effect on the organisms immuno-stimulatory properties, suggestive the non-aggregative phenotype may exhibit a certain level of immune evasion.

microbiology↗