Individual and Military Factors That Modify the Association Between Recent Sexual Trauma and Health Outcomes Among U.S. Service Members and Veterans.

Sexual trauma (ST), which includes both sexual harassment and sexual assault, is associated with a variety of adverse mental and physical health outcomes in military and civilian populations. However, little is known about whether certain individual or military attributes or prior experiences may modify the relationship between recent ST and mental or physical health outcomes. Data from a longitudinal cohort study of current and former military members were used to examine whether individual and military factors modify the association between recent ST and health outcomes (posttraumatic stress disorder, depression, multiple somatic symptoms, and insomnia).

Study of Modifications Induced by Continued Direct Oral Anticoagulant Therapy during Atrial Fibrillation Ablation Procedures on Standard Hemostasis Parameters.

Background: Unfractionated heparin (UFH) is used as an anticoagulant during the atrial fibrillation (AF) ablation procedure to prevent the occurrence of thromboembolic events. Guidelines recommend an activated clotting time (ACT) greater than 300 s (s) based on studies of patients treated with vitamin K antagonist (VKA) for their AF. However, direct oral anticoagulants (DOACs) have supplanted VKAs in AF and are now used as first-line therapy.

The processes and context of innovation in mental healthcare: Oxfordshire as a case study.

This article introduces the four following articles and the Classic Text. They describe the development of a sequence of innovative local mental health services in Oxfordshire, and explore the processes of innovation, led by the humane pragmatism practised by Dr Bertram Mandelbrote, who was Physician Superintendent at Littlemore Hospital in Oxford from 1959 to 1988. The articles describe emerging patterns of therapeutic community practice, and trace the events leading to a set of discrete service developments outside the hospital.

Innovation in mental health care: Bertram Mandelbrote, the Phoenix Unit and the therapeutic community approach.

Bertram Mandelbrote was Physician Superintendent and Consultant Psychiatrist at Littlemore Hospital in Oxford from 1959 to 1988. A humane pragmatist rather than theoretician, Mandelbrote was known for his facilitating style of leadership and working across organisational boundaries. He created the Phoenix Unit, an innovative admission unit run on therapeutic community lines which became a hub for community outreach.

Structural patterns for transmedia storytelling.

Transmedia storytelling involves telling a story using multiple distinct media. The remit of stories that fall under this broad definition is vast, consequently causing theorists to examine different phenomena using tools that are not suitable for all forms of transmedia storytelling. The lack of critical tools means we are unable to describe, compare and analyse different experiences using common language.

Novel method for action potential measurements from intact cardiac monolayers with multiwell microelectrode array technology.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biology and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP).

International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment.

To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated the concentration dependence and sources of variability of electrophysiologic responses to 28 drugs linked to low, intermediate, and high torsades de pointes (TdP) risk categories using two commercial cell lines and standardized protocols in a blinded multisite study using multielectrode array or voltage-sensing optical approaches. Logistical and ordinal linear regression models were constructed using drug responses as predictors and TdP risk categories as outcomes. Three of seven predictors (drug-induced arrhythmia-like events and prolongation of repolarization at either maximum tested or maximal clinical exposures) categorized drugs with reasonable accuracy (area under the curve values of receiver operator curves ∼0.

Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays: Results from a Blinded CiPA Pilot Study.

Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC-CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies).

Comparative analysis of media effects on human induced pluripotent stem cell-derived cardiomyocytes in proarrhythmia risk assessment.

Introduction: Cardiotoxicity assessment using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) forms a key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). A potentially impactful factor on iPSC-CM testing is the presence of serum in the experimental media. Generally, serum-free media is used to most accurately reproduce "free" drug concentration.

Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes.

Drug-drug interactions pose a difficult drug safety problem, given the increasing number of individuals taking multiple medications and the relative complexity of assessing the potential for interactions. For example, sofosbuvir-based drug treatments have significantly advanced care for hepatitis C virus-infected patients, yet recent reports suggest interactions with amiodarone may cause severe symptomatic bradycardia and thus limit an otherwise extremely effective treatment. Here, we evaluated the ability of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to recapitulate the interaction between sofosbuvir and amiodarone in vitro, and more generally assessed the feasibility of hiPSC-CMs as a model system for drug-drug interactions.

Thalamic state control of cortical paired-pulse dynamics.

Unlabelled: Sensory stimulation drives complex interactions across neural circuits as information is encoded and then transmitted from one brain region to the next. In the highly interconnected thalamocortical circuit, these complex interactions elicit repeatable neural dynamics in response to temporal patterns of stimuli that provide insight into the circuit properties that generated them. Here, using a combination of in vivo voltage-sensitive dye (VSD) imaging of cortex, single-unit recording in thalamus, and optogenetics to manipulate thalamic state in the rodent vibrissa pathway, we probed the thalamocortical circuit with simple temporal patterns of stimuli delivered either to the whiskers on the face (sensory stimulation) or to the thalamus directly via electrical or optogenetic inputs (artificial stimulation).

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation.

Response reliability observed with voltage-sensitive dye imaging of cortical layer 2/3: the probability of activation hypothesis.

A central assertion in the study of neural processing is that our perception of the environment directly reflects the activity of our sensory neurons. This assertion reinforces the intuition that the strength of a sensory input directly modulates the amount of neural activity observed in response to that sensory feature: an increase in the strength of the input yields a graded increase in the amount of neural activity. However, cortical activity across a range of sensory pathways can be sparse, with individual neurons having remarkably low firing rates, often exhibiting suprathreshold activity on only a fraction of experimental trials.

Electrical and Optical Activation of Mesoscale Neural Circuits with Implications for Coding.

Unlabelled: Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery of circuit function and for engineered approaches to alleviate various disorders of the nervous system. However, evidence suggests that neural activity generated by artificial stimuli differs dramatically from normal circuit function, in terms of both the local neuronal population activity at the site of activation and the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown.

Optogenetic feedback control of neural activity.

Optogenetic techniques enable precise excitation and inhibition of firing in specified neuronal populations and artifact-free recording of firing activity. Several studies have suggested that optical stimulation provides the precision and dynamic range requisite for closed-loop neuronal control, but no approach yet permits feedback control of neuronal firing. Here we present the 'optoclamp', a feedback control technology that provides continuous, real-time adjustments of bidirectional optical stimulation in order to lock spiking activity at specified targets over timescales ranging from seconds to days.

Microchannel-based regenerative scaffold for chronic peripheral nerve interfacing in amputees.

Neurally controlled prosthetics that cosmetically and functionally mimic amputated limbs remain a clinical need because state of the art neural prosthetics only provide a fraction of a natural limb's functionality. Here, we report on the fabrication and capability of polydimethylsiloxane (PDMS) and epoxy-based SU-8 photoresist microchannel scaffolds to serve as viable constructs for peripheral nerve interfacing through in vitro and in vivo studies in a sciatic nerve amputee model where the nerve lacks distal reinnervation targets. These studies showed microchannels with 100 μm × 100 μm cross-sectional areas support and direct the regeneration/migration of axons, Schwann cells, and fibroblasts through the microchannels with space available for future maturation of the axons.

The adaptive trade-off between detection and discrimination in cortical representations and behavior.

It has long been posited that detectability of sensory inputs can be sacrificed in favor of improved discriminability and that sensory adaptation may mediate this trade-off. The extent to which this trade-off exists behaviorally and the complete picture of the underlying neural representations that likely subserve the phenomenon remain unclear. In the rodent vibrissa system, an ideal observer analysis of cortical activity measured using voltage-sensitive dye imaging in anesthetized animals was combined with behavioral detection and discrimination tasks, thalamic recordings from awake animals, and computational modeling to show that spatial discrimination performance was improved following adaptation, but at the expense of the ability to detect weak stimuli.

Behavioral and electrophysiological effects of cortical microstimulation parameters.

Electrical microstimulation has been widely used to artificially activate neural circuits on fast time scales. Despite the ubiquity of its use, little is known about precisely how it activates neural pathways. Current is typically delivered to neural tissue in a manner that provides a locally balanced injection of positive and negative charge, resulting in negligible net charge delivery to avoid the neurotoxic effects of charge accumulation.

System identification of the nonlinear dynamics in the thalamocortical circuit in response to patterned thalamic microstimulation in vivo.

Objective: Nonlinear system identification approaches were used to develop a dynamical model of the network level response to patterns of microstimulation in vivo.

Approach: The thalamocortical circuit of the rodent vibrissa pathway was the model system, with voltage sensitive dye imaging capturing the cortical response to patterns of stimulation delivered from a single electrode in the ventral posteromedial thalamus. The results of simple paired stimulus experiments formed the basis for the development of a phenomenological model explicitly containing nonlinear elements observed experimentally.

Comparison of blood and synovial fluid th17 and novel peptidase inhibitor 16 Treg cell subsets in juvenile idiopathic arthritis.

Objective: Early recognition and treatment of juvenile idiopathic arthritis (JIA) can prevent joint damage and minimize side effects of medication. The balance between proinflammatory and antiinflammatory mechanisms is known to be important in JIA, and we therefore investigated T cell subsets including Th cells, autoaggressive Th17 cells, and regulatory T cells (Treg), including a novel Treg subset in peripheral blood (PB) and synovial fluid (SF) of patients with JIA.

Methods: Fifty children with JIA were enrolled in our study.

PI16 is expressed by a subset of human memory Treg with enhanced migration to CCL17 and CCL20.

The peptidase inhibitor PI16 was shown previously by microarray analysis to be over-expressed by CD4-positive/CD25-positive Treg compared with CD4-positive/CD25-negative Th cells. Using a monoclonal antibody to the human PI16 protein, we found that PI16-positive Treg have a memory (CD45RO-positive) phenotype and express higher levels of FOXP3 than PI16-negative Treg. PI16-positive Treg are functional in suppressor assays in vitro with potency similar to PI16-negative Treg.

Detection of tactile inputs in the rat vibrissa pathway.

The rapid detection of sensory inputs is crucial for survival. Sensory detection explicitly requires the integration of incoming sensory information and the ability to distinguish between relevant information and ongoing neural activity. In this study, head-fixed rats were trained to detect the presence of a brief deflection of their whiskers resulting from a focused puff of air.

Voltage-sensitive dye imaging reveals improved topographic activation of cortex in response to manipulation of thalamic microstimulation parameters.

Voltage-sensitive dye imaging was used to quantify in vivo, network level spatiotemporal cortical activation in response to electrical microstimulation of the thalamus in the rat vibrissa pathway. Thalamic microstimulation evoked a distinctly different cortical response than natural sensory stimulation, with response to microstimulation spreading over a larger area of cortex and being topographically misaligned with the cortical column to which the stimulated thalamic region projects. Electrical stimulation with cathode-leading asymmetric waveforms reduced this topographic misalignment while simultaneously increasing the spatial specificity of the cortical activation.