Commercial insurance delays direct-acting antiviral treatment for hepatitis C kidney transplantation into uninfected recipients.

INTRODUCTION: The advent of direct-acting antivirals (DAAs) has created an avenue for transplantation of hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-). The donor transmission of HCV is then countered by DAA administration during the post-operative period. However, initiation of DAA treatment is ultimately dictated by insurance companies. METHODS: A retrospective chart review of 52 D+/R- kidney recipients who underwent DAA treatment post-transplant was performed. Patients were grouped according to their prescription coverage plans, managed by either commercial or government pharmacy benefit managers (PBMs). RESULTS: Thirty-nine patients had government PBMs and 13 had commercial PBMs. Demographics were similar between the two groups. All patients developed HCV viremia, but cleared the virus after treatment with DAA. Patients with government PBMs were treated earlier compared to those with commercial PBMs (11 days vs 26 days, P = .01). Longer time to DAA initiation resulted in higher peak viral loads (ß = 0.39, R2  = .15, P = .01) and longer time to HCV viral load clearance (ß = 0.41, R2  = .17, P = .01). CONCLUSIONS: D+/R- transplantation offers patients an alternative strategy to increase access. However, treatment can be profoundly delayed by a third-party payer authorization process that may be subjecting patients to unnecessary risks and worsened outcomes.

The Motor Cortex Has Independent Representations for Ipsilateral and Contralateral Arm Movements But Correlated Representations for Grasping.

Motor commands for the arm and hand generally arise from the contralateral motor cortex, where most of the relevant corticospinal tract originates. However, the ipsilateral motor cortex shows activity related to arm movement despite the lack of direct connections. The extent to which the activity related to ipsilateral movement is independent from that related to contralateral movement is unclear based on conflicting conclusions in prior work. Here we investigate bilateral arm and hand movement tasks completed by two human subjects with intracortical microelectrode arrays implanted in the left hand and arm area of the motor cortex. Neural activity was recorded while they attempted to perform arm and hand movements in a virtual environment. This enabled us to quantify the strength and independence of motor cortical activity related to continuous movements of each arm. We also investigated the subjects' ability to control both arms through a brain-computer interface. Through a number of experiments, we found that ipsilateral arm movement was represented independently of, but more weakly than, contralateral arm movement. However, the representation of grasping was correlated between the two hands. This difference between hand and arm representation was unexpected and poses new questions about the different ways the motor cortex controls the hands and arms.

An expanded HIV screening strategy in the Emergency Department fails to identify most patients with undiagnosed infection: insights from a blinded serosurvey.

Screening for HIV in Emergency Departments (EDs) is recommended to address the problem of undiagnosed HIV. Serosurveys are an important method for estimating the prevalence of undiagnosed HIV and can provide insight into the effectiveness of an HIV screening strategy. We performed a blinded serosurvey in an ED offering non-targeted HIV screening to determine the proportion of patients with undiagnosed HIV who were diagnosed during their visit. The study was conducted in a high-volume, urban ED and included patients who had blood drawn for clinical purposes and had sufficient remnant specimen to undergo deidentified HIV testing. Among 4752 patients not previously diagnosed with HIV, 1403 (29.5%) were offered HIV screening and 543 (38.7% of those offered) consented. Overall, undiagnosed HIV was present in 12 patients (0.25%): six among those offered screening (0.4%), and six among those not offered screening (0.2%). Among those with undiagnosed HIV, two (16.7%) consented to screening and were diagnosed during their visit. Despite efforts to increase HIV screening, more than 80% of patients with undiagnosed HIV were not tested during their ED visit. Although half of those with undiagnosed HIV were missed because they were not offered screening, the yield was further diminished because a substantial proportion of patients declined screening. To avoid missed opportunities for diagnosis in the ED, strategies to further improve implementation of HIV screening and optimize rates of consent are needed.

Tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (NHPRTR).

The non-human primate reference transcriptome resource (NHPRTR, available online at http://nhprtr.org/) aims to generate comprehensive RNA-seq data from a wide variety of non-human primates (NHPs), from lemurs to hominids. In the 2012 Phase I of the NHPRTR project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼ 20 tissues in 15 species and subspecies. Here we describe a major expansion of NHPRTR by adding 10.1 billion fragments of tissue-specific RNA-seq data. For this effort, we selected 11 of the original 15 NHP species and subspecies and constructed total RNA libraries for the same ∼ 15 tissues in each. The sequence quality is such that 88% of the reads align to human reference sequences, allowing us to compute the full list of expression abundance across all tissues for each species, using the reads mapped to human genes. This update also includes improved transcript annotations derived from RNA-seq data for rhesus and cynomolgus macaques, two of the most commonly used NHP models and additional RNA-seq data compiled from related projects. Together, these comprehensive reference transcriptomes from multiple primates serve as a valuable community resource for genome annotation, gene dynamics and comparative functional analysis.

Blending of brain-machine interface and vision-guided autonomous robotics improves neuroprosthetic arm performance during grasping.

BACKGROUND: Recent studies have shown that brain-machine interfaces (BMIs) offer great potential for restoring upper limb function. However, grasping objects is a complicated task and the signals extracted from the brain may not always be capable of driving these movements reliably. Vision-guided robotic assistance is one possible way to improve BMI performance. We describe a method of shared control where the user controls a prosthetic arm using a BMI and receives assistance with positioning the hand when it approaches an object. METHODS: Two human subjects with tetraplegia used a robotic arm to complete object transport tasks with and without shared control. The shared control system was designed to provide a balance between BMI-derived intention and computer assistance. An autonomous robotic grasping system identified and tracked objects and defined stable grasp positions for these objects. The system identified when the user intended to interact with an object based on the BMI-controlled movements of the robotic arm. Using shared control, BMI controlled movements and autonomous grasping commands were blended to ensure secure grasps. RESULTS: Both subjects were more successful on object transfer tasks when using shared control compared to BMI control alone. Movements made using shared control were more accurate, more efficient, and less difficult. One participant attempted a task with multiple objects and successfully lifted one of two closely spaced objects in 92 % of trials, demonstrating the potential for users to accurately execute their intention while using shared control. CONCLUSIONS: Integration of BMI control with vision-guided robotic assistance led to improved performance on object transfer tasks. Providing assistance while maintaining generalizability will make BMI systems more attractive to potential users. TRIAL REGISTRATION: NCT01364480 and NCT01894802 .

Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation.

Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4(+) T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation. Importance: The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.

The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics.

RNA-based next-generation sequencing (RNA-Seq) provides a tremendous amount of new information regarding gene and transcript structure, expression and regulation. This is particularly true for non-coding RNAs where whole transcriptome analyses have revealed that the much of the genome is transcribed and that many non-coding transcripts have widespread functionality. However, uniform resources for raw, cleaned and processed RNA-Seq data are sparse for most organisms and this is especially true for non-human primates (NHPs). Here, we describe a large-scale RNA-Seq data and analysis infrastructure, the NHP reference transcriptome resource (http://nhprtr.org); it presently hosts data from12 species of primates, to be expanded to 15 species/subspecies spanning great apes, old world monkeys, new world monkeys and prosimians. Data are collected for each species using pools of RNA from comparable tissues. We provide data access in advance of its deposition at NCBI, as well as browsable tracks of alignments against the human genome using the UCSC genome browser. This resource will continue to host additional RNA-Seq data, alignments and assemblies as they are generated over the coming years and provide a key resource for the annotation of NHP genomes as well as informing primate studies on evolution, reproduction, infection, immunity and pharmacology.

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands.

Manual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participant's ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

Comparing Routine HIV and Hepatitis C Virus Screening to Estimate the Effect of Required Consent on HIV Screening Rates Among Hospitalized Patients.

OBJECTIVES: Routine screening for HIV and hepatitis C virus (HCV) among specified age cohorts is recommended. New York State requires consent before screening for HIV but not HCV. We sought to estimate the effect of the consent requirement on screening rates for HIV. METHODS: We performed a retrospective study of patients hospitalized in 2015-2016 at a tertiary care hospital in the Bronx, New York, during a period when prompts in the electronic health record facilitated screening for HIV and HCV among specified age cohorts. We compared proportions of patients eligible for screening for HIV and/or HCV who underwent screening and used generalized estimating equations and a meta-analytic weighted average to estimate an adjusted risk difference between undergoing HIV screening and undergoing HCV screening. RESULTS: Among 11 938 hospitalized patients eligible for HIV and/or HCV screening, 38.5% underwent screening for HIV and 59.1% underwent screening for HCV. The difference in screening rates persisted after adjusting for patient and admission characteristics (adjusted risk difference = 22.0%; 95% CI, 20.6%-23.4%). CONCLUSIONS: Whereas the requirement for consent was the only difference in the processes of screening for HIV compared with screening for HCV, differences in how the 2 viruses are perceived may also have contributed to the difference in screening rates. Nevertheless, our findings suggest that requiring consent continues to impede progress toward the public health goal of routine HIV screening.

Generalizable cursor click decoding using grasp-related neural transients.

Objective.Intracortical brain-computer interfaces (iBCI) have the potential to restore independence for individuals with significant motor or communication impairments. One of the most realistic avenues for clinical translation of iBCI technology is enabling control of a computer cursor-i.e. movement-related neural activity is interpreted (decoded) and used to drive cursor function. Here we aim to improve cursor click decoding to allow for both point-and-click and click-and-drag control.Approach.Using chronic microelectrode arrays implanted in the motor cortex of two participants with tetraplegia, we identified prominent neural responses related to attempted hand grasp. We then developed a new approach for decoding cursor click (hand grasp) based on the most salient responses.Main results.We found that the population-wide response contained three dominant components related to hand grasp: an onset transient response, a sustained response, and an offset transient response. The transient responses were larger in magnitude-and thus more reliably detected-than the sustained response, and a click decoder based on these transients outperformed the standard approach of binary state classification.Significance.A transient-based approach for identifying hand grasp can provide a high degree of cursor click control for both point-and-click and click-and-drag applications. This generalized click functionality is an important step toward high-performance cursor control and eventual clinical translation of iBCI technology.

Perception of microstimulation frequency in human somatosensory cortex.

Microstimulation in the somatosensory cortex can evoke artificial tactile percepts and can be incorporated into bidirectional brain-computer interfaces (BCIs) to restore function after injury or disease. However, little is known about how stimulation parameters themselves affect perception. Here, we stimulated through microelectrode arrays implanted in the somatosensory cortex of two human participants with cervical spinal cord injury and varied the stimulus amplitude, frequency, and train duration. Increasing the amplitude and train duration increased the perceived intensity on all tested electrodes. Surprisingly, we found that increasing the frequency evoked more intense percepts on some electrodes but evoked less-intense percepts on other electrodes. These different frequency-intensity relationships were divided into three groups, which also evoked distinct percept qualities at different stimulus frequencies. Neighboring electrode sites were more likely to belong to the same group. These results support the idea that stimulation frequency directly controls tactile perception and that these different percepts may be related to the organization of somatosensory cortex, which will facilitate principled development of stimulation strategies for bidirectional BCIs.

Neural stimulation and recording performance in human sensorimotor cortex over 1500 days.

Objective.Intracortical microstimulation (ICMS) in somatosensory cortex can restore sensation to people with spinal cord injury. However, the recording quality from implanted microelectrodes can degrade over time and limitations in stimulation longevity have been considered a potential barrier to the clinical use of ICMS. Our objective was to evaluate recording stability of intracortical electrodes implanted in the motor and somatosensory cortex of one person. The electrodes in motor cortex had platinum tips and were not stimulated, while the electrodes in somatosensory cortex had sputtered iridium oxide film (SIROF) tips and were stimulated. Additionally, we measured how well ICMS was able to evoke sensations over time.Approach. We implanted microelectrode arrays with SIROF tips in the somatosensory cortex (SIROF-sensory) of a human participant with a cervical spinal cord injury. We regularly stimulated these electrodes to evoke tactile sensations on the hand. Here, we quantify the stability of these electrodes in comparison to non-stimulated platinum electrodes implanted in the motor cortex (platinum-motor) over 1500 days with recorded signal quality and electrode impedances. Additionally, we quantify the stability of ICMS-evoked sensations using detection thresholds.Main results. We found that recording quality, as assessed by the number of electrodes with high-amplitude waveforms (>100µV peak-to-peak), peak-to-peak voltage, noise, and signal-to-noise ratio, decreased over time on SIROF-sensory and platinum-motor electrodes. However, SIROF-sensory electrodes were more likely to continue to record high-amplitude signals than platinum-motor electrodes. Interestingly, the detection thresholds for stimulus-evoked sensations decreased over time from a median of 31.5µA at day 100-10.4µA at day 1500, with the largest changes occurring between day 100 and 500.Significance. These results demonstrate that ICMS in human somatosensory cortex can be provided over long periods of time without deleterious effects on recording or stimulation capabilities. In fact, the sensitivity to stimulation improved over time.

A brain-computer interface that evokes tactile sensations improves robotic arm control.

Prosthetic arms controlled by a brain-computer interface can enable people with tetraplegia to perform functional movements. However, vision provides limited feedback because information about grasping objects is best relayed through tactile feedback. We supplemented vision with tactile percepts evoked using a bidirectional brain-computer interface that records neural activity from the motor cortex and generates tactile sensations through intracortical microstimulation of the somatosensory cortex. This enabled a person with tetraplegia to substantially improve performance with a robotic limb; trial times on a clinical upper-limb assessment were reduced by half, from a median time of 20.9 to 10.2 seconds. Faster times were primarily due to less time spent attempting to grasp objects, revealing that mimicking known biological control principles results in task performance that is closer to able-bodied human abilities.

Intracortical Microstimulation Feedback Improves Grasp Force Accuracy in a Human Using a Brain-Computer Interface.

After a spinal cord injury, a person may grasp objects using a brain-computer interface (BCI) to control a robot arm. However, most BCIs do not restore somatosensory percepts that would enable someone to sense grasp force. Intracortical microstimulation (ICMS) in the somatosensory cortex can evoke tactile sensations and may therefore offer a viable solution to provide grasp force feedback. We investigated whether a bidirectional BCI could improve grasp force control over a BCI using only visual feedback. When evaluating the error of the applied force during a force matching task, we found that ICMS feedback improved overall applied grasp force accuracy.

Artifact-free recordings in human bidirectional brain-computer interfaces.

OBJECTIVE: Intracortical microstimulation has shown promise as a means of evoking somatosensory percepts as part of a bidirectional brain-computer interface (BCI). However, microstimulation generates large electrical artifacts that dominate the recordings necessary for BCI control. These artifacts must be eliminated from the signal in real-time to allow for uninterrupted BCI decoding. APPROACH: We present a simple, robust modification to an existing clinical BCI system to allow for simultaneous recording and stimulation using a combination of signal blanking and digital filtering, without needing to explicitly account for varying parameters such as electrode locations or amplitudes. We validated our artifact rejection scheme by recording from microelectrodes in primary motor cortex (M1) while stimulating in somatosensory cortex of a person with a spinal cord injury. MAIN RESULTS: M1 recordings were digitally blanked using a sample-and-hold circuit triggered just prior to stimulus onset and a first-order 750 Hz high-pass Butterworth filter was used to reduce distortion of the remaining artifact. This scheme enabled spike detection in M1 to resume as soon as 740 µs after each stimulus pulse. We demonstrated the effectiveness of the complete bidirectional BCI system by comparing functional performance during a 5 degree of freedom robotic arm control task, with and without stimulation. When stimulation was delivered without this artifact rejection scheme, the number of objects the subject was able to move across a table in 2 min under BCI control declined significantly compared to trials without stimulation (p < 0.01). When artifact rejection was implemented, performance was no different than in trials that did not include stimulation (p = 0.621). SIGNIFICANCE: The proposed technique uses simple changes in filtering and digital signal blanking with FDA-cleared hardware and enables artifact-free recordings during bidirectional BCI control.

Just Culture: Practical Implementation for Radiologist Peer Review.

Peer review is a cornerstone of quality improvement programs and serves to support the peer learning process. Peer review in radiology incorporates the review of diagnostic imaging interpretation, interventional procedures, communication, and the evaluation of untoward patient events. A just culture is an environment in which errors and near-miss events are evaluated in a deliberately nonpunitive framework, avoiding a culture of blame and responsibility and focusing instead on error prevention and fostering a culture of continuous quality improvement. Adoption of a just culture requires careful attention to detail and relies on continuous coaching of individuals and teams to ensure future systems improvements and a culture of safety. The authors describe the practical implementation of a just culture framework for peer review in an academic radiology department and highlight its application to interpretive, noninterpretive, and procedural domains through case examples.

Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control.

Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-ß and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.

Author Correction: Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Implicit Grasp Force Representation in Human Motor Cortical Recordings.

In order for brain-computer interface (BCI) systems to maximize functionality, users will need to be able to accurately modulate grasp force to avoid dropping heavy objects while also being able to handle fragile items. We present a case-study consisting of two experiments designed to identify whether intracortical recordings from the motor cortex of a person with tetraplegia could predict intended grasp force. In the first task, we were able classify neural responses to attempted grasps of four objects, each of which required similar grasp kinematics but different implicit grasp force targets, with 69% accuracy. In the second task, the subject attempted to move a virtual robotic arm in space to grasp a simple virtual object. For each trial, the subject was asked to grasp the virtual object with the force appropriate for one of the four objects from the first experiment, with the goal of measuring an implicit representation of grasp force. While the subject knew the grasp force during all phases of the trial, accurate classification was only achieved during active grasping, not while the hand moved to, transported, or released the object. In both tasks, misclassifications were most often to the object with an adjacent force requirement. In addition to the implications for understanding the representation of grasp force in motor cortex, these results are a first step toward creating intelligent algorithms to help BCI users grasp and manipulate a variety of objects that will be encountered in daily life. Clinical Trial Identifier: NCT01894802 https://clinicaltrials.gov/ct2/show/NCT01894802.

Telementoring of primary care providers delivering hepatitis C treatment in New York City: Results from Project INSPIRE.

INTRODUCTION: The recent availability of highly effective, easily administered, and relatively nontoxic treatments for hepatitis C virus (HCV) infection provides an opportunity for clinicians to treat HCV in nonspecialist settings with appropriate support. Project INSPIRE provides care coordination to HCV patients and a web-based training program (telementoring) on disease management and treatment by HCV specialists to primary care providers inexperienced in HCV treatment. Weekly telementoring sessions use a didactic and case-based approach to instruct non-HCV providers on how to identify and assess HCV treatment candidates and prescribe appropriate treatment. METHODS: We used mixed methods to assess the telementoring service, including provider surveys and semistructured interviews. Quantitative data were analyzed using descriptive statistics, and qualitative data were analyzed to identify dominant themes. RESULTS: Provider survey responses indicated an increased ability to identify and evaluate HCV treatment candidates and increased confidence in sharing knowledge with peers and patients. Interviews revealed a high degree of satisfaction with the telementoring service and Project INSPIRE overall. The telementoring service was viewed as having enhanced providers' knowledge, confidence, and ability to treat their own HCV-infected patients rather than having to refer them to an HCV specialist with resulting benefits for continuity of care. Providers reported comradery and collegiality with other INSPIRE providers and satisfaction with professional growth from attaining new knowledge and skills via the telementoring service. CONCLUSIONS: Using readily available web conferencing technology, telementoring can facilitate knowledge transfer between specialists and primary care providers, facilitating continuity of care for patients and increased provider satisfaction.