Publications by authors named "Jeffrey M Weiss"

26 Publications

  • Page 1 of 1

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

Public Health Rep 2021 Mar 5:33354921999170. Epub 2021 Mar 5.

368074 Department of Medicine, University of South Carolina School of Medicine, Greenville, SC, USA.

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.
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http://dx.doi.org/10.1177/0033354921999170DOI Listing
March 2021

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

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3355-3358

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.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717497PMC
July 2020

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

Transpl Infect Dis 2021 Feb 3;23(1):e13449. Epub 2020 Sep 3.

Albert Einstein College of Medicine, Bronx, NY, USA.

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 (β = 0.39, R  = .15, P = .01) and longer time to HCV viral load clearance (β = 0.41, R  = .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.
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http://dx.doi.org/10.1111/tid.13449DOI Listing
February 2021

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

Cereb Cortex 2020 Sep;30(10):5400-5409

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, United States.

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.
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http://dx.doi.org/10.1093/cercor/bhaa120DOI Listing
September 2020

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

Nat Commun 2019 11 8;10(1):5101. Epub 2019 Nov 8.

Department of Immunology, University of Washington, Seattle, WA, USA.

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-β 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.
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http://dx.doi.org/10.1038/s41467-019-12987-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841668PMC
November 2019

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

AIDS Care 2020 02 30;32(2):202-208. Epub 2019 May 30.

Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.

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.
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http://dx.doi.org/10.1080/09540121.2019.1619663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884659PMC
February 2020

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

Learn Health Syst 2018 Jul 10;2(3). Epub 2018 May 10.

Heathcare Policy & Research, Weill Cornell Medical College, New York City, New York.

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.
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http://dx.doi.org/10.1002/lrh2.10056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508766PMC
July 2018

Just Culture: Practical Implementation for Radiologist Peer Review.

J Am Coll Radiol 2019 Mar 22;16(3):384-388. Epub 2018 Dec 22.

Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.

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.
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http://dx.doi.org/10.1016/j.jacr.2018.10.021DOI Listing
March 2019

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

J Neural Eng 2019 02 16;16(1):016002. Epub 2018 Nov 16.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States of America. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America.

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.
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http://dx.doi.org/10.1088/1741-2552/aae748DOI Listing
February 2019

Implicit Grasp Force Representation in Human Motor Cortical Recordings.

Front Neurosci 2018 31;12:801. Epub 2018 Oct 31.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States.

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. NCT01894802 https://clinicaltrials.gov/ct2/show/NCT01894802.
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http://dx.doi.org/10.3389/fnins.2018.00801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220062PMC
October 2018

Evaluating Serial Strategies for Preventing Wrong-Patient Orders in the NICU.

Pediatrics 2017 May;139(5)

Division of Hospital Medicine.

Background: NICU patients have characteristics believed to increase their risk for wrong-patient errors; however, little is known about the frequency of wrong-patient errors in the NICU or about effective interventions for preventing these errors. We conducted a quality improvement study to evaluate the frequency of wrong-patient orders in the NICU and to assess the effectiveness of an ID reentry intervention and a distinct naming convention (eg, "Wendysgirl") for reducing these errors, using non-NICU pediatric units as a comparator.

Methods: Using a validated measure, we examined the rate of wrong-patient orders in NICU and non-NICU pediatric units during 3 periods: baseline (before implementing interventions), ID reentry intervention (reentry of patient identifiers before placing orders), and combined intervention (addition of a distinct naming convention for newborns).

Results: We reviewed >850 000 NICU orders and >3.5 million non-NICU pediatric orders during the 7-year study period. At baseline, wrong-patient orders were more frequent in NICU than in non-NICU pediatric units (117.2 vs 74.9 per 100 000 orders, respectively; odds ratio 1.56; 95% confidence interval, 1.34-1.82). The ID reentry intervention reduced the frequency of errors in the NICU to 60.2 per 100 000 (48.7% reduction; < .001). The combined ID reentry and distinct naming interventions yielded an additional decrease to 45.6 per 100 000 (61.1% reduction from baseline; < .001).

Conclusions: The risk of wrong-patient orders in the NICU was significantly higher than in non-NICU pediatric units. Implementation of a combined ID reentry intervention and distinct naming convention greatly reduced this risk.
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http://dx.doi.org/10.1542/peds.2016-2863DOI Listing
May 2017

Expanded HIV Testing Strategy Leveraging the Electronic Medical Record Uncovers Undiagnosed Infection Among Hospitalized Patients.

J Acquir Immune Defic Syndr 2017 05;75(1):27-34

*Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY; †Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY; and ‡Department of Pediatrics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.

Background: Routine HIV testing of hospitalized patients is recommended, but few strategies to expand testing in the hospital setting have been described. We assessed the impact of an electronic medical record (EMR) prompt on HIV testing for hospitalized patients.

Methods: We performed a pre-post study at 3 hospitals in the Bronx, NY. We compared the proportion of admissions of patients 21-64 years old with an HIV test performed, characteristics of patients tested, and rate of new HIV diagnoses made by screening while an EMR prompt recommending HIV testing was inactive vs. active. The prompt appeared for patients with no previous HIV test or a high-risk diagnosis after their last HIV test.

Results: Among 36,610 admissions while the prompt was inactive, 9.5% had an HIV test performed. Among 18,943 admissions while the prompt was active, 21.8% had an HIV test performed. Admission while the prompt was active was associated with increased HIV testing among total admissions [adjusted odds ratio (aOR) 2.78, 95% confidence interval (CI): 2.62 to 2.96], those without a previous HIV test (aOR 4.03, 95% CI: 3.70 to 4.40), and those with a previous negative test (aOR 1.52, 95% CI: 1.37 to 1.68) (P < 0.0001 for all). Although the prompt was active, testing increased across all patient characteristics. New HIV diagnoses made by screening increased from 8.2/100,000 admissions to 37.0/100,000 admissions while the prompt was inactive and active, respectively (OR 4.51 95% CI: 1.17 to 17.45, P = 0.03).

Conclusions: An EMR prompt for hospitalized patients was associated with a large increase in HIV testing, a diversification of patients tested, and an increase in diagnoses made by screening.
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http://dx.doi.org/10.1097/QAI.0000000000001299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388580PMC
May 2017

A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection.

Cell Rep 2017 01;18(3):816-829

Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA. Electronic address:

The unprecedented 2013-2016 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.
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http://dx.doi.org/10.1016/j.celrep.2016.12.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289750PMC
January 2017

Intracortical microstimulation of human somatosensory cortex.

Sci Transl Med 2016 10 13;8(361):361ra141. Epub 2016 Oct 13.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Intracortical microstimulation of the somatosensory cortex offers the potential for creating a sensory neuroprosthesis to restore tactile sensation. Whereas animal studies have suggested that both cutaneous and proprioceptive percepts can be evoked using this approach, the perceptual quality of the stimuli cannot be measured in these experiments. We show that microstimulation within the hand area of the somatosensory cortex of a person with long-term spinal cord injury evokes tactile sensations perceived as originating from locations on the hand and that cortical stimulation sites are organized according to expected somatotopic principles. Many of these percepts exhibit naturalistic characteristics (including feelings of pressure), can be evoked at low stimulation amplitudes, and remain stable for months. Further, modulating the stimulus amplitude grades the perceptual intensity of the stimuli, suggesting that intracortical microstimulation could be used to convey information about the contact location and pressure necessary to perform dexterous hand movements associated with object manipulation.
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http://dx.doi.org/10.1126/scitranslmed.aaf8083DOI Listing
October 2016

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

J Neuroeng Rehabil 2016 Mar 18;13:28. Epub 2016 Mar 18.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.

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 .
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http://dx.doi.org/10.1186/s12984-016-0134-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797113PMC
March 2016

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

Nucleic Acids Res 2015 Jan 11;43(Database issue):D737-42. Epub 2014 Nov 11.

Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA Institute for Computational Biology (ICB), Weill Cornell Medical College, New York, NY 10065, USA Feil Family Brain and Mind Research Institute (BMRI), Weill Cornell Medical College, New York, NY 10065, USA

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.
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http://dx.doi.org/10.1093/nar/gku1110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383927PMC
January 2015

Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance.

Science 2014 Nov 30;346(6212):987-91. Epub 2014 Oct 30.

Department of Microbiology, University of Washington, Seattle, WA, USA. Washington National Primate Research Center, Seattle, WA, USA.

Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
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http://dx.doi.org/10.1126/science.1259595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241145PMC
November 2014

Multiple low-dose challenges in a rhesus macaque AIDS vaccine trial result in an evolving host response that affects protective outcome.

Clin Vaccine Immunol 2014 Dec 1;21(12):1650-60. Epub 2014 Oct 1.

Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, University of Washington, Seattle, Washington, USA

Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.
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http://dx.doi.org/10.1128/CVI.00455-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248781PMC
December 2014

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

J Virol 2014 Jul 7;88(14):7962-72. Epub 2014 May 7.

Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, University of Washington, Seattle, Washington, USA

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.
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http://dx.doi.org/10.1128/JVI.00543-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097788PMC
July 2014

A comprehensive collection of systems biology data characterizing the host response to viral infection.

Sci Data 2014 14;1:140033. Epub 2014 Oct 14.

J. Craig Venter Institute , La Jolla, CA 92037, USA ; Department of Pathology, University of California , San Diego, CA 92093, USA.

The Systems Biology for Infectious Diseases Research program was established by the U.S. National Institute of Allergy and Infectious Diseases to investigate host-pathogen interactions at a systems level. This program generated 47 transcriptomic and proteomic datasets from 30 studies that investigate in vivo and in vitro host responses to viral infections. Human pathogens in the Orthomyxoviridae and Coronaviridae families, especially pandemic H1N1 and avian H5N1 influenza A viruses and severe acute respiratory syndrome coronavirus (SARS-CoV), were investigated. Study validation was demonstrated via experimental quality control measures and meta-analysis of independent experiments performed under similar conditions. Primary assay results are archived at the GEO and PeptideAtlas public repositories, while processed statistical results together with standardized metadata are publically available at the Influenza Research Database (www.fludb.org) and the Virus Pathogen Resource (www.viprbrc.org). By comparing data from mutant versus wild-type virus and host strains, RNA versus protein differential expression, and infection with genetically similar strains, these data can be used to further investigate genetic and physiological determinants of host responses to viral infection.
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http://dx.doi.org/10.1038/sdata.2014.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410982PMC
December 2015

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

Nucleic Acids Res 2013 Jan 29;41(Database issue):D906-14. Epub 2012 Nov 29.

Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.

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.
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http://dx.doi.org/10.1093/nar/gks1268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531109PMC
January 2013

Understanding and preventing wrong-patient electronic orders: a randomized controlled trial.

J Am Med Inform Assoc 2013 Mar-Apr;20(2):305-10. Epub 2012 Jun 29.

Departments of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10467, USA.

Objective: To evaluate systems for estimating and preventing wrong-patient electronic orders in computerized physician order entry systems with a two-phase study.

Materials And Methods: In phase 1, from May to August 2010, the effectiveness of a 'retract-and-reorder' measurement tool was assessed that identified orders placed on a patient, promptly retracted, and then reordered by the same provider on a different patient as a marker for wrong-patient electronic orders. This tool was then used to estimate the frequency of wrong-patient electronic orders in four hospitals in 2009. In phase 2, from December 2010 to June 2011, a three-armed randomized controlled trial was conducted to evaluate the efficacy of two distinct interventions aimed at preventing these errors by reverifying patient identification: an 'ID-verify alert', and an 'ID-reentry function'.

Results: The retract-and-reorder measurement tool effectively identified 170 of 223 events as wrong-patient electronic orders, resulting in a positive predictive value of 76.2% (95% CI 70.6% to 81.9%). Using this tool it was estimated that 5246 electronic orders were placed on wrong patients in 2009. In phase 2, 901 776 ordering sessions among 4028 providers were examined. Compared with control, the ID-verify alert reduced the odds of a retract-and-reorder event (OR 0.84, 95% CI 0.72 to 0.98), but the ID-reentry function reduced the odds by a larger magnitude (OR 0.60, 95% CI 0.50 to 0.71).

Discussion And Conclusion: Wrong-patient electronic orders occur frequently with computerized provider order entry systems, and electronic interventions can reduce the risk of these errors occurring.
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http://dx.doi.org/10.1136/amiajnl-2012-001055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638184PMC
August 2013

Quantitative proteomic analysis of HIV-1 infected CD4+ T cells reveals an early host response in important biological pathways: protein synthesis, cell proliferation, and T-cell activation.

Virology 2012 Jul 26;429(1):37-46. Epub 2012 Apr 26.

Department of Microbiology, University of Washington, Seattle, WA 98195-8070, USA.

Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value ≤ 0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.
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http://dx.doi.org/10.1016/j.virol.2012.03.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358407PMC
July 2012

Development and application of pyrolysis gas chromatography/mass spectrometry for the analysis of bound trinitrotoluene residues in soil.

Environ Sci Technol 2004 Apr;38(7):2167-74

Department of Microbiology, Wing Hall, Cornell University, Ithaca, New York 14853, USA.

TNT (trinitrotoluene) is a contaminant of global environmental significance, yet determining its environmental fate has posed longstanding challenges. To date, only differential extraction-based approaches have been able to determine the presence of covalently bound, reduced forms of TNT in field soils. Here, we employed thermal elution, pyrolysis, and gas chromatography/mass spectrometry (GC/MS) to distinguish between covalently bound and noncovalently bound reduced forms of TNT in soil. Model soil organic matter-based matrixes were used to develop an assay in which noncovalently bound (monomeric) aminodinitrotoluene (ADNT) and diaminonitrotoluene (DANT) were desorbed from the matrix and analyzed at a lower temperature than covalently bound forms of these same compounds. A thermal desorption technique, evolved gas analysis, was initially employed to differentiate between covalently bound and added 15N-labeled monomeric compounds. A refined thermal elution procedure, termed "double-shot analysis" (DSA), allowed a sample to be sequentially analyzed in two phases. In phase 1, all of an added 15N-labeled monomeric contaminant was eluted from the sample at relatively low temperature. In phase 2 during high-temperature pyrolysis, the remaining covalently bound contaminants were detected. DSA analysis of soil from the Louisiana Army Ammunition Plant (LAAP; approximately 5000 ppm TNT) revealed the presence of DANT, ADNT, and TNT. After scrutinizing the DSA data and comparing them to results from solvent-extracted and base/ acid-hydrolyzed LAAP soil, we concluded that the TNT was a noncovalently bound "carryover" from phase 1. Thus, the pyrolysis-GC/MS technique successfully defined covalently bound pools of ADNT and DANT in the field soil sample.
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http://dx.doi.org/10.1021/es034911vDOI Listing
April 2004