Search

Although largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and chronic phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster model to characterize and compare the effects of infection with SARS-CoV-2 and influenza A virus (IAV) on the sensory nervous system. We detected SARS-CoV-2 transcripts but no infectious material in the cervical and thoracic spinal cord and dorsal root ganglia (DRGs) within the first 24 hours of intranasal virus infection. SARS-CoV-2–infected hamsters exhibited mechanical hypersensitivity that was milder but prolonged compared with that observed in IAV-infected hamsters. RNA sequencing analysis of thoracic DRGs 1 to 4 days after infection suggested perturbations in predominantly neuronal signaling in SARS-CoV-2–infected animals as opposed to type I interferon signaling in IAV-infected animals. Later, 31 days after infection, a neuropathic transcriptome emerged in thoracic DRGs from SARS-CoV-2–infected animals, which coincided with SARS-CoV-2–specific mechanical hypersensitivity. These data revealed potential targets for pain management, including the RNA binding protein ILF3, which was validated in murine pain models. This work elucidates transcriptomic signatures in the DRGs triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities.

We developed an accelerated virtual reality (VR) suprathreshold hemifield perimetry algorithm, the median cut hemifield test (MCHT). This study examines the ability of the MCHT to determine ptosis severity and its reversibility with an artificial improvement by eyelid taping on an HTC Vive Pro Eye VR headset and the Humphrey visual field analyzer (HVFA) to assess the capabilities of emerging technologies in evaluating ptosis.In a single visit, the MCHT was administered along with the HVFA 30-2 on ptotic untaped and taped eyelids in a randomized order. The primary end points were a superior field visibility comparison with severity of VF loss and VF improvement after taping for MCHT and HVFA. Secondary end points included evaluating patients' Likert-scaled survey responses on the comfort, speed, and overall experience with both testing modalities.VR's MCHT superior field degrees visible correlated well for severe category margin to reflex distance (r = 0.78) compared with HVFA's (r = -0.21). The MCHT also demonstrated noninferiority (83.3% agreement; P = 1) against HVFA for detection of 30% or more superior visual field improvement after taping, warranting a corrective surgical intervention. In comparing hemi-VF in untaped eyes, both tests demonstrated relative obstruction to the field when comparing normal controls to severe ptosis (HVFA P0.05; MCHT P0.001), which proved sufficient to demonstrate percent improvement with taping. The secondary end point of patient satisfaction favored VR vision testing presentation mode in terms of comfort (P0.01), speed (P0.001), and overall experience (P0.01).This pilot trial supports the use of MCHT for the quantitative measurement of visual field loss owing to ptosis and the reversibility of ptosis that is tested when conducting a presurgical evaluation. We believe the adoption of MCHT testing in oculoplastic clinics could decrease patient burden and accelerate time to corrective treatment.In this study, we look at vision field outputs in patients with ptosis to evaluate its severity and improvement with eyelid taping on a low-profile VR-based technology and compare it with HVFA. Our results demonstrate that alternative, portable technologies such as VR can be used to grade the degree of ptosis and determine whether ptosis surgery could provide a significant superior visual field improvement of 30% or more, all while ensuring a more comfortable experience and faster testing time.

Despite being largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and long-lasting phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster infection model to characterize the effects of SARS-CoV-2 versus Influenza A virus (IAV) infection on the sensory nervous system. Efforts to detect the presence of virus in the cervical/thoracic spinal cord and dorsal root ganglia (DRGs) demonstrated detectable levels of SARS-CoV-2 by quantitative PCR and RNAscope uniquely within the first 24 hours of infection. SARS-CoV-2-infected hamsters demonstrated mechanical hypersensitivity during acute infection; intriguingly, this hypersensitivity was milder, but prolonged when compared to IAV-infected hamsters. RNA sequencing (RNA-seq) of thoracic DRGs from acute infection revealed predominantly neuron-biased signaling perturbations in SARS-CoV-2-infected animals as opposed to type I interferon signaling in tissue derived from IAV-infected animals. RNA-seq of 31dpi thoracic DRGs from SARS-CoV-2-infected animals highlighted a uniquely neuropathic transcriptomic landscape, which was consistent with substantial SARS-CoV-2-specific mechanical hypersensitivity at 28dpi. Ontology analysis of 1, 4, and 30dpi RNA-seq revealed novel targets for pain management, such as ILF3. Meta-analysis of all SARS-CoV-2 RNA-seq timepoints against preclinical pain model datasets highlighted both conserved and unique pro-nociceptive gene expression changes following infection. Overall, this work elucidates novel transcriptomic signatures triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities while also highlighting several therapeutic targets for alleviation of infection-induced hypersensitivity.One Sentence SummarySARS-CoV-2 infection results in an interferon-associated transcriptional response in sensory tissues underlying time-dependent hypersensitivity.

Opioid analgesics exert their therapeutic and adverse effects by activating

Chronic pain is a complex neuropsychiatric disorder, characterized by sensory, cognitive, and affective symptoms. Over the last two decades, researchers have made significant progress towards understanding the impact of mesolimbic dopamine circuitry in acute and chronic pain. These efforts have provided insights into the circuits and intracellular pathways in the brain reward center that are implicated in sensory and affective manifestations of chronic pain. Studies have also identified novel therapeutic targets as well as factors that impact treatment responsiveness. Dysregulation of dopamine function in the brain reward center may further promote comorbid mood disorders and vulnerability to addiction. This review discusses recent clinical and preclinical findings on the neuroanatomical and neurochemical adaptations triggered by prolonged pain states in the brain reward pathway. Furthermore, this discussion highlights evidence of mechanisms underlying comorbidities between pain, depression, and addiction.

SUMMARYSARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.

Vision impairment continues to be a major global problem, as the WHO estimates 2.2 billion people struggling with vision loss or blindness. One billion of these cases, however, can be prevented by expanding diagnostic capabilities. Direct global healthcare costs associated with these conditions totaled $255 billion in 2010, with a rapid upward projection to $294 billion in 2020. Accordingly, WHO proposed 2030 targets to enhance integration and patient-centered vision care by expanding refractive error and cataract worldwide coverage. Due to the limitations in cost and portability of adapted vision screening models, there is a clear need for new, more accessible vision testing tools in vision care. This comparative, systematic review highlights the need for new ophthalmic equipment and approaches while looking at existing and emerging technologies that could expand the capacity for disease identification and access to diagnostic tools. Specifically, the review focuses on portable hardware- and software-centered strategies that can be deployed in remote locations for detection of ophthalmic conditions and refractive error. Advancements in portable hardware, automated software screening tools, and big data-centric analytics, including machine learning, may provide an avenue for improving ophthalmic healthcare.

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found capable of inducing long term effects commonly referred to as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. To define the molecular basis of this condition, we compared the short- and long-term responses to influenza A virus and SARSCoV-2 in the golden hamster model. These data demonstrated that SARS-CoV-2 resulted in sustained changes to lung, kidney, and brain. The most significant change in response to SARS-CoV-2 was observed in the olfactory bulb, where persistent inflammation was visible beyond one month post infection. This was characterized by microglial activation, pro-inflammatory cytokine production, and a Type I interferon (IFN-I) response in the absence of detectable virus. Given the connection between olfactory bulb injury and neurological disorders, we postulate that this prolonged inflammation is an underlying cause of long COVID. Funding Information: This work was funded by generous support from the Marc Haas Foundation, the National Institutes of Health (NCI (R01CA234614) and NIAID (2R01AI107301) and NIDDK (R01DK121072 and 1RO3DK117252) to Department of Medicine, Weill Cornell Medicine (R.E.S.)), and DARPA’s PREPARE Program (HR0011-20-2-0040). The work was further funded by NINDS (NS111251, NSO86444, NSO86444S1)(V.Z., R.A.S.). Ethics Approval Statement: The Tissue Procurement Facility operates under Institutional Review Board (IRB) approved protocol and follows guidelines set by Health Insurance Portability and Accountability Act (HIPAA). Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the IRB at the Weill Cornell Medicine. The autopsy samples are considered human tissue research and were collected under IRB protocols 20-04021814 and 19-11021069. All autopsies have consent for research use from next of kin, and these studies were determined as exempt by IRB at Weill Cornell Medicine under those protocol numbers.

BACKGROUND: HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation. METHODS: We utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund’s Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia. RESULTS: Using the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation. CONCLUSIONS: Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.

Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and female mice. Using paradigms of peripheral inflammation and nerve injury, we show that the prevention of RGS4 action leads to recovery from mechanical and cold allodynia and increases the motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's Adjuvant (CFA) model of hindpaw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity pathway analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, Western blot analysis shows increased expression of metabotropic glutamate receptor 2 in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target.SIGNIFICANCE STATEMENTThere is an imminent need for safe and efficient chronic pain medications. Regulator of G-protein signaling 4 (RGS4) is a multifunctional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominent role in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice, we show a dynamic role of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hindpaw inflammation or hindlimb nerve injury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in the mouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states and demonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.

Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid–Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid–Gal1R heteromer.

Objectives: Free medical clinics provide healthcare to populations with limited options for insurance coverage and are thus key medical safety nets. Such clinics have limited operating budgets due in part to their lack of revenue streams through insurance reimbursements. Thus, pharmaceutical acquisitions can impose significant financial burdens in light of rising and volatile prices [1]. The goal of this study was to provide clinics with a real-time comparison of national retail pharmacy acquisition prices against clinic purchasing prices to determine potentially overpriced drugs. Methods: Historical ledger data from the East Harlem Health Outreach Program (EHHOP) at Mount Sinai was used to determine the clinic’s average price and volatility for specific drugs over time. Average prices were cross-referenced against the publicly available National Average Drug Acquisition Cost (NADAC) database, which outlines the average acquisition cost of drugs by retail pharmacies across the United States. Results: This analysis demonstrated that 36% (16/45) of EHHOP drug price averages were significantly different than relative NADAC values, with 9% (4/45) more expensive and 27% (12/45) cheaper. Price volatility between EHHOP and NADAC acquisition prices varied. Assuming the NADAC benchmark for significantly more expensive EHHOP purchases resulted in potential savings of $4,424 (6% of budget) over the projected period. Conclusions: Clinic drug acquisition price comparison to NADAC database prices serves as an effective benchmark for cost reduction. In order to implement change after expensive drug identification, we developed a decision-tree model that outlines several steps that can reduce drug expenditures. Using this process can potentially save financial resources for medical clinics.