Macrophage Migration Inhibitory Factor (MIF) Makes Complex Contributions to Pain-Related Hyperactivity of Nociceptors after Spinal Cord Injury.

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the central nervous system, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity (OA) that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive OA after SCI. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. Probable nociceptors isolated from male rats and exposed to a MIF concentration reported in human plasma (1 ng/ml) showed hyperactivity similar to that induced by SCI, although, surprisingly, a ten-fold higher concentration failed to increase excitability. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Unlike after SCI, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors from Naïve animals, after SCI induced a long-lasting conversion from a highly excitable nonaccommodating type to a rapidly accommodating, hypoexcitable type, possibly as a homeostatic response to prolonged depolarization. Treatment with conditioned medium from cultures of dorsal root ganglion (DRG) cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from Naïve rats. Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain.Significance Statement:Chronic neuropathic pain is a major challenge for people with spinal cord injury (SCI). Pain can drastically impair quality of life, and produces substantial economic and social burdens. Available treatments, including opioids, remain inadequate. This study shows that the cytokine macrophage migration inhibitory factor (MIF) can induce pain-like behavior and plays an important role in driving persistent ongoing electrical activity in injury-detecting sensory neurons (nociceptors) in a rat SCI model. The results indicate that SCI produces an increase in MIF release within sensory ganglia. Low MIF levels potently excite nociceptors, but higher levels trigger a long-lasting hypoexcitable state. These findings suggest that therapeutic targeting of MIF in neuropathic pain states may reduce pain and sensory dysfunction by curbing nociceptor hyperactivity.

Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.

PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC. RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis. SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.

Exploring the vagus nerve and the inflammatory reflex for therapeutic benefit in chronic spinal cord injury.

PURPOSE OF REVIEW: To describe features and implications of chronic systemic inflammation in individuals with spinal cord injury (SCI) and to summarize the growing therapeutic possibilities to explore the vagus nerve-mediated inflammatory reflex in this context. RECENT FINDINGS: The discovery of the inflammatory reflex provides a rationale to explore neuromodulation modalities, that is, electrical vagus nerve stimulation and pharmacological cholinergic modalities to regulate inflammation after SCI. SUMMARY: Inflammation in individuals with SCI may negatively impact functional recovery and medical consequences after SCI. Exploring the potential of the vagus nerve-based inflammatory reflex to restore autonomic regulation and control inflammation may provide a novel approach for functional improvement in SCI.

3-Dimensional Printed Alternative to the Standard Synthetic Flocked Nasopharyngeal Swabs Used for Coronavirus Disease 2019 Testing.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), can be detected in respiratory samples by real-time reverse transcriptase polymerase chain reaction (RT-PCR) or other molecular methods. Accessibility of diagnostic testing for COVID-19 has been limited by intermittent shortages of supplies required for testing, including flocked nasopharyngeal (FLNP) swabs. METHODS: We developed a 3-dimensional printed nasopharyngeal (3DP) swab as a replacement of the FLNP swab. The performance of 3DP and FLNP swabs were compared in a clinical trial of symptomatic patients at 3 clinical sites (n = 291) using 3 SARS-CoV-2 emergency use authorization tests: a modified version of the Centers for Disease Control and Prevention (CDC) RT-PCR Diagnostic Panel and 2 commercial automated formats, Roche Cobas and NeuMoDx. RESULTS: The cycle threshold-C(t)-values from the gene targets and the RNase P gene control in the CDC assay showed no significant differences between swabs for both gene targets (P = .152 and P = .092), with the RNase P target performing significantly better in the 3DP swabs (P < .001). The C(t) values showed no significant differences between swabs for both viral gene targets in the Roche cobas assay (P = .05 and P = .05) as well as the NeuMoDx assay (P = .401 and P = .484). The overall clinical correlation of COVID-19 diagnosis between all methods was 95.88% (Kappa 0.901). CONCLUSIONS: The 3DP swabs were equivalent to standard FLNP in 3 testing platforms for SARS-CoV-2. Given the need for widespread testing, 3DP swabs printed onsite are an alternate to FLNP that can rapidly scale in response to acute needs when supply chain disruptions affect availability of collection kits.

Systemic gene expression profiles according to pain types in individuals with chronic spinal cord injury.

Pain affects most individuals with traumatic spinal cord injury (SCI). Major pain types after SCI are neuropathic or nociceptive, often experienced concurrently. Pain after SCI may be refractory to treatments and negatively affects quality of life. Previously, we analyzed whole blood gene expression in individuals with chronic SCI compared to able-bodied (AB) individuals. Most participants with SCI reported pain (N = 19/28). Here, we examined gene expression of participants with SCI by pain status. Compared to AB, participants with SCI with pain had 468 differentially expressed (DE) genes; participants without pain had 564 DE genes (FDR < 0.05). Among DE genes distinct to participants with SCI with pain, Gene Ontology Biological Process (GOBP) analysis showed upregulated genes were enriched in categories related to T cell activation or inflammation; downregulated genes were enriched in categories related to protein proteolysis and catabolism. Although most participants with pain reported multiple pain types concurrently, we performed a preliminary comparison of gene expression by worst pain problem type. Compared to AB, participants with SCI who ranked neuropathic (N = 9) as worst had one distinct DE gene (TMEM156); participants who ranked nociceptive (N = 10) as worst had 61 distinct DE genes (FDR < 0.05). In the nociceptive group, the GOBP category with the lowest P-value identified among upregulated genes was "positive regulation of T cell activation"; among downregulated genes it was "receptor tyrosine kinase binding". An exploratory comparison of pain groups by principal components analysis also showed that the nociceptive group was enriched in T-cell related genes. A correlation analysis identified genes significantly correlated with pain intensity in the neuropathic or nociceptive groups (N = 145, 65, respectively, Pearson's correlation r > 0.8). While this pilot study highlights challenges of identifying gene expression profiles that correlate with specific types of pain in individuals with SCI, it suggests that T-cell signaling should be further investigated in this context.

Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation.

STUDY DESIGN: This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation. OBJECTIVES: 1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation. MATERIALS AND METHODS: Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury. CONCLUSIONS: Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as "placebo" require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.

Cardiovascular Autonomic Dysfunction in Spinal Cord Injury: Epidemiology, Diagnosis, and Management.

Spinal cord injury (SCI) disrupts autonomic circuits and impairs synchronistic functioning of the autonomic nervous system, leading to inadequate cardiovascular regulation. Individuals with SCI, particularly at or above the sixth thoracic vertebral level (T6), often have impaired regulation of sympathetic vasoconstriction of the peripheral vasculature and the splanchnic circulation, and diminished control of heart rate and cardiac output. In addition, impaired descending sympathetic control results in changes in circulating levels of plasma catecholamines, which can have a profound effect on cardiovascular function. Although individuals with lesions below T6 often have normal resting blood pressures, there is evidence of increases in resting heart rate and inadequate cardiovascular response to autonomic provocations such as the head-up tilt and cold face tests. This manuscript reviews the prevalence of cardiovascular disorders given the level, duration and severity of SCI, the clinical presentation, diagnostic workup, short- and long-term consequences, and empirical evidence supporting management strategies to treat cardiovascular dysfunction following a SCI.

Neurochemical biomarkers in spinal cord injury.

STUDY DESIGN: This is a narrative review of the literature on neurochemical biomarkers in spinal cord injury (SCI). OBJECTIVES: The objective was to summarize the literature on neurochemical biomarkers in SCI and describe their use in facilitating clinical trials for SCI. Clinical trials in spinal cord injury (SCI) have been notoriously difficult to conduct, as exemplified by the paucity of definitive prospective randomized trials that have been completed, to date. This is related to the relatively low incidence and the complexity and heterogeneity of the human SCI condition. Given the increasing number of promising approaches that are emerging from the laboratory which are vying for clinical evaluation, novel strategies to help facilitate clinical trials are needed. METHODS: A literature review was conducted, with a focus on neurochemical biomarkers that have been described in human neurotrauma. RESULTS: We describe advances in our understanding of neurochemical biomarkers as they pertain to human SCI. The application of biomarkers from serum and cerebrospinal fluid (CSF) has been led by efforts in the human traumatic brain injury (TBI) literature. A number of promising biomarkers have been described in human SCI whereby they may assist in stratifying injury severity and predicting outcome. CONCLUSIONS: Several time-specific biomarkers have been described for acute SCI and for chronic SCI. These appear promising for stratifying injury severity and potentially predicting outcome. The subsequent application within a clinical trial will help to demonstrate their utility in facilitating the study of novel approaches for SCI.

Glucocorticoids and macrophage migration inhibitory factor (MIF) are neuroendocrine modulators of inflammation and neuropathic pain after spinal cord injury.

Traumatic spinal cord injury (SCI) activates the hypothalamic-pituitary-adrenal (HPA) axis, a potent neuroendocrine regulator of stress and inflammation. SCI also elicits a profound and sustained intraspinal and systemic inflammatory response. Together, stress hormones and inflammatory mediators will affect the growth and survival of neural and non-neural cells and ultimately neurologic recovery after SCI. Glucocorticoids (GCs) are endogenous anti-inflammatory steroids that are synthesized in response to stress or injury, in part to regulate inflammation. Exogenous synthetic GCs are often used for similar purposes in various diseases; however, their safety and efficacy in pre-clinical and clinical SCI is controversial. The relatively recent discovery that macrophage migration inhibitory factor (MIF) is produced throughout the body and can override the anti-inflammatory effects of GCs may provide unique insight to the importance of endogenous and exogenous GCs after SCI. Here, we review both GCs and MIF and discuss the potential relevance of their interactions after SCI, especially their role in regulating maladaptive mechanisms of plasticity and repair that may contribute to the onset and maintenance of neuropathic pain.

A structural investigation of FISLE-412, a peptidomimetic compound derived from saquinavir that targets lupus autoantibodies.

FISLE-412 is the first reported small molecule peptidomimetic that neutralizes anti-dsDNA autoantibodies associated with systemic lupus erythematosus (SLE) pathogenesis. FISLE-412 is a complex small molecule that involves a challenging synthesis scheme, but has attractive pharmacological activities as a potential small molecule therapeutic in lupus. Therefore, we initiated a Structure-Activity Relationship study to simplify the complexity of FISLE-412. We synthesized a small library of mimetopes around the FISLE-412 structure and identified several analogues which could neutralize anti-DNA lupus antibodies in vitro and ex vivo. Our strategies reduced the structural complexity of FISLE-412 and provide important information that may guide development of potential autoantibody-targeted lupus therapeutics.

Elevated circulating levels of the pro-inflammatory cytokine macrophage migration inhibitory factor in individuals with acute spinal cord injury.

OBJECTIVE: To test the hypothesis that macrophage migration inhibitory factor (MIF) is elevated in the circulation of individuals with acute spinal cord injury (SCI) compared with uninjured individuals. DESIGN: Prospective, observational pilot study. SETTING: Academic medical center. PARTICIPANTS: Adults with acute traumatic SCI (n=18) and uninjured participants (n=18), comparable in age and sex distribution. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome measure was the plasma MIF levels. Potential correlations were examined between MIF and clinical/demographic variables. The secondary outcome was to determine if other immune mediators were elevated in participants with acute SCI and if their levels correlated with the MIF. RESULTS: MIF was significantly elevated in subjects with acute SCI compared with control subjects at 0 to 3 (P<.0029), 4 to 7 (P<.0001), and 8 to 11 (P<.0015) days postinjury (DPI). At 0 to 3 DPI, levels of cytokines interleukin-6 (P<.00017), interleukin-9 (P<.0047), interleukin-16 (P<.007), interleukin-18 (P<.014), chemokines growth-related oncogene α/chemokine (C-X-C motif) ligand 1 (P<.0127) and macrophage inflammatory protein 1-ß/chemokine (C-C motif) ligand 4 (P<.0015), and growth factors hepatocyte growth factor (HGF) (P<.0001) and stem cell growth factor-ß (P<.0103) were also significantly elevated in subjects with acute SCI. With the exception of interleukin-9, all of these factors remained significantly elevated at 4 to 7 DPI; a subset (interleukin-16, HGF, stem cell growth factor-ß) remained elevated throughout the study. Within individuals, MIF levels correlated with HGF (P<.018) and interleukin-16 (P<.01). CONCLUSIONS: These data demonstrate that MIF is significantly elevated in subjects with acute SCI, supporting further investigation of MIF and other inflammatory mediators in acute SCI, where they may contribute to primary and secondary functional outcomes.

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies, many of which are directed against nuclear antigens, in particular double-stranded (ds) DNA. Both clinical studies and animal models have shown that anti-dsDNA antibodies contribute to kidney disease, which is present in 50% of lupus patients and is a major cause of mortality. We previously demonstrated that a subset of nephrotoxic anti-dsDNA antibodies also recognizes the pentapeptide consensus sequence D/E W D/E Y S/G (DWEYS) present in the NR2A and NR2B subunits of the N-methyl-d-aspartate receptor (NMDAR). Autoantibodies with this specificity are present in ≈40% of lupus patient sera and are both nephrotoxic and neurotoxic. Elevated titers are present in cerebrospinal fluid of patients with central nervous system manifestations of SLE. Administration of the nonnaturally occurring D form of the DWEYS pentapeptide prevents these antibodies from depositing in glomeruli and from mediating neuronal excitotoxicity. To craft a more useful therapeutic, we used the structural features of the DWEYS peptide to design a unique, selective, and potent small molecule peptidomimetic, FISLE-412, which neutralizes anti-dsDNA/NMDAR lupus autoantibodies and prevents their pathogenic interaction with tissue antigens. This compound, or others derived from it, may provide a unique strategy for the development of lupus therapeutics.

Pilot study: elevated circulating levels of the proinflammatory cytokine macrophage migration inhibitory factor in patients with chronic spinal cord injury.

OBJECTIVE: To test the hypothesis that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) is elevated in the circulation of patients with chronic spinal cord injury (SCI) relative to uninjured subjects, and secondarily to identify additional immune mediators that are elevated in subjects with chronic SCI. DESIGN: Prospective, observational pilot study. SETTING: Outpatient clinic of a department of physical medicine and rehabilitation and research institute in an academic medical center. PARTICIPANTS: Individuals with chronic (>1y from initial injury) SCI (n=22) and age- and sex-matched uninjured subjects (n=19). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plasma levels of MIF, as determined by a commercially available multiplex suspension immunoassay. The relationship between MIF levels and clinical/demographic variables was also examined. As a secondary outcome, we evaluated other cytokines, chemokines, and growth factors. RESULTS: Plasma MIF levels were significantly higher in subjects with chronic SCI than in control subjects (P<.001). Elevated MIF levels were not correlated significantly with any one clinical or demographic characteristic. Subjects with SCI also exhibited significantly higher plasma levels of monokine induced by interferon-gamma/chemokine C-X-C motif ligand 9 (P<.03), macrophage colony stimulating factor (P<.035), interleukin-3 (P<.044), and stem cell growth factor beta (SCGF-ß) (P<.016). Among subjects with SCI, the levels of SCGF-ß increased with the time from initial injury. CONCLUSIONS: These data confirm the hypothesis that MIF is elevated in subjects with chronic SCI and identify additional novel immune mediators that are also elevated in these subjects. This study suggests the importance of examining the potential functional roles of MIF and other immune factors in subjects with chronic SCI.

Pressure injury prevalence and characteristics in patients with COVID-19 admitted to acute inpatient rehabilitation unit.

Objective: To investigate the incidence and severity of pressure injuries among COVID-19 patients who required acute hospitalization and subsequent acute inpatient rehabilitation (AIR). Design: Data was collected retrospectively from medical charts of COVID-19 patients who were admitted to AIR during April 2020-April 2021. Setting: Acute Inpatient Rehabilitation at a single hospital in the greater New York metropolitan area. Participants: Subjects included COVID-19 patients (N = 120) who required acute hospitalization and subsequent acute inpatient rehabilitation, of whom 39 (32.5%) had pressure injuries. Interventions: Not applicable. Main outcome measures: The incidence, location, and severity of pressure injuries in COVID-19 patients, as well as demographic and clinical characteristics of the acute hospitalization. Results: Among patients who developed pressure injuries, more patients received mechanical ventilation (59% vs. 33%, P < 0.05) and tracheostomy (67% vs. 17%, P < 0.00001). The lengths of stay were longer in both the intensive care unit (ICU) (34 vs. 15 days, P < 0.005), and in acute inpatient rehabilitation (22 vs. 17 days P < 0.05). Conclusion: Pressure injuries were more common in COVID-19 patients who had longer lengths of stay, received mechanical ventilation or tracheostomy, during acute hospitalization. This supports the use of protocols to prioritize pressure offloading in this patient population.

Experiences and recommendations from people with spinal cord injury following participation in a disability education session at an allopathic medical school: a qualitative study.

BACKGROUND: Students in half of US medical schools do not receive formal instruction in providing medical care for people with disabilities. To address this gap in training, our medical school developed several strategies, including a session for second year medical students to address communication skills, knowledge, and attitudes relevant to delivering healthcare for people with disabilities. Here, our objective was to explore perceptions of people with spinal cord injury (SCI) who participated in the session on its content and structure. METHODS: Qualitative research using a focus group of people with SCI who participated in an educational session for medical students in an LCME accredited allopathic US medical school. A purposive sample of adults with SCI (N = 8) participated in a focus group. Data were analyzed using a six-phase thematic analysis. RESULTS: Participants favorably viewed the educational session, felt their participation was valuable, and had suggestions for its improvement. Four major themes were identified: (1) session format, content; (2) addressing student discomfort and avoidance behaviors; (3) increasing student knowledge and preparation; and (4): important lessons from discussions of past and role-played doctor-patient interactions. CONCLUSIONS: First-person input from people with SCI is critical to improve medical education and healthcare provision to the SCI community. To our knowledge, this is the first study to report feedback from stakeholders providing specific recommendations for teaching disabilities awareness to undergraduate medical students. We expect these recommendations to be relevant to the SCI and medical education communities in improving healthcare for people with SCI and other disabilities.

Development of the Spinal Cord Injury COVID-19 Pandemic Experience Survey (SCI-CPES).

CONTEXT: Early during the COVID-19 pandemic, rehabilitation providers received reports from people with spinal cord injury (SCI) of considerable disruptions in caregiver services, medical and nursing care, and access to equipment and supplies; concomitantly, the medical community raised concerns related to the elevated risk of acquiring the infection due to SCI-specific medical conditions. Due to the novel nature of the pandemic, few tools existed to systematically investigate the outcomes and needs of people with SCI during this emergency. OBJECTIVE: To develop a multidimensional assessment tool for surveying the experience of the COVID-19 pandemic on physical and psychological health, employment, caregiving services, medical supplies and equipment, and the delivery of medical care for people with SCI. METHODS: The Spinal Cord Injury COVID-19 Pandemic Experience Survey (SCI-CPES) study, conducted between July 2020 through August 2021, surveyed people with SCI about their experiences during the early COVID-19 pandemic. The SCI-CPES was developed by a SCI care and research consortium using an iterative process. RESULTS: Two hundred and twenty-three people completed the survey. Most respondents resided in the consortium catchment area. As the survey progressed, online informed consent became available allowing dissemination of the SCI-CPES nationally. CONCLUSIONS: The consortium rapidly implemented the capture of experiences with COVID-19 pandemic directly from people with SCI, including survey creation, institutional approvals, distribution, online e-consenting, and data collection. In the future, the SCI-CPES is adaptable for use in other types of emergencies and disasters.

Health impacts reported in the Spinal Cord Injury COVID-19 Pandemic Experience Survey (SCI-CPES).

CONTEXT: In people with spinal cord injury (SCI), infections are a leading cause of death, and there is a high prevalence of diabetes mellitus, obesity, and hypertension, which are all comorbidities associated with worse outcomes after COVID-19 infection. OBJECTIVE: To characterize self-reported health impacts of COVID-19 on people with SCI related to exposure to virus, diagnosis, symptoms, complications of infection, and vaccination. METHODS: The Spinal Cord Injury COVID-19 Pandemic Experience Survey (SCI-CPES) study was administered to ask people with SCI about their health and other experiences during the COVID-19 pandemic. RESULTS: 223 community-living people with SCI (male = 71%; age = 52±15 years [mean±SD]; paraplegia = 55%) completed the SCI-CPES. Comorbidities first identified in the general population as associated with poor outcomes after COVID-19 infection were commonly reported in this SCI sample: hypertension (30%) and diabetes (13%). 23.5% of respondents reported a known infection exposure from someone who visited (13.5%) or lived in their home (10%). During the study, which included a timeframe when testing was either unavailable or scarce, 61% of respondents were tested for COVID-19; 14% tested or were presumed positive. Fever, fatigue, and chills were the most common symptoms reported. Of the 152 respondents surveyed after COVID-19 vaccines became available, 82% reported being vaccinated. Race and age were significantly associated with positive vaccination status: most (78%) individuals who were vaccinated identified as Non-Hispanic White and were older than those who reported being unvaccinated (57±14 vs. 43±13 years, mean±SD). CONCLUSIONS: Self-reported COVID-19 symptoms were relatively uncommon and not severe in this sample of people with SCI. Potential confounders and limitations include responder, recruitment and self-reporting biases and changing pandemic conditions. Future studies on this topic should query social distancing and other behavioral strategies. Large retrospective chart review studies may provide additional data on incidence and prevalence of COVID-19 infections, symptoms, and severities in the SCI population.

Profiling Immunological Phenotypes in Individuals During the First Year After Traumatic Spinal Cord Injury: A Longitudinal Analysis.

Abstract Individuals with SCI are severely affected by immune system changes, resulting in increased risk of infections and persistent systemic inflammation. While recent data support that immunological changes after SCI differ in the acute and chronic phases of living with SCI, only limited immunological phenotyping in humans is available. To characterize dynamic molecular and cellular immune phenotypes over the first year, we assess RNA (bulk-RNA sequencing), protein, and flow cytometry (FACS) profiles of blood samples from 12 individuals with SCI at 0-3 days and at 3, 6, and 12 months post injury (MPI) compared to 23 uninjured individuals (controls). We identified 967 differentially expressed (DE) genes in individuals with SCI (FDR <0.001) compared to controls. Within the first 6 MPI we detected a reduced expression of NK cell genes, consistent with reduced frequencies of CD56bright, CD56dim NK cells present at 12 MPI. Over 6MPI, we observed increased and prolonged expression of genes associated with inflammation (e.g. HMGB1, Toll-like receptor signaling) and expanded frequencies of monocytes acutely. Canonical T-cell related DE genes (e.g. FOXP3, TCF7, CD4) were upregulated during the first 6 MPI and increased frequencies of activated T cells at 3-12 MPI. Neurological injury severity was reflected in distinct whole blood gene expression profiles at any time after SCI, verifying a persistent 'neurogenic' imprint. Overall, 2876 DE genes emerge when comparing motor complete to motor incomplete SCI (ANOVA, FDR <0.05), including those related to neutrophils, inflammation, and infection. In summary, we identify a dynamic immunological phenotype in humans, including molecular and cellular changes which may provide potential targets to reduce inflammation, improve immunity, or serve as candidate biomarkers of injury severity.