Racial differences in serological markers across the first year of injury in spinal cord injury: a retrospective analysis of a multi-center interventional study.

STUDY DESIGN: Secondary analysis of a randomized, multi-center, placebo-controlled study(Sygen®). OBJECTIVES: To evaluate racial differences in serological markers in individuals with spinal cord injury(SCI) across the first year of injury. SETTING: Hospitals in North America. METHODS: Serological markers (e.g.,cell count, liver, kidney, and pancreatic function, metabolism, and muscle damage) were assessed among 316 participants (247 White, 69 Black) at admission, weeks 1, 2, 4, 8, and 52 post-injury. Linear mixed models were employed to explore the main effects of time, race (Black vs. White), and their interaction, with adjustment of covariates such as study center, polytrauma, injury (level, completeness), treatment group, and sex. RESULTS: A main effect of race was observed where White individuals had higher alanine transaminase, blood urea nitrogen(BUN), BUN/Creatinine ratio, sodium, and chloride, while Black individuals had higher calcium, total serum protein, and platelets. For markers with interaction effects, post-hoc comparisons showed that at week 52, White individuals had higher mature neutrophils, hematocrit, hemoglobin, mean corpuscular hemoglobin, albumin, and triglycerides, and Black individuals had higher amylase. Eosinophils, monocytes, red blood cells, aspartate aminotransferase, bilirubin, cholesterol, partial thromboplastin time, urine specific gravity, urine pH, CO2, and inorganic phosphorus did not differ between races. CONCLUSIONS: Our results revealed racial differences in serological markers and underscores the importance of considering race as a determinant of physiological responses. Future studies are warranted to explore the causes and implications of these racial disparities to facilitate tailored clinical management and social policy changes that can improve health equity.

International surveillance study in acute spinal cord injury confirms viability of multinational clinical trials.

BACKGROUND: The epidemiological international landscape of traumatic spinal cord injury (SCI) has evolved over the last decades along with given inherent differences in acute care and rehabilitation across countries and jurisdictions. However, to what extent these differences may influence neurological and functional recovery as well as the integrity of international trials is unclear. The latter also relates to historical clinical data that are exploited to inform clinical trial design and as potential comparative data. METHODS: Epidemiological and clinical data of individuals with traumatic and ischemic SCI enrolled in the European Multi-Center Study about Spinal Cord Injury (EMSCI) were analyzed. Mixed-effect models were employed to account for the longitudinal nature of the data, efficiently handle missing data, and adjust for covariates. The primary outcomes comprised demographics/injury characteristics and standard scores to quantify neurological (i.e., motor and sensory scores examined according to the International Standards for the Neurological Classification of Spinal Cord Injury) and functional recovery (walking function). We externally validated our findings leveraging data from a completed North American landmark clinical trial. RESULTS: A total of 4601 patients with acute SCI were included. Over the course of 20 years, the ratio of male to female patients remained stable at 3:1, while the distribution of age at injury significantly shifted from unimodal (2001/02) to bimodal distribution (2019). The proportional distribution of injury severities and levels remained stable with the largest percentages of motor complete injuries. Both, the rate and pattern of neurological and functional recovery, remained unchanged throughout the surveillance period despite the increasing age at injury. The findings related to recovery profiles were confirmed by an external validation cohort (n=791). Lastly, we built an open-access and online surveillance platform ("Neurosurveillance") to interactively exploit the study results and beyond. CONCLUSIONS: Despite some epidemiological changes and considerable advances in clinical management and rehabilitation, the neurological and functional recovery following SCI has remained stable over the last two decades. Our study, including a newly created open-access and online surveillance tool, constitutes an unparalleled resource to inform clinical practice and implementation of forthcoming clinical trials targeting neural repair and plasticity in acute spinal cord injury.

Perspectives on Data Sharing in Persons With Spinal Cord Injury.

Open data sharing of clinical research aims to improve transparency and support novel scientific discoveries. There are also risks, including participant identification and the potential for stigmatization. The perspectives of persons participating in research are needed to inform open data-sharing policies. The aim of the current study was to determine perspectives on data sharing in persons with spinal cord injury (SCI), including risks and benefits, and types of data people are most willing to share. A secondary aim was to examine predictors of willingness to share data. Persons with SCIs in the United States and Canada completed a survey developed and disseminated through various channels, including our community partner, the North American Spinal Cord Injury Consortium. The study collected data from 232 participants, with 52.2% from Canada and 42.2% from the United States, and the majority completed the survey in English. Most participants had previously participated in research and had been living with an SCI for ≥5 years. Overall, most participants reported that the potential benefits of data sharing outweighed the negatives, with persons with SCI seen as the most trustworthy partners for data sharing. The highest levels of concern were that information could be stolen and companies might use the information for marketing purposes. Persons with SCI were generally supportive of data sharing for research purposes. Clinical trials should consider including a statement on open data sharing in informed consents to better acknowledge the contribution of research participants in future studies.

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Natural Progression of Routine Laboratory Markers after Spinal Trauma: A Longitudinal, Multi-Cohort Study.

Our objective was to track and quantify the natural course of serological markers over the 1st year following spinal cord injury. For that purpose, data on serological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau study). The primary outcomes were concentration/levels/amount of commonly collected serological markers at multiple time points. Two-way analysis of variance (ANOVA) and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of serological markers contained in both data sources were compared using the slope of progression. Our results show that, at baseline (≤ 2 weeks post-injury), most serological markers were at pathological levels, but returned to normal values over the course of 6-12 months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g., hematocrit, ANOVA test; χ2 = 68.93, df = 3, adjusted p value <0.001, and χ2 = 73.80, df = 3, adjusted p value <0.001, in the Sygen and Murnau studies, respectively). Comparing the two databases revealed some differences in the serological markers, which are likely attributable to differences in study design, sample size, and standard of care. We conclude that because of trauma-induced physiological perturbations, serological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important, as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance web site (https://jutzelec.shinyapps.io/Haemosurveillance/) and GitHub repository (https://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury).

The reporting of observational studies of drug effectiveness and safety: recommendations to extend existing guidelines.

INTRODUCTION: The use of observational data to assess drug effectiveness and safety can provide relevant information, much of which may not be feasible to obtain through randomized clinical trials. Because observational studies provide critical drug safety and effectiveness information that influences drug policy and prescribing practices, transparent, consistent, and accurate reporting of these studies is critical. AREAS COVERED: We provide recommendations to extend existing reporting guidelines, covering the main components of primary research studies (methods, results, discussion). EXPERT OPINION: Our recommendations include extending drug safety and effectiveness guidelines to include explicit checklist items on: study registration, causal diagrams, rationale for measures of effect, comprehensive assessment of bias, comprehensive data cleaning steps, drug equivalents, subject-level drug data visualization, sex and gender-based analyses and results, patient-oriented outcomes, and patient involvement in research.

Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: Since December 2019, a novel coronavirus (SARS-CoV-2) has triggered a world-wide pandemic with an enormous medical and societal-economic toll. Thus, our aim was to gather all available information regarding comorbidities, clinical signs and symptoms, outcomes, laboratory findings, imaging features, and treatments in patients with coronavirus disease 2019 (COVID-19). METHODS: EMBASE, PubMed/Medline, Scopus, and Web of Science were searched for studies published in any language between December 1st, 2019 and March 28th, 2020. Original studies were included if the exposure of interest was an infection with SARS-CoV-2 or confirmed COVID-19. The primary outcome was the risk ratio of comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatments, outcomes, and complications associated with COVID-19 morbidity and mortality. We performed random-effects pairwise meta-analyses for proportions and relative risks, I2, T2, and Cochrane Q, sensitivity analyses, and assessed publication bias. RESULTS: 148 studies met the inclusion criteria for the systematic review and meta-analysis with 12'149 patients (5'739 female) and a median age of 47.0 [35.0-64.6] years. 617 patients died from COVID-19 and its complication. 297 patients were reported as asymptomatic. Older age (SMD: 1.25 [0.78-1.72]; p < 0.001), being male (RR = 1.32 [1.13-1.54], p = 0.005) and pre-existing comorbidity (RR = 1.69 [1.48-1.94]; p < 0.001) were identified as risk factors of in-hospital mortality. The heterogeneity between studies varied substantially (I2; range: 1.5-98.2%). Publication bias was only found in eight studies (Egger's test: p < 0.05). CONCLUSIONS: Our meta-analyses revealed important risk factors that are associated with severity and mortality of COVID-19.

The Effect of Non-Gabapentinoid Anticonvulsants on Sensorimotor Recovery After Human Spinal Cord Injury.

BACKGROUND: Recent observational studies have shown an association between gabapentinoid anticonvulsants and greater motor recovery after spinal cord injury. There is preclinical evidence to suggest that other anticonvulsants, such as sodium channel blockers, may also confer beneficial effects. PURPOSE: The aim of the current study was to determine if non-gabapentinoid anticonvulsants were associated with neurological recovery after acute, traumatic spinal cord injury. METHODS: This was an observational cohort study using data from the Sygen clinical trial. The primary outcome was total motor score recovery in the first year after injury. Anticonvulsant use was extracted from concomitant medication records; individuals were classified based on early administration (within 30 days of injury), or late/no administration. Motor recovery was compared using linear mixed effects regression models with a drug-by-time interaction, and adjustment for confounders. A secondary analysis incorporated a propensity score matched cohort. RESULTS: Of the cohort (n = 570), 6% received anticonvulsants (carbamazepine, phenytoin, clonazepam, phenobarbital, and valproic acid) early after injury. After adjustments for initial injury level and severity, early exposure to non-gabapentinoid anticonvulsants was not associated with motor neurological outcomes (p = 0.38 for all anticonvulsants, p = 0.83 for sodium channel blockers, p = 0.82 in propensity-matched cohort). CONCLUSION: Non-gabapentinoid anticonvulsant exposure was not associated with greater or lesser neurological recovery. This suggests that these medications, as administered for the acute management of spinal cord injury, do not impact long-term neurological outcomes.

A Longitudinal Study of the Neurologic Safety of Acute Baclofen Use After Spinal Cord Injury.

The objective of our study was to determine whether treatment with baclofen is neurologically safe with respect to exposure during recovery from spinal cord injury. We performed a secondary longitudinal analysis of a cohort of adult patients with traumatic acute spinal cord injury. Cumulative baclofen dose was computed over the first 4 weeks following injury from concomitant medication information from a completed clinical trial. The main outcome measure was neurologic status, which was assessed over 52 weeks with "marked recovery" defined as the conversion to higher sensory and motor function. To complete the drug safety profile, drug toxicity was assessed with assays from standard blood work. Multivariable Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the cohort (n = 651), 18% (n = 115) received baclofen within 4 weeks post injury. Baclofen use was associated with higher rates of marked neurologic recovery, even after adjustment for injury severity (HR = 2.1, 95% CI 1.5-3.0 for high dose vs none). Baclofen exposure was not associated with liver or renal side effects. The use of other medications indicated for spasticity was not associated with neurological outcomes. Overall, this longitudinal analysis provides level 3 evidence on the neurologic safety of baclofen and potential beneficial effects on recovery in the early days after acute traumatic spinal cord injury. The usefulness of concomitant medication files from completed clinical trials is highlighted. We also highlight the importance of incorporating logical patient questions and neurological outcomes into research addressing drug safety.

Serum Albumin Predicts Long-Term Neurological Outcomes After Acute Spinal Cord Injury.

BACKGROUND: There is a need to identify reliable biomarkers of spinal cord injury recovery for clinical practice and clinical trials. OBJECTIVE: Our objective was to correlate serum albumin levels with spinal cord injury neurological outcomes. METHODS: We performed a secondary analysis of patients with traumatic spinal cord injury (n = 591) participating in the Sygen clinical trial. Serum albumin concentrations were obtained as part of routine blood chemistry analysis, at trial entry (24-72 hours), 1, 2, and 4 weeks after injury. The primary outcomes were "marked recovery" and lower extremity motor scores, derived from the International Standards for the Neurological Classification of Spinal Cord Injury. Data were analyzed with multivariable logistic and linear regression to adjust for potential confounders. RESULTS: Serum albumin was significantly associated with spinal cord injury neurological outcomes. Higher serum albumin concentrations at 1, 2, and 4 weeks were associated with higher 52-week lower extremity motor score. Similarly, the odds of achieving "marked neurological recovery" was greater for individuals with higher serum albumin concentrations. The association between serum albumin concentrations and neurological outcomes was independent of initial injury severity, treatment with GM-1, and polytrauma. CONCLUSIONS: In spinal cord injury, serum albumin is an independent marker of long-term neurological outcomes. Serum albumin could serve as a feasible biomarker for prognosis at the time of injury and stratification in clinical trials.