Multivariable Prediction Models for Traumatic Spinal Cord Injury: A Systematic Review.

Background: Traumatic spinal cord injuries (TSCI) greatly affect the lives of patients and their families. Prognostication may improve treatment strategies, health care resource allocation, and counseling. Multivariable clinical prediction models (CPMs) for prognosis are tools that can estimate an absolute risk or probability that an outcome will occur. Objectives: We sought to systematically review the existing literature on CPMs for TSCI and critically examine the predictor selection methods used. Methods: We searched MEDLINE, PubMed, Embase, Scopus, and IEEE for English peer-reviewed studies and relevant references that developed multivariable CPMs to prognosticate patient-centered outcomes in adults with TSCI. Using narrative synthesis, we summarized the characteristics of the included studies and their CPMs, focusing on the predictor selection process. Results: We screened 663 titles and abstracts; of these, 21 full-text studies (2009-2020) consisting of 33 distinct CPMs were included. The data analysis domain was most commonly at a high risk of bias when assessed for methodological quality. Model presentation formats were inconsistently included with published CPMs; only two studies followed established guidelines for transparent reporting of multivariable prediction models. Authors frequently cited previous literature for their initial selection of predictors, and stepwise selection was the most frequent predictor selection method during modelling. Conclusion: Prediction modelling studies for TSCI serve clinicians who counsel patients, researchers aiming to risk-stratify participants for clinical trials, and patients coping with their injury. Poor methodological rigor in data analysis, inconsistent transparent reporting, and a lack of model presentation formats are vital areas for improvement in TSCI CPM research.

Progeria-based vascular model identifies networks associated with cardiovascular aging and disease.

Hutchinson-Gilford Progeria syndrome (HGPS) is a lethal premature aging disorder caused by a de novo heterozygous mutation that leads to the accumulation of a splicing isoform of Lamin A termed progerin. Progerin expression deregulates the organization of the nuclear lamina and the epigenetic landscape. Progerin has also been observed to accumulate at low levels during normal aging in cardiovascular cells of adults that do not carry genetic mutations linked with HGPS. Therefore, the molecular mechanisms that lead to vascular dysfunction in HGPS may also play a role in vascular aging-associated diseases, such as myocardial infarction and stroke. Here, we show that HGPS patient-derived vascular smooth muscle cells (VSMCs) recapitulate HGPS molecular hallmarks. Transcriptional profiling revealed cardiovascular disease remodeling and reactive oxidative stress response activation in HGPS VSMCs. Proteomic analyses identified abnormal acetylation programs in HGPS VSMC replication fork complexes, resulting in reduced H4K16 acetylation. Analysis of acetylation kinetics revealed both upregulation of K16 deacetylation and downregulation of K16 acetylation. This correlates with abnormal accumulation of error-prone nonhomologous end joining (NHEJ) repair proteins on newly replicated chromatin. The knockdown of the histone acetyltransferase MOF recapitulates preferential engagement of NHEJ repair activity in control VSMCs. Additionally, we find that primary donor-derived coronary artery vascular smooth muscle cells from aged individuals show similar defects to HGPS VSMCs, including loss of H4K16 acetylation. Altogether, we provide insight into the molecular mechanisms underlying vascular complications associated with HGPS patients and normative aging.

Is the level of consent to a national research registry associated with patient outcomes following traumatic spinal cord injury? A population-based study from the Rick Hansen Spinal Cord Injury Registry (RHSCIR).

OBJECTIVE: We examined the impact of consenting to the Rick Hansen Spinal Cord Injury Registry (RHSCIR) on outcomes: acute length of stay (LOS), in-hospital mortality, medical complications (pressure injuries and pneumonia), and the final discharge destination following a spinal cord injury (SCI) using the national RHSCIR dataset. DESIGN: A retrospective cohort study was conducted using RHSCIR participant data from 2014 to 2019. Participants approached for enrollment were grouped into 1) PC: provided full consent including community follow-up (CFU) interviews, 2) DWC: declined CFU interviews but accepted minimal data collection that may include initial/final interviews and/or those who later withdrew consent, and 3) DC: declined consent to any participation. As no data was collected for the DC group, descriptive, bivariate, and multivariable regression analysis was limited to the PC and DWC groups. RESULTS: Of 2811 participants, 2101 (74.7%) were PC, 553 (19.7%) were DWC, and 157 (5.6%) were DC. DWC participants had significantly longer acute LOS, more acute pneumonias/pressure injuries, and were less likely to be discharged home than PC participants. All these associations - except pneumonia - remained significant in the multivariable analyses. CONCLUSION: Not participating fully in RHSCIR was associated with more complications and longer hospital stays.

Cannabinoid CB1 Receptor Expression and Localization in the Dorsal Horn of Male and Female Rat and Human Spinal Cord.

Background: Preclinical and clinical evidence suggests that cannabis has potential analgesic properties. However, cannabinoid receptor expression and localization within spinal cord pain processing circuits remain to be characterized across sex and species. Aims: We aimed to investigate the differential expression of the cannabinoid type 1 (CB1) receptor across dorsal horn laminae and cell populations in male and female adult rats and humans. Methods: To investigate and quantify CB1 receptor expression in the spinal dorsal horn across species, we refined immunohistochemical procedures for successful rat and human fixed tissue staining and confocal imaging. Immunohistochemical results were complemented with analysis of CB1 gene (CNR1) expression within rodent and human dorsal horn using single-cell/nuclei RNA sequencing data sets. Results: We found that CB1 was preferentially localized to the neuropil within the superficial dorsal horn of both rats and humans, with CB1 somatic staining across dorsal horn laminae. CB1 receptor immunoreactivity was significantly higher in the superficial dorsal horn compared to the deeper dorsal horn laminae for both rats and humans, which was conserved across sex. Interestingly, we found that CB1 immunoreactivity was not primarily localized to peptidergic afferents in rats and humans and that CNR1 (CB1) but not CNR2 (CB2) was robustly expressed in dorsal horn neuron subpopulations of both rodents and humans. Conclusions: The conserved preferential expression of CB1 receptors in the superficial dorsal horn in male and female rodents and humans has significant implications for understanding the roles of this cannabinoid receptor in spinal mechanisms of nociception and analgesia.

Contexte: Les données probantes précliniques et cliniques indiquent que le cannabis possède des propriétés analgésiques potentielles. Cependant, l'expression et la localisation des récepteurs cannabinoïdes au sein des circuits de traitement de la douleur de la moelle épinière restent à caractériser selon le sexe et les espèces.Objectifs: Nous avons cherché à étudier l'expression différenciée du récepteur cannabinoïde de type 1 (CB1) dans les différentes couches de la corne dorsale et les populations cellulaires chez des rats et des êtres humains adultes de sexe masculin et féminin.Méthodes: Pour étudier et quantifier l'expression des récepteurs CB1 dans la corne dorsale de la moelle épinière chez différentes espèces, nous avons perfectionné les procédures d'immunohistochimie pour obtenir des résultats de coloration réussis sur des échantillons de tissus provenant de rats et d'êtres humains, ainsi que des images confocales. Les résultats immunohistochimiques ont été complétés par l'analyse de l'expression du gène CB1 (CNR1) dans la corne dorsale des rongeurs et des humains en utilisant des ensembles de données de séquençage d'ARN au niveau des cellules uniques et des noyaux.Résultats: Nous avons constaté que le CB1 était principalement localisé dans le neuropile au sein de la corne dorsale superficielle chez les rats et les humains, avec une coloration somatique du CB1 dans les différentes couches de la corne dorsale. Chez les deux espèces, l'immunoréactivité du récepteur CB1 était significativement plus élevée dans la couche superficielle de la corne dorsale par rapport aux couches plus profondes, indépendamment du sexe. De manière intéressante, nous avons constaté que l'immunoréactivité du CB1 n'était pas principalement localisée dans les afférences peptidergiques chez les rats et les humains. De plus, nous avons observé une forte expression du gène CNR1 (CB1), mais pas du CNR2 (CB2), au sein de sous-populations de neurones de la corne dorsale chez les rongeurs et les êtres humains.Conclusions: La localisation privilégiée et constante des récepteurs CB1 dans la couche superficielle de la corne dorsale chez les rongeurs et les humains, quel que soit leur sexe, revêt une importance majeure pour la compréhension des fonctions de ce récepteur des cannabinoïdes dans les mécanismes médullaires de la nociception et de l'analgésie.

Enabling knowledge translation: implementation of a web-based tool for independent walking prediction after traumatic spinal cord injury.

Introduction: Several clinical prediction rules (CPRs) have been published, but few are easily accessible or convenient for clinicians to use in practice. We aimed to develop, implement, and describe the process of building a web-based CPR for predicting independent walking 1-year after a traumatic spinal cord injury (TSCI). Methods: Using the published and validated CPR, a front-end web application called "Ambulation" was built using HyperText Markup Language (HTML), Cascading Style Sheets (CSS), and JavaScript. A survey was created using QualtricsXM Software to gather insights on the application's usability and user experience. Website activity was monitored using Google Analytics. Ambulation was developed with a core team of seven clinicians and researchers. To refine the app's content, website design, and utility, 20 professionals from different disciplines, including persons with lived experience, were consulted. Results: After 11 revisions, Ambulation was uploaded onto a unique web domain and launched (www.ambulation.ca) as a pilot with 30 clinicians (surgeons, physiatrists, and physiotherapists). The website consists of five web pages: Home, Calculation, Team, Contact, and Privacy Policy. Responses from the user survey (n = 6) were positive and provided insight into the usability of the tool and its clinical utility (e.g., helpful in discharge planning and rehabilitation), and the overall face validity of the CPR. Since its public release on February 7, 2022, to February 28, 2023, Ambulation had 594 total users, 565 (95.1%) new users, 26 (4.4%) returning users, 363 (61.1%) engaged sessions (i.e., the number of sessions that lasted 10 seconds/longer, had one/more conversion events e.g., performing the calculation, or two/more page or screen views), and the majority of the users originating from the United States (39.9%) and Canada (38.2%). Discussion: Ambulation is a CPR for predicting independent walking 1-year after TSCI and it can assist frontline clinicians with clinical decision-making (e.g., time to surgery or rehabilitation plan), patient education and goal setting soon after injury. This tool is an example of adapting a validated CPR for independent walking into an easily accessible and usable web-based tool for use in clinical practice. This study may help inform how other CPRs can be adopted into clinical practice.