A straightforward path to successful scientific translation remains uncharted, particularly in a complex progressive condition such as spinal cord injury (SCI), which affects multiple body functions simultaneously. Evolving regulatory requirements add to the complexity and expense of attaining a treatment that is both safe and efficacious. Although rare, there are examples of SCI scientists who have successfully navigated the "valley of death" from discovery science to completed clinical trials. This article reflects the translational journey of five SCI scientists who have encountered similar and different scenarios while striving to launch or complete a clinical trial. Learning from these experiences has identified lessons learned and gaps, particularly with respect to funding and support for SCI translation.

ImportancePressure ulcers (PUs) are (1) prevalent secondary complications after spinal cord injury (SCI), (2) present with elevated systemic inflammatory tone, and (3) may interfere with healing processes underlying neurological recovery (disrepair). ObjectiveTo investigate whether PUs acquired during initial hospitalization are associated with neurological and functional long-term outcome and survival after SCI. Design, Setting, and ParticipantsMulticenter cohort study at 20 centers of the prospective SCI Model Systems (SCIMS) Database (Birmingham, AL). Patients with acute traumatic cervical SCI with relevant motor impairment (ie, American Spinal Injury Association [ASIA] impairment scale [AIS] A, B, and C) were enrolled from January 1996 to September 2006 and followed up until June 2016. Data were analyzed from April 2021 to September 2024. ExposuresPUs acquired during surgical or first rehabilitative SCI care. Main outcomes and measuresThe change in the ASIA motor score at 1 year after SCI was the primary end point. Secondary end points included the recovery of functional independence measure (FIM) motor score at 1 year after SCI and mortality up to 10 years. ASIA and FIM motor score were analyzed applying linear mixed models with random intercept adjusted for baseline neurological level, AIS, and sociodemographic factors. Mortality was analyzed using Cox regression. ResultsThe study included 1282 patients with a mean (SD) age of 38.0 (15.7) years and consisted of 1028 (80.2%) male patients. Regarding race and ethnicity, 349 of 1249 (27.9%) were African American patients, 1139 of 1273 (89.5%) were non-Hispanic patients, and 834 of 1249 (66.8%) were White patients. During initial hospitalization, 594 patients (45.7%) acquired PUs. Exposure to PUs was associated with impaired motor recovery 1 year after SCI compared with unexposed patients (-9.1 ASIA motor score points; 95% CI, -12.3 to -6.0; P < .001). In addition, PUs were associated with lower recovery of physical independence 1 year after SCI (-8.3 FIM motor score points; 95% CI: -11.1 to -5.5; P < .001). Cox regression confirmed PUs as a risk marker for death up to 10 years after SCI (hazard ratio, 1.41; 95% CI, 1.09 to 1.82; P = .01). Conclusions and RelevanceIn this cohort study, PUs acquired during initial hospitalization after SCI were independently associated with poor long-term neurofunctional outcome. PUs constitute a modifiable factor associated with risk for worse long-term disability (recovery confounder) and elevated mortality.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Experiencing a spinal cord injury (SCI) is extremely distressing, both physically and psychologically, and throws people into a complex, unfamiliar world of medical procedures, terminology, and decision making. You may have already had surgery to stabilize the spinal column and reduce the possibility of further damage. You are understandably distressed about the functions you may have lost below the level of spinal injury. You wish to recover any lost abilities as soon as possible. You, your family, or friends may have searched the Internet for treatments and cures.

Objective: To describe the impact of an education program to prevent falls in full-time manual wheelchair users (MWU) living with Spinal Cord Injury (SCI).Design: Pre/post.At baseline, participants reported the frequency of falls over the past six months and completed the Community Participation Indicators(CPI) and the World Health Organization Quality of Life (short version -WHO-QOL BREF) assessment.Transfer quality to and from a mat table was assessed using the Transfer Assessment Instrument (TAI) and boundaries of seated stability were evaluated using standardized procedures.After baseline testing, a structured education program designed to decrease fall frequency was implemented.After the intervention, participants were asked to prospectively track fall frequency for 12 weeks.After 12 weeks, the assessment, as described above, was repeated.Participant/methods: 18 fulltime MWUs with SCI participated in the study.Participants were an average of 35.78 ± 13.89 y.o. and lived with their SCI for an average of 17 ± 15 years.The majority of participants were female (n = 11, 61.1%).Level of injury ranged from C4-L3, AIS A-C.To examine the differences in outcomes pre and post exposure to the education program, seated stability was evaluated using a paired t-test.Nonparametric Wilcoxon tests were used to evaluate all other variables due to the ordinal or non-normally distributed nature of the data.Results: After exposure to the intervention, fall frequency significantly decreased, (Pre: 1.37 ± 1.62 falls per month, Post: 0.67 ± 0.82, p = 0.047).A trend in the data indicated improvements in seated stability (Pre: 1.22 ± .26,Post: 1.35 ± .26,p = 0.06).Finally, significant improvements were found in the Post: 75.61 ± 16.38 p = 0.05) and Psychological (Pre: 69.06 ± 14.67, Post: 76.17 ± 17.62, p = 0.040) domains.No significant differences were found among TAI or CPI scores. Conclusion:The structured fall prevention education program specifically designed for MWUs living with SCI appears to have potential to reduce fall frequency and improve quality of life.Additional research in the form of a large-scale, controlled investigation of the program is needed to further assess program effectiveness.

ANSI X3.9-1978 FORTRAN is not convenient for use in various application areas. Examples of such application areas include numerical analysis, industrial control, and computer graphics. A means is required to permit application- oriented extensions of FORTRAN by users with special application requirements that does not burden all users. Such a means is not presently available without changes to FORTRAN itself. This position states the nature of the changes required to FORTRAN. It then suggests constraints to be observed by all application-oriented extension modules.

Objective: To investigate whether prevalent hospital-acquired pneumonia and wound infection affect the clinical long-term outcome after acute traumatic spinal cord injury (SCI).Methods: This was a longitudinal cohort study within the prospective multicenter National Spinal Cord Injury Database (Birmingham, Alabama). We screened datasets of 3,834 patients enrolled in 20 trial centers from 1995 to 2005 followed up until 2016. Eligibility criteria were cervical SCI and American Spinal Cord Injury Association impairment scale A, B, and C. Pneumonia or postoperative wound infections (Pn/Wi) acquired during acute medical care/inpatient rehabilitation were analyzed for their association with changes in the motor items of the Functional Independence Measure (FIMmotor) using regression models (primary endpoint 5-year follow-up). Pn/Wi-related mortality was assessed as a secondary endpoint (10-year follow-up).Results: A total of 1,203 patients met the eligibility criteria. During hospitalization, 564 patients (47%) developed Pn/Wi (pneumonia n = 540; postoperative wound infection n 5 11; pneumonia and postoperative wound infection n = 13). Adjusted linear mixed models after multiple imputation revealed that Pn/Wi are significantly associated with lower gain in FIMmotor up to 5 years after SCI (-7.4 points, 95% confidence interval [CI] -11.5 to -3.3). Adjusted Cox regression identified Pn/Wi as a highly significant risk factor for death up to 10 years after SCI (hazard ratio 1.65, 95% CI 1.26 to 2.16).Conclusion: Hospital-acquired Pn/Wi are predictive of propagated disability and mortality after SCI. Pn/Wi qualify as a potent and targetable outcome-modifying factor. Pn/Wi prevention constitutes a viable strategy to protect functional recovery and reduce mortality. Pn/Wi can be considered as rehabilitation confounders in clinical trials.

Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI.

Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome (“disease modifying factor”). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic’ including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury.

Infections are a common threat to patients after spinal cord injury. Furthermore, infections might propagate neuronal death, and consequently contribute to the restriction of neurological recovery. We investigated the association of infections (i.e. pneumonia and/or postoperative wound infections) with functional neurological outcome after acute severe traumatic spinal cord injury. We screened data sets of 24 762 patients enrolled in a prospective cohort study (National Spinal Cord Injury Database, Birmingham, AL, USA). Patients were assessed according to the ASIA classification. ASIA impairment scale-classified A and B patients recruited within 24 h post-trauma (n = 1436) were selected as being a major recruitment population for interventional trials. Patients with documented pneumonia and/or postoperative wound infections (n = 581) were compared with control subjects (non-documented infections, n = 855). The functional neurological outcome parameters (i) upward ASIA impairment scale conversions; (ii) gain of ASIA motor scores; and (iii) gain of motor and sensory levels were consecutively analysed over time up to 1 year after spinal cord injury. The group with pneumonia and/or postoperative wound infections revealed less ASIA impairment scale upward conversions after 1 year than the control group (ASIA impairment scale A: 17.2 versus 23.9%, P = 0.03; ASIA impairment scale B: 57.1 versus 74.7%, P = 0.009). ASIA motor score gain [median (interquartile range)] was lower in patients with infections [ASIA impairment scale A: 8 (4-12) versus 10 (5-17), P = 0.01; ASIA impairment scale B: 19.5 (8-53.5) versus 42 (20.5-64), P = 0.03)]. Analysis of acquired motor/sensory levels supported these findings. In ASIA impairment scale A patients, the gain in motor levels (21.7 versus 33.3%, P = 0.04) and sensory levels (24.4 versus 38 of 102, 37.3%, P = 0.03) was significantly lower in the group with pneumonia and/or postoperative wound infections than in the control group. Multiple regression analysis identified pneumonia and/or postoperative wound infections as independent risk factors for impaired ASIA impairment scale upward conversion (odds ratio: 1.89, 95% confidence interval: 1.36-2.63, P < 0.0005) or lower gain in ASIA motor score (regression coefficient: -8.21, 95% confidence interval: -12.29 to -4.14, P < 0.0005). Infections associated with spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury.

A causal treatment for traumatic Spinal Cord Injury (SCI) is the goal of the charitable Wings for Life Spinal Cord Research Foundation, located in Salzburg. In order realize this ambitioned endeavour, since 2004 Wings for Life competitively funds selected scientific projects aiming at the neurobiological repair of the injured spinal cord.

Lumbar spinal stenosis (LSS) comprises narrowing of the spinal canal with subsequent neural compression, and is frequently associated with symptoms of neurogenic claudication. To establish a diagnosis of LSS, clinical history, physical examination results and radiological changes all need to be considered. Patients who exhibit mild to moderate symptoms of LSS should undergo multimodal conservative treatment, such as patient education, pain medication, delordosing physiotherapy and epidural injections. in patients with severe symptoms, surgery is indicated if conservative treatment proves ineffective after 3-6 months. Clinically relevant motor deficits or symptoms of cauda equina syndrome remain absolute indications for surgery. The first randomized, prospective studies have provided class I-II evidence that supports a more rapid and profound decline of LSS symptoms after decompressive surgery than with conservative therapy. in the absence of a valid paraclinical diagnostic marker, however, more evidence-based data are needed to identify those patients for whom the benefit of surgery would outweigh the risk of developing complications. in this review, we briefly survey the underlying pathophysiology and clinical appearance of LSS, and explore the available diagnostic and therapeutic options, with particular emphasis on neuroradiological findings and outcome predictors.

Myelin inhibitory ligands of the Nogo-66 receptor (NgR1) limit axon regeneration in the adult CNS. Recent findings have identified additional co-receptors (functional homologues) of the trimeric NgR1 complex, post-translational modifications of the co-receptors within the cell membrane and novel Ca2+-dependent cytoplasmic-protein phosphorylation mechanisms. Such unique signalling pathways provide the potential to transduce myelin-derived growth inhibitory signals to the axonal cytoskeleton, and have been areas of intense investigation in recent years. Here, we summarize current understanding of the molecular basis of myelin-derived axon-growth inhibition in the CNS.

Detailed pathophysiological findings of secondary damage phenomena after spinal cord injury (SCI) as well as the identification of inhibitory and neurotrophic proteins have yielded a plethora of experimental therapeutic approaches. Main targets are (i) to minimize secondary damage progression (neuroprotection), (ii) to foster axon conduction (neurorestoration) and (iii) to supply a permissive environment to promote axonal sprouting (neuroregenerative therapies). Pre-clinical studies have raised hope in functional recovery through the antagonism of growth inhibitors, application of growth factors, cell transplantation, and vaccination strategies. To date, even though based on successful pre-clinical animal studies, results of clinical trials are characterized by dampened effects attributable to difficulties in the study design (patient heterogeneity) and species differences. A combination of complementary therapeutic strategies might be considered pre-requisite for future synergistic approaches. Here, we line out pre-clinical interventions resulting in improved functional neurological outcome after spinal cord injury and track them on their intended way to bedside.

Context By contrast with the glial scar, myelin was considered a constitutive static inhibitory barrier unreactive to lesions in the central nervous system (CNS). However, recent results suggest considerable add-on inhibition of myelin as a result of CNS injury. Furthermore, catastrophic events cause morphological and biochemical changes in the axon itself This results in the accumulation of cytoskeleton components and intraaxonal transported proteins paralleled by extensive membrane remodelling at the axonal tip (a process called axotomy) which might modify the axonal response to its inhibitory environment.Starting point Ji-Eun Kim and colleagues recently reported an axonal subpopulation with a different capacity to respond to myelin inhibitors (Neuron 2004; 44: 439-51). Axonal specificity but also evidence for injury reactivity summarised here challenges our understanding of axon-growth inhibition in the injured CNS. This might be due to (i) qualitative and quantitative enrichment of the periaxonal environment by myelin/oligodendrocytes, (ii) increased axonal sensitivity to its inhibitory environment, and (iii) axons and lesion-induced, altered axonal signalling.Where next? Postlesional reactive inhibition of myelin or the oligodendrocyte necessitates the development of novel screening approaches and therapeutic agents to promote axonal regeneration. Moreover, we need to improve our understanding of the pathophysiology of the lesion to find more efficient experimental strategies to restore neurological function.

During development, precerebellar neurons migrate dorsoventrally from the rhombic lip to the floor plate. Some of these neurons cross the midline while others stop. We have identified a role for the slit receptor Rig-1/Robo3 in directing this process. During their tangential migration, neurons of all major hindbrain precerebellar nuclei express high levels of Rig-1 mRNA. Rig-1 expression is rapidly downregulated as their leading process crosses the floor plate. Interestingly, most precerebellar nuclei do not develop normally in Rig-1-deficient mice, as they fail to cross the midline. In addition, inferior olivary neurons, which normally send axons into the contralateral cerebellum, project ipsilaterally in Rig-1 mutant mice. Similarly, neurons of the lateral reticular nucleus and basilar pons are unable to migrate across the floor plate and instead remain ipsilateral. These results demonstrate that Rig-1 controls the ability of both precerebellar neuron cell bodies and their axons to cross the midline.

> Pendant le developpement embryonnaire, les neurones du systeme nerveux etablissent des milliards de connexions en emettant de longs prolongements, les axones, qui vont croitre rapidement dans le cerveau. Cette croissance n’est pas aleatoire, mais precisement orientee, guidee par des molecules situees dans l’environnement cellulaire que traverse l’axone. Chez la plupart des especes animales, les moities droite et gauche du systeme nerveux sont presque parfaitement symetriques, organisees en miroir de part et d’autre d’un axe longitudinal appele aussi ligne mediane. Chez les vertebres, la plaque du plancher, constituee de cellules allongees specialisees, correspond a la partie ventrale de cette ligne mediane. Une des premieres decisions que doit prendre un axone en croissance est de traverser ou de ne pas traverser la ligne mediane1. Qui plus est, un axone qui traverse la ligne mediane (on parle aussi d’axone commissural) ne sera capable de le faire qu’une NOUVELLE