Reducing Pericyte-Derived Scarring Promotes Recovery after Spinal Cord Injury.

CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.

Dexterous Hand Movements and Their Recovery After Central Nervous System Injury.

Hand dexterity has uniquely developed in higher primates and is thought to rely on the direct corticomotoneuronal (CM) pathway. Recent studies have shown that rodents and carnivores lack the direct CM pathway but can control certain levels of dexterous hand movements through various indirect CM pathways. Some homologous pathways also exist in higher primates, and among them, propriospinal (PrS) neurons in the mid-cervical segments (C3-C4) are significantly involved in hand dexterity. When the direct CM pathway was lesioned caudal to the PrS and transmission of cortical commands to hand motoneurons via the PrS neurons remained intact, dexterous hand movements could be significantly recovered. This recovery model was intensively studied, and it was found that, in addition to the compensation by the PrS neurons, a large-scale reorganization in the bilateral cortical motor-related areas and mesolimbic structures contributed to recovery. Future therapeutic strategies should target these multihierarchical areas.

ICAM-1 Deletion Using CRISPR/Cas9 Protects the Brain from Traumatic Brain Injury-Induced Inflammatory Leukocyte Adhesion and Transmigration Cascades by Attenuating the Paxillin/FAK-Dependent Rho GTPase Pathway.

Intercellular adhesion molecule-1 (ICAM-1) is identified as an initiator of neuroinflammatory responses that lead to neurodegeneration and cognitive and sensory-motor deficits in several pathophysiological conditions including traumatic brain injury (TBI). However, the underlying mechanisms of ICAM-1-mediated leukocyte adhesion and transmigration and its link with neuroinflammation and functional deficits following TBI remain elusive. Here, we hypothesize that blocking of ICAM-1 attenuates the transmigration of leukocytes to the brain and promotes functional recovery after TBI. The experimental TBI was induced in vivo by fluid percussion injury (25 psi) in male and female wild-type and ICAM-1-/- mice and in vitro by stretch injury (3 psi) in human brain microvascular endothelial cells (hBMVECs). We treated hBMVECs and animals with ICAM-1 CRISPR/Cas9 and conducted several biochemical analyses and demonstrated that CRISPR/Cas9-mediated ICAM-1 deletion mitigates blood-brain barrier (BBB) damage and leukocyte transmigration to the brain by attenuating the paxillin/focal adhesion kinase (FAK)-dependent Rho GTPase pathway. For analyzing functional outcomes, we used a cohort of behavioral tests that included sensorimotor functions, psychological stress analyses, and spatial memory and learning following TBI. In conclusion, this study could establish the significance of deletion or blocking of ICAM-1 in transforming into a novel preventive approach against the pathophysiology of TBI.

Transplantation of dorsal root ganglia overexpressing the NaChBac sodium channel improves locomotion after complete SCI.

Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRGs) genetically modified to express the NaChBac sodium channel could serve as a therapeutic option for functionally complete SCI. We found that NaChBac expression increased the intrinsic excitability of DRG neurons and promoted cell survival and neurotrophic factor secretion in vitro. Transplantation of NaChBac-expressing dissociated DRGs improved voluntary locomotion 7 weeks after injury compared to control groups. Animals transplanted with NaChBac-expressing DRGs also possessed higher tubulin-positive neuronal fiber and myelin preservation, although serotonergic descending fibers remained unaffected. We observed early preservation of the corticospinal tract 14 days after injury and transplantation, which was lost 7 weeks after injury. Nevertheless, transplantation of NaChBac-expressing DRGs increased the neuronal excitatory input by an increased number of VGLUT2 contacts immediately caudal to the injury. Our work suggests that the transplantation of NaChBac-expressing dissociated DRGs can rescue significant motor function, retaining an excitatory neuronal relay activity immediately caudal to injury.

Dendrite regeneration mediates functional recovery after complete dendrite removal.

Unlike many cell types, neurons are not typically replaced if damaged. Therefore, regeneration of damaged cellular domains is critical for maintenance of neuronal function. While axon regeneration has been documented for several hundred years, it has only recently become possible to determine whether neurons respond to dendrite removal with regeneration. Regrowth of dendrite arbors has been documented in invertebrate and vertebrate model systems, but whether it leads to functional restoration of a circuit remains unknown. To test whether dendrite regeneration restores function, we used larval Drosophila nociceptive neurons. Their dendrites detect noxious stimuli to initiate escape behavior. Previous studies of Drosophila sensory neurons have shown that dendrites of single neurons regrow after laser severing. We removed dendrites from 16 neurons per animal to clear most of the dorsal surface of nociceptive innervation. As expected, this reduced aversive responses to noxious touch. Surprisingly, behavior was completely restored 24 â€‹h after injury, at the stage when dendrite regeneration has begun, but the new arbor has only covered a small portion of its former territory. This behavioral recovery required regenerative outgrowth as it was eliminated in a genetic background in which new growth is blocked. We conclude that dendrite regeneration can restore behavior.

Compensatory changes after spinal cord injury in a remyelination deficient mouse model.

The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury-induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3-month-old mice. The present analysis investigated two potential mechanisms by which animals can re-establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage-gated sodium channel, a sub-type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.

An agonist of CXCR4 induces a rapid recovery from the neurotoxic effects of Vipera ammodytes and Vipera aspis venoms.

People bitten by Alpine vipers are usually treated with antivenom antisera to prevent the noxious consequences caused by the injected venom. However, this treatment suffers from a number of drawbacks and additional therapies are necessary. The venoms of Vipera ammodytes and of Vipera aspis are neurotoxic and cause muscle paralysis by inducing neurodegeneration of motor axon terminals because they contain a presynaptic acting sPLA2 neurotoxin. We have recently found that any type of damage to motor axons is followed by the expression and activation of the intercellular signaling axis consisting of the CXCR4 receptor present on the membrane of the axon stump and of its ligand, the chemokine CXCL12 released by activated terminal Schwann cells. We show here that also V. ammodytes and V. aspis venoms cause the expression of the CXCL12-CXCR4 axis. We also show that a small molecule agonist of CXCR4, dubbed NUCC-390, induces a rapid regeneration of the motor axon terminal with functional recovery of the neuromuscular junction. These findings qualify NUCC-390 as a promising novel therapeutics capable of improving the recovery from the paralysis caused by the snakebite of the two neurotoxic Alpine vipers.

Nicotinamide Riboside Regulates Chemotaxis to Decrease Inflammation and Ameliorate Functional Recovery Following Spinal Cord Injury in Mice.

Changes in intracellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in various disease states. A decrease in NAD+ levels has been noted following spinal cord injury (SCI). Nicotinamide riboside (NR) serves as the precursor of NAD+. Previous research has demonstrated the anti-inflammatory and apoptosis-reducing effects of NR supplements. However, it remains unclear whether NR exerts a similar role in mice after SCI. The objective of this study was to investigate the impact of NR on these changes in a mouse model of SCI. Four groups were considered: (1) non-SCI without NR (Sham), (2) non-SCI with NR (Sham +NR), (3) SCI without NR (SCI), and (4) SCI with NR (SCI + NR). Female C57BL/6J mice aged 6-8 weeks were intraperitoneally administered with 500 mg/kg/day NR for a duration of one week. The supplementation of NR resulted in a significant elevation of NAD+ levels in the spinal cord tissue of mice after SCI. In comparison to the SCI group, NR supplementation exhibited regulatory effects on the chemotaxis/recruitment of leukocytes, leading to reduced levels of inflammatory factors such as IL-1ß, TNF-α, and IL-22 in the injured area. Moreover, NR supplementation notably enhanced the survival of neurons and synapses within the injured area, ultimately resulting in improved motor functions after SCI. Therefore, our research findings demonstrated that NR supplementation had inhibitory effects on leukocyte chemotaxis, anti-inflammatory effects, and could significantly improve the immune micro-environment after SCI, thereby promoting neuronal survival and ultimately enhancing the recovery of motor functions after SCI. NR supplementation showed promise as a potential clinical treatment strategy for SCI.

Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Therapeutic administration of mouse mast cell protease 6 improves functional recovery after traumatic spinal cord injury in mice by promoting remyelination and reducing glial scar formation.

Traumatic spinal cord injury (SCI) most often leads to permanent paralysis due to the inability of axons to regenerate in the adult mammalian central nervous system (CNS). In the past, we have shown that mast cells (MCs) improve the functional outcome after SCI by suppressing scar tissue formation at the lesion site via mouse mast cell protease 6 (mMCP6). In this study, we investigated whether recombinant mMCP6 can be used therapeutically to improve the functional outcome after SCI. Therefore, we applied mMCP6 locally via an intrathecal catheter in the subacute phase after a spinal cord hemisection injury in mice. Our findings showed that hind limb motor function was significantly improved in mice that received recombinant mMCP6 compared with the vehicle-treated group. In contrast to our previous findings in mMCP6 knockout mice, the lesion size and expression levels of the scar components fibronectin, laminin, and axon-growth-inhibitory chondroitin sulfate proteoglycans were not affected by the treatment with recombinant mMCP6. Surprisingly, no difference in infiltration of CD4+ T cells and reactivity of Iba-1+ microglia/macrophages at the lesion site was observed between the mMCP6-treated mice and control mice. Additionally, local protein levels of the pro- and anti-inflammatory mediators IL-1ß, IL-2, IL-4, IL-6, IL-10, TNF-α, IFNγ, and MCP-1 were comparable between the two treatment groups, indicating that locally applied mMCP6 did not affect inflammatory processes after injury. However, the increase in locomotor performance in mMCP6-treated mice was accompanied by reduced demyelination and astrogliosis in the perilesional area after SCI. Consistently, we found that TNF-α/IL-1ß-astrocyte activation was decreased and that oligodendrocyte precursor cell (OPC) differentiation was increased after recombinant mMCP6 treatment in vitro. Mechanistically, this suggests effects of mMCP6 on reducing astrogliosis and improving (re)myelination in the spinal cord after injury. In conclusion, these data show for the first time that recombinant mMCP6 is therapeutically active in enhancing recovery after SCI.

Changes in Noradrenergic Synthesis and Dopamine Beta-Hydroxylase Activity in Response to Oxidative Stress after Iron-induced Brain Injury.

Noradrenaline (NA) levels are altered during the first hours and several days after cortical injury. NA modulates motor functional recovery. The present study investigated whether iron-induced cortical injury modulated noradrenergic synthesis and dopamine beta-hydroxylase (DBH) activity in response to oxidative stress in the brain cortex, pons and cerebellum of the rat. Seventy-eight rats were divided into two groups: (a) the sham group, which received an intracortical injection of a vehicle solution; and (b) the injured group, which received an intracortical injection of ferrous chloride. Motor deficits were evaluated for 20 days post-injury. On the 3rd and 20th days, the rats were euthanized to measure oxidative stress indicators (reactive oxygen species (ROS), reduced glutathione (GSH) and oxidized glutathione (GSSG)) and catecholamines (NA, dopamine (DA)), plus DBH mRNA and protein levels. Our results showed that iron-induced brain cortex injury increased noradrenergic synthesis and DBH activity in the brain cortex, pons and cerebellum at 3 days post-injury, predominantly on the ipsilateral side to the injury, in response to oxidative stress. A compensatory increase in contralateral noradrenergic activity was observed, but without changes in the DBH mRNA and protein levels in the cerebellum and pons. In conclusion, iron-induced cortical injury increased the noradrenergic response in the brain cortex, pons and cerebellum, particularly on the ipsilateral side, accompanied by a compensatory response on the contralateral side. The oxidative stress was countered by antioxidant activity, which favored functional recovery following motor deficits.

Occupational nerve injuries.

Occupational nerve injuries span a broad array of pathologies and contribute toward functional limitation, disability, and economic impact. Early and accurate recognition, treatment, and management of workplace factors rely on a thorough understanding of the anatomic and biomechanical factors that drive nerve injury. This review explores the interplay between anatomy, biomechanics, and nerve pathology common to occupational nerve injury and provides the treating physician with a rational, evidence-based approach to diagnosis and to occupational aspects of management. Assessment of potential occupational nerve injury begins with a detailed understanding of the employee's work duties through a biomechanical lens. One must consider likelihood of occupational causation while accounting for predisposing conditions or preexisting symptoms. Beyond overt crush injury or laceration, potential mechanisms of nerve injury, with effects compounded over time, include compression, stretch, vibration, and repetitive or high-force movements of regional muscles and joints. Injury often occurs at nerve locations that experience higher pressures, changes in pressure over time, or abrupt changes in trajectory, often near a tethered point. This understanding, coupled with condition-specific knowledge presented in this review, equips managing physicians to diagnose occupational nerve injury and enhance treatment recommendations with rational activity modifications or equipment that can protect the nerve or decrease likelihood of continued injury. Long-term management often involves follow-up to assess effectiveness of interventions in the setting of the work environment, with gradual progression of the worker toward return to unrestricted duty or to a point of maximal medical improvement.

Appropriate dosage, timing, and site of intramuscular injections of brain-derived neurotrophic factor (BDNF) promote motor recovery after facial nerve injury in rats.

INTRODUCTION/AIMS: Daily intramuscular injections of fibroblast growth factor 2 (FGF2) but not of brain-derived neurotrophic factor (BDNF) significantly improve whisking behavior and mono-innervation of the rat levator labii superioris (LLS) muscle 56 days after buccal nerve transection and suture (buccal-buccal anastomosis, BBA). We explored the dose-response of BDNF, FGF2, and insulin growth factor 2 (IGF2) on the same parameters, asking whether higher doses of BDNF would promote recovery. METHODS: After BBA, growth factors were injected (30 µL volume) daily into the LLS muscle over 14, 28, or 56 days. At 56 days, video-based motion analysis of vibrissal whisking was performed and the extent of mono- and poly-reinnervation of the reinnervated neuromuscular junctions (NMJs) of the muscle determined with immunostaining of the nerve with ß-tubulin and histochemical staining of the endplates with Alexa Fluor 488-conjugated α-bungarotoxin. RESULTS: The dose-response curve demonstrated significantly higher whisking amplitudes and corresponding increased mono-innervation of the NMJ in the reinnervated LLS muscle at concentrations of 20-30 µg/mL BDNF administered daily for 14-28 days after BBA surgery. In contrast, high doses of IGF2 and FGF2, or doses of 20 and 40 µg/mL of BDNF administered for 14-56 days had no effect on either whisking behavior or in reducing poly-reinnervation of endplates in the muscle. DISCUSSION: These data suggest that the re-establishment of mono-innervation of whiskerpad muscles and the improved motor function by injections of BDNF into the paralyzed vibrissal musculature after facial nerve injury have translation potential and promote clinical application.

Parenchymal volume preservation during partial nephrectomy: improved methodology to assess impact and predictive factors.

OBJECTIVE: To rigorously evaluate the impact of the percentage of parenchymal volume preserved (PPVP) and how well the preserved parenchyma recovers from ischaemia (Recischaemia) on functional outcomes after partial nephrectomy (PN) using an accurate and objective software-based methodology for estimating parenchymal volumes and split renal function (SRF). A secondary objective was to assess potential predictors of the PPVP. PATIENTS AND METHODS: A total of 894 PN patients with available studies (2011-2014) were evaluated. The PPVP was measured from cross-sectional imaging at ≤3 months before and 3-12 months after PN using semi-automated software. Pearson correlation evaluated relationships between continuous variables. Multivariable linear regression evaluated predictors of ipsilateral glomerular filtration rate (GFR) preserved and the PPVP. Relative-importance analysis was used to evaluate the impact of the PPVP on ipsilateral GFR preserved. Recischaemia was defined as the percentage of ipsilateral GFR preserved normalised by the PPVP. RESULTS: The median tumour size and R.E.N.A.L. nephrometry score were 3.4 cm and 7, respectively. In all, 49 patients (5.5%) had a solitary kidney. In all, 538 (60%)/251 (28%)/104 (12%) patients were managed with warm/cold/zero ischaemia, respectively. The median pre/post ipsilateral GFRs were 40/31 mL/min/1.73 m2, and the median (interquartile range [IQR]) percentage of ipsilateral GFR preserved was 80% (71-88%). The median pre/post ipsilateral parenchymal volumes were 181/149 mL, and the median (IQR) PPVP was 84% (76-92%). In all, 330 patients (37%) had a PPVP of <80%, while only 34 (4%) had a Recischaemia of <80%. The percentage of ipsilateral GFR preserved correlated strongly with the PPVP (r = 0.83, P < 0.01) and loss of parenchymal volume accounted for 80% of the loss of ipsilateral GFR. Multivariable analysis confirmed that the PPVP was the strongest predictor of ipsilateral GFR preserved. Greater tumour size and endophytic and nearness properties of the R.E.N.A.L. nephrometry score were associated with a reduced PPVP (all P ≤ 0.01). Solitary kidney and cold ischaemia were associated with an increased PPVP (all P < 0.05). CONCLUSIONS: A reduced PPVP predominates regarding functional decline after PN, although a low Recischaemia can also contribute. Tumour-related factors strongly influence the PPVP, while surgical efforts can improve the PPVP as observed for patients with solitary kidneys.

Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke.

Development of functional recovery therapies is critical to reduce the global impact of stroke as the leading cause of long-term disability. Our previous studies found that acute-phase protein orosomucoid (ORM) could provide an up to 6h therapeutic time window to reduce infarct volume in acute ischemic stroke by improving endothelial function. However, its role in neurons and functional recovery post-stroke remains largely unknown. Here, we showed that exogenous ORM administration with initial injection at 0.5h (early) or 12h (delayed) post-MCAO daily for consecutive 7 days significantly decreased infarct area, improved motor and cognitive functional recovery, and promoted mitochondrial biogenesis after MCAO. While neuron-specific knockout of ORM2, a dominant subtype of ORM in the brain, produced opposite effects which could be rescued by exogenous ORM. In vitro, exogenous ORM protected SH-SY5Y cells from OGD-induced damage and promoted mitochondrial biogenesis, while endogenous ORM2 deficiency worsened these processes. Mechanistically, inactivation of CCR5 or AMPK eliminated the protective effects of ORM on neuronal damage and mitochondrial biogenesis. Taken together, our findings demonstrate that ORM, mainly ORM2, is an endogenous regulator of neuronal mitochondrial biogenesis by activating CCR5/AMPK signaling pathway, and might act as a potential therapeutic target for the functional recovery post-stroke.

Frailty and Other Factors Associated With Early Outcomes in Middle-to Older Age Trauma Patients: A Prospective Cohort Study.

OBJECTIVES: To prospectively investigate associations of frailty and other predictor variables with functional recovery and health outcomes in middle-aged and older patients with trauma. DESIGN: Single-center prospective cohort study. SETTING: Emergency department of Wan Fang Hospital in Taiwan. PARTICIPANTS: Trauma patients aged 45 and older. MEASUREMENTS: Frailty was assessed with the Clinical Frailty Scale (CFS). Injury mechanisms, pre-existing diseases, and fracture locations were recorded at baseline. The primary outcome was functional recovery assessed using the Barthel Index (BI). Secondary outcomes were new care needs, unscheduled return visits, and falls 3 months postinjury. RESULTS: A total of 588 participants were included in the final analysis. For every one-point increase in the CFS, the multivariable-adjusted odds ratio (OR, 95% confidence interval [CI]) of failure to retain the preinjury BI was 1.34 (1.16-1.55); associations were consistent across levels of age and injury severities. Significant joint associations of frailty and age with poor functional recovery were observed. CFS was also associated with new care needs (OR for every one-point increase, 1.36, 95% CI, 1.17-1.58), unscheduled return visits (OR 1.26, 95% CI, 1.04-1.51), and falls (OR 1.23, 95% CI, 1.01-1.51). Other variables associated with failure to retain preinjury BI included road traffic accident and presence of hip fracture. CONCLUSION: Frailty was significantly associated with poor functional and health outcomes regardless of injury severity in middle-aged and older patients with trauma. Injury mechanisms and fracture locations were also significant predictors of functional recovery postinjury.

Early robotic gait training after stroke (ERA Stroke): study protocol for a randomized clinical trial.

BACKGROUND: Walking impairment after stroke is associated with substantial limitations in functional independence, quality of life, and long-term survival. People in the subacute phase after stroke who are unable to walk are most likely to benefit the greatest from use of overground robotic gait training (RGT). This study will provide preliminary evidence regarding the clinical use and efficacy of RGT during the subacute phase of stroke recovery as well as observational findings associated with the safety, tolerability, feasibility, and cost of delivering RGT during inpatient stroke rehabilitation. METHODS: This prospectively registered randomized controlled trial will enroll 54 patients admitted to inpatient rehabilitation within six months of stroke. Admitted patients will be screened at admission to inpatient rehabilitation for eligibility. Consented patients will be randomized based on stroke severity to receive either RGT or usual care for 90 minutes per week of gait training intervention during inpatient rehabilitation length of stay. Patients will complete assessments on walking and health outcomes at admission and discharge from inpatient rehabilitation and at 1- and 3-month follow-up. Intent-to-treat and per protocol analysis will be performed to evaluate safety [rate of adverse events, visual analog scale, and treatment completion rate], walking function [gait speed via 10-Meter Walk Test, Functional Ambulation Category, gait endurance via 6-Minute Walk Test] and health outcomes [Modified Rankin Scale, Stroke Rehabilitation Assessment of Movement, Continuity Assessment Record and Evaluation Tool, 5 Times Sit-to-Stand Test, Berg Balance Scale, and Stroke Impact Scale-16], and cost-analysis. DISCUSSION: This study will provide foundational evidence regarding the clinical use and efficacy of a RGT program during the subacute phase of stroke recovery with specific findings associated with the safety, tolerability, feasibility, and cost-analysis of delivering RGT during inpatient stroke rehabilitation. TRIAL REGISTRATION: NCT06430632.

Development and Testing of the Spinal Cord Injury Bladder and Bowel Control Questionnaire (SCI-BBC-Q).

INTRODUCTION: Recovery of lower urinary tract (LUT) and lower gastrointestinal tract (LGIT) is a high priority for people with lived experience following spinal cord injury (SCI). A universally accepted validated patient-reported outcome (PRO) measure of the individual sensory and motor components of LGIT and LUT function, which allows tracking of recovery is lacking. To address this literature gap, the SCI Bladder and Bowel Control Questionnaire (SCI-BBC-Q) was developed. METHODS: The SCI-BBC-Q was developed as a direct assessment of the micturition and defecation experiences of an individual with SCI with possible neurogenic LUT and LGIT dysfunction. The SCI-BBC-Q development process consisted of two phases, measure development and evaluation. Measure development was guided by a conceptual framework, review of existing instruments and literature, and an iterative process of item incorporation, review, feedback, and consensus revision. Evaluation included cognitive interviewing, and assessments of feasibility, reliability, and content validity. RESULTS: The final 6-item SCI-BBC-Q is a PRO, which assesses motor and sensory function related to micturition and defecation, requiring ~5 min to complete. Assessments of clarity of the instrument components with regard to understanding of what is being asked in the questionnaire, feasibility of administration, reliability, internal consistency, and agreement with proxy measures have demonstrated that the SCI-BBC-Q provides consistent, stable, and reproducible data. Significant correlations were found between SCI-BBC-Q scores and the anorectal motor and sensory components of the International Standards for the Neurological Classification of SCI. CONCLUSION: The SCI-BBC-Q is a practical and reliable method for baseline and ongoing evaluation of patients with neurogenic LUT and LGIT dysfunction, especially in the acute and subacute period when function is changing due to neurological plasticity. It is also appropriate for use in monitoring response to treatments related to neurological recovery.

Challenges in evaluating pelvic floor physiotherapy based strategies in low anterior resection syndrome: a systematic review and qualitative analysis.

AIM: Physiotherapy is an established treatment strategy for low anterior resection syndrome (LARS). However, data on its efficacy are limited. This is in part due to the inherent challenges in study design in this context. This systematic review aims to analyse the methodology of studies using pelvic floor physiotherapy for treatment of LARS to elucidate the challenges and limitations faced, which may inform the design of future prospective trials. METHODOLOGY: A systematic review of the literature was undertaken through MEDLINE, Embase and Cochrane Library, yielding 345 unique records for screening. Five studies were identified for review. Content thematic analysis of study limitations was carried out using the Braun and Clarke method. Line-by-line coding was used to organize implicit and explicit challenges and limitations under broad organizing categories. RESULTS: Key challenges fell into five overarching categories: patient-related issues, cancer-related issues, adequate symptomatic control, intervention-related issues and measurement of outcomes. Adherence, attrition and randomization contributed to potential bias within these studies, with imbalance in the baseline patient characteristics, particularly gender and baseline pelvic floor function scores. Outcome measurements consisted of patient-reported measures and quality of life measures, where significant improvements in bowel function according to patient-reported outcome measures were not reflected in the quality of life scores. CONCLUSION: Upcoming trial design in the area of pelvic floor physiotherapy for faecal incontinence related to rectal cancer surgery can be cognisant of and design around the challenges identified in this systematic review, including the reduction of bias, exclusion of the placebo effect and the potential cultural differences in attitude towards a sensitive intervention.

Association between galectin-3 and the prognosis of patients with stroke: A meta-analysis of observational studies.

AIM: This meta-analysis aimed to investigate the prognostic value of galectin-3 among patients with stroke. DATA SYNTHESIS: Electronic databases, such as PubMed, Web of Science, Embase, Cochrane, and Clinical Trials, were utilized for conducting searches from database inception to November 2022. Two reviewers independently screened the papers, extracted the data, and used the Newcastle-Ottawa Scale to determine the risk of bias. Stata 17 was employed to conduct the meta-analysis, while the funnel plot was utilized to identify potential publication bias. Subgroup and meta-regression analyses were employed to examine the sources of heterogeneity. Nine studies that satisfied the inclusion criteria were included. Galectin-3 levels were higher post-stroke in patients with poor outcomes and mortality compared to those in patients with good outcomes (standardized mean difference [SMD], 2.83; 95 % confidence interval [CI], 1.25-4.40; P<0.001) and stroke survivors (SMD, 1.18; 95 % CI, 0.96-1,39; P< 0.001), and elevated galectin-3 levels were associated with poor stroke outcomes (odds ratio [OR], 1.19; 95 % CI, 1.06-1.33; P<0.001). Further, higher post-stroke galectin-3 levels were associated with a higher risk of mortality (OR, 1.16; 95 % CI, 1.08-1.25; P<0.001), and this relationship was maintained after trim-and-fill analyses (OR, 1.14; 95 % CI, 1.06-1.22). CONCLUSIONS: Galectin-3 levels post-stroke are increased in patients with a poor prognosis, and this elevation is associated with poor stroke outcomes and mortality. It is recommended that further high-caliber investigations with expanded sample sizes corroborate the outcomes of this study.