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Background Equine-assisted services (EAS) involves the use of horses within therapy, learning or horsemanship sessions and has been used with military veterans suffering from post-traumatic stress disorder (PTSD). This study systematically reviewed existing research on the use of EAS in the treatment of PTSD in military veterans and evaluated its effectiveness. Methods A systematic review was performed, in May 2023, with searches and data extraction carried out from three separate databases (PubMed, JSTOR and Science Direct) related to testing the effect of EAS on PTSD outcomes in veterans. A risk of bias assessment of included studies was conducted and meta-analysis of outcomes performed when two or more studies reported the same outcomes. Other effects of EAS on veterans’ health were also discussed. Results A total of 13 studies were identified based on our inclusion and exclusion criteria with 11 originating from the US and the remaining two from Australia and Israel. There were 344 participants amongst all of the studies with a mean age of 47 years and a male:female ratio of 19:6. Eight out of the 13 studies reported PTSD scores, as measured by either PTSD Checklist for DSM-5 (PCL-5) or PCL-Veteran/-Military versions (PCL-V/-M), and results suggested a reduction in PTSD score after EAS treatment of 22.6%. A meta-analysis confirmed that EAS favored a significantly lower PTSD score after treatment, with a mean difference of 12.46, 95% CI [9.03,15.88], p  < 0.00001. However, only one study had low risk of bias whilst all the rest of the studies had some concerns to high risk of bias. Conclusions EAS appeared to have a positive influence on PTSD symptoms in military veterans, significantly reducing PTSD severity scores. Other benefits of EAS may be peer support, social integration, learning new skills and bonding. However, the results of this systematic review must be interpreted with caution as almost all of the studies were of low quality. Therefore, further rigorous research is required with larger participants to be able to draw conclusions about the benefits of EAS on PTSD severity.

Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.

Spinal cord injury (SCI) is a significant cause of lifelong disability, with no available disease-modifying treatments to promote neuroprotection and axon regeneration after injury. Photobiomodulation (PBM) is a promising therapy which has proven effective at restoring lost function after SCI in pre-clinical models. However, the precise mechanism of action is yet to be determined. Here, we used an in-vivo model of SCI in adult rats that received daily PBM (660 nm, 24 mW/cm 2 , 1 min) and at three days post-injury, the injured spinal cord segment was harvested and subjected to whole transcriptome sequencing and subsequent pathway analysis (generally applicable gene-set enrichment (GAGE)). Pathway analysis demonstrated 1275 differentially expressed genes (DEGs) after PBM treatment, of which 397 were upregulated and 878 were downregulated. Key pathways were significantly enriched, including 8.6-fold enrichment of “neuron projection morphogenesis” (adjusted p  = 8.10 × 10 − 14 ), with upregulation of Notch3, Slit1/Robo2 and Sema3g pathways. Ribosomal and oxidative phosphorylation pathways and NADH dehydrogenase were downregulated, and there was upregulation of ATP-dependent activity, cAMP and calcium signalling pathways. Key genes in apoptotic pathways were downregulated, as were S100 and cyclo-oxygenase components. Together, our study supports the favourable effects of PBM in promoting neuroregeneration and suppressing apoptosis after neurological injury. Further findings from pathway analysis suggest that downregulation of metabolism-associated pathways is a mechanism by which acute post-injury mitochondrial dysfunction may be averted by PBM therapy.

Apoptotic cell death within the brain represents a significant contributing factor to impaired post-traumatic tissue function and poor clinical outcome after traumatic brain injury. After irradiation with light in the wavelength range of 600–1200 nm (photobiomodulation), previous investigations have reported a reduction in apoptosis in various tissues. This study investigates the effect of 660 nm photobiomodulation on organotypic slice cultured hippocampal tissue of rats, examining the effect on apoptotic cell loss. Tissue optical Raman spectroscopic changes were evaluated. A significantly higher proportion of apoptotic cells 62.8±12.2% vs 48.6±13.7% (P<0.0001) per region were observed in the control group compared with the photobiomodulation group. After photobiomodulation, Raman spectroscopic observations demonstrated 1440/1660 cm -1 spectral shift. Photobiomodulation has the potential for therapeutic utility, reducing cell loss to apoptosis in injured neurological tissue, as demonstrated in this in vitro model. A clear Raman spectroscopic signal was observed after apparent optimal irradiation, potentially integrable into therapeutic light delivery apparatus for real-time dose metering.

BackgroundThe paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy.MethodsAntibodies specific for mHER2 were generated, screened for affinity and specificity, tested for immunohistochemical staining of HER2 on normal tissues, and used for HER2-targeted CAR design. CAR candidates were evaluated for T-cell surface expression and the ability to induce T-cell proliferation, cytokine production, and cytotoxicity when transduced T cells were co-cultured with mHER2+ tumor cells in vitro. Safety and efficacy of various HER2 CARs was evaluated in two tumor models and normal non-tumor-bearing mice.ResultsMice express HER2 in the same epithelial tissues as humans, rendering these tissues vulnerable to recognition by systemically administered HER2 CAR T cells. CAR T cells designed with single-chain variable fragment (scFvs) that have high-affinity for HER2 infiltrated and caused toxicity to normal HER2-positive tissues but exhibited poor infiltration into tumors and antitumor activity. In contrast, CAR T cells designed with an scFv with low-affinity for HER2 infiltrated HER2-positive tumors and controlled tumor growth without toxicity. Toxicity mediated by high-affinity CAR T cells was independent of tumor burden and correlated with proliferation of CAR T cells post infusion.ConclusionsOur findings illustrate the disadvantage of high-affinity CARs for targets such as HER2 that are expressed on normal tissues. The use of low-affinity HER2 CARs can safely regress tumors identifying a potential path for therapy of solid tumors that exhibit high levels of HER2.

Spinal cord injury (SCI) is a cause of profound and irreversible damage, with no effective therapy to promote functional recovery. Photobiomodulation (PBM) may provide a viable therapeutic approach using red or near‐infrared light to promote recovery after SCI by mitigating neuroinflammation and preventing neuronal apoptosis. Our current study aimed to optimize PBM dose regimens and develop and validate the efficacy of an invasive PBM delivery paradigm for SCI. Dose optimization studies were performed using a serum withdrawal model of injury in cultures of primary adult rat dorsal root ganglion neurons (DRGN). Implantable and transcutaneous PBM delivery protocols were developed and validated using cadaveric modeling. The efficacy of PBM in promoting recovery after SCI in vivo was studied in a dorsal column crush injury model of SCI in adult rats. Optimal neuroprotection in vitro was achieved between 4 and 22 mW/cm2. 11 mW/cm2 for 1 min per day (0.66 J/cm2) increased cell viability by 45% over 5 days (p <0.0001), increasing neurite outgrowth by 25% (p <0.01). A method for invasive application of PBM was developed using a diffusion‐tipped optogenetics fiber optic. Delivery methods for PBM were developed and validated for both invasive (iPBM) and noninvasive (transcutaneous) (tcPBM) application. iPBM and tcPBM (24 mW/cm2 at spinal cord, 1 min per day (1.44 J/cm2) up to 7 days) increased activation of regeneration‐associated protein at 3 days after SCI, increasing GAP43+ axons in DRGN from 18.0% (control) to 41.4% ± 10.5 (iPBM) and 45.8% ± 3.4 (tcPBM) (p <0.05). This corresponded to significant improvements at 6 weeks post‐injury in functional locomotor and sensory function recovery (p <0.01), axonal regeneration (p <0.01), and reduced lesion size (p <0.01). Our results demonstrated that PBM achieved a significant therapeutic benefit after SCI, either using iPBM or tcPBM application and can potentially be developed for clinical use in SCI patients.

Mild traumatic brain injury (mTBI) is a common consequence of head injury but there are no recognized interventions to promote recovery of the brain. We previously showed that photobiomodulation (PBM) significantly reduced the number of apoptotic cells in adult rat hippocampal organotypic slice cultures. In this study, we first optimized PBM delivery parameters for use in mTBI, conducting cadaveric studies to calibrate 660 and 810 nm lasers for transcutaneous delivery of PBM to the cortical surface. We then used an in vivo weight drop mTBI model in adult rats and delivered daily optimized doses of 660, 810 nm, or combined 660/810 nm PBM. Functional recovery was assessed using novel object recognition (NOR) and beam balance tests, whilst histology and immunohistochemistry were used to assess the mTBI neuropathology. We found that PBM at 810, 660 nm, or 810/660 nm all significantly improved both NOR and beam balance performance, with 810 nm PBM having the greatest effects. Histology demonstrated no overt structural damage in the brain after mTBI, however, immunohistochemistry using brain sections showed significantly reduced activation of both CD11b+ microglia and glial fibrillary acidic protein (GFAP)+ astrocytes at 3 days post‐injury. Significantly reduced cortical localization of the apoptosis marker, cleaved caspase‐3, and modest reductions in extracellular matrix deposition after PBM treatment, limited to choroid plexus and periventricular areas were also observed. Our results demonstrate that 810 nm PBM optimally improved functional outcomes after mTBI, reduced markers associated with apoptosis and astrocyte/microglial activation, and thus may be useful as a potential regenerative therapy.

Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after TBI. Raman spectroscopy (RS) is a powerful, label-free, optical tool which can provide detailed biochemical data in vivo. A systematic review of the literature is presented of available evidence for the use of RS in TBI. Seven research studies met the inclusion/exclusion criteria with all studies being performed in pre-clinical models. None of the studies reported the in vivo application of RS, with spectral acquisition performed ex vivo and one performed in vitro. Four further studies were included that related to the use of RS in analogous brain injury models, and a further five utilised RS in ex vivo biofluid studies for diagnosis or monitoring of TBI. RS is identified as a potential means to identify injury severity and metabolic dysfunction which may hold translational value. In relation to the available evidence, the translational potentials and barriers are discussed. This systematic review supports the further translational development of RS in TBI to fully ascertain its potential for enhancing patient care.

Background Arachnoid cysts (AC) are associated with a risk of rupture or haemorrhage following head impact and pose a potential predisposing factor for significant complications of sport-related concussion. Despite a recognised association between ACs and intracranial haemorrhage/cyst rupture, the risk profile of participating in contact sports with AC is not well defined. We report a retrospective case series of players presenting to the Birmingham Sports Concussion Clinic between 2017 and 2023 and underwent MRI head, with a comprehensive review of the prior literature. Results 432 athletes underwent MRI of which 11 were identified to have AC (middle fossa n = 8; posterior fossa n = 2, intraventricular n = 1). Average maximal diameter was 4.1 ± 1.2 cm. 64% had a protracted recovery (≥ 3 months). 9% experienced an AC specific complication (cyst rupture, complete neurological recovery, maximal diameter 6.5 cm, Galassi II, 4 previous concussions). 91% of patients (mean maximal diameter 3.9 ± 1.0 cm) experienced no complications despite multiple previous accumulated sports-related concussions (mean 3.3, range 1–9). Case studies from the literature are summarised (n = 63), with 98% reporting complications, none of which resulted in adverse or unfavourable neurological outcomes. Across prospective and retrospective cohort studies, 1.5% had a structural injury, and (where outcome was reported) all had a favourable outcome. Conclusions AC is an incidental finding in athletes, with the majority in our cohort having sustained serial concussions without AC complication. The single complication within this cohort occurred in the largest AC, and AC size is proposed as a tentative factor associated with increased risk of contact sports participation. Complications of AC appear to be a rare occurrence. This case series and review has not identified evidence to suggest that participation in sports with AC is of significant risk, though individualised assessment and discussion of the potential risks of contact sports participation should be offered. Key Points Incidental arachnoid cysts were found to occur in 2.5% of athletes presenting after sports-related concussion. Of 11 athletes with AC and a history of concussion, one (9%) had experienced a prior complication of AC (cyst rupture) and made a full recovery. A comprehensive review of the prior literature suggests an overall risk of complications of 1.5%, with all reported outcomes from cases describing a full neurological recovery. Overall, complications of AC in athletes after sport-related concussion appear to be rare, with no recorded cases of significant neurological consequences.

Although neurons in the adult mammalian CNS are inherently incapable of regeneration after injury, we previously showed that exogenous delivery of pigment epithelium-derived factor (PEDF), a 50-kDa neurotrophic factor (NTF), promoted adult retinal ganglion cell neuroprotection and axon regeneration. Here, we show that PEDF and other elements of the PEDF pathway are highly upregulated in dorsal root ganglion neurons (DRGN) from regenerating dorsal column (DC) injury paradigms when compared with non-regenerating DC injury models. Exogenous PEDF was neuroprotective to adult DRGN and disinhibited neurite outgrowth, whilst overexpression of PEDF after DC injury in vivo promoted significant DC axon regeneration with enhanced electrophysiological, sensory, and locomotor function. Our findings reveal that PEDF is a novel NTF for adult DRGN and may represent a therapeutically useful factor to promote functional recovery after spinal cord injury.