Ophthalmic findings in marginally housed women in a Canadian city.

OBJECTIVE: To assess the prevalence and common causes of ocular pathology experienced by vulnerable women with marginalized housing and/or a history of abuse, violence, and trafficking. METHODS: Using a stratified random sampling technique, we recruited 93 women living in 10 randomly selected women's shelters in Toronto, Canada between May and November of 2018. All English-speaking females older than the age of 18 were eligible to participate. Data on demographics, medical or ocular history, subjective visual acuity, and access to eye care were obtained. Comprehensive visual screening and dilated fundoscopy were performed for each participant. RESULTS: The median age was 40 years (interquartile range, 30.5-54 years) and the median duration of homelessness was 8 months (interquartile range, 2.25-20.5 months); 63.4% of participants reported a history of abuse, 44.9% experienced head trauma, 15.9% experienced eye trauma, 22.5% identified as refugees, and 2.17% (2 of 92) had been victims of human trafficking. The above variables were not significantly related to vision problem severity on univariate analysis. Based on the presenting visual acuity, 27.8% of participants (95% CI [18.9-38.2]) were found to have visual impairment. Visual impairment was mainly related to refractive error (54.8% [51 of 93]), however, nonrefractive pathology was also observed. Of all the participants, 64.5% had one or more abnormal findings during the vision screening, and 40.9% needed follow-up by an ophthalmologist. Most participants (96.7%) expressed interest in accessing free eye examinations. CONCLUSIONS: Visual impairment is highly prevalent among homeless women living in Toronto. Routine vision-screening programs present an opportunity to improve the ocular health of this vulnerable population.

Harnessing the Secretome of Mesenchymal Stromal Cells for Traumatic Spinal Cord Injury: Multicell Comparison and Assessment of In Vivo Efficacy.

Cell therapy offers significant promise for traumatic spinal cord injury (SCI), which despite many medical advances, has limited treatment strategies. Able to address the multifactorial and dynamic pathophysiology of SCI, cells present various advantages over standard pharmacological approaches. However, the use of live cells is also severely hampered by logistical and practical considerations. These include specialized equipment and expertise, standardization of cell stocks, sustained cell viability post-thawing, and cryopreservation-induced delayed-onset cell death. For this reason, we suggest a novel and clinically translatable alternative to live-cell systemic infusion, which retains the efficacy of the latter while overcoming many of its limitations. This strategy involves the administration of concentrated cell secretome and exploits the trophic mechanism by which stromal cells function. In this study, we compare the efficacy of intravenously delivered concentrated conditioned media (CM) from human umbilical cord matrix cells (HUCMCs), bone marrow mesenchymal stromal cells, as well as newborn and adult fibroblasts in a rat model of moderately severe cervical clip compression/contusion injury (C7--T1, 35 g). This is further paired with a thorough profile of the CM cytokines, chemokines, and angiogenic factors. The HUCMC-derived CM was most effective at limiting acute (48 h post-SCI) vascular pathology, specifically lesion volume, and functional vascularity. Principle component analysis (PCA), hierarchical clustering, and interaction analysis of proteins highly expressed in the HUCMC secretome suggest involvement of the MAPK/ERK, JAK/STAT, and immune cell migratory pathways. This "secretotherapeutic" strategy represents a novel and minimally invasive method to target multiple organ systems and several pathologies shortly after traumatic SCI.

Somatosensory evoked fields predict response to vagus nerve stimulation.

There is an unmet need to develop robust predictive algorithms to preoperatively identify pediatric epilepsy patients who will respond to vagus nerve stimulation (VNS). Given the similarity in the neural circuitry between vagus and median nerve afferent projections to the primary somatosensory cortex, the current study hypothesized that median nerve somatosensory evoked field(s) (SEFs) could be used to predict seizure response to VNS. Retrospective data from forty-eight pediatric patients who underwent VNS at two different institutions were used in this study. Thirty-six patients ("Discovery Cohort") underwent preoperative electrical median nerve stimulation during magnetoencephalography (MEG) recordings and 12 patients ("Validation Cohort") underwent preoperative pneumatic stimulation during MEG. SEFs and their spatial deviation, waveform amplitude and latency, and event-related connectivity were calculated for all patients. A support vector machine (SVM) classifier was trained on the Discovery Cohort to differentiate responders from non-responders based on these input features and tested on the Validation Cohort by comparing the model-predicted response to VNS to the known response. We found that responders to VNS had significantly more widespread SEF localization and greater functional connectivity within limbic and sensorimotor networks in response to median nerve stimulation. No difference in SEF amplitude or latencies was observed between the two cohorts. The SVM classifier demonstrated 88.9% accuracy (0.93 area under the receiver operator characteristics curve) on cross-validation, which decreased to 67% in the Validation cohort. By leveraging overlapping neural circuitry, we found that median nerve SEF characteristics and functional connectivity could identify responders to VNS.

Prevalence and impact of eye disease in an urban homeless and marginally housed population.

OBJECTIVE: Homeless and marginally housed (HMH) populations have a higher prevalence of visual impairment than the general population. This study is the first to conduct a comprehensive ophthalmic examination using portable equipment at various homeless shelter locations in an urban population to identify objective ocular pathologies in a randomly selected sample. METHODS: Ten adult shelters were randomly selected in Toronto, Ontario, Canada, and 143 individuals were randomly selected based on their shelter bed numbers at each shelter, in proportion to the shelter's bed capacity. Participants completed a sociodemographic survey and clinical eye examination. Finally, a dilated ocular examination was performed using a portable slit lamp, autorefractor, tonometer, indirect ophthalmoscope, and fundus camera. RESULTS: The median age of participants was 53.3 years; 82.5% were male and 17.5% female. The age-standardized prevalence of visual impairment was 27.4% (95% confidence interval [CI], 20.6-35.1) for study participants. Refractive error was present in 48% of participants, 34% with myopia and 11% with hyperopia, and 37.8% (95% CI, 32.2-45.9) of this study population were diagnosed with at least one nonrefractive ocular pathology. Low income and low educational attainment were associated with increased odds of being diagnosed with nonrefractive ocular pathologies. CONCLUSIONS: A clear health care gap exists between the ophthalmological disease burden of the HMH population and the amount of resources allocated directed toward their needs. Addressing risk factors such as low income and education, as well as increasing access to free eye examinations and visual aids, may be an effective method of attending to this lack of health equity.

OCTA: A Practical Method of Image Averaging Using Adobe Photoshop Software.

BACKGROUND AND OBJECTIVE: To describe a method for averaging ocular coherence tomography angiography (OCTA) images using a commercially available photo editing software: Adobe Photoshop CC 2017. PATIENTS AND METHODS: This single-center study assessed the feasibility of using Adobe Photoshop as an OCTA image averaging tool. Three 3.0 mm × 3.0 mm OCTA images from each eye were obtained using commercially available OCTA devices. Captured OCTA images were exported in high-resolution TIFF format, imported as an image stack, aligned using an automated function, and averaged by creating a Smart Object using Photoshop CC 2017 software. In conjunction with qualitative assessment, the main outcome of the study was image grader preferences with respect to clarity of the foveal avascular zone (FAZ), blood vessel delineation, and the ability to identify abnormal vasculature. RESULTS: After removing OCTA scans with significant image distortion, 25 sets of images were included in the analysis. Adobe Photoshop CC 2017 successfully aligned and averaged all images of the superficial and deep retinal plexuses that contained a minimum 40% overlap. Three independent retinal specialists found the averaged images to be slightly or definitely preferable to the original 87%, 89%, and 69% of the time with respect to clarity of the FAZ, clarity of blood vessel delineation, and the ability to identify abnormal vasculature, respectively. CONCLUSIONS: Adobe Photoshop CC 2017 is an excellent tool for image averaging, producing high-quality resulting OCTA images. As an easily accessible software, Photoshop has the potential for use in a diversity of pathological conditions. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:802-807.].

Connectomic Profiling Identifies Responders to Vagus Nerve Stimulation.

OBJECTIVE: Vagus nerve stimulation (VNS) is a common treatment for medically intractable epilepsy, but response rates are highly variable, with no preoperative means of identifying good candidates. This study aimed to predict VNS response using structural and functional connectomic profiling. METHODS: Fifty-six children, comprising discovery (n = 38) and validation (n = 18) cohorts, were recruited from 3 separate institutions. Diffusion tensor imaging was used to identify group differences in white matter microstructure, which in turn informed beamforming of resting-state magnetoencephalography recordings. The results were used to generate a support vector machine learning classifier, which was independently validated. This algorithm was compared to a second classifier generated using 31 clinical covariates. RESULTS: Treatment responders demonstrated greater fractional anisotropy in left thalamocortical, limbic, and association fibers, as well as greater connectivity in a functional network encompassing left thalamic, insular, and temporal nodes (p < 0.05). The resulting classifier demonstrated 89.5% accuracy and area under the receiver operating characteristic (ROC) curve of 0.93 on 10-fold cross-validation. In the external validation cohort, this model demonstrated an accuracy of 83.3%, with a sensitivity of 85.7% and specificity of 75.0%. This was significantly superior to predictions using clinical covariates alone, which exhibited an area under the ROC curve of 0.57 (p < 0.008). INTERPRETATION: This study provides the first multi-institutional, multimodal connectomic prediction algorithm for VNS, and provides new insights into its mechanism of action. Reliable identification of VNS responders is critical to mitigate surgical risks for children who may not benefit, and to ensure cost-effective allocation of health care resources. ANN NEUROL 2019;86:743-753.

Electroencephalography in Psychiatric Surgery: Past Use and Future Directions.

The last two decades have seen a re-emergence of surgery for intractable psychiatric disease, in large part due to increased use of deep brain stimulation. The development of more precise, image-guided, less invasive interventions has improved the safety of these procedures, even though the relative merits of modulation at various targets remain under investigation. With an increase in the number and type of interventions for modulating mood/anxiety circuits, the need for biomarkers to guide surgeries and predict treatment response is as critical as ever. Electroencephalography (EEG) has a long history in clinical neurology, cognitive neuroscience, and functional neurosurgery, but has limited prior usage in psychiatric surgery. MEDLINE, Embase, and Psyc-INFO searches on the use of EEG in guiding psychiatric surgery yielded 611 articles, which were screened for relevance and quality. We synthesized three important themes. First, considerable evidence supports EEG as a biomarker for response to various surgical and non-surgical therapies, but large-scale investigations are lacking. Second, intraoperative EEG is likely more valuable than surface EEG for guiding target selection, but comes at the cost of greater invasiveness. Finally, EEG may be a promising tool for objective functional feedback in developing "closed-loop" psychosurgeries, but more systematic investigations are required.

Presurgical and Intraoperative Augmented Reality in Neuro-Oncologic Surgery: Clinical Experiences and Limitations.

Virtual reality (VR) and augmented reality (AR) represent novel adjuncts for neurosurgical planning in neuro-oncology. In addition to established use in surgical and medical training, VR/AR are gaining traction for clinical use preoperatively and intraoperatively. To understand the utility of VR/AR in the clinical setting, we conducted a literature search in Ovid MEDLINE and EMBASE with various search terms designed to capture the use of VR/AR in neurosurgical procedures for resection of cranial tumors. The search retrieved 302 articles, of which 35 were subjected to full-text review; 19 full-text articles were included in the review. Key findings highlighted by the individual authors were extracted and summarized into themes to present the value of VR/AR in the clinical setting. These studies included various VR/AR systems applied to surgeries involving heterogeneous pathologies and outcome measures. Overall, VR/AR were found to be qualitatively advantageous due to enhanced visualization of complex anatomy and improved intraoperative lesion localization. When these technologies were compared with existing neuronavigation systems, quantitative clinical benefits were also reported. The capacity to visualize three-dimensional images superimposed on patient anatomy is a potentially valuable tool in complex neurosurgical environments. Surgical limitations may be addressed through future advances in image registration and tracking as well as intraoperatively acquired imaging with the ability to yield real-time virtual models.

Thalamocortical dysrhythmia in intraoperative recordings of focal epilepsy.

Resonant interactions between the thalamus and cortex subserve a critical role for maintenance of consciousness as well as cognitive functions. In states of abnormal thalamic inhibition, thalamocortical dysrhythmia (TCD) has been described. The characteristics of TCD include a slowing of resting oscillations, ectopic high-frequency activity, and increased cross-frequency coupling. Here, we demonstrate the presence of TCD in four patients who underwent resective epilepsy surgery with chronically implanted electrodes under anesthesia, continuously recording activity from brain regions at the periphery of the epileptogenic zone before and after resection. Following resection, we report an acceleration of the large-scale network resting frequency coincident with decreases in cross-frequency phase-amplitude coupling. Interregional functional connectivity in the surrounding cortex was also increased following resection of the epileptogenic focus. These findings provide evidence for the presence of TCD in focal epilepsy and highlight the importance of reciprocal thalamocortical oscillatory interactions in defining novel biomarkers for resective surgeries. NEW & NOTEWORTHY Thalamocortical dysrhythmia (TCD) occurs in the context of thalamic dysfacilitation and is characterized by slowing of resting oscillations, ectopic high-frequency activity, and cross-frequency coupling. We provide evidence for TCD in focal epilepsy by studying electrophysiological changes occurring at the periphery of the resection margin. We report acceleration of resting activity coincident with decreased cross-frequency coupling and increased functional connectivity. The study of TCD in epilepsy has implications as a biomarker and therapeutic target.

Association between weekend admissions and mortality after aneurysmal subarachnoid hemorrhage: the "weekend effect" revisited.

OBJECTIVE: Higher mortality has been reported with weekend or after-hours patient admission across a wide range of surgical and medical specialties, a phenomenon termed the "weekend effect." The authors evaluated whether weekend admission contributed to death and long-term neurological outcome in patients following aneurysmal subarachnoid hemorrhage. METHODS: A post hoc analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) study was conducted. Univariable and stepwise multivariable logistic regression analyses were performed to assess the associations between weekend admission and mortality and long-term neurological outcome. RESULTS: Of 413 subjects included in the CONSCIOUS-1 study, 140 patients had been admitted during the weekend. A significant interaction was identified between weekend admission and neurological grade on presentation, suggesting that the outcomes of patients who had initially presented with a poor grade were disproportionately influenced by the weekend admission. On stepwise multivariable logistic regression in the subgroup of patients who had presented with a poor neurological grade (29 of 100 patients), admission on the weekend was found to be independently associated with death (OR 6.59, 95% CI 1.62-26.88, p = 0.009). Weekend admission was not associated with long-term neurological outcome. CONCLUSIONS: Weekend admission was an independent risk factor for death within 12 weeks following aneurysmal subarachnoid hemorrhage in patients presenting with a poor neurological grade. Further work is required to identify and mitigate any mediating factors.

Early Intravenous Infusion of Mesenchymal Stromal Cells Exerts a Tissue Source Age-Dependent Beneficial Effect on Neurovascular Integrity and Neurobehavioral Recovery After Traumatic Cervical Spinal Cord Injury.

Localized vascular disruption after traumatic spinal cord injury (SCI) triggers a cascade of secondary events, including inflammation, gliosis, and scarring, that can further impact recovery. In addition to immunomodulatory and neurotrophic properties, mesenchymal stromal cells (MSCs) possess pericytic characteristics. These features make MSCs an ideal candidate for acute cell therapy targeting vascular disruption, which could reduce the severity of secondary injury, enhance tissue preservation and repair, and ultimately promote functional recovery. A moderately severe cervical clip compression/contusion injury was induced at C7-T1 in adult female rats, followed by an intravenous tail vein infusion 1 hour post-SCI of (a) term-birth human umbilical cord perivascular cells (HUCPVCs); (b) first-trimester human umbilical cord perivascular cells (FTM HUCPVCs); (c) adult bone marrow mesenchymal stem cells; or (d) vehicle control. Weekly behavioral testing was performed. Rats were sacrificed at 24 hours or 10 weeks post-SCI and immunohistochemistry and ultrasound imaging were performed. Both term and FTM HUCPVC-infused rats displayed improved (p < .05) grip strength compared with vehicle controls. However, only FTM HUCPVC-infusion led to significant weight gain. All cell infusion treatments resulted in reduced glial scarring (p < .05). Cell infusion also led to increased axonal, myelin, and vascular densities (p < .05). Although post-traumatic cavity volume was reduced with cell infusion, this did not reach significance. Taken together, we demonstrate selective long-term functional recovery alongside histological improvements with HUCPVC infusion in a clinically relevant model of cervical SCI. Our findings highlight the potential of these cells for acute therapeutic intervention after SCI.

Presurgical hyperconnectivity of the ablation volume is associated with seizure-freedom after magnetic resonance-guided laser interstitial thermal therapy.

PURPOSE: Magnetic Resonance-guided Laser Interstitial Thermal Therapy (MRgLITT) is an emerging minimally-invasive alternative to resective surgery for medically-intractable epilepsy. The precise lesioning effect produced by MRgLITT supplies opportunities to glean insights into epileptogenic regions and their interactions with functional brain networks. In this exploratory analysis, we sought to characterize associations between MRgLITT ablation zones and large-scale brain networks that portended seizure outcome using resting-state fMRI. METHODS: Presurgical fMRI and intraoperatively volumetric structural imaging were obtained, from which the ablation volume was segmented. The network properties of the ablation volume within the brain's large-scale brain networks were characterized using graph theory and compared between children who were and were not rendered seizure-free. RESULTS: Of the seventeen included children, five achieved seizure freedom following MRgLITT. Greater functional connectivity of the ablation volume to canonical resting-state networks was associated with seizure-freedom (p < 0.05, FDR-corrected). The ablated volume in children who subsequently became seizure-free following MRgLITT had significantly greater strength, and eigenvector centrality within the large-scale brain network. CONCLUSIONS: These findings provide novel insights into the interaction between epileptogenic cortex and large-scale brain networks. The association between ablation volume and resting-state networks may supply novel avenues for presurgical planning and patient stratification.

Splenic involvement in umbilical cord matrix-derived mesenchymal stromal cell-mediated effects following traumatic spinal cord injury.

BACKGROUND: The spleen plays an important role in erythrocyte turnover, adaptive immunity, antibody production, and the mobilization of monocytes/macrophages (Mφ) following tissue injury. In response to trauma, the spleen initiates production of inflammatory cytokines, which in turn recruit immune cells to the inflamed tissue, exacerbating damage. Our previous work has shown that intravenous mesenchymal stromal cell (MSC) infusion has potent immunomodulatory effects following spinal cord injury (SCI), associated with the transplanted cells homing to and persisting within the spleen. Therefore, this work aimed to characterize the relationship between the splenic inflammatory response and SCI pathophysiology, emphasizing splenic involvement in MSC-mediated effects. METHODS: Using a rodent model of cervical clip-compression SCI, secondary tissue damage and functional recovery were compared between splenectomised rodents and those with a sham procedure. Subsequently, 2.5 million MSCs from the term human umbilical cord matrix cells (HUCMCs) were infused via tail vein at 1-h post-SCI and the effects were assessed in the presence or absence of a spleen. RESULTS: Splenectomy alone had no effect on lesion volume, hemorrhage, or inflammation. There was also no significant difference between the groups in functional recovery and those in lesion morphometry. Yet, while the infusion of HUCMCs reduced spinal cord hemorrhage and increased systemic levels of IL-10 in the presence of a spleen, these effects were lost with splenectomy. Further, HUCMC infusion was shown to alter the expression levels of splenic cytokines, suggesting that the spleen is an important target and site of MSC effects. CONCLUSIONS: Our results provide a link between MSC function and splenic inflammation, a finding that can help tailor the cells/transplantation approach to enhance therapeutic efficacy.

Early Intravenous Delivery of Human Brain Stromal Cells Modulates Systemic Inflammation and Leads to Vasoprotection in Traumatic Spinal Cord Injury.

UNLABELLED: : Spinal cord injury (SCI) is a life-threatening condition with multifaceted complications and limited treatment options. In SCI, the initial physical trauma is closely followed by a series of secondary events, including inflammation and blood spinal cord barrier (BSCB) disruption, which further exacerbate injury. This secondary pathology is partially mediated by the systemic immune response to trauma, in which cytokine production leads to the recruitment/activation of inflammatory cells. Because early intravenous delivery of mesenchymal stromal cells (MSCs) has been shown to mitigate inflammation in various models of neurologic disease, this study aimed to assess these effects in a rat model of SCI (C7-T1, 35-gram clip compression) using human brain-derived stromal cells. Quantitative polymerase chain reaction for a human-specific DNA sequence was used to assess cell biodistribution/clearance and confirmed that only a small proportion (approximately 0.001%-0.002%) of cells are delivered to the spinal cord, with the majority residing in the lung, liver, and spleen. Intriguingly, although cell populations drastically declined in all aforementioned organs, there remained a persistent population in the spleen at 7 days. Furthermore, the cell infusion significantly increased splenic and circulating levels of interleukin-10-a potent anti-inflammatory cytokine. Through this suppression of the systemic inflammatory response, the cells also reduced acute spinal cord BSCB permeability, hemorrhage, and lesion volume. These early effects further translated into enhanced functional recovery and tissue sparing 10 weeks after SCI. This work demonstrates an exciting therapeutic approach whereby a minimally invasive cell-transplantation procedure can effectively reduce secondary damage after SCI through systemic immunomodulation. SIGNIFICANCE: Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention within the scientific community. In addition to being recognized as major players in neurotrauma, pericytes have been discovered to share a common origin and potentially function with traditionally defined mesenchymal stromal cells (MSCs). Although there have been several in vitro comparisons, the in vivo therapeutic application of human brain-derived stromal cells has not been previously evaluated. This study demonstrates that these cells not only display a MSC phenotype in vitro but also have similar in vivo immunomodulatory effects after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of great interest for therapeutic use in spinal cord injury.