Different Effects of Phototherapy for Rat Glioma during Sleep and Wakefulness.

There is an association between sleep quality and glioma-specific outcomes, including survival. The critical role of sleep in survival among subjects with glioma may be due to sleep-induced activation of brain drainage (BD), that is dramatically suppressed in subjects with glioma. Emerging evidence demonstrates that photobiomodulation (PBM) is an effective technology for both the stimulation of BD and as an add-on therapy for glioma. Emerging evidence suggests that PBM during sleep stimulates BD more strongly than when awake. In this study on male Wistar rats, we clearly demonstrate that the PBM course during sleep vs. when awake more effectively suppresses glioma growth and increases survival compared with the control. The study of the mechanisms of this phenomenon revealed stronger effects of the PBM course in sleeping vs. awake rats on the stimulation of BD and an immune response against glioma, including an increase in the number of CD8+ in glioma cells, activation of apoptosis, and blockage of the proliferation of glioma cells. Our new technology for sleep-phototherapy opens a new strategy to improve the quality of medical care for patients with brain cancer, using promising smart-sleep and non-invasive approaches of glioma treatment.

Technology of the photobiostimulation of the brain's drainage system during sleep for improvement of learning and memory in male mice.

In this study on healthy male mice using confocal imaging of dye spreading in the brain and its further accumulation in the peripheral lymphatics, we demonstrate stronger effects of photobiomodulation (PBM) on the brain's drainage system in sleeping vs. awake animals. Using the Pavlovian instrumental transfer probe and the 2-objects-location test, we found that the 10-day course of PBM during sleep vs. wakefulness promotes improved learning and spatial memory in mice. For the first time, we present the technology for PBM under electroencephalographic (EEG) control that incorporates modern state of the art facilities of optoelectronics and biopotential detection and that can be built of relatively cheap and commercially available components. These findings open a new niche in the development of smart technologies for phototherapy of brain diseases during sleep.

Machine Learning Technology for EEG-Forecast of the Blood-Brain Barrier Leakage and the Activation of the Brain's Drainage System during Isoflurane Anesthesia.

Anesthesia enables the painless performance of complex surgical procedures. However, the effects of anesthesia on the brain may not be limited only by its duration. Also, anesthetic agents may cause long-lasting changes in the brain. There is growing evidence that anesthesia can disrupt the integrity of the blood-brain barrier (BBB), leading to neuroinflammation and neurotoxicity. However, there are no widely used methods for real-time BBB monitoring during surgery. The development of technologies for an express diagnosis of the opening of the BBB (OBBB) is a challenge for reducing post-surgical/anesthesia consequences. In this study on male rats, we demonstrate a successful application of machine learning technology, such as artificial neural networks (ANNs), to recognize the OBBB induced by isoflurane, which is widely used in surgery. The ANNs were trained on our previously presented data obtained on the sound-induced OBBB with an 85% testing accuracy. Using an optical and nonlinear analysis of the OBBB, we found that 1% isoflurane does not induce any changes in the BBB, while 4% isoflurane caused significant BBB leakage in all tested rats. Both 1% and 4% isoflurane stimulate the brain's drainage system (BDS) in a dose-related manner. We show that ANNs can recognize the OBBB induced by 4% isoflurane in 57% of rats and BDS activation induced by 1% isoflurane in 81% of rats. These results open new perspectives for the development of clinically significant bedside technologies for EEG-monitoring of OBBB and BDS.

Mechanisms of Photostimulation of Brain's Waste Disposal System: The Role of Singlet Oxygen.

There is strong evidence that augmentation of the brain's waste disposal system via stimulation of the meningeal lymphatics might be a promising therapeutic target for preventing neurological diseases. In our previous studies, we demonstrated activation of the brain's waste disposal system using transcranial photostimulation (PS) with a laser 1267 nm, which stimulates the direct generation of singlet oxygen in the brain tissues. Here we investigate the mechanisms underlying this phenomenon. Our results clearly demonstrate that PS-mediated stimulation of the brain's waste disposal system is accompanied by activation of lymphatic contractility associated with subsequent intracellular production of the reactive oxygen species and the nitric oxide underlying lymphatic relaxation. Thus, PS stimulates the brain's waste disposal system by influencing the mechanisms of regulation of lymphatic pumping.

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma.

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level laser treatment (LLLT, 1268 nm) in the mouse cortex. LLLT-BBBO is accompanied by activation of the brain drainage system contributing effective delivery of liposomes into glioblastoma (GBM). The LLLT induces the generation of singlet oxygen without photosensitizers (PSs) in the blood endothelial cells and astrocytes, which can be a trigger mechanism of BBBO. LLLT-BBBO causes activation of the ABC-transport system with a temporal decrease in the expression of tight junction proteins. The BBB recovery is accompanied by activation of neuronal metabolic activity and stabilization of the BBB permeability. LLLT-BBBO can be used as a new opportunity of interstitial PS-free photodynamic therapy (PDT) for modulation of brain tumor immunity and improvement of immuno-therapy for GBM in infants in whom PDT with PSs, radio- and chemotherapy are strongly limited, as well as in adults with a high allergic reaction to PSs.

Photomodulation of Lymphatic Delivery of Bevacizumab to the Brain: The Role of Singlet Oxygen.

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. Therefore, the development of safe methods for an effective delivery of medications to the brain can be a revolutionary step in overcoming this limitation. Using a quantum-dot-based 1267 nm laser (photosensitiser-free generation of singlet oxygen), we clearly show the photostimulation of lymphatic delivery of bevacizumab (BMZ) to the brain tissues and the meninges. These pilot findings open promising perspectives for photomodulation of a lymphatic brain drug delivery bypassing the BBB, and potentially enabling a breakthrough strategy in therapy of glioma using BMZ and other chemotherapy drugs.

Music improves the therapeutic effects of bevacizumab in rats with glioblastoma: Modulation of drug distribution to the brain.

Background: The development of new methods for modulation of drug distribution across to the brain is a crucial step in the effective therapies for glioblastoma (GBM). In our previous work, we discovered the phenomenon of music-induced opening of the blood-brain barrier (OBBB) in healthy rodents. In this pilot study on rats, we clearly demonstrate that music-induced BBB opening improves the therapeutic effects of bevacizumab (BZM) in rats with GBM via increasing BZM distribution to the brain along the cerebral vessels. Methods: The experiments were performed on Wistar male rats (200-250 g, n=161) using transfected C6-TagRFP cell line and the loud rock music for OBBB. The OBBB was assessed by spectrofluorometric assay of Evans Blue (EB) extravasation and confocal imaging of fluorescent BZM (fBZM) delivery into the brain. Additionally, distribution of fBZM and Omniscan in the brain was studied using fluorescent and magnetic resonance imaging (MRI), respectively. To analyze the therapeutic effects of BZM on the GBM growth in rats without and with OBBB, the GBM volume (MRI scans), as well as immunohistochemistry assay of proliferation (Ki67 marker) and apoptosis (Bax marker) in the GBM cells were studied. The Mann-Whitney-Wilcoxon test was used for all analysis, the significance level was p < 0.05, n=7 in each group. Results: Our finding clearly demonstrates that music-induced OBBB increases the delivery of EB into the brain tissues and the extravasation of BZM into the brain around the cerebral vessels of rats with GBM. Music significantly increases distribution of tracers (fBZM and Omniscan) in the rat brain through the pathways of brain drainage system (perivascular and lymphatic), which are an important route of drug delivery into the brain. The music-induced OBBB improves the suppressive effects of BZM on the GBM volume and the cellular mechanisms of tumor progression that was accompanied by higher survival among rats in the GBM+BZM+Music group vs. other groups. Conclusion: We hypothesized that music improves the therapeutic effects of BZM via OBBB in the normal cerebral vessels and lymphatic drainage of the brain tissues. This contributes better distribution of BZM in the brain fluids and among the normal cerebral vessels, which are used by GBM for invasion and co-opt existing vessels as a satellite tumor form. These results open the new perspectives for an improvement of therapeutic effects of BZM via the music-induced OBBB for BZM in the normal cerebral vessels, which are used by GBM for migration and progression.

Lung ultrasound findings in asymptomatic healthy children with asthma.

BACKGROUND: Lung ultrasound (LUS) has been shown to be an effective tool to rapidly diagnose certain causes of pediatric respiratory distress. However, very little is known about LUS findings in pediatric asthma. OBJECTIVES: The primary objective of this study was to characterize LUS findings in a cohort of pediatric patients with a definitive diagnosis of asthma, outside of an asthma exacerbation. METHODS: Eligible patients, aged 6-17 years old and diagnosed with asthma, underwent LUS during an outpatient visit. LUS was conducted using a six-zone scanning protocol. Presence of a LUS artifact was defined by one or more of the following: ≥3 B-lines per intercostal space, pulmonary consolidation, and/or pleural abnormality. Images were interpreted by an expert sonographer blinded to patient clinical characteristics. RESULTS: Fifty-two patients were included. 10/52 (19.2%) patients demonstrated the presence of LUS artifacts: 8 with ≥3 B-lines, 1 with consolidation >1 cm, and 7 with subpleural consolidations <1 cm, 1 with a pleural line abnormality. Artifacts were seen in the right anterior and lateral zones in 60% of participants and were limited to 1-2 intercostal space(s) within one lung zone in all participants. No association was found between presence of LUS artifacts and asthma control or severity. CONCLUSION: To our knowledge, this is the first report of LUS findings in outpatient pediatric asthma. LUS artifacts in asthmatic children can be seen outside of acute exacerbations. Such baseline findings need to be taken into consideration when using LUS for the acute evaluation of a pediatric patient with asthma.

GB20 Pharmacopuncture As a Potential Method for Brain Drug Delivery via the Perivascular Spaces.

Background: The development of new methods of drug brain delivery is a crucial step for the effective therapy of the brain diseases. Pharma- and acupuncture are the forms of alternative therapy of the brain pathology, including an increase in the permeability of blood-brain barrier. However, the mechanisms of pharma- and acupuncture-mediated effects on the brain physiology remain not fully understood. Results: This pilot study on healthy mice clearly demonstrates the Evans Blue spreading in the mouse head and in the brain via the perivascular spaces (PVSs) of the trigeminal structure and the cribriform plate after the dye injection into the Feng Chi point (Galbladder 20, GB20). Conclusion: These results suggest that pharmacopuncture at GB20 can be a perspective method for brain drug delivery via PVSs.

Paediatric post-concussive symptoms: symptom clusters and clinical phenotypes.

OBJECTIVE: To assess the co-occurrence and clustering of post-concussive symptoms in children, and to identify distinct patient phenotypes based on symptom type and severity. METHODS: We performed a secondary analysis of the prospective, multicentre Predicting and Preventing Post-concussive Problems in Pediatrics (5P) cohort study, evaluating children 5-17 years of age presenting within 48 hours of an acute concussion. Our primary outcome was the simultaneous occurrence of two or more persistent post-concussive symptoms on the Post-Concussion Symptom Inventory at 28 days post-injury. Analyses of symptom and patient clusters were performed using hierarchical cluster analyses of symptom severity ratings. RESULTS: 3063 patients from the parent 5P study were included. Median age was 12.1 years (IQR: 9.2-14.6 years), and 1857 (60.6%) were male. Fatigue was the most common persistent symptom (21.7%), with headache the most commonly reported co-occurring symptom among patients with fatigue (55%; 363/662). Headache was common in children reporting any of the 12 other symptoms (range: 54%-72%). Physical symptoms occurred in two distinct clusters: vestibular-ocular and headache. Emotional and cognitive symptoms occurred together more frequently and with higher severity than physical symptoms. Fatigue was more strongly associated with cognitive and emotional symptoms than physical symptoms. We identified five patient groups (resolved/minimal, mild, moderate, severe and profound) based on symptom type and severity. CONCLUSION: Post-concussive symptoms in children occur in distinct clusters, facilitating the identification of distinct patient phenotypes based on symptom type and severity. Care of children post-concussion must be comprehensive, with systems designed to identify and treat distinct post-concussion phenotypes.

Characterizing pediatric lung ultrasound findings during a chemically induced bronchospasm.

BACKGROUND: Lung ultrasound (LUS) has been shown to be a useful clinical tool in pediatrics, but very little is known about the LUS findings of asthma in children. OBJECTIVES: The primary objective was to characterize LUS findings of pediatric patients before and after a chemically induced bronchospasm. The secondary objective was to evaluate the effect of bronchodilators on LUS findings. METHODS: Eligible children 6-17 years old presenting for a methacholine challenge test (MCT) in a pediatric respiratory clinic were recruited. Patients with viral symptoms were excluded. A six-zone LUS protocol was performed before and after the MCT, and after bronchodilator administration; video recordings were analysed by an expert blinded to the patient characteristics and MCT results. RESULTS: Forty-four patients were included in the study. Five patients had positive LUS findings at baseline. Nine patients out of 29 (31%) had new-onset positive LUS following a reactive MCT. There was a significant association between having a chemically induced bronchospasm and a positive LUS post-MCT (odds ratio [95% confidence interval]: 5.3 [1.0-27.7]; p = 0.05). Among patients who developed positive LUS findings post-MCT, four out of nine returned to having a negative LUS postbronchodilator administration. CONCLUSIONS: This is the first known report of an association between LUS findings and bronchospasm in pediatric patients. It is also the first documentation of resolution of LUS findings postbronchodilator administration. Most LUS findings observed were small and limited to a few intercostal spaces. Further research is required to quantify these findings and evaluate the effect of salbutamol on LUS.

Management of Pediatric Post-Concussion Headaches: National Survey of Abortive Therapies Used in the Emergency Department.

Children frequently present to an Emergency Department (ED) after concussion, and headache is the most commonly associated symptom. Recent guidelines emphasize the importance of analgesia for post-concussion headache (PCH), yet evidence to inform treatment is lacking. We sought to characterize abortive therapies used to manage refractory PCH in the pediatric ED and factors associated with treatment. A scenario-based survey was distributed to ED physicians at all 15 Canadian tertiary pediatric centers. Participants were asked questions regarding ED treatment of acute (48 h) and persistent (1 month) PCH refractory to appropriate doses of acetaminophen/ibuprofen. Logistic regression was used to assess factors associated with treatment. Response rate was 63% (137/219). Nearly all physicians (128/137, 93%) endorsed treatment in the ED for acute PCH of severe intensity, with most selecting intravenous treatments (116/137, 84.7%). Treatments were similar for acute and persistent PCH. The most common treatments were metoclopramide (72%), physiologic saline (47%), and nonsteroidal anti-inflammatory agents (NSAIDS; 35%). Second-line ED treatments were more variable. For acute PCH of moderate intensity, overall treatment was lower (102/137, 74%; p < 0.0001), and NSAIDS (48%) were most frequently selected. In multi-variable regression analyses, no physician- or ED-level factor was associated with receiving treatment, or treatment using metoclopramide specifically. Treatment for refractory PCH in the pediatric ED is highly variable. Importantly, patients with severe PCH are most likely to receive intravenous therapies, often with metoclopramide, despite a paucity of evidence supporting these choices. Further research is urgently needed to establish the comparative effectiveness of pharmacotherapeutic treatments for children with refractory PCH.

Intranasal Delivery of Liposomes to Glioblastoma by Photostimulation of the Lymphatic System.

The blood-brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice.

Patient-Reported Experience in the Pediatric Emergency Department: What Matters Most?

INTRODUCTION: Although the Child Hospital Consumer Assessment of Healthcare Providers and Systems is a validated tool for the inpatient experience, it may not address features unique to the pediatric emergency department (PED). There is currently no publicly available validated patient-reported experience survey for the PED, and what matters most in this setting remains unknown. METHODS: Twelve semistructured interviews were conducted with a convenience sample of parents of children younger than 14 years at a Canadian PED. Data analysis was performed using inductive thematic analysis to identify aspects of patient-reported experiences that matter most to parents in the PED. RESULTS: Five themes were identified: (1) making waiting a positive experience, (2) taking the time to provide care, (3) forging a positive partnership, (4) speak up for safe care, and (5) making the environment feel safer. Parents highlighted that while waiting for care is not desirable, it is made more acceptable through the communication of wait time estimates and the presence of child activities in the waiting room. Furthermore, although interactions with providers are brief, parents emphasized the importance of creating an environment of partnership with open communication, taking the time to examine their child, and actively demonstrating the provision of safe, quality care. CONCLUSIONS: Results from this study suggest that a patient-reported experience survey in the PED may need to embed elements not currently captured in Child Hospital Consumer Assessment of Healthcare Providers and Systems, such as waiting room experience, comprehensiveness of health assessments, and observations of safety measures. Future studies can use these findings to develop a patient-reported experience survey for use in the PED.

Symptom Burden, School Function, and Physical Activity One Year Following Pediatric Concussion.

OBJECTIVES: To characterize symptom burden, school function, and physical activity in youth 1 year following acute concussion and those with subsequent repeat concussion. STUDY DESIGN: Secondary analysis of Predicting Persistent Postconcussive Problems in Pediatrics prospective, multicenter cohort study conducted in 9 Canadian emergency departments. Participants were children between ages 5 and 18 years who presented consecutively ≤48 hours of concussion and agreed to participate in a post hoc electronic survey 1 year after injury. Outcomes were assessed using a standardized 25-question symptom scale derived from the Post-Concussion Symptom Inventory-Parent; school function and physical activity outcomes were queried. The primary outcome was total symptom score 1 year following concussion, defined as the number of symptoms experienced more than before injury. RESULTS: Of 3052 youth enrolled in the Predicting Persistent Postconcussive Problems in Pediatrics study, 432 (median [IQR] age, 11.5 [9,14] years; 266 [62%] male) completed the 1-year survey; 34 respondents reported a repeat concussion. Following acute concussion, youth were more likely to be symptom-free than following repeat concussion (75% vs 50%; difference = 25% [95% CI 8-41]; P = .002) and to have recovered fully (90% vs 74%; difference = 17% [95% CI 5-34]; P = .002) after 1 year. Although physical symptoms were less 1 year after initial emergency department presentation for both groups (P < .001), youth with a repeat concussion reported greater headache persistence (26% vs 13%; difference = 13% [95% CI 1,31]; P = .024). Both groups returned to their normal school routine (100% vs 95%; difference = 5% [95% CI -5 to 8; P = .618). Youth without repeat concussion more frequently returned to normal physical activities (98% vs 85%; difference = 13% [95% CI 4-28]; P < .0001) and sport (95% vs 82%; difference = 13% [95% CI 3-29]; P = .009). CONCLUSIONS: Most youth are symptom-free and fully recovered 1 year following concussion. Some children with repeat concussion have worse outcomes and have delays in returning to normal school routines and sport.

Feasibility of Early Active Rehabilitation for Concussion Recovery in Youth: A Randomized Trial.

OBJECTIVE: The primary objective is to evaluate the feasibility (safety and acceptability) of implementing early active rehabilitation (AR) for concussion management in youth with symptoms persisting 2 weeks after injury. A secondary and exploratory objective was to estimate the potential efficacy of early AR compared with standard AR. We hypothesize that AR at 2-weeks postconcussion will be safe and acceptable to patients. DESIGN: Randomized clinical trial. SETTING: The Montreal Children's Hospital of the McGill University Health Center (MCH-MUHC), a tertiary care pediatric teaching hospital affiliated with McGill University in Montreal, Canada. PARTICIPANTS: Twenty youth aged 9 to 17 years old with postconcussion symptoms for at least 2 weeks. INTERVENTION: Active rehabilitation (aerobic exercise, coordination drills, visualization, and education/reassurance) was administered by physiotherapists in-person, and then continued as a home program. METHODS: Twenty participants were randomized to either early AR (initiated 2 weeks after injury) or standard AR (initiated 4 weeks after injury). RESULTS: Two adverse events (one in each group) were identified through an online survey more than one-month postconcussion. Postconcussion symptoms decreased over time for both groups. CONCLUSIONS: The results from this pilot study indicate that a full clinical trial estimating the efficacy of early AR (starting 2 weeks after injury) is feasible. Further study is needed to determine the superiority of this strategy over current treatment approaches.

Adapting two American Decision Aids for Mild Traumatic Brain Injury to the Canadian Context Using the Nominal Group Technique.

BACKGROUND: Decision aids are patient-focused tools that have the potential to reduce the overuse of head computed tomography (CT) scans. OBJECTIVE: The objective of this study was to create a consensus among Canadian mild traumatic brain injury and emergency medicine experts on modifications required to adapt two American decision aids about head CT use for adult and paediatric mild traumatic brain injury to the Canadian context. METHODS: We invited 21 Canadian stakeholders and the two authors of the American decision aids to a Nominal Group Technique consensus meeting to generate suggestions for adapting the decision aids. This method encourages idea generation and sharing between team members. Each idea was discussed and then prioritised using a voting system. We collected data using videotaping, writing material and online collaborative writing tools. The modifications proposed were analysed using a qualitative thematic content analysis. RESULTS: Twenty-one participants took part in the meeting, including researchers and clinician researchers (n = 9; 43%), patient partners (n = 3; 14%) and decision makers (n = 2; 10%). A total of 84 ideas were generated. Participants highlighted the need to clarify the purpose of the decision aids, the nature of the problem being addressed and the target population. The tools require sociocultural adaptations, better identification of their target population, better description of head CT utility, advantages and related risks, modification of the visual and written representation of the risk of brain injury and head CT use, and locally adapted, patient follow-up plans. CONCLUSIONS: This study based on a Nominal Group Technique identified several adaptations for two American decision aids about head CT use for mild traumatic brain injury to support their use in Canada's different healthcare, social, cultural and legal context. These adaptations concerned the target users of the decision aids, the information presented, and how the benefits and risks were communicated in the decision aids. Future steps include prototyping the two adapted decision aids, conducting formative evaluations with actual emergency department patients and clinicians, and measuring the impact of the adapted tools on CT scan use.

A mild traumatic brain injury (also called concussion) can happen when the brain moves around in the skull after an impact to the head. A concussion is not a brain bleed and you cannot see a concussion. Concussions do not show up on a computed tomography (CT) scan. Brain bleeds do. Computed tomography scans are specialised X-ray machines that can detect serious brain injuries. Unfortunately, CT scan use also exposes patients to radiation and a future increased risk of cancer.Shared decision making involves health professionals and patients making decisions together based on the best available evidence, health professionals' experience, and patients' values and preferences. Shared decision making improves appropriate diagnostic test use.Two decision aids created in the USA are available to facilitate shared decision making regarding the use of head CT scans for patients with concussion. These decision aids are not fully adapted for use in Canada because the healthcare, social and legal context is different. Our study brought together patients and experts in the field of concussion and shared decision making to analyse these decision aids and propose adaptations that would increase their acceptance in Canadian emergency departments. We used a technique called the Nominal Group Technique to create a consensus about the most important changes to make to both original decision aids. The main adaptations needed for the Canadian context concerned avoiding information about cost and removing any information that does not change clinical management. This project will help us adapt two decision aids for clinical use in Canada and support appropriate CT scan use for patients with concussion.

Photobiomodulation of lymphatic drainage and clearance: perspective strategy for augmentation of meningeal lymphatic functions.

There is a hypothesis that augmentation of the drainage and clearing function of the meningeal lymphatic vessels (MLVs) might be a promising therapeutic target for preventing neurological diseases. Here we investigate mechanisms of photobiomodulation (PBM, 1267 nm) of lymphatic drainage and clearance. Our results obtained at optical coherence tomography (OCT) give strong evidence that low PBM doses (5 and 10 J/cm2) stimulate drainage function of the lymphatic vessels via vasodilation (OCT data on the mesenteric lymphatics) and stimulation of lymphatic clearance (OCT data on clearance of gold nanorods from the brain) that was supported by confocal imaging of clearance of FITC-dextran from the cortex via MLVs. We assume that PBM-mediated relaxation of the lymphatic vessels can be possible mechanisms underlying increasing the permeability of the lymphatic endothelium that allows molecules transported by the lymphatic vessels and explain PBM stimulation of lymphatic drainage and clearance. These findings open new strategies for the stimulation of MLVs functions and non-pharmacological therapy of brain diseases.

Early versus delayed emergency department presentation following mild Traumatic Brain Injury and the presence of symptom at 1, 4 and 12 weeks in children.

OBJECTIVES: We evaluated the association between timing of presentation and postconcussive symptoms (PCS) at 1, 4 and 12 weeks after injury. METHODS: This was a secondary analysis of a prospective cohort study conducted in nine Canadian paediatric EDs in 2013-2015 (5P study). Participants were children who suffered a head injury within the preceding 48 hours and met Zurich consensus concussion diagnostic criteria. The exposure was the time between head injury and ED presentation. The primary outcome was the presence of PCS at 1 week defined by the presence of at least three symptoms on the Post-Concussion Symptom Inventory (PCSI). Secondary outcomes evaluated PCS at 4 and 12 weeks. Multivariable logistic regression analyses were adjusted for ED PCSI and other potential confounders. RESULTS: There were 3041 patients with a concussion in which timing of the injury was known. 2287 (75%) participants sought care in the first 12 hours, 388 (13%) 12-24 hours after trauma and 366 (12%) between 24 and 48 hours. Compared with children who sought care >24 hours after trauma, children who sought care in the first 12 hours had a significantly lower incidence of PCS at 1 week (OR: 0.55 (95% CI 0.41 to 0.75)) and 4 weeks (OR: 0.74 (95% CI 0.56 to 0.99)) but not at 12 weeks (OR: 0.88 (95% CI 0.63 to 1.23)). CONCLUSIONS: Patients who present early after a concussion appear to have a shorter duration of PCS than those presenting more than 12 hours later. Patients/families should be informed of the higher probability of PCS in children with delayed presentation.

Pilot study of transcranial photobiomodulation of lymphatic clearance of beta-amyloid from the mouse brain: breakthrough strategies for non-pharmacologic therapy of Alzheimer's disease.

In this pilot study, we analyzed effects of transcranial photobiomodulation (tPBM, 1267 nm, 32 J/cm2) on clearance of beta-amyloid (Aß) from the mouse brain. The immunohistochemical and confocal data clearly demonstrate the significant reduction of deposition of Aß plaques in mice after tPBM vs. untreated animals. The behavior tests showed that tPBM improved the cognitive, memory and neurological status of mice with Alzheimer's disease (AD). Using of our original method based on optical coherence tomography (OCT) analysis of clearance of gold nanorods (GNRs) from the brain, we proposed possible mechanism underlying tPBM-stimulating effects on clearance of Aß via the lymphatic system of the brain and the neck. These results open breakthrough strategies for a non-pharmacological therapy of Alzheimer's disease and clearly demonstrate that tPBM might be a promising therapeutic target for preventing or delaying Alzheimer's disease.