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Background Disruption of cerebrospinal fluid (CSF)/interstitial fluid (ISF) exchange in the spinal cord is likely to contribute to central nervous system (CNS) diseases that involve abnormal fluid accumulation, including spinal cord oedema and syringomyelia. However, the physiological factors that govern fluid transport in the spinal cord are poorly understood. The aims of this study were to determine the effects of cardiac pulsations and respiration on tracer signal increase, indicative of molecular movement following infusion into the spinal cord grey or white matter. Methods In Sprague Dawley rats, physiological parameters were manipulated such that the effects of spontaneous breathing (generating alternating positive and negative intrathoracic pressures), mechanical ventilation (positive intrathoracic pressure only), tachycardia (heart atrial pacing), as well as hypertension (pharmacologically induced) were separately studied. Since fluid outflow from the spinal cord cannot be directly measured, we assessed the molecular movement of fluorescent ovalbumin (AFO-647), visualised by an increase in tracer signal, following injection into the cervicothoracic spinal grey or white matter. Results Tachycardia and hypertension increased AFO-647 tracer efflux, while the concomitant negative and positive intrathoracic pressures generated during spontaneous breathing did not when compared to the positive-pressure ventilated controls. Following AFO-647 tracer injection into the spinal grey matter, increasing blood pressure and heart rate resulted in increased tracer movement away from the injection site compared to the hypotensive, bradycardic animals (hypertension: p = 0.05, tachycardia: p Conclusions Arterial pulsations have profound effects on spinal cord interstitial fluid homeostasis, generating greater tracer efflux than intrathoracic pressure changes that occur over the respiratory cycle, demonstrated by increased craniocaudal CSF tracer movement in the spinal cord parenchyma.

STUDY OBJECTIVES: Oral appliance (OA) therapy usage can be objectively measured through temperature-sensing data chips embedded in the appliance. Initial reports of group data for short-term treatment usage suggest good nightly hours of usage. However, individual variability in treatment usage patterns has not been assessed. We aimed to identify OA treatment usage subtypes in the first 60 days and the earliest predictors of these usage patterns. METHODS: OSA patients were recruited for a study of OA therapy with an embedded compliance chip (DentiTrac, Braebon, Canada). Fifty-eight participants with 60 days of downloadable treatment usage data (5-minute readings) were analyzed. A hierarchical cluster analysis was used to group participants with similar usage patterns. A random forest classification model was used to identify the minimum number of days to predict usage subtype. RESULTS: Three user groups were identified and named: “Consistent Users” (48.3%), “Inconsistent Users,” (32.8%) and “Non-Users” (19.0%). The first 20 days provided optimal data to predict the treatment usage group a patient would belong to at 60 days (90% accuracy). The strongest predictors of user group were downloaded usage data, average wear time, and number of days missed. CONCLUSIONS: Granular analysis of OA usage data suggests the existence of treatment user subtypes (Consistent, Inconsistent, and Non-Users). Our data suggest that 60-day usage patterns can be identified in the first 20 days of treatment using downloaded treatment usage data. Understanding initial treatment usage patterns provide an opportunity for early intervention to improve long-term usage and outcomes. CITATION: Sutherland K, Almeida FR, Kim T, et al. Treatment usage patterns of oral appliances for obstructive sleep apnea over the first 60 days: a cluster analysis. J Clin Sleep Med. 2021;17(9):1785–1792.

Circulation of fluid through the central nervous system maintains fluid homeostasis and is involved in solute clearance. The glymphatic system is hypothesised to facilitate waste clearance in the brain, with inflow via periarterial spaces, bulk flow through the parenchyma, and outflow via perivenous spaces. The driving force for this mechanism is unknown. Previous modelling in the spinal cord suggests that timing offsets between arterial and subarachnoid space pressure pulses can enable net inflow in perivascular spaces (PVS). This study adapted the spinal pulse offset mechanism to the brain and simulated movement of tracer particles used in experiments. Both bulk flow and diffusive movement of tracer were simulated. Intracranial pressure pulses were applied to one end of a 300-μm-long perivascular space combined with a moving arterial wall simulating arterial pulsations. The simulations indicate the pulse offset mechanism can enable net inflow via PVS; however, it is unknown whether the temporal offset required is physiologically realistic. Increasing the positive component of the ICP (intracranial pressure) pulse increased net flow. Tracer particles driven by bulk flow reached the outlet of the PVS with a net speed of ~ 16 μm/s when the permeability was two orders of magnitude higher than values in the literature. These particles were unable to penetrate into the parenchyma in the absence of diffusion. Dispersion dominated tracer movement in the parenchyma. Further research is required to reconcile discrepancies between these results, and both experimental and computational studies.

Tongue and upper airway dilator muscle movement patterns during quiet breathing vary in people with obstructive sleep apnea (OSA). Many patients have inadequate or counterproductive responses to inspiratory negative airway pressure that likely contributes to their OSA. This may be due, at least in part, to inadequate or nonhomogeneous reflex drive to different regions of the largest upper airway dilator, genioglossus. To investigate potential regional heterogeneity of genioglossus reflex responses in OSA, brief suction pulses were applied via a nasal breathing mask and an electromyogram (EMG) was recorded in four regions (anterior oblique, anterior horizontal, posterior oblique, and posterior horizontal) using intramuscular fine wire electrodes in 15 people with OSA. Genioglossus short-latency reflex excitation amplitude had regional heterogeneity (horizontal vs. oblique regions) when expressed in absolute units but homogeneity when normalized as a percentage of the immediate (100 ms) prestimulus EMG. Regional variability in reflex morphology (excitation and inhibition) was present in one-third of the participants. The minimum cross-sectional area (CSA) of the pharyngeal airway was quantified using MRI and may be related to the amplitude of the short-latency reflex response to negative pressure as we found that people with a smaller CSA tended to have a greater reflex amplitude (e.g., horizontal region

It is often assumed that a child restraint with a five or six-point internal harness provides greater protection for children in frontal crashes than a booster seat with a lap-sash seat belt. However, most research comparing these restraint types has focused on protection for children aged up to approximately 3–4 years of age. Recently, harnessed child restraints for older children up to approximately 8 years of age have become available, but there is little data on their performance compared to booster seats for children over 4 years of age. This study aimed to compare frontal crash performance of a series of harnessed child restraints for children aged 4–8 years to booster seats. Four large harnessed child restraints (Type G in the Australian Standard, AS/NZS 1754:2013) and six high back booster seats (Type E in AS/NZS 1754:2013) were tested in frontal impact on a deceleration sled. Head and pelvis accelerations were recorded and head excursions were measured from high speed video. Head excursion was an average of 92 mm greater in the large harnessed child restraints than the high back booster seats. The initial position of the head in Type G restraints, an average of 58 mm further forward compared to Type E boosters, was the main contributor to the larger head excursion during impact. Conversely, peak head accelerations in the impact phase were, on average, 37.2 g lower in the large harnessed child restraints than the high back booster seats. These data suggest that recommendations for harnessed restraints and booster seats for children aged 4–8 years is not as obvious as is sometimes assumed. Harnessed restraints allow greater head excursion in frontal impacts, potentially increasing the chances of head impacts, especially in vehicles with limited clearance between the restraint and the seat in front. The likelihood, and types of, incorrect use that occur in each restraint type, the vehicle occupant space, and the restraint’s crash performance under ideal conditions should be considered in recommending restraints for these older children.

KEY POINTS Respiration plays a key role in the circulation of cerebrospinal fluid (CSF) around the central nervous system. During inspiration increased venous return from the cranium is believed to draw CSF rostrally. However, this mechanism does not explain why CSF has also been observed to move caudally during inspiration. We show that during inspiration decreased intrathoracic pressure draws venous blood from the cranium and lumbar spine towards the thorax. We also show that the abdominal pressure was associated with rostral CSF displacement. However, a caudal shift of cervical CSF was seen with low abdominal pressure and comparably negative intrathoracic pressures. These results suggest that the effects of epidural blood flow within the spinal canal need to be considered, as well as the cranial blood volume balance, to understand respiratory-related CSF flow. These results may prove useful for the treatment of CSF obstructive pathology and understanding the behaviour of intrathecal drug injections. ABSTRACT It is accepted that during inspiration, cerebrospinal fluid (CSF) flows rostrally to compensate for decreased cranial blood volume, caused by venous drainage due to negative intrathoracic pressure. However, this mechanism does not explain observations of caudal CSF displacement during inspiration. Determining the drivers of respiratory CSF flow is crucial for understanding the pathophysiology of CSF flow disorders. To quantify the influence of respiration on CSF flow, real-time phase-contrast magnetic resonance imaging (MRI) was used to record CSF and blood flow, while healthy subjects (5:5 M:F, 25-50 years) performed either a brief expiratory or inspiratory effort between breaths. Transverse images were taken perpendicular to the spinal canal in the middle of the C3 and L2 vertebrae. The same manoeuvres were then performed after a nasogastric pressure catheter was used to measure the intrathoracic and abdominal pressures. During expiratory-type manoeuvres that elevated abdominal and intrathoracic pressures, epidural blood flow into the spinal canal increased and CSF was displaced rostrally. With inspiratory manoeuvres, the negative intrathoracic pressure drew venous blood from C3 and L2 towards the thoracic spinal canal, and cervical CSF was displaced both rostrally and caudally, despite the increased venous drainage. Regression analysis showed that rostral displacement of CSF at both C3 (adjusted R2 = 0.53; P

Study Objectives To characterize how mandibular advancement enlarges the upper airway via posterior tongue advancement in people with obstructive sleep apnea (OSA) and whether this is associated with mandibular advancement splint (MAS) treatment outcome. Methods One-hundred and one untreated people with OSA underwent a 3T magnetic resonance (MRI) scan. Dynamic mid-sagittal posterior tongue and mandible movements during passive jaw advancement were measured with tagged MRI. Upper airway cross-sectional areas were measured with the mandible in a neutral position and advanced to 70% of maximum advancement. Treatment outcome was determined after a minimum of 9 weeks of therapy. Results Seventy-one participants completed the study: 33 were responders (AHI50% AHI reduction), 11 were partial responders (>50% AHI reduction but AHI>10 events/hr), and 27 nonresponders (AHI reduction 4 mm). In comparison, a model using only baseline AHI correctly classified 50.0% of patients (5-fold cross-validated 52.5%, n = 40). Conclusions Tongue advancement and upper airway enlargement with mandibular advancement in conjunction with baseline AHI improve treatment response categorization to a satisfactory level (69.2%, 5-fold cross-validated 62.5%).

To compare how errors in child restraint use influence crash injury risk in rearward and forward-facing restraints for a 1-year old occupant. Three convertible child restraint systems (CRS) were subjected to frontal dynamic sled tests at 56 km/h in rearward-facing and forward-facing modes in a correct use (baseline) condition and in five incorrect use conditions: loose securing belt, loose harness, partial harness use, top tether slack, and three minor errors. Excursion, head, and chest 3 ms resultant acceleration, HIC15, and neck forces and moments of a Q1 anthropomorphic test device (ATD) seated in the restraints were measured. The effect of incorrect use on each outcome and restraint type was analyzed. The influence of errors varied across different outcome variables, the three restraints tested and orientation modes. Excursion increased in four of five incorrect use conditions in both rearward and forward-facing orientations. A very loose harness increased four of five outcome variables in at least one forward-facing restraint, whereas only excursion was increased when rearward-facing. Overall, there tended to be a more negative effect of incorrect use (demonstrated through increases in outcome variables compared to the baseline) in the forward-facing orientation. Overall, errors in use tended to have a larger negative impact on forward-facing restraints than rearward-facing restraints. Given the widespread nature of errors in use, this adds further weight to arguments to keep children rearward-facing to 12 months of age and older. The results also highlight a variation in response to errors across differently designed restraints, suggesting the influence of errors may be minimized by restraint design that is more resistant to errors.

During swallowing, we observed two distinct, stereotyped muscle activation patterns that define the horizontal (monophasic, maximal EMG) and oblique (biphasic, submaximal EMG) neuromuscular compartments of genioglossus. In contrast, volitional tongue protrusions produced uniform activation across compartments. This provides evidence for task-dependent, functionally discrete neuromuscular control of the oblique and horizontal compartments of genioglossus. The magnitude and temporal patterning of genioglossus EMG during swallowing may help guide electrode placement in tongue EMG studies.

Ergonomic design of child restraint systems (CRS) may facilitate optimal travel behavior and crash protection of child passengers during motor vehicle trips. However there have been few studies examining the relationship between CRS design and child passenger travel behavior. The aim of this study was to examine whether associations between CRS design features and child passenger behavior exist during real-world, everyday vehicle trips. Video from a naturalistic driving study (NDS) was analyzed in this study. Families drove an instrumented study vehicle for approximately two weeks with at least one child aged between one and eight years traveling in their own forward-facing (FF) CRS or belt positioning booster (BPB). Video for one child passenger was randomly selected from each trip for analysis. Video was coded for five-second epochs at nine time points (5%, 17%, 25%, 30%, 50%, 53%, 75%, 89% and 95% of trip length). Two types of child passenger travel behaviors were identified by manual review of the video and audio recordings: (i) optimal/suboptimal head position and (ii) correct/incorrect use of the internal harness/shoulder belt. Video screenshots were used to characterize CRS design features. Random effects logistic regression models were used to examine the associations between specific CRS design features and the travel behaviors of interest, whilst accounting for clustering of data by child and trip. Suboptimal head position was associated with the absence of a height adjustable headrest and a narrow headrest wing width in FFCRS. Incorrect harness use in a FFCRS was associated with the absence of an adjustable headrest, in addition to headrest features such as wing width and depth. In BPBs, a reduction in suboptimal head position was associated with the absence of a sash belt guide, however no restraint design features were associated with incorrect shoulder belt use. Some CRS design features may influence undesirable child passenger travel behavior. These early findings support enhanced and user-centric CRS design as a likely important mechanism to improve child passenger safety.

Chiari malformation is characterised by the herniation of the cerebellar tonsils through the foramen magnum. However, tonsillar herniation and other 2D morphometric measurements of the posterior cranial fossa (PCF) have a weak association with patients' symptoms and clinical outcomes. This study aimed to contrast current 2D metrics with a novel 3D shape analysis of the PCF and the hindbrain, to determine if 3D measurements provides further insight into the pathophysiology of Chiari. The cranium of 12 controls and 21 Chiari malformation patients with (N = 9) and without (N = 12) a syrinx were scanned. The morphology of the PCF was quantified with typical 2D measurements. Additionally, a correspondence-based shape model that normalised the PCF volume, was used to find 3D differences in the shape of the PCF, and the distance of the hindbrain from the inner surfaces of the PCF. Shape analysis showed that, compared to controls, the caudal (p = 0.007; 2.3 mm, IQR: 1.6-3.3 mm) and anterior (p = 0.027; 1.3 mm,IQR: 1.1-1.6 mm) surfaces of the hindbrain were closer to the PCF in patients with and without a syrinx, respectively. However, there were negligible differences in the shape of the PCF between patient groups (p 0.39). Current morphometric measures should be normalised for variation in PCF volume, so that shape measures are not biased. The reduced CSF space between the hindbrain and PCF will alter CSF dynamics, which may compress cerebellar vasculature and contribute to patient symptomatology.

Serious cervical spine injuries have been documented from falls into foam pits at trampoline parks. To address the lack of evidence on how foam pits should be designed for mitigating neck injury risk, this study aimed to quantify neck loads during head-first entry into varying foam pit designs. An instrumented Hybrid III anthropomorphic test device was dropped head-first from a height of up to 1.5 m into three differently constructed foam pits, each using a different mechanism to prevent direct contact between the falling person and the floor (foam slab, trampoline or net bed). Measured neck loads were compared to published injury reference values. In the simplest, foam-only pit design, increasing foam depth tended to reduce peak compressive force. At least one injury assessment reference metric was exceeded in all pit conditions tested for 1.5 m falls, most commonly the time-dependent neck compression criterion. The results highlight the importance of adequate foam depth in combination with appropriate pit design in minimizing injury risk. The risk of cervical spine injury may not be reduced sufficiently with current foam pit designs.

To examine the effect of age on the dynamic performance of child restraint systems in frontal crashes.A sample of used (3-269 months from manufacture) and newly purchased child restraints were subjected to frontal crash simulations of more than 56 km/h and peak deceleration approximately 33 g on a deceleration sled. Restraints were monitored for evidence of damage before and after each impact. Anthropometric test device (ATD) head and chest responses and peak head excursions were recorded for rearward facing restraints using the Q1 ATD and for forward facing restraints and booster seats using the Q6 ATD. The influence of restraint age on peak 3 ms head acceleration, HIC15, head excursion, peak 3 ms chest acceleration and restraint damage were analyzed.In all impacts, the ATD remained within the restraint and secured to the test bench demonstrating the crash protection offered by the old and used restraints. There was no apparent relationship between ATD responses and restraint age for any restraint type. Older forward facing restraint systems had a very modest increase in forward head excursion (ROverall, degradation in restraint dynamic performance in older restraints, including some that are much older than the currently recommended 10-year lifetime, is minimal. However newer restraints may provide better protection due to marginal improvements in restraint design over time. Furthermore, the results of this study confirm previous recommendations that restraints should not be re-used after crash involvement.

Study Objectives To investigate the effect of upper airway fat composition on tongue inspiratory movement and obstructive sleep apnea (OSA). Methods Participants without or with untreated OSA underwent a 3T magnetic resonance imaging (MRI) scan. Anatomical measurements were obtained from T2-weighted images. Mid-sagittal inspiratory tongue movements were imaged using tagged MRI during wakefulness. Tissue volumes and percentages of fat were quantified using an mDIXON scan. Results Forty predominantly overweight participants with OSA were compared to 10 predominantly normal weight controls. After adjusting for age, BMI, and gender, the percentage of fat in the tongue was not different between groups (analysis of covariance [ANCOVA], p = 0.45), but apnoeic patients had a greater tongue volume (ANCOVA, p = 0.025). After adjusting for age, BMI, and gender, higher OSA severity was associated with larger whole tongue volume (r = 0.51, p < 0.001), and greater dilatory motion of the anterior horizontal tongue compartment (r = −0.33, p = 0.023), but not with upper airway fat percentage. Higher tongue fat percentage was associated with higher BMI and older age (Spearman r = 0.43, p = 0.002, and r =0.44, p = 0.001, respectively), but not with inspiratory tongue movements. Greater inspiratory tongue movement was associated with larger tongue volume (e.g. horizontal posterior compartment, r = −0.44, p = 0.002) and smaller nasopharyngeal airway (e.g. oblique compartment, r = 0.29, p = 0.040). Conclusions Larger tongue volume and a smaller nasopharynx are associated with increased inspiratory tongue dilation during wakefulness in people with and without OSA. This compensatory response was not influenced by higher tongue fat content. Whether this is also true in more obese patient populations requires further investigation.

The glymphatic system is proposed to be a unidirectional fluid and solute circulation pathway in the brain involving transport through perivascular spaces, brain interstitium and glial cells. Some aspects of the glymphatic hypothesis are controversial, particularly the outflow pathway, and little is known about the forces that govern such fluid transport at each stage. Computational and mathematical modelling approaches can be valuable for testing hypotheses and are a useful adjunct to experimental research in this field. This article presents an overview of computational modelling studies associated with glymphatic fluid transport in the brain, from fluid inflow, transparenchymal transport and outflow. A broad range of modelling approaches have been used to investigate fluid and solute transport from purely analytical models to hydraulic resistance networks and computational fluid dynamics models. Most of the modelling attention has focused on periarterial inflow and transport through the parenchyma. Collectively these studies suggest that arterial pulsation is unlikely to be the sole inflow driving force, and diffusion is most likely the dominant mode of transport in the parenchymal extracellular spaces. Models of efflux are limited and have not been able to shed light on the driving forces for fluid outflow from the central nervous system.

Tracheal displacement is thought to be the primary mechanism by which changes in lung volume influence upper airway patency. Caudal tracheal displacement during inspiration may help preserve the integrity of the upper airway in response to increasing negative airway pressure by stretching and stiffening pharyngeal tissues. However, tracheal displacement has not been previously quantified in obstructive sleep apnea (OSA). Accordingly, we aimed to measure tracheal displacements in awake individuals with and without OSA. The upper head and neck of 34 participants [apnea-hypopnea index (AHI) = 2–74 events/h] were imaged in the midsagittal plane using dynamic magnetic resonance imaging (MRI) during supine awake quiet breathing. MRI data were analyzed to identify peak tracheal displacement and its timing relative to inspiration. Epiglottic pressure was measured separately for a subset of participants ( n = 30) during similar experimental conditions. Nadir epiglottic pressure and its timing relative to inspiration were quantified. Peak tracheal displacement ranged from 1.0–9.6 mm, with a median (25th–75th percentile) of 2.3 (1.7–3.5) mm, and occurred at 89 (78–99)% of inspiratory time. Peak tracheal displacement increased with increasing OSA severity (AHI) ( R2 = 0.28, P = 0.013) and increasing negative nadir epiglottic pressure ( R2 = 0.47, P = 0.023). Relative inspiratory timing of peak tracheal displacement also correlated with OSA severity, with peak displacement occurring earlier in inspiration with increasing AHI ( R2 = 0.36, P = 0.002). Tracheal displacements during quiet breathing are larger in individuals with more severe OSA and tend to reach peak displacement earlier in the inspiratory cycle. Increased tracheal displacement may contribute to maintenance of upper airway patency during wakefulness in OSA, particularly in those with severe disease. NEW & NOTEWORTHY Tracheal displacement is thought to play an important role in stabilizing the upper airway by stretching/stiffening the pharyngeal musculature. Using dynamic magnetic resonance imaging, this study shows that caudal tracheal displacement is more pronounced during inspiration in obstructive sleep apnea (OSA) compared with healthy individuals. Softer pharyngeal muscles and greater inspiratory forces in OSA may underpin greater tracheal excursion. These findings suggest that tracheal displacement may contribute to maintenance of pharyngeal patency during wakefulness in OSA.

Objective The pathogenesis of Chiari malformation type 1 (CM-1)—associated Valsalva headache is unknown, but it may be caused by abnormal cerebellar tonsil tissue strain. Advances in cardiac-gated magnetic resonance imaging (MRI) techniques such as balanced fast-field echo (bFFE) allow quantification of the motion of anatomic structures and can be used to measure tissue strain. The current study investigated the relationship between Valsalva heachache and tonsillar motion in patients with CM-1. Methods A retrospective review of patients with CM-1 who had undergone cardiac-gated bFFE MRI was performed. Headache symptoms were retrieved from the medical records. Anatomic landmarks were manually selected on the cine bFFE, and a validated motion-tracking software was used to assess motion over the cardiac cycle in patients at rest. For each patient, displacement, strain, and strain rate were calculated for 3 anatomic segments. Patients undergoing surgery were examined before and after surgery. Results From 88 patients, a total of 108 bFFE sequences were analyzed. Valsalva headache was present in 50% of patients. Cerebellar tonsil displacement (P = 0.003), strain (P = 0.012), and maximum strain rate (P = 0.04) were reduced after surgery (n = 20). There was no statistically significant association between tissue motion and headache symptoms. Conclusion The results of this study do not support a relationship between cardiac cycle cerebellar strain and Valsalva headache in patients with CM-1. It is possible that cerebellar strain related to respiratory maneuvers is associated with headache in Chiari patients. Further investigation of tissue strain is warranted because it represents a potential biomarker for outcomes after surgery.

BackgroundIncorrect use of child restraints is a long-standing problem that increases the risk of injury in crashes. We used user-centred design to develop prototype child restraint instructional materials. The objective of this study was to evaluate these materials in terms of comprehension and errors in the use of child restraints. The relationship between comprehension and errors in use was also explored.MethodsWe used a parallel-group randomised controlled trial in a laboratory setting. The intervention group (n=22) were provided with prototype materials and the control group (n=22) with existing instructional materials for the same restraint. Participants installed the restraint in a vehicle buck, secured an appropriately sized mannequin in the restraint and underwent a comprehension test. Our primary outcome was overall correct use, and our secondary outcomes were (1) comprehension score and (2) percent errors in the installation trial.ResultsThere was 27% more overall correct use (p=0.042) and a higher mean comprehension score in the intervention group (mean 17, 95% CI 16 to 18) compared with the control group (mean 12, 95% CI 10 to 14, pConclusionsConsumer-driven design of informational materials can increase the correct use of child restraints. Targeting improved comprehension of informational materials may be an effective mechanism for reducing child restraint misuse.

Objective: Cross-chest clips are widely used in North American child restraints but are less common in other countries, partially due to concerns over anterior neck contacts in frontal crashes. The...

Cerebrospinal fluid (CSF) enters nervous tissues through perivascular spaces. Flow through these pathways is important for solute transport and to prevent fluid accumulation. Syringomyelia is commonly associated with subarachnoid space obstructions such as Chiari I malformation. However, the mechanism of development of these fluid-filled cavities is unclear. Studies have suggested that changes in the arterial and CSF pressures could alter normal perivascular flow. This study uses an idealised model of the perivascular space to investigate how variation in the arterial pulse influences fluid flow. The model used simulated subarachnoid pressures from healthy controls (N = 9), Chiari patients with (N = 7) and without (N = 8) syringomyelia. A parametric analysis was conducted to determine how features of the arterial pulse altered flow. The features of interest included: the timing and magnitude of the peak displacement, and the area under the curve in the phases of uptake and decline. A secondary aim was to determine if the previously observed differences between subject groups were sensitive to variation in the arterial pulse wave. The study demonstrated that the Chiari patients without a syrinx maintained a significantly higher level of perivascular inflow over a physiologically likely range of pulse wave shapes. The analysis also suggested that age-related changes in the arterial pulse (i.e. increased late systolic pulse amplitude and faster diastolic decay), could increase resistance to perivascular inflow affecting solute transport.

Background A lack of predictive indicators for mandibular advancement splint (MAS) efficacy limits their use in the treatment of obstructive sleep apnoea (OSA). The absence of a tendinous pterygomandibular raphe (PMR) in the lateral nasopharynx on MRI may predict MAS efficacy, however MRI is time and resource intensive. We aimed to assess the feasibility of ultrasound in determining PMR absence compared to MRI. Methods 10 healthy participants were recruited to undergo both MRI and ultrasound of the lateral airway. Surrounding anatomical landmarks were examined to establish the presence or absence of the PMR. These results will be compared to MRI to determine parameters on ultrasound which correlate to an absent PMR. Progress to date 8 of the 10 participants have undergone both MRI and ultrasound, of which half were women, mean age 53 years, mean BMI 28 and mean AHI 3. In all 8 participants so far parameters for assessment of the PMR were identified and described, including presence of anatomical landmarks, localisation and width of the PMR space, and presence of a hyperechoic structure within the space. Comparison of these parameters with MRI to determine predictors of PMR presence or absence is currently underway. Intended outcome and impact Validation of ultrasound in the assessment for presence or absence of a tendinous PMR will enable further study of this structure as a predictive marker for MAS efficacy in OSA. This could assist clinicians in identifying suitable patients for MAS therapy.

Introduction Mandibular advancement splint (MAS) treatment outcome prediction for obstructive sleep apnoea (OSA) is currently unreliable. Lower baseline AHI has been associated with better MAS response but is a poor predictor on its own. Imaging markers may enhance prediction. We investigate how the upper airway enlarges via posterior tongue advancement, using tagged MRI during mandibular advancement, as a potential predictor of MAS treatment response. Methods 101 untreated OSA participants (AHI 10–102 events/hr) underwent an MRI scan wearing a MAS. Mid-sagittal tagged MRI images were collected to quantify tongue movement during passive jaw advancement. Upper airway cross-sectional areas were measured with the mandible in a neutral position and advanced to 70% of the maximum protrusion. Treatment outcome was determined after a minimum of 9 weeks of therapy. Results 71 participants completed the study: 33 were responders (AHI50% AHI reduction), 11 were partial responders (>50% AHI reduction but AHI>10 events/hr), and 27 non-responders (AHI reduction Conclusions Tongue advancement and upper airway enlargement with mandibular advancement in conjunction with baseline AHI improves MAS treatment response categorisation to a satisfactory level.

Heparin-based hydrogels are attractive for cell encapsulation and drug delivery because of the ability of heparin to bind native proteins. However, heparin-based hydrogels have received little attention for their potential as stimuli-sensitive materials. Biosynthetic, poly(vinyl alcohol) (PVA)-heparin hydrogels were formed using dynamic, covalent cross-linking. Hydrogel stimuli-sensitivity was tailored by tuning the concentration of heparin to PVA. Relatively thermally and pH stable hydrogels were produced when formed from only the synthetic, nonionic PVA polymer cross-linked via hydrazone bonds. Cross-linking in the ionic biopolymer heparin, to form PVA-heparin gels, has a profound impact on thermal stability, with degradation ranging from over 6 months to only 4 days across 25-50 °C. PVA-heparin hydrogels degrade within 18 days at basic pH (10), while not fully degrading over 6 months at lower pH (4, 7.4). This finding is attributed to the anionic repulsion of carboxyls and sulfates in heparin. PVA-heparin macromers were cytocompatible and enabled mild cell encapsulation, in addition to providing pH-controlled growth factor release. Overall, it is demonstrated that the biopolymer heparin can be used to create pH and temperature-responsive hydrogel biomaterials for cell and drug delivery.

Elastography has become widely used clinically for characterising changes in soft tissue mechanics that are associated with altered tissue structure and composition. However, some soft tissues, such as muscle, are not isotropic as is assumed in clinical elastography implementations. This limits the ability of these methods to capture changes in anisotropic tissues associated with disease. The objective of this study was to develop and validate a novel elastography reconstruction technique suitable for estimating the linear viscoelastic mechanical properties of transversely isotropic soft tissues. We derived a divergence-free formulation of the governing equations for acoustic wave propagation through a linearly transversely isotropic viscoelastic material, and transformed this into a weak form. This was then implemented into a finite element framework, enabling the analysis of wave input data and tissue structural fibre orientations, in this case based on diffusion tensor imaging. To validate the material constants obtained with this method, numerous in silico phantom experiments were run which encompassed a range of variations in wave input directions, material properties, fibre structure and noise. The method was also tested on ex vivo muscle and in vivo human volunteer calf muscles, and compared with a previous curl-based inversion method. The new method robustly extracted the transversely isotropic shear moduli ( G ⊥ ′ , G ∥ ′ , G ″ ) from the in silico phantom tests with minimal bias, including in the presence of experimentally realistic levels of noise in either fibre orientation or wave data. This new method performed better than the previous method in the presence of noise. Anisotropy estimates from the ex vivo muscle phantom agreed well with rheological tests. In vivo experiments on human calf muscles were able to detect increases in muscle shear moduli with passive muscle stretch. This new reconstruction method can be applied to quantify tissue mechanical properties of anisotropic soft tissues, such as muscle, in health and disease.

Soft tissue mechanical characterisation is important in many areas of medical research. Examples span from surgery training, device design and testing, sudden injury and disease diagnosis. The liver is of particular interest, as it is the most commonly injured organ in frontal and side motor vehicle crashes, and also assessed for inflammation and fibrosis in chronic liver diseases. Hence, an extensive rheological characterisation of liver tissue would contribute to advancements in these areas, which are dependent upon underlying biomechanical models. The aim of this paper is to define a liver constitutive equation that is able to characterise the nonlinear viscoelastic behaviour of liver tissue under a range of deformations and frequencies. The tissue response to large amplitude oscillatory shear (1–50%) under varying preloads (1–20%) and frequencies (0.5–2 Hz) is modelled using viscoelastic-adapted forms of the Mooney–Rivlin, Ogden and exponential models. These models are fit to the data using classical or modified objective norms. The results show that all three models are suitable for capturing the initial nonlinear regime, with the latter two being capable of capturing, simultaneously, the whole deformation range tested. The work presented here provides a comprehensive analysis across several material models and norms, leading to an identifiable constitutive equation that describes the nonlinear viscoelastic behaviour of the liver.

Study Objectives To characterize how mandibular advancement splint (MAS) alters inspiratory tongue movement in people with obstructive sleep apnea (OSA) during wakefulness and whether this is associated with MAS treatment outcome. Methods A total of 87 untreated OSA participants (20 women, apnea–hypopnea index (AHI) 7–102 events/h, aged 19–76 years) underwent a 3T MRI with a MAS in situ. Mid-sagittal tagged images quantified inspiratory tongue movement with the mandible in a neutral position and advanced to 70% of the maximum. Movement was quantified with harmonic phase methods. Treatment outcome was determined after at least 9 weeks of therapy. Results A total of 72 participants completed the study: 34 were responders (AHI < 5 or AHI ≤ 10events/h with >50% reduction in AHI), 9 were partial responders (>50% reduction in AHI but AHI > 10 events/h), and 29 nonresponders (change in AHI 1 mm) were nonresponders and 71% (5/7) of those who changed to beneficial (anterior movement >1 mm) were partial or complete responders. Conclusions The mandibular advancement action on upper airway dilator muscles differs between individuals. When mandibular advancement alters inspiratory tongue movement, therapeutic response to MAS therapy was more common among those who convert to a beneficial movement pattern.

Circulation of fluid through the central nervous system maintains fluid homeostasis and is involved in solute clearance. The glymphatic system is hypothesised to facilitate waste clearance in the brain, with inflow via periarterial spaces, bulk flow through the parenchyma, and outflow via perivenous spaces. The driving force for this mechanism is unknown. Previous modelling in the spinal cord suggests that timing offsets between arterial and subarachnoid space pressure pulses can enable net inflow in perivascular spaces (PVS). This study adapted the spinal pulse offset mechanism to the brain and simulated movement of tracer particles used in experiments. Both bulk flow and diffusive movement of tracer were simulated. Intracranial pressure pulses were applied to one end of a 300-μm-long perivascular space combined with a moving arterial wall simulating arterial pulsations. The simulations indicate the pulse offset mechanism can enable net inflow via PVS; however, it is unknown whether the temporal offset required is physiologically realistic. Increasing the positive component of the ICP (intracranial pressure) pulse increased net flow. Tracer particles driven by bulk flow reached the outlet of the PVS with a net speed of ~ 16 μm/s when the permeability was two orders of magnitude higher than values in the literature. These particles were unable to penetrate into the parenchyma in the absence of diffusion. Dispersion dominated tracer movement in the parenchyma. Further research is required to reconcile discrepancies between these results, and both experimental and computational studies.

Background Syringomyelia is a serious complication of spinal cord trauma, occurring in approximately 28% of spinal cord injuries. Treatment options are limited and often produce unsatisfactory results. Post-traumatic syringomyelia (PTS) is presumably related to abnormalities of cerebrospinal fluid (CSF) and interstitial fluid hydrodynamics, but the exact mechanisms are unknown. Methods Transmission electron microscopy (TEM) was used to investigate in detail the interfaces between fluid and tissue in the spinal cords of healthy Sprague–Dawley rats (n = 3) and in a rat model of PTS (n = 3). PTS was induced by computer-controlled impact (75 kDyn) to the spinal cord between C6 and C8, followed by a subarachnoid injection of kaolin to produce focal arachnoiditis. Control animals received a laminectomy only to C6 and C7 vertebrae. Animals were sacrificed 12 weeks post-surgery, and spinal cords were prepared for TEM. Ultra-thin spinal cord sections at the level of the injury were counterstained for structural anatomy. Results Spinal cords from animals with PTS displayed several abnormalities including enlarged perivascular spaces, extracellular edema, cell death and loss of tissue integrity. Additionally, alterations to endothelial tight junctions and an abundance of pinocytotic vesicles, in tissue adjacent to syrinx, suggested perturbations to blood-spinal cord barrier (BSCB) function. Conclusions These findings support the hypothesis that perivascular spaces are important pathways for CSF flow into and out of the spinal cord, but also suggest that fluid may enter the cord through vesicular transport and an altered BSCB.

Study Objectives To investigate whether the presence of tendinous PMR could predict treatment outcome and how it affects lateral wall mechanical properties. Mandibular advancement increases the lateral dimensions of the nasopharyngeal airway via a direct connection from the airway to the ramus of the mandible. The anatomical structure in this region is the pterygomandibular raphe (PMR), but a tendinous component is not always present. Whether tendon presence influences treatment outcome is unknown. Methods In total, 105 participants with obstructive sleep apnea completed detailed anatomical magnetic resonance imaging with and without mandibular advancement. The study design was case–control. Variables were compared between participants with and without the tendon present. Results The amount of maximum mandibular advancement decreased when pterygomandibular tendon was present (4.0 ± 1.2 mm present versus 4.6 ± 1.4 mm absent, p = 0.04). PMR tendon-absent participants had a lower posttreatment apnea hypopnea index (16 ± 12 events/hour tendon present versus 9 ± 9 events/hour absent, p = 0.007) and were more likely to have complete response (63% versus 36%, p = 0.02). However, tendon-absent participants were more likely to not complete the study (χ 2 (3) = 10.578, p = 0.014). Tendon-absent participants had a greater increase in midline anteroposterior airway diameter (1.6 ± 1.7 mm versus 0.6 ± 2.3 mm, p = 0.04). Conclusion When PMR tendon is absent, treatment response and amount of maximum advancement improve, possibly at the expense of reduced splint tolerability. Tendon presence may help predict a group less likely to respond to mandibular advancement splint therapy.

Chiari Malformation is a congenital disorder of the hindbrain, in which the cerebellar tonsils protrude through the foramen magnum, impeding normal cerebrospinal fluid (CSF) flow into the spinal canal. It is associated with pain, dizziness and headaches, particularly related to coughing and straining. The mechanisms by which Chiari malformation gives rise to these symptoms are not understood. In a large proportion of patients, a fluid-filled cavity develops in the spinal cord, called a syrinx. Syrinxes can cause additional neurological deficits, including sensory changes, weakness and upper limb pain. Syrinxes are associated with disturbances to normal CSF dynamics, usually as a result of obstructions in the spinal canal, but precisely how this occurs is not known. Animal studies suggest that fluid transport into the spinal cord is increased in the presence of spinal canal obstructions, likely via annular spaces surrounding penetrating arteries (perivascular spaces). Human phase contrast magnetic resonance imaging studies can quantify both cardiac driven motion of cerebrospinal fluid flow, and, more recently, respiratory and other influences. These data can be used to generate subject-specific computational fluid dynamics models of the hindbrain and spinal canal to estimate spinal canal pressure dynamics in patients with Chiari malformation, patients with syrinxes, and healthy controls. Computational models of perivascular space flow can be linked to these macroscopic models, to enable investigation of the feasibility of hypotheses about mechanisms of syrinx formation. To date, these studies have demonstrated that several popular hypotheses about Chiari mechanisms and syrinx formation are inconsistent with the mechanics of CSF flow, and generated novel mechanistic hypotheses. Subject-specific image based modelling provide a useful adjunct to human and animal experimental research into CSF flow disorders such as Chiari malformation and syringomyelia.

Genioglossus was stimulated intramuscularly to determine the effect of regional activation of the muscle on tongue movement in eight healthy adults. Stimulation at motor threshold was delivered with a needle electrode inserted to different depths in the anterior and posterior regions of genioglossus. The current amplitude that induced muscle contraction was ∼80% higher for anterior than posterior sites. Evoked tongue movements were determined from stimulus-triggered averages (150 pulses) of the outputs from an accelerometer fixed to the posterosuperior surface of the tongue. The median amplitude [95% confidence intervals] for the resultant acceleration was 0.0 m/s2 [0.0, 0.2] for anterior and 0.6 m/s2 [0.1, 2.8] for posterior sites. There was a positive relationship between acceleration amplitude and stimulation depth in the posterior of genioglossus (p < 0.001), but acceleration amplitude did not vary with stimulation depth in the anterior region (p = 0.83). This heterogeneity in acceleration responses between muscle regions may contribute to differences in collapsibility of the upper airway.

Traffic crashes have high mortality and morbidity for young children. Though many specialized child restraint systems improve injury outcomes, no large-scale studies have investigated the cross-chest clip's role during a crash, despite concerns in some jurisdictions about the potential for neck contact injuries from the clips. This study aimed to investigate the relationship between cross-chest clip use and injury outcomes in children between 0 and 4 years of age.Child passengers between 0 and 4 years of age were selected from the NASS-CDS data sets (2003-2014). Multiple regression analysis was used to model injury outcomes while controlling for age, crash severity, crash direction, and restraint type. The primary outcomes were overall Abbreviated Injury Score (AIS) 2+ injury, and the presence of any neck injury.Across all children aged 0-4 years, correct chest clip use was associated with decreased Abbreviated Injury Scale (AIS) 2+ injury (odds ratio [OR] = 0.44, 95% confidence interval [CI], 0.21-0.91) and was not associated with neck injury. However, outcomes varied by age. In children12 months old, chest clip use was associated with decreased AIS 2+ injury (OR = 0.09, 95% CI, 0.02-0.44). Neck injury (n = 7, all AIS 1) for this age group only occurred with correct cross-chest clip use. For 1- to 4-year-old children, cross-chest clip use had no association with AIS 2+ injury, and correct use significantly decreased the odds of neck injury (OR = 0.49; 95% CI, 0.27-0.87) compared to an incorrectly used or absent cross-chest clip. No serious injuries were directly caused by the chest clips.Correct cross-chest clip use appeared to reduce injury in crashes, and there was no evidence of serious clip-induced injury in children in 5-point harness restraints.

Introduction We propose a novel sleep apnea therapy whereby a viral vector construct induces opsin expression and therefore light sensitivity to the upper airway muscles. Pulsed light to these muscles during sleep will enhance muscle contractions resulting in airway dilation and apnea prevention. Here we investigate the therapy’s feasibility, and determine whether a muscle-specific promotor induces superior expression and light-evoked EMG responses compared to a non-specific promotor. Superiority will be determined by the strength and specificity of opsin expression as restricting expression to the tongue minimises the likelihood of immune responses and unwanted sensation, movement or pain with light application. Methods 10 rats received an intramuscular injection of a viral vector construct to induce opsin expression in the tongue. 4 rats received a non-specific construct and 6 received a muscle-specific construct. Pulsed light was applied directly to the tongue, and genioglossus EMG activity was recorded. Confocal imaging of the brainstem and tongue quantified the strength and specificity of opsin expression. Results Despite the greater titer of the non-specific construct, the muscle-specific construct consistently drove stronger expression in the tongue and subsequently greater light-evoked EMG activity. Additionally, whilst the non-specific construct drove retrograde gene expression in hypoglossal motor neurons, no retrograde expression was induced by the muscle-specific construct. Conclusions This study provides proof-of-concept of a non-invasive optogenetic stimulation-based therapy for OSA. The superior expression and light induced EMG activity generated by the muscle-specific promotor indicates that it is the preferred promotor for future studies employing direct optogenetic stimulation of skeletal muscle.

Objective Misuse of child restraint systems is a widespread and long-standing problem impacting risk of injury and death in car crashes. Discomfort has been suggested as a causative factor for misuse, particularly in errors introduced by children while they use the restraints. However, the relationship between comfort and errors in use has never been studied. In this study we examine the reliability and sensitivity of a newly developed observational method for assessing comfort in children in vehicles. We then use this method to examine the relationship between comfort and errors in use of booster seats. Methods A novel method was developed for assessing comfort by counting fidgeting and postural adjustment behaviors to derive a Discomfort Avoidance Behavior (DAB) score. The sensitivity of the DAB score was examined by observing children in four different seating conditions designed as “comfortable” and “uncomfortable” (Part 1). Paired-samples t-tests were used to compare differences in DAB between seating conditions. The reliability of the DAB score was assessed by calculating the intraclass correlation coefficient (ICC) between DAB scores recorded by different researchers. The association between comfort and correctness of use was examined by observing children using booster seats (Part 2). The association between DAB score and number of usage errors was tested using linear regression analysis. Participants were children ages 4–8 years. Fourteen children participated in Part 1 and 15 children in Part 2. Results The DAB score was sensitive to changes in seat condition (p < 0.01), and was repeatable between different researchers (ICC 0.98, 95% confidence interval [CI] 0.954–0.991). Increases in DAB were associated with increases in the number of use errors among children using booster seats (errors in use = 3.89 × DAB − 2.18, p < 0.0001). Conclusion The DAB score is a reliable and valid measure of comfort of children in child restraints but could be improved by incorporating a measurement of postural positioning. Comfort, as characterized by fidgeting and postural adjustment behaviors, is associated with correct use of child restraints. The broader implication is that this confirms ergonomic design of child restraints as important for minimizing errors in use. There is a need for further study of the impact of specific restraint design features on comfort experienced by children.

Purpose To determine if healthy hepatic mechanical properties differ between pediatric and adult subjects at magnetic resonance (MR) elastography. Materials and Methods Liver shear moduli in 24 healthy pediatric participants (13 children aged 5-14 years [seven boys, six girls] and 11 adolescents aged 15-18 years [six boys, five girls]) and 10 healthy adults (aged 22-36 years [five men, five women]) were obtained with 3-T MR elastography at 28, 56, and 84 Hz. Relationships between shear moduli and age were assessed with Spearman correlations. Differences between age groups were determined with one-way analysis of variance and Tukey multiple comparisons tests. Results Liver stiffness values (means ± standard deviations) were significantly lower in children and adolescents than in adults at 56 Hz (children, 2.2 kPa ± 0.3; adolescents, 2.2 kPa ± 0.2; adults, 2.6 kPa ± 0.3; analysis of variance, P = .009) and 84 Hz (children, 5.6 kPa ± 0.8; adolescents, 6.5 kPa ± 1.2; adults, 7.8 kPa ± 1.2; analysis of variance, P = .0003) but not at 28 Hz (children, 1.2 kPa ± 0.2; adolescents, 1.3 kPa ± 0.3; adults, 1.2 kPa ± 0.2; analysis of variance, P = .40). At 56 and 84 Hz, liver stiffness increased with age (Spearman correlation, r = 0.38 [P = .03] and r = 0.54 [P = .001], respectively). Stiffness varied less with frequency in children and adolescents than in adults (analysis of variance, P = .0009). No significant differences were found in shear moduli at 28, 56, or 84 Hz or frequency dependence between children and adolescents (P = .38, P = .99, P = .14, and P = .30, respectively, according to Tukey tests). Conclusion Liver stiffness values are lower and vary less with frequency in children and adolescents than in adults. Stiffness increases with age during normal development and approaches adult values during adolescence. Comparing pediatric liver stiffness to adult baseline values to detect pediatric liver mechanical abnormalities may not allow detection of mild disease and may lead to underestimation of severity.

STUDY OBJECTIVES Mandibular advancement splints (MAS) are the leading treatment alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). However, not all patients experience clinical benefit and treatment prediction remains challenging. Understanding the effects of mandibular advancement on pharyngeal collapsibility and muscle function may provide valuable information on the mechanisms of MAS, and thereby help to develop novel approaches for patient selection. Thus, we aimed to determine dose-dependent effects of mandibular advancement on pharyngeal collapsibility and muscle function concurrently in OSA patients undergoing MAS therapy. METHODS Twelve (11 male) MAS-naive patients underwent a detailed physiology sleep study (polysomnography) to quantify pharyngeal collapsibility (PCRIT), pharyngeal muscle responsiveness to negative pharyngeal pressure (via genioglossus intramuscular electromyography and an epiglottic pressure sensor) and effectiveness to restore airflow and minute ventilation (Vi) after 1-minute transient CPAP reductions (induced airflow-limitation) at three mandibular advancement positions: 0% (habitual bite), 50% and 100% of the maximum comfortable mandibular advancement. Standard clinical polysomnography after MAS therapy optimization was performed to determine treatment outcome. RESULTS Overall, participants were obese with severe OSA (mean ± SD: BMI = 31 ± 4 kg/m2, apnea-hypopnea index [AHI] = 33 ± 14 events/hour). PCRIT decreased with mandibular advancement in a dose-dependent manner (1.8 ± 3.9 vs. -0.9 ± 2.9 vs. -4.0 ± 3.6 cmH2O; p < 0.001). There was no systematic change in genioglossus muscle responsiveness (p = 0.09) or effectiveness to restore peak airflow (p = 0.4) or Vi (p = 0.7) with mandibular advancement. CONCLUSIONS Mandibular advancement reduces pharyngeal collapsibility in a dose-dependent manner without systematically changing genioglossus muscle function in a predominantly obese and severe OSA population. This indicates that the primary mode of action of MAS therapy is via improvement in passive pharyngeal anatomy.