Single site quasi-experimental implementation studies provide opportunities to learn about implementation in context. There is limited guidance on how to best utilise these studies to maximise opportunities for learning at scale. This study evaluated the use of a consensus process to develop and implement standardised perioperative pathways, and aimed to provide practical insights on conducting rigorous, theory-informed evaluations that can generate transferable insights for implementation science. A multi-method quasi-experimental study was conducted in a private hospital in Australia. Six consensus-based surgical care pathways were developed and implemented by different clinical teams, following a four-stage implementation process using the Exploration, Preparation, Implementation and Sustainment (EPIS) framework. Implementation outcomes were explored through participant observations (16 h) and semi-structured interviews (n = 9), which were analysed thematically using an interpretive descriptive approach. Normalisation Process Theory (NPT) was then applied to understand the mechanisms of change in greater depth. Pathway fidelity was assessed via medical record audits from a random patient sample (n = 90) from four surgical cohorts. Implementing standardised perioperative pathways using a multi-faceted consensus-based implementation plan was perceived as acceptable, appropriate, and feasible. However, fidelity to clinical actions improved in only two of four surgical cohorts. Implementation was operationalised through the four generative mechanisms of NPT and was influenced by factors that related to all four constructs and 12/16 elements of the EPIS framework. Factors relating to the Inner Context and the Innovation were most frequently identified as having a greater influence on implementation across all EPIS phases. The implementation plan targeted Collective Action and Coherence to a greater extent than other mechanisms. Participants linked greater uptake and implementation to the importance of co-designing implementation strategies with frontline staff (improving Legitimation and Coherence) and tailoring strategies to specific disciplines. This project provides a practical case study for how to undertake theory-informed, implementation evaluations in real-world contexts. It offers valuable insights for others seeking to operationalise implementation science principles in everyday healthcare settings including how individual strategies may work to drive local change.

Chiari malformation is characterised by the herniation of the cerebellar tonsils through the foramen magnum. It is commonly assumed that the tonsils obstruct normal cerebrospinal fluid (CSF) flow, resulting in cough-associated headaches. However, the mechanisms that cause these headaches are unknown, leading to varied and often unsatisfactory treatment outcomes for patients with Chiari. In this study real-time phase contrast MRI (PC-MRI) was used to determine whether the tonsils restrict CSF flow during coughs, and shape models of the posterior fossa were used to identify morphological differences between patients with and without cough headache. Twenty Chiari patients with cough headache, seven without, and twelve age and sex matched controls underwent MR imaging of the head and neck. 3D models of the hindbrain, CSF and vertebrobasilar arteries were constructed from T1-weighted MRI. PC-MRI was collected at the foramen magnum and mid-C3 to measure CSF flow, plus arterial and venous flow. The shape models showed that the CSF space anterior to the pons was narrower in Chiari patients than in controls. Additionally, the CSF space around the vertebrobasilar arteries was more restricted in patients with cough headache than those without. The flow of CSF across the foramen magnum was not restricted, and CSF velocities were ∼2 times greater in Chiari patients than in controls. These findings suggest that overcrowding of the posterior fossa creates high velocity CSF flow across the pons, medulla, and vertebrobasilar arteries. This high velocity flow through the restricted CSF space may stress the cranial vasculature and contribute to headache.

Aims: The goal of this study was to establish a simple model of 3D endothelial spheroids with mosaic gene expression using adeno-associated virus (AAV) transduction, with a future aim being to study the activity of post-zygotic mutations common to vascular malformations. Methods: In this study, 96-well U-bottom plates coated with a commercial repellent were seeded with two immortalized human endothelial cell lines and aggregation monitored using standard microscopy or live-cell analysis. The eGFP expression was used to monitor the AAV transduction. Results: HUVEC-TERT2 could not form spheroids spontaneously. The inclusion of collagen I in the growth medium could stimulate cell aggregation; however, these spheroids were not stable. In contrast, the hCMEC/D3 cells aggregated spontaneously and formed reproducible, robust 3D spheroids within 3 days, growing steadily for at least 4 weeks without the need for media refreshment. The hCMEC/D3 spheroids spontaneously developed a basement membrane, including collagen I, and expressed endothelial-specific CD31 at the spheroid surface. Serotypes AAV1 and AAV2QUADYF transduced these spheroids without toxicity and established sustained, mosaic eGFP expression. Conclusions: In the future, this simple approach to endothelial spheroid formation combined with live-cell imaging could be used to rapidly assess the 3D phenotypes and drug and radiation sensitivities arising from mosaic mutations common to brain vascular malformations.

Purpose The purpose of this study was to train a deep learning -based method for the prediction of postoperative recurrence of symptoms in Chiari malformation type 1 (CM1) patients undergoing surgery. Studies suggest that certain radiological and clinical features do exist in patients with treatment failure, though these are inconsistent and poorly defined. Methodology This study was a retrospective cohort study of patients who underwent primary surgical intervention for CM1 from January 2010 to May 2020. Only patients who completed pre- and postoperative 12 -item short form (SF -12) surveys were included and these were used to classify the recurrence or persistence of symptoms. Forty patients had an improvement in overall symptoms while 17 had recurrence or persistence. After magnetic resonance imaging (MRI) data augmentation, a ResNet50, pre -trained on the ImageNet dataset, was used for feature extraction, and then clustering -constrained attention multiple instance learning (CLAM), a weakly supervised multi -instance learning framework, was trained for prediction of recurrence. Five -fold cross -validation was used for the development of MRI only, clinical features only, and a combined machine learning model. Results This study included 57 patients who underwent CM1 decompression. The recurrence rate was 30%. The combined model incorporating MRI, pre -operative SF -12 physical component scale (PCS), and extent of cerebellar ectopia performed best with an area under the curve (AUC) of 0.71 and an F1 score of 0.74. Conclusion This is the first study to our knowledge to explore the prediction of postoperative recurrence of symptoms in CM1 patients using machine learning methods and represents the first step toward developing a clinically useful prognostication machine learning model. Further studies utilizing a similar deep learning approach with a larger sample size are needed to improve the performance.

Background In the past, evidence-based medicine (EBM) and shared decision-making (SDM) have been taught separately in health sciences and medical education. However, recognition is increasing of the importance of EBM training that includes SDM, whereby practitioners incorporate all steps of EBM, including person-centered decision-making using SDM. However, there are few empirical investigations into the benefits of training that integrates EBM and SDM (EBM-SDM) for junior doctors, and their influencing factors. This study aimed to explore how integrated EBM-SDM training can influence junior doctors' attitudes to and practice of EBM and SDM; to identify the barriers and facilitators associated with junior doctors' EBM-SDM learning and practice; and to examine how supervising consultants' attitudes and authority impact on junior doctors' opportunities for EBM-SDM learning and practice.Methods We developed and ran a series of EBM-SDM courses for junior doctors within a private healthcare setting with protected time for educational activities. Using an emergent qualitative design, we first conducted pre- and post-course semi-structured interviews with 12 junior doctors and thematically analysed the influence of an EBM-SDM course on their attitudes and practice of both EBM and SDM, and the barriers and facilitators to the integrated learning and practice of EBM and SDM. Based on the responses of junior doctors, we then conducted interviews with ten of their supervising consultants and used a second thematic analysis to understand the influence of consultants on junior doctors' EBM-SDM learning and practice.Results Junior doctors appreciated EBM-SDM training that involved patient participation. After the training course, they intended to improve their skills in person-centered decision-making including SDM. However, junior doctors identified medical hierarchy, time factors, and lack of prior training as barriers to the learning and practice of EBM-SDM, whilst the private healthcare setting with protected learning time and supportive consultants were considered facilitators. Consultants had mixed attitudes towards EBM and SDM and varied perceptions of the role of junior doctors in either practice, both of which influenced the practice of junior doctors.Conclusions These findings suggested that future medical education and research should include training that integrates EBM and SDM that acknowledges the complex environment in which this training must be put into practice, and considers strategies to overcome barriers to the implementation of EBM-SDM learning in practice.

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery.Evidence level: 1Technical Efficacy: Stage 3

Posttraumatic syringomyelia (PTS) is an enigmatic condition characterized by the development of fluid-filled cysts (syrinxes) within the spinal cord. Perivascular spaces (PVS) are a critical component of fluid transport within the central nervous system (CNS), with dilated PVSs variably implicated in the pathogenesis of syringomyelia. The extent and spatial distribution of dilated PVSs in syringomyelia, however, remains unclear. This study aims to develop a method to assess PVS dimensions across multiple spinal cord segments in rats with PTS. Syrinxes were induced in two Sprague–Dawley rats at C6/7 with computer-controlled motorized spinal cord impaction; two control rats underwent sham laminectomies. Spinal cord segments were obtained at C4, C6 and C8, cleared via tissue clearing protocols, stained with immunofluorescent antibodies and imaged under confocal microscopy. Qualitative and quantitative analyses of PVS size were performed. Arteriolar PVSs were enlarged in the perisyringeal region of the spinal cord, compared to the control cord. No PVS enlargement was observed above or below the syrinx. These results confirm previous incidental findings of enlarged PVSs in the perisyringeal region, providing new insights into PVS dimensions across multiple spinal segments, and providing a novel method for quantifying spinal cord perivascular space size distributions.

EDITORIAL article Front. Hum. Neurosci., 07 June 2023Sec. Brain Health and Clinical Neuroscience Volume 17 - 2023 | https://doi.org/10.3389/fnhum.2023.1212184

CSF venous fistula (CVF) is a rare cause of spontaneous intracranial hypotension (SIH) which is estimated to be found in 2.5% of patients with orthostatic headaches.1 In patients with persistent SIH symptoms, advanced imaging techniques such as magnetic resonance (MR) or computer tomography (CT) myelography are recommended to detect the location of the cerebrospinal fluid (CSF) leak. However, up to 10–15% of patients may not have a visible leak on conventional imaging.2 3 This obviates the need for more advanced spinal imaging with intrathecal contrast administration to identify the presence of perineural cysts and draining venous networks. The main imaging modality for the diagnosis of CVFs is digital subtraction myelography (DSM), wherein the CVF is seen as a vessel filling with contrast, usually arising from a nerve root sleeve. We describe a case of a 76-year old male who presented with chronic orthostatic headaches in which initial brain imaging demonstrated features of SIH but with no further evidence of CSF leak on conventional spinal imaging. Subsequent DSM confirmed the presence of a T9 perineural cyst with an associated CVF, in the setting of multiple thoracic perineural pseudocysts. Surgical correction with coagulation of the draining vessel, has led to improvement of his symptoms. References Schievink WI, Maya MM, Jean-Pierre S, Nuño M, Prasad RS, Moser FG. A classification system of spontaneous spinal CSF leaks. Neurology. 2016 Aug 16;87(7):673–9. Schievink WI, Moser FG, Maya MM. CSF-venous fistula in spontaneous intracranial hypotension. Neurology. 2014 Jul 29;83(5):472–3. Goldberg J, Häni L, Jesse CM, Zubak I, Piechowiak EI, Gralla J, et al. Spontaneous Intracranial Hypotension Without CSF Leakage—Concept of a Pathological Cranial to Spinal Fluid Shift. Front Neurol. 2021 Nov 1;12:760081.

Aquaporin-4 (AQP4) has been implicated in post-traumatic syringomyelia (PTS), a disease characterised by the formation of fluid-filled cysts in the spinal cord. This study investigated the expression of AQP4 around a mature cyst (syrinx) and the effect of pharmacomodulation of AQP4 on syrinx size. PTS was induced in male Sprague–Dawley rats by computerized spinal cord impact and subarachnoid kaolin injection. Immunofluorescence of AQP4 was carried out on mature syrinx tissue 12 weeks post-surgery. Increased AQP4 expression corresponded to larger, multiloculated cysts (R 2 = 0.94), yet no localized changes to AQP4 expression in perivascular regions or the glia limitans were present. In a separate cohort of animals, at 6 weeks post-surgery, an AQP4 agonist (AqF026), antagonist (AqB050), or vehicle was administered daily over 4 days, with MRIs performed before and after the completion of treatment. Histological analysis was performed at 12 weeks post-surgery. Syrinx volume and length were not altered with AQP4 modulation. The correlation between increased AQP4 expression with syrinx area suggests that AQP4 or the glia expressing AQP4 are recruited to regulate water movement. Given this, further investigation should examine AQP4 modulation with dose regimens at earlier time-points after PTS induction, as these may alter the course of syrinx development.

Chiari I malformation has been defined as cerebellar tonsillar descent greater than 5 mm below the foramen magnum. Suboccipital decompression remains the mainstay of treatment for symptomatic patients. Other conditions sometimes have imaging features that mimic Chiari I malformation. These patients are at risk of misdiagnosis and mismanagement, including surgery that may be unnecessary or may even worsen the underlying condition. The aim of this study was to analyse a series of Chiari I malformation mimics and identify differentiating imaging features. The mimics are categorised as post-traumatic cranio-cervical junction arachnoiditis, dural band, spontaneous intracranial hypotension, idiopathic intracranial hypertension, and cysts. Better understanding of these conditions will assist with diagnosis and optimal management, including avoiding unnecessary surgery.

BACKGROUND:Moyamoya vasculopathy is a rare steno-occlusive cerebrovascular disorder presenting with ischemia or hemorrhage. There are racial and geographic differences in presentation and outcome. There is little information regarding moyamoya in Australia. METHODS:Moyamoya patients undergoing surgery from 2001 to 2022 were studied retrospectively. The outcomes of revascularization surgery in adult and pediatric patients, with ischemic and hemorrhagic disease were analyzed, including functional outcomes, postoperative complications, bypass patency, and long-term rates of ischemic and hemorrhagic events. RESULTS:A total of 68 patients with 122 revascularized hemispheres and 8 posterior circulation revascularizations were included in this study. Eighteen patients were of Asian descent and 46 were of Caucasian origin. Presentation was with ischemia in 124 hemispheres and hemorrhage in six hemispheres. There were 92 direct, 34 indirect, and 4 combined revascularization surgeries performed. Early postoperative complications occurred in 3.1% (n = 4) of operations and delayed complications (infection, subdural hematoma) occurred after 4.6% (n = 6) of operations. Mean follow-up was 6.5 years (3-252 months). There was 100% patency of direct grafts at last follow-up. There were no hemorrhagic events following surgery and 1 new ischemic event 2 years after surgery. There was significant improvement in physical health functional outcomes at most recent follow-up (P < 0.05); mental health outcomes were not different between preoperative and postoperative assessments. CONCLUSIONS:The majority of Australian moyamoya patients are Caucasian and the most common clinical presentation is ischemia. Revascularization surgery had excellent outcomes with very low rates of ischemia and hemorrhage, comparing favorably to the natural history of moyamoya vasculopathy.

Background Cerebrospinal fluid (CSF) circulation in the brain has garnered considerable attention in recent times. In contrast, there have been fewer studies focused on the spine, despite the expected importance of CSF circulation in disorders specific to the spine, including syringomyelia. The driving forces that regulate spinal CSF flow are not well defined and are likely to be different to the brain given the anatomical differences and proximity to the heart and lungs. The aims of this study were to determine the effects of heart rate, blood pressure and respiration on the distribution of CSF tracers in the spinal subarachnoid space, as well as into the spinal cord interstitium. 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), tachy/bradycardia, as well as hyper/hypotension were separately studied. To investigate spinal CSF hydrodynamics, in vivo near-infrared imaging of intracisternally infused indocyanine green was performed. CSF tracer transport was further characterised with in vivo two-photon intravital imaging. Tracer influx at a microscopic level was quantitatively characterised by ex vivo epifluorescence imaging of fluorescent ovalbumin. Results Compared to mechanically ventilated controls, spontaneous breathing animals had significantly greater movement of tracer in the subarachnoid space. There was also greater influx into the spinal cord interstitium. Hypertension and tachycardia had no significant effect on spinal subarachnoid spinal CSF tracer flux and exerted less effect than respiration on tracer influx into the spinal cord. Conclusions Intrathoracic pressure changes that occur over the respiratory cycle, particularly decreased intrathoracic pressures generated during inspiration, have a profound effect on tracer movement after injection into spinal CSF and increase cord parenchymal tracer influx. Arterial pulsations likely drive fluid transport from perivascular spaces into the surrounding interstitium, but their overall impact is less than that of the respiratory cycle on net tracer influx.

EDITORIAL article Front. Mol. Neurosci., 28 December 2022Sec. Brain Disease Mechanisms Volume 15 - 2022 | https://doi.org/10.3389/fnmol.2022.1119980

Introduction Patient-centred care is pivotal to clinical practice and medical education. The practice of evidence-based medicine (EBM) and shared decision-making (SDM) are complementary aspects of patient-centred care, but they are frequently taught and reported as independent entities. To effectively perform all steps of EBM, clinicians need to include patients in SDM conversations, however, the uptake of this has been slow and inconsistent. A solution may be the incorporation of SDM into EBM training programmes, but such programmes do not routinely include SDM skills development. This scoping review will survey the literature on the kinds of EBM and SDM educational programmes that exist for recently qualified doctors, programmes that incorporate the teaching of both EBM and SDM skills, as well as identifying research gaps in the literature. Methods and analysis Literature searches will be conducted in the databases Medline, Embase, Scopus and Cochrane Library. Bibliographies of key articles and their citing references will also be hand-searched and assessed for inclusion. Selected grey literature will be included. Papers must be written in English, or provide English abstracts, and date from 1996 to the present day. Two independent reviewers will screen titles and abstracts, check full texts of selected papers for eligibility and extract the data. Any disagreement will be resolved, and consensus reached, if necessary, with the assistance of a third reviewer. Qualitative and quantitative studies that address educational interventions for either EBM, SDM or both will be included. Data extraction tables will present bibliographic information, populations, interventions, context and outcomes. Data will be summarised using tables and figures and a description of findings. Ethics and dissemination This review will synthesise information from publicly available publications and does not require ethics approval. The results will be disseminated via conference presentations and publications in medical journals.

PURPOSE:To train deep learning convolutional neural network (CNN) models for classification of clinically significant Chiari malformation type I (CM1) on MRI to assist clinicians in diagnosis and decision making.METHODS:A retrospective MRI dataset of patients diagnosed with CM1 and healthy individuals with normal brain MRIs from the period January 2010 to May 2020 was used to train ResNet50 and VGG19 CNN models to automatically classify images as CM1 or normal. A total of 101 patients diagnosed with CM1 requiring surgery and 111 patients with normal brain MRIs were included (median age 30 with an interquartile range of 23-43; 81 women with CM1). Isotropic volume transformation, image cropping, skull stripping, and data augmentation were employed to optimize model accuracy. K-fold cross validation was used to calculate sensitivity, specificity, and the area under receiver operating characteristic curve (AUC) for model evaluation.RESULTS:The VGG19 model with data augmentation achieved a sensitivity of 97.1% and a specificity of 97.4% with an AUC of 0.99. The ResNet50 model achieved a sensitivity of 94.0% and a specificity of 94.4% with an AUC of 0.98.CONCLUSIONS:VGG19 and ResNet50 CNN models can be trained to automatically detect clinically significant CM1 on MRI with a high sensitivity and specificity. These models have the potential to be developed into clinical support tools in diagnosing CM1.

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.

PURPOSE:Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension.METHODS:Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur.RESULTS:The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve.CONCLUSIONS:In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect.

Endothelial cells are highly sensitive to ionizing radiation, and exposure leads to multiple adaptive changes. Remarkably, part of this response is the translocation of normally intracellular proteins to the cell surface. It is unclear whether this ectopic expression has a protective or deleterious function, but, regardless, these surface-exposed proteins may provide unique discriminatory targets for radiation-guided drug delivery to vascular malformations or tumor vasculature. We investigated the ability of an antibody–thrombin conjugate targeting mitochondrial PDCE2 (E2 subunit of pyruvate dehydrogenase) to induce precision thrombosis on irradiated endothelial cells in a parallel-plate flow system. Click-chemistry was used to create antibody–thrombin conjugates targeting PDCE2 as the vascular targeting agent (VTA). VTAs were injected into the parallel-plate flow system with whole human blood circulating over irradiated cells. The efficacy and specificity of fibrin-thrombus formation was assessed relative to non-irradiated controls. The PDCE2-targeting VTA dose-dependently increased thrombus formation: minimal thrombosis was induced in response to 5 Gy radiation; doses of 15 and 25 Gy induced significant thrombosis with equivalent efficacy. Negligible VTA binding or thrombosis was demonstrated in the absence of radiation or with non-targeted thrombin. PDCE2 represents a unique discriminatory target for radiation-guided drug delivery and precision thrombosis in pathological vasculature.