Nucleus pulposus structure and function assessed in shear using magnetic resonance elastography, quantitative MRI, and rheometry.

Background: In vivo quantification of the structure-function relationship of the intervertebral disc (IVD) via quantitative MRI has the potential to aid objective stratification of disease and evaluation of restorative therapies. Magnetic resonance elastography (MRE) is an imaging technique that assesses tissue shear properties and combined with quantitative MRI metrics reflective of composition can inform structure-function of the IVD. The objectives of this study were to (1) compare MRE- and rheometry-derived shear modulus in agarose gels and nucleus pulposus (NP) tissue and (2) correlate MRE and rheological measures of NP tissue with composition and quantitative MRI. Method: MRE and MRI assessment (i.e., T1ρ and T2 mapping) of agarose samples (2%, 3%, and 4% (w/v); n = 3-4/%) and of bovine caudal IVDs after equilibrium dialysis in 5% or 25% PEG (n = 13/PEG%) was conducted. Subsequently, agarose and NP tissue underwent torsional mechanical testing consisting of a frequency sweep from 1 to 100 Hz at a rotational strain of 0.05%. NP tissue was additionally evaluated under creep and stress relaxation conditions. Linear mixed-effects models and univariate regression analyses evaluated the effects of testing method, %agarose or %PEG, and frequency, as well as correlations between parameters. Results: MRE- and rheometry-derived shear moduli were greater at 100 Hz than at 80 Hz in all agarose and NP tissue samples. Additionally, all samples with lower water content had higher complex shear moduli. There was a significant correlation between MRE- and rheometry-derived modulus values for homogenous agarose samples. T1ρ and T2 relaxation times for agarose and tissue were negatively correlated with complex shear modulus derived from both techniques. For NP tissue, shear modulus was positively correlated with GAG/wet-weight and negatively correlated with %water content. Conclusion: This work demonstrates that MRE can assess hydration-induced changes in IVD shear properties and further highlights the structure-function relationship between composition and shear mechanical behaviors of NP tissue.

Implementing an electromagnetic tracking navigation system improves the precision of endoscopic transgastric necrosectomy in an ex vivo model.

Endoscopic transgastric necrosectomy is crucial in the management of complications resulting from necrotizing pancreatitis. However, both real-time and visual-spatial information is lacking during the procedure, thereby jeopardizing a precise positioning of the endoscope. We conducted a proof-of-concept study with the aim of overcoming these technical difficulties. For this purpose, a three-dimensional (3D) phantom of a stomach and pancreatic necroses was 3D-printed based on spatial information from individual patient CT scans and subsequently integrated into a silicone torso. An electromagnetic (EM) sensor was adjusted inside the endoscope´s working channel. A software interface enabled real time visualization. The accuracy of this novel assistant system was tested ex vivo by four experienced interventional endoscopists who were supposed to reach seven targets inside the phantom in six different experimental runs of simulated endoscopic transgastric necrosectomy. Supported by endoscopic camera view combined with real-time 3D visualization, all endoscopists reached the targets with a targeting error ranging between 2.6 and 6.5 mm in a maximum of eight minutes. In summary, the EM tracking system might increase efficacy and safety of endoscopic transgastric necrosectomy at the experimental level by enhancing visualization. Yet, a broader feasibility study and further technical improvements are mandatory before aiming at implementation into clinical setting.

Modic changes in the lumbar vertebral column of chondrodystrophic and non-chondrodystrophic dogs with intervertebral disc disease.

Introduction: Modic changes (MC) are signs of vertebral pathology visible on magnetic resonance (MR) images that have been associated with low back pain (LBP) and disc degeneration in people. Multiple breeds of dogs also develop MCs and coincident back pain. However, the association between breed, MC, and spinal pathologies has yet to be fully elucidated. This study aimed to identify the prevalence of MC that occur spontaneously in the lumbar vertebral column of dogs diagnosed with intervertebral disc disease (IVDD) and examine their association with demographic criteria and the disc width index (DWI). Methods: Medical records and lumbar vertebral column MR images were examined from 104 dogs (831 intervertebral disc spaces and adjacent vertebrae), which were divided into three groups: chondrodystrophic dogs (CD; n =54) and non-chondrodystrophic dogs (NCD; n =30) with IVDD as the primary diagnosis, and control dogs (n =20) with other spinal diseases as their primary diagnosis. Results: Increasing age and a diagnosis of IVDD were significantly associated with MC in dogs (p < 0.001 and p = 0.0062, respectively). In CD dogs with IVDD, Type 2 MC were most prevalent, whereas, in NCD dogs, Type 3 MC were the most prevalent type. Type 2 MC were distributed nearly equally across the lumbar vertebral column, while Type 3 MC were primarily detected at the level of L7-S1. Discussion: This study demonstrated that MC developed spontaneously in dogs, are common in dogs diagnosed with IVDD, and the type observed varies by breed. Further research is needed to understand the pathogenesis of MC; however, the increased presence of Type 2 MC in CD dogs, similar to what is found in people with disc degeneration, suggests that CD dogs could serve as models for MC in people.

Characterization and modulation of the pro-inflammatory effects of immune cells in the canine intervertebral disk.

Background: Intervertebral disk (IVD) degeneration affects both humans and canines and is a major cause of low back pain (LBP). Mast cell (MC) and macrophage (MØ) infiltration has been identified in the pathogenesis of IVD degeneration (IVDD) in the human and rodent model but remains understudied in the canine. MC degranulation in the IVD leads to a pro-inflammatory cascade and activates protease activated receptor 2 (PAR2) on IVD cells. The objectives of the present study are to: (1) highlight the pathophysiological changes observed in the degenerate canine IVD, (2) further characterize the inflammatory effect of MCs co-cultured with canine nucleus pulposus (NP) cells, (3) evaluate the effect of construct stiffness on NP and MCs, and (4) identify potential therapeutics to mitigate pathologic changes in the IVD microenvironment. Methods: Canine IVD tissue was isolated from healthy autopsy research dogs (beagle) and pet dogs undergoing laminectomy for IVD herniation. Morphology, protein content, and inflammatory markers were assessed. NP cells isolated from healthy autopsy (Mongrel hounds) tissue were co-cultured with canine MCs within agarose constructs and treated with cromolyn sodium (CS) and PAR2 antagonist (PAR2A). Gene expression, sulfated glycosaminoglycan content, and stiffness of constructs were assessed. Results: CD 31+ blood vessels, mast cell tryptase, and macrophage CD 163+ were increased in the degenerate surgical canine tissue compared to healthy autopsy. Pro-inflammatory genes were upregulated when canine NP cells were co-cultured with MCs and the stiffer microenvironment enhanced these effects. Treatment with CS and PAR2 inhibitors mediated key pro-inflammatory markers in canine NP cells. Conclusion: There is increased MC, MØs, and vascular ingrowth in the degenerate canine IVD tissue, similar to observations in the clinical population with IVDD and LBP. MCs co-cultured with canine NP cells drive inflammation, and CS and PAR2A are potential therapeutics that may mitigate the pathophysiology of IVDD in vitro.

Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain.

Painful musculoskeletal disorders such as intervertebral disc (IVD) degeneration associated with chronic low back pain (termed "Discogenic back pain", DBP), are a significant socio-economic burden worldwide and contribute to the growing opioid crisis. Yet there are very few if any successful interventions that can restore the tissue's structure and function while also addressing the symptomatic pain. Here we have developed a novel non-viral gene therapy, using engineered extracellular vesicles (eEVs) to deliver the developmental transcription factor FOXF1 to the degenerated IVD in an in vivo model. Injured IVDs treated with eEVs loaded with FOXF1 demonstrated robust sex-specific reductions in pain behaviors compared to control groups. Furthermore, significant restoration of IVD structure and function in animals treated with FOXF1 eEVs were observed, with significant increases in disc height, tissue hydration, proteoglycan content, and mechanical properties. This is the first study to successfully restore tissue function while modulating pain behaviors in an animal model of DBP using eEV-based non-viral delivery of transcription factor genes. Such a strategy can be readily translated to other painful musculoskeletal disorders.

Modeling the effects of hydration on viscoelastic properties of nucleus pulposus tissue in shear using the fractional Zener model.

Nucleus pulposus (NP) tissue in the intervertebral disc (IVD) is a viscoelastic material exhibiting both solid- and fluid-like mechanical behaviors. Advances in viscoelastic models incorporating fractional calculus, such as the Fractional Zener (FZ) model, have potential to describe viscoelastic behaviors. The objectives of this study were to determine whether the FZ model can accurately describe the shear viscoelastic properties of NP tissue and determine if the fractional order (α) is related to tissue hydration. 30 caudal IVDs underwent equilibrium dialysis in 5% or 25% polyethylene glycol solutions to alter tissue hydration. Excised NP tissue underwent stress relaxation testing in shear and unconfined compression. Stress relaxation data was fitted to the FZ model to obtain viscoelastic properties. In both loading modes, the initial modulus was greater for the less hydrated 25% equilibrated samples compared to 5% with no change in the equilibrium modulus. Samples with lower water content (25% samples) had shorter relaxation times in shear and longer time constants in compression, highlighting the different interactions between the fluid and solid matrix in loading modes. Samples with lower water content had α values closer to 0, indicating that less hydrated samples behaved more solid-like on the viscoelastic spectrum. Tissue hydration correlated with α values for 25% samples in shear. This study demonstrates that the FZ model may be used to describe IVD tissue behavior under both loading modes; however, the greatest utility of the FZ model is in describing flow-independent shear behaviors, and α may inform tissue hydration in shear.

SERUM FENTANYL CONCENTRATIONS AND BEHAVIOR ASSOCIATED WITH TRANSDERMAL FENTANYL APPLICATION ON HEALTHY CORN SNAKES (PANTHEROPHIS GUTTATUS).

Snakes are common household pets and frequently managed in zoos. Geriatric snakes commonly develop osteoarthritis, leading to a declining quality of life that often results in euthanasia. Anecdotally, the application of transdermal fentanyl patches (TFP) appears to contribute to clinical improvement, including increased activity level, in osteoarthritic snakes presumed to be in pain. This study evaluated serum fentanyl concentrations over time and the effects of TFP on the normal behavior of healthy, captive, adult corn snakes (Pantherophis guttatus) using constant video monitoring. Serum fentanyl concentrations were evaluated over 4 wk during 12.5 µg/h TFP application, and the results demonstrated long-lasting (>4 wk) serum concentrations that were consistent with analgesic efficacy in mammalian species during TFP application. At 4 wk of TFP application, mean serum fentanyl concentrations were 11.5 ± 5.5 ng/ml. Snakes were videotaped for 1 wk prior to and 2 wk after 12.5 µg/h TFP application, and behavior was evaluated by an ethogram. Behavioral changes associated with TFP application included decreased mean time spent active, decreased mean number of climbs, and decreased mean number of water visits; feeding behavior was unchanged. Overall, these results suggest that TFP application may provide safe, clinically effective analgesia in healthy corn snakes for at least 4 wk without inducing deleterious side effects, and may therefore be appropriate analgesia for management of osteoarthritic snakes.

Transcriptional profiling of human cartilage endplate cells identifies novel genes and cell clusters underlying degenerated and non-degenerated phenotypes.

BACKGROUND: Low back pain is a leading cause of disability worldwide and is frequently attributed to intervertebral disc (IVD) degeneration. Though the contributions of the adjacent cartilage endplates (CEP) to IVD degeneration are well documented, the phenotype and functions of the resident CEP cells are critically understudied. To better characterize CEP cell phenotype and possible mechanisms of CEP degeneration, bulk and single-cell RNA sequencing of non-degenerated and degenerated CEP cells were performed. METHODS: Human lumbar CEP cells from degenerated (Thompson grade ≥ 4) and non-degenerated (Thompson grade ≤ 2) discs were expanded for bulk (N=4 non-degenerated, N=4 degenerated) and single-cell (N=1 non-degenerated, N=1 degenerated) RNA sequencing. Genes identified from bulk RNA sequencing were categorized by function and their expression in non-degenerated and degenerated CEP cells were compared. A PubMed literature review was also performed to determine which genes were previously identified and studied in the CEP, IVD, and other cartilaginous tissues. For single-cell RNA sequencing, different cell clusters were resolved using unsupervised clustering and functional annotation. Differential gene expression analysis and Gene Ontology, respectively, were used to compare gene expression and functional enrichment between cell clusters, as well as between non-degenerated and degenerated CEP samples. RESULTS: Bulk RNA sequencing revealed 38 genes were significantly upregulated and 15 genes were significantly downregulated in degenerated CEP cells relative to non-degenerated cells (|fold change| ≥ 1.5). Of these, only 2 genes were previously studied in CEP cells, and 31 were previously studied in the IVD and other cartilaginous tissues. Single-cell RNA sequencing revealed 11 unique cell clusters, including multiple chondrocyte and progenitor subpopulations with distinct gene expression and functional profiles. Analysis of genes in the bulk RNA sequencing dataset showed that progenitor cell clusters from both samples were enriched in "non-degenerated" genes but not "degenerated" genes. For both bulk- and single-cell analyses, gene expression and pathway enrichment analyses highlighted several pathways that may regulate CEP degeneration, including transcriptional regulation, translational regulation, intracellular transport, and mitochondrial dysfunction. CONCLUSIONS: This thorough analysis using RNA sequencing methods highlighted numerous differences between non-degenerated and degenerated CEP cells, the phenotypic heterogeneity of CEP cells, and several pathways of interest that may be relevant in CEP degeneration.

Direct comparison of multiple computer-aided polyp detection systems.

BACKGROUND AND STUDY AIMS: Artificial intelligence (AI)-based systems for computer-aided detection (CADe) of polyps receive regular updates and occasionally offer customizable detection thresholds, both of which impact their performance, but little is known about these effects. This study aimed to compare the performance of different CADe systems on the same benchmark dataset. METHODS: 101 colonoscopy videos were used as benchmark. Each video frame with a visible polyp was manually annotated with bounding boxes, resulting in 129 705 polyp images. The videos were then analyzed by three different CADe systems, representing five conditions: two versions of GI Genius, Endo-AID with detection Types A and B, and EndoMind, a freely available system. Evaluation included an analysis of sensitivity and false-positive rate, among other metrics. RESULTS: Endo-AID detection Type A, the earlier version of GI Genius, and EndoMind detected all 93 polyps. Both the later version of GI Genius and Endo-AID Type B missed 1 polyp. The mean per-frame sensitivities were 50.63 % and 67.85 %, respectively, for the earlier and later versions of GI Genius, 65.60 % and 52.95 %, respectively, for Endo-AID Types A and B, and 60.22 % for EndoMind. CONCLUSIONS: This study compares the performance of different CADe systems, different updates, and different configuration modes. This might help clinicians to select the most appropriate system for their specific needs.

Optimization of inpatient medication administration among persons with Parkinson's disease: recommendations on pharmacy technology and workflow.

Individuals with Parkinson's disease (PD) are vulnerable during hospitalizations due to the underlying complexities o1f symptoms, and acute illness or medication changes often lead to decompensation. Complications during hospitalizations are often due to worsening motor and nonmotor symptoms and commonly result from inaccurate medication regimens. Although the accuracy of medication administration relies on an interplay of factors, including patient status, transitions of care, coordination between the hospital prescriber and outpatient neurologist, etc., hospital pharmacists play an integral role in pharmacotherapy. The main aspects of pharmacy strategies aim to achieve timely administration of levodopa-containing medications, reduction of substitution and omissions of antiparkinsonian medications, and avoidance of antidopaminergic medications. This paper highlights critical areas for improvement and recommendations to minimize the impact of other factors from the pharmacy standpoint.

MRI-based multivariate gray matter volumetric distance for predicting motor symptom progression in Parkinson's disease.

While Parkinson's disease (PD)-related neurodegeneration is associated with structural changes in the brain, conventional magnetic resonance imaging (MRI) has proven less effective for clinical diagnosis due to its inability to reliably identify subtle changes early in the disease course. In this study, we aimed to develop a structural MRI-based biomarker to predict the rate of progression of motor symptoms in the early stages of PD. The study included 88 patients with PD and 120 healthy controls from the Parkinson's Progression Markers Initiative database; MRI at baseline and motor symptom scores assessed using the MDS-UPDRS-III at two time points (baseline and 48 months) were selected. Group-level volumetric analyses revealed that the volumetric reductions in the left striatum were associated with the decline in motor functioning. Then, we developed a patient-specific multivariate gray matter volumetric distance and demonstrated that it could significantly predict changes in motor symptom scores (P < 0.05). Further, we classified patients as relatively slower and faster progressors with 89% accuracy using a support vector machine classifier. Thus, we identified a promising structural MRI-based biomarker for predicting the rate of progression of motor symptoms and classifying patients based on motor symptom severity.

Evaluation of a questionnaire to assess the indication for screening colonoscopy for asymptomatic patients.

INTRODUCTION: Colorectal cancer is the second most common cause of cancer death worldwide. Screening colonoscopy is a very effective measure to prevent colorectal cancer and can reduce mortality at the population level. However, the participation rates of screening programs are low.To provide easily accessible information on screening colonoscopy and to increase the participation rates of screening programs, we developed a questionnaire for asymptomatic patients based on the German guidelines to assess the indication for screening colonoscopy. We evaluated the questionnaire with reference to the indications given by specialists in gastroenterology. METHODS: Patients who visited a specialist in gastroenterology in an outpatient clinic of a tertiary hospital for other reasons than a colonoscopy were eligible for the study. A maximum of seven questions to assess the indication for screening colonoscopy were answered by the patients. Afterward, the indication for screening colonoscopy was given or not by a specialist in gastroenterology. The accuracy of the questionnaire was measured in terms of sensitivity, specificity, and predictive values. RESULTS: In total, 335 patients were included in the analyses, of whom 50 and 285 patients were given and were not given an indication for screening colonoscopy by the specialists, respectively. In 0/50 patients, the questionnaire was false negative and in 8/285 patients false positive. Thus, the questionnaire had a sensitivity of 100% (95% confidence interval: 93-100%), a specificity of 97% (95-99%), a negative predictive value of 100% (99-100%), and a positive predictive value of 86% (75-94%).A subgroup analysis including patients who had never had a colonoscopy (n=109) showed comparable results: sensitivity of 100% (92-100%), specificity of 92% (83-97%), negative predictive value of 100% (94-100%), and positive predictive value of 90% (87-97%). CONCLUSION: The self-assessment questionnaire for asymptomatic individuals to assess the recommendation for screening colonoscopy is very sensitive and specific compared to a specialist in gastroenterology.The questionnaire can be found at: https://www.interdisziplinaere-endoskopie.mri.tum.de/de/infos-patienten/index.php.

End of life care of hospitalized patients with Parkinson disease: a retrospective analysis and brief review.

Background: Towards the end of life (EOL), persons with parkinsonism (PwP) have complex needs and can present with unique palliative care (PC) challenges. There are no widely accepted guidelines to aid neurologists, hospitalists, or PC clinicians in managing the symptoms of PwP at EOL. We examined a population of PwP at EOL, aiming to describe trends of in-hospital management and utilization of PC services. Methods: All PwP admitted to two hospitals during 2018 (N = 727) were examined retrospectively, assessing those who died in hospital or were discharged with hospice (EOL group, N = 35) and comparing them to the main cohort. Their demographics, clinical data, engagement of multidisciplinary and palliative services, code status changes, invasive care, frequency of admissions, and medication administration were assessed. Results: Among the EOL group, 8 expired in hospital, and 27 were discharged to hospice. Forty-six percent of EOL patients received a PC consultation during their admission. The median interval from admission to death was 37 days. Seventy-seven percent had a full code status on admission. Compared to hospice patients, those who expired in hospital had higher rates of invasive procedures and intensive care unit transfers (41% vs. 75%, in both variables), and lower rates of PC involvement (52% vs. 25%). The transition of code status change for the EOL group from Full code to Do Not Resuscitate (DNR) occurred at a median 4-5 days from admission. For patients that passed in the hospital, the median days from transition of code status to death was 0(IQR 0-1). Levodopa dose deviations were frequent in both EOL and non-EOL group, but contraindicated medications were infrequently administered (11% in EOL group vs. 9% in non-EOL group). Conclusion: Our data suggest a low utilization of PC services and delayed discussions of goals of care. More work is needed to raise awareness of inpatient teams managing PwP regarding the unique but common challenges facing PwP with advanced disease. A brief narrative review summarizing the suggested management of symptoms common to hospitalized PwP near EOL is provided.

A novel MRI-based volumetric index for monitoring the motor symptoms in Parkinson's disease.

BACKGROUND: Conventional MRI scans have limited usefulness in monitoring Parkinson's disease as they typically do not show any disease-specific brain abnormalities. This study aimed to identify an imaging biomarker for tracking motor symptom progression by using a multivariate statistical approach that can combine gray matter volume information from multiple brain regions into a single score specific to each PD patient. METHODS: A cohort of 150 patients underwent MRI at baseline and had their motor symptoms tracked for up to 10 years using MDS-UPDRS-III, with motor symptoms focused on total and subscores, including rigidity, bradykinesia, postural instability, and gait disturbances, resting tremor, and postural-kinetic tremor. Gray matter volume extracted from MRI data was summarized into a patient-specific summary score using Mahalanobis distance, MGMV. MDS-UPDRS-III's progression and its association with MGMV were modeled via linear mixed-effects models over 5- and 10-year follow-up periods. RESULTS: Over the 5-year follow-up, there was a significant increase (P < 0.05) in MDS-UPDRS-III total and subscores, except for postural-kinetic tremor. Over the 10-year follow-up, all MDS-UPDRS-III scores increased significantly (P < 0.05). A higher baseline MGMV was associated with a significant increase in MDS-UPDRS-III total, bradykinesia, postural instability and gait disturbances, and resting tremor (P < 0.05) over the 5-year follow-up, but only with total, bradykinesia, and postural instability and gait disturbances during the 10-year follow-up (P < 0.05). CONCLUSIONS: Higher MGMV scores were linked to faster motor symptom progression, suggesting it could be a valuable marker for clinicians monitoring Parkinson's disease over time.

The Parkinson's disease waiting room of the future: measurements, not magazines.

Utilizing technology to precisely quantify Parkinson's disease motor symptoms has evolved over the past 50 years from single point in time assessments using traditional biomechanical approaches to continuous monitoring of performance with wearables. Despite advances in the precision, usability, availability and affordability of technology, the "gold standard" for assessing Parkinson's motor symptoms continues to be a subjective clinical assessment as none of these technologies have been fully integrated into routine clinical care of Parkinson's disease patients. To facilitate the integration of technology into routine clinical care, the Develop with Clinical Intent (DCI) model was created. The DCI model takes a unique approach to the development and integration of technology into clinical practice by focusing on the clinical problem to be solved by technology rather than focusing on the technology and then contemplating how it could be integrated into clinical care. The DCI model was successfully used to develop the Parkinson's disease Waiting Room of the Future (WROTF) within the Center for Neurological Restoration at the Cleveland Clinic. Within the WROTF, Parkinson's disease patients complete the self-directed PD-Optimize application on an iPad. The PD-Optimize platform contains cognitive and motor assessments to quantify PD symptoms that are difficult and time-consuming to evaluate clinically. PD-Optimize is completed by the patient prior to their medical appointment and the results are immediately integrated into the electronic health record for discussion with the movement disorder neurologist. Insights from the clinical use of PD-Optimize has spurred the development of a virtual reality technology to evaluate instrumental activities of daily living in PD patients. This new technology will undergo rigorous assessment and validation as dictated by the DCI model. The DCI model is intended to serve as a health enablement roadmap to formalize and accelerate the process of bringing the advantages of cutting-edge technology to those who could benefit the most: the patient.