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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance elastography (MRE) is an imaging technique that can noninvasively assess the shear properties of the intervertebral disc (IVD). Unlike the standard gradient recalled echo (GRE) MRE technique, a spin‐echo echo‐planar imaging (SE‐EPI) sequence has the potential to improve imaging efficiency and patient compliance. Purpose: To validate the use of an SE‐EPI sequence for MRE of the IVD compared against the standard GRE sequence. Study Type: Cross‐over. Subjects: Twenty‐eight healthy volunteers (15 males and 13 females, age range: 19–55). Field Strength/Sequence: 3 T; GRE, SE‐EPI with breath holds (SE‐EPI‐BH) and SE‐EPI with free breathing (SE‐EPI‐FB) MRE sequences. Assessment: MRE‐derived shear stiffnesses were calculated via principal frequency analysis. SE‐EPI derived shear stiffness and octahedral shear strain signal‐to‐noise ratios (OSS‐SNR) were compared against those derived using the GRE sequence. The reproducibility and repeatability of SE‐EPI stiffness measurements were determined. Shear stiffness was evaluated in the nucleus pulposus (NP) and annulus fibrosus (AF) regions of the disc. Scan times between sequences were compared. Statistical Tests: Linear mixed models, Bland–Altman plots, and Lin's concordance correlation coefficients (CCCs) were used with P < 0.05 considered statistically significant. Results: Good correlation was observed between shear stiffnesses derived from the SE‐EPI sequences with those derived from the GRE sequence with CCC values greater than 0.73 and 0.78 for the NP and AF regions, respectively. OSS‐SNR was not significantly different between GRE and SE‐EPI sequences (P > 0.05). SE‐EPI sequences generated highly reproducible and repeatable stiffness measurements with CCC values greater than 0.97 in the NP and AF regions and reduced scan time by at least 51% compared to GRE. SE‐EPI‐BH and SE‐EPI‐FB stiffness measurements were similar with CCC values greater than 0.98 for both regions. Data Conclusion: SE‐EPI‐based MRE‐derived stiffnesses were highly reproducible and repeatable and correlated with current standard GRE MRE‐derived stiffness estimates while reducing scan times. Level of Evidence: 1 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

This article presents an effort toward building an artificial intelligence (AI) assisted framework, coined ReconGAN, for creating a realistic digital twin of the human vertebra and predicting the risk of vertebral fracture (VF). ReconGAN consists of a deep convolutional generative adversarial network (DCGAN), image‐processing steps, and finite element (FE) based shape optimization to reconstruct the vertebra model. This DCGAN model is trained using a set of quantitative micro‐computed tomography (micro‐QCT) images of the trabecular bone obtained from cadaveric samples. The quality of synthetic trabecular models generated using DCGAN are verified by comparing a set of its statistical microstructural descriptors with those of the imaging data. The synthesized trabecular microstructure is then infused into the vertebra cortical shell extracted from the patient's diagnostic CT scans using an FE‐based shape optimization approach to achieve a smooth transition between trabecular to cortical regions. The final geometrical model of the vertebra is converted into a high‐fidelity FE model to simulate the VF response using a continuum damage model under compression and flexion loading conditions. A feasibility study is presented to demonstrate the applicability of digital twins generated using this AI‐assisted framework to predict the risk of VF in a cancer patient with spinal metastasis. [ABSTRACT FROM AUTHOR]

We present the application of ReconGAN, introduced in a previous study, for simulating the vertebroplasty (VP) operation and its impact on the fracture response of a vertebral body. ReconGAN consists of a Deep Convolutional Generative Adversarial Network (DCGAN) and a finite element based shape optimization algorithm to virtually reconstruct the trabecular bone microstructure. The VP procedure involves injecting shear‐thinning liquid bone cement through a needle in the trabecular region to reinforce a diseased or fractured vertebra. To simulate this treatment modality, computational fluid dynamics (CFD) is employed to predict the morphology of the injected cement within the bone microstructure. A power‐law equation is utilized to characterize the non‐Newtonian shear‐thinning behavior of the polymethyl methacrylate (PMMA) bone cement during injection simulations. The CFD model is coupled with the level‐set method to simulate the motion of the interface separating bone cement and bone marrow. After predicting the cement morphology, a data co‐registration algorithm is employed to transform the CFD model to a high‐fidelity continuum damage mechanics (CDM) finite element model of the augmented vertebra for predicting the fracture response. A feasibility study is presented to demonstrate the ability of this CFD‐CDM framework to investigate the effect of VP on the mechanical integrity of the vertebral body in a cancer patient with a lytic metastatic tumor. [ABSTRACT FROM AUTHOR]

Background: Daily physiologic loading causes fluctuations in hydration of the intervertebral disc (IVD); thus, the embedded cells experience cyclic alterations to their osmotic environment. These osmotic fluctuations have been described as a mechanism linking mechanics and biology, and have previously been shown to promote biosynthesis in chondrocytes. However, this phenomenon has yet to be fully interrogated in the IVD. Additionally, the specialized extracellular matrix surrounding the cells, the pericellular matrix (PCM), transduces the biophysical signals that cells ultimately experience. While it is known that the PCM is altered in disc degeneration, whether it disrupts normal osmotic mechanotransduction has yet to be determined. Thus, our objectives were to assess: (1) whether dynamic osmotic conditions stimulate biosynthesis in nucleus pulposus cells, and (2) whether pericellular heparan sulfate proteoglycans (HSPGs) modulate the biosynthetic response to osmotic loading. Methods: Bovine nucleus pulposus cells isolated with retained PCM were encapsulated in 1.5% alginate beads and treated with or without heparinase III, an enzyme that degrades the pericellular HSPGs. Beads were subjected to 1 h of daily iso‐osmotic, hyper‐osmotic, or hypo‐osmotic loading for 1, 2, or 4 weeks. At each timepoint the total amount of extracellular and pericellular sGAG/DNA were quantified. Additionally, whether osmotic loading triggered alterations to HSPG sulfation was assessed via immunohistochemistry for the heparan sulfate 6‐O‐sulfertransferase 1 (HS6ST1) enzyme. Results: Osmotic loading significantly influenced sGAG/DNA accumulation with a hyper‐osmotic change promoting the greatest sGAG/DNA accumulation in the pericellular region compared with iso‐osmotic conditions. Heparanase‐III treatment significantly reduced extracellular sGAG/DNA but pericellular sGAG was not affected. HS6ST1 expression was not affected by osmotic loading. Conclusion: Results suggest that hyper‐osmotic loading promotes matrix synthesis and that modifications to HSPGs directly influence the metabolic responses of cells to osmotic fluctuations. Collectively, results suggest degeneration‐associated modifications to pericellular HSPGs may contribute to the altered mechanobiology observed in disease. [ABSTRACT FROM AUTHOR]

This work evaluates an exceptionally complex natural laboratory, the Middle Triassic Latemar isolated platform in the northern Italian Dolomite Mountains and explores spatial and temporal gradients in processes and products related to contact metamorphism, dolomitization and dedolomitization of marine limestones. The relation between petrographic change and re‐equilibration of geochemical proxy data is evaluated from the perspective of carbonate‐archive research. Hydrothermal dolomitization of the limestone units is triggered by dykes and associated hydrothermal fluids radiating from the nearby Predazzo Intrusion. Detailed petrography, fluid inclusion analysis, δ13C and δ18O data and 87Sr/86Sr isotope ratios shed light on the extreme textural and geochemical complexity. Metamorphic and diagenetic patterns include: (i) peak‐metamorphic and retrograde‐metamorphic phases including three dolomite marbles, two dedolomite marbles, brucite, magnesium silicates and late‐stage meteoric/vadose cement at the contact aureole; (ii) four spatially defined episodes of dolomitization, authigenic quartz, low magnesium calcite and late‐stage meteoric cement at the Latemar isolated platform; and (iii) kilometre‐scale gradients in δ13C values from the contact aureole towards the platform interior. Results shown here are relevant for two reasons: first, the spatial analysis of alteration products ranging from high‐grade metamorphic overprint of marbles at temperatures of 700°C in the contact aureole to moderately altered limestones in the platform interior at temperatures <100°C, allows the observation of processes that commonly occur along vertical (prograde) gradients from shallow burial to metamorphism at depths >20 km. Second, under rock‐buffered conditions, and irrespective of metamorphic to diagenetic fluid−rock interactions, both marbles, and low‐temperature hydrothermal dolomites have conservative marine δ13C and δ18O values. The fact that metamorphism and hydrothermal dolomitization of precursor limestones and early diagenetic dolostones did not per se reset environmental proxy data is of interest for those concerned with carbonate archive research in Earth's deep time. [ABSTRACT FROM AUTHOR]

Early marine diagenetic dolomite is a rather thermodynamically‐stable carbonate phase and has potential to act as an archive of marine porewater properties. However, the variety of early to late diagenetic dolomite phases that can coexist within a single sample can result in extensive complexity. Here, the archive potential of early marine dolomites exposed to extreme post‐depositional processes is tested using various types of analyses, including: petrography, fluid inclusion data, stable δ13C and δ18O isotopes, 87Sr/86Sr ratios, and U‐Pb age dating of various dolomite phases. In this example, a Triassic carbonate platform was dissected and overprinted (diagenetic temperatures of 50 to 430°C) in a strike‐slip zone in Southern Spain. Eight episodes of dolomitization, a dolostone cataclasite and late stage meteoric/vadose cementation were recognized. The following processes were found to be diagenetically relevant: (i) protolith deposition and fabric‐preservation, and marine dolomitization of precursor aragonite and calcite during the Middle–Late Triassic; (ii) intermediate burial and formation of zebra saddle dolomite and precipitation of various dolomite cements in a Proto‐Atlantic opening stress regime (T ca 250°C) during the Early–Middle Jurassic; (iii) dolomite cement precipitation during early Alpine tectonism, rapid burial to ca 15 km, and high‐grade anchizone overprint during Alpine tectonic evolution in the Early Eocene to Early Miocene; (iv) brecciation of dolostones to cataclasite during the onset of the Carboneras Fault Zone activity during the Middle Miocene; and (v) late‐stage regression and subsequent meteoric overprint. Data shown here document that, under favourable conditions, early diagenetic marine dolomites and their archive data may resist petrographic and geochemical resetting over time intervals of 108 or more years. Evidence for this preservation includes preserved Late Triassic seawater δ13CDIC values and primary fluid inclusion data. Data also indicate that oversimplified statements based on bulk data from other petrographically‐complex dolomite archives must be considered with caution. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration is a major contributor to chronic low back pain and is characterized by decreases in cellularity and proteoglycan synthesis, upregulation of matrix degradation, and increases in pro‐inflammatory factors with neurovascular invasion. Current treatments fail to target the underlying pathology or promote tissue repair and approaches such as viral transfection raise safety concerns due to mutagenesis and unwarranted immune responses. To avoid such concerns, nonviral transfection is a viable method of gene delivery into the host cell while bypassing the caveats of viral delivery. Brachyury is expressed in the developing notochord and is associated with an immature healthy nucleus pulposus (NP). We hypothesize that Brachyury can reprogram degenerate NP cells to a healthy pro‐anabolic phenotype with increased proteoglycan content and decreased expression of catabolic, inflammatory, and neurovascular markers. NP cells obtained from human autopsy and surgical tissues were transfected with plasmids encoding for Brachyury or an empty vector control via bulk electroporation. Post transfection, cells were seeded in three‐dimensional agarose constructs cultured over 4 weeks and analyzed for viability, gene expression, and proteoglycan. Results demonstrated successful transfection of both autopsy and surgical NP cells. We observed long‐term Brachyury expression, significant increased expression of NP phenotypic markers FOXF1, KRT19, and chondrogenic marker SOX9 with decreases in inflammatory cytokines IL1‐β/IL6, NGF, and MMPs and significant increases in glycosaminoglycan accumulation. These results highlight nonviral transfection with developmental transcription factors, such as Brachyury, as a promising method to reprogram degenerate human disc cells toward a healthy NP phenotype. Clinical significance: This project proposes a novel translational approach for the treatment of intervertebral disc degeneration via direct reprogramming of diseased human patient‐derived IVD cells to a healthy phenotype. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2389–2400, 2019 [ABSTRACT FROM AUTHOR]

Background and Aim The intake of polyethylene glycol ( PEG) prior colonoscopy is frequently associated with nausea and abdominal discomfort. The aim of this study was to investigate whether sodium picosulfate and magnesium citrate ( PMC) is superior to a polyethylene glycol ( PEG) preparation in regard to patient acceptance. Furthermore, it investigates possible differences in efficiency and patient safety. Methods In a randomised, prospective, and endoscopist-blinded study patients were 1:1 randomized to either use PMC or 4- L PEG in order to prepare for colonoscopy. Cleansing regimes consisted of a split-dose administration in the PEG arm and standard administration in the PMC arm. Primary end point was proportion of patients evaluating the bowel preparation procedure as 'very distressing,' defined as ≥ 8 points on a 10-point numeric rating scale ( NRS). Secondary end points were quality of bowel preparation and electrolyte parameters. Results PMC bowel-cleansing procedure was better tolerated compared with PEG ( PMCNRS<8 = 89.9% vs PEGNRS<8 = 79.2%, P = 0.037). Mean declines in serum sodium (ΔSodiumPEG = −0.76 ± 3.07 vs ΔSodiumPMC = −3.38 ± 3.56 mmol/L; P < 0.001), chloride (ΔChloridePEG = −1.00 ± 3.22 vs ΔChloridePMC = −3.49 ± 3.51 mmol/L; P < 0.001), and osmolality (ΔOsmolalityPEG = −4.23 ± 6.82 vs ΔOsmolalityPMC = −8.83 ± 7.43 mosmol/kg; P < 0.001) were higher in the PMC arm than in the PEG arm. Hyponatremia after bowel preparation occurred more often in PMC (21.2%) than in PEG (4.0%) ( P < 0.001). Successful preparation was achieved more frequently in the PEG arm (42.9% vs 82.2%; P < 0.001). Conclusion Standard picosulfate/magnesium citrate is better accepted than a split-dose PEG regimen. From the perspective of successful preparation and patients' safety, PEG is superior to PMC. [ABSTRACT FROM AUTHOR]

Purpose: Functional MRI (fMRI) can provide insights into the functioning of the sensorimotor system, which is of particular interest in studying people with movement disorders or chronic pain conditions. This creates a demand for manipulanda that can fit and operate within the environment of a MRI scanner. Here, the authors present a magnetomechanical device that delivers a vibrotactile sensation to the skin with a force of approximately 9 N. Methods: MRI compatibility of the device was tested in a 3 T scanner using a phantom to simulate the head. Preliminary investigation into the effectiveness of the device at producing cortical and subcortical activity was also conducted with a group of seven healthy subjects. The vibration was applied to the right extensor carpi ulnaris tendon to induce a kinesthetic illusion of flexion and extension of the wrist. Results: The MRI compatibility tests showed the device did not produce image artifacts and the generated electromagnetic field did not disrupt the static magnetic field of the scanner or its operation. The subject group results showed activity in the contralateral putamen, premotor cortex, and dorsal lateral prefrontal cortex. Ipsilaterally, there was increased activity in the superior and inferior parietal lobules. Areas that activated bilaterally included the thalamus, anterior cingulate, secondary somatosensory areas (S2), temporal lobes, and visual association areas. Conclusions: This device offers an effective tool with precise control over the vibratory stimulus, delivering higher forces than some other types of devices (e.g., piezoelectric actuators). It can be useful for investigating sensory systems and sensorimotor integration. [ABSTRACT FROM AUTHOR]

Although applicant-employee fit has emerged as an important topic in recruitment research, little is known about how job seekers' perceived similarity with the employees working for an organization affects employer attraction. In this research, we introduce temporal construal as a crucial moderating variable and study how the temporal decision context affects the weighting of applicant-employee fit. In particular, we argue that applicant-employee fit is construed in abstract, high-level terms, and exerts a stronger influence when prospective applicants hold a distant time perspective. In contrast, instrumental attributes such as pay level represent low-level construals and gain greater relevance when prospective applicants hold a near time perspective. Two experiments involving a student sample and a sample of unemployed job seekers supported these predictions. [ABSTRACT FROM AUTHOR]

While the use of deep brain stimulation (DBS) for the treatment of neurological disorders has risen substantially over the last decade, it is often difficult to compare the results from different studies due to the lack of consistent reporting of key study parameters. We present guidelines to standardize the reporting of clinical studies of DBS for Parkinson's disease (PD). These guidelines provide a minimal set of required data elements to facilitate the interpretation and comparison of results across published clinical studies. The guidelines, summarized in the format of a checklist, may also have utility in the planning of clinical studies of DBS for PD as well as other neurological and psychiatric disorders. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The Resource Conservation and Recovery Act of 1976 (RCRA) assigns the Environmental Protection Agency responsibility for protecting the public from hazards created by industrial wastes. The Agency has understandably used its mandate to construct cradle to grave regulation of waste substances that pose health hazards. The regulations, however, are likely to hike costs of legal disposal by increasing the demand for disposal sites, while at the same time reducing the supply. The higher cost of disposal may give an advantage to larger, existing firms, may deter entry of new firms to both waste generating and disposal industries, and promote illicit disposal. RCRA therefore may have the paradoxical result of increasing public exposure to hazardous wastes. [ABSTRACT FROM AUTHOR]

This article discusses a study that compared the outcomes of using an automated motion sensor-based functional mapping (SBFM) system for deep brain stimulation (DBS) programming versus standard-of-care (SoC) programming with experienced clinicians. The study found that SBFM significantly reduced the number of settings tested and showed a trend towards shorter programming time and lower stimulation amplitude compared to SoC programming. Both groups showed significant improvements in symptoms, and SBFM achieved similar outcomes to SoC with fewer settings tested. The study suggests that SBFM can improve programming efficiency and extend expert programming strategies to populations without access to specialized DBS centers. The given document is a reference to a study titled "CLOVER-DBS: algorithm-guided deep brain stimulation programming based on external sensor feedback evaluated in a prospective, randomized, crossover, double-blind, two-center study." The study explores the use of an algorithm-guided deep brain stimulation programming technique called CLOVER-DBS. The study design and programming procedures are described in the supplementary materials. The document also mentions that additional supporting information can be found in the online version of the article. [Extracted from the article]