Background: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent. Methods: Patients from a single center with newly diagnosed glioblastoma (n = 7) underwent preoperative Q-space magnetic resonance imaging (QSI; 3T, 64 gradient directions, b = 1000 s/mm2) between 2018 and 2019. Tumors were manually segmented, and patterns of inter-voxel coherence spatially intersecting each segmentation were generated to represent tumor-associated tractography. One patient additionally underwent regional biopsy of diffusion tract- versus non-tract-associated tissue during tumor resection for RNA sequencing. Imaging data from this cohort were compared with a historical cohort of n = 66 glioblastoma patients who underwent similar QSI scans. Associations of tractography-derived metrics with survival were assessed using t-tests, linear regression, and Kaplan-Meier statistics. Patient-derived glioblastoma xenograft (PDX) mice generated with the sub-hippocampal injection of human-derived glioblastoma stem cells (GSCs) were scanned under high-field conditions (QSI, 7T, 512 gradient directions), and tumor-associated tractography was compared with the 3D microscopic reconstruction of immunostained GSCs. Results: In the principal enrollment cohort of patients with glioblastoma, all cases displayed tractography patterns with tumor-intersecting tract bundles extending into brain parenchyma, a phenotype which was reproduced in PDX mice as well as in a larger comparison cohort of glioblastoma patients (n = 66), when applying similar methods. Reconstructed spatial patterns of GSCs in PDX mice closely mirrored tumor-associated tractography. On a Kaplan-Meier survival analysis of n = 66 patients, the calculated intra-tumoral mean diffusivity predicted the overall survival (p = 0.037), as did tractography-associated features including mean tract length (p = 0.039) and mean projecting tract length (p = 0.022). The RNA sequencing of human tissue samples (n = 13 tumor samples from a single patient) revealed the overexpression of transcripts which regulate cell motility in tract-associated samples. Conclusions: QSI discriminates tumor-specific patterns of inter-voxel coherence believed to represent white matter pathways which may be susceptible to glioblastoma invasion. These findings may lay the groundwork for future work on therapeutic targeting, patient stratification, and prognosis in glioblastoma.

Gastroparesis is a chronic disorder characterized by a constellation of foregut symptoms, including postprandial nausea, vomiting, distension, epigastric pain, and regurgitation in the absence of gastric outlet obstruction. Despite considerable research over the past decades, there remains to be only nominal understanding of disease classification, diagnostic criteria, pathogenesis, and preferred therapy. We critically reassess current approaches for disease identification and stratification, theories of causation, and treatment for gastroparesis. Gastric scintigraphy, long considered a diagnostic standard, has been re-evaluated in light of evidence showing low sensitivity, whereas newer testing modalities are incompletely validated. Present concepts of pathogenesis do not provide a unified model linking biological impairments with clinical manifestations, whereas available pharmacological and anatomical treatments lack explicit selection criteria or evidence for sustained effectiveness. We propose a disease model that embodies the re-programming of distributed neuro-immune interactions in the gastric wall by inflammatory perturbants. These interactions, combined with effects on the foregut hormonal milieu and brain-gut axis, are postulated to generate the syndromic attributes characteristically linked with gastroparesis. Research linking models of immunopathogenesis with diagnostic and therapeutic paradigms will lead to reclassifications of gastroparesis that guide future trials and technological developments. • The term gastroparesis embodies a heterogenous array of symptoms and clinical findings based on a complex assimilation of afferent and efferent mechanisms, gastrointestinal locations, and pathologies. • There currently exists no single test or group of tests with sufficient capacity to be termed a definitional standard for gastroparesis. • Present research regarding pathogenesis suggests the importance of immune regulation of intrinsic oscillatory activity involving myenteric nerves, interstitial cells of Cajal, and smooth muscle cells. • Prokinetic pharmaceuticals remain the mainstay of management, although novel treatments are being studied that are directed to alternative muscle/nerve receptors, electromodulation of the brain-gut axis, and anatomical (endoscopic, surgical) interventions.

BACKGROUND:Global indices of right ventricle (RV) function provide limited insights into mechanisms underlying RV remodeling in pulmonary hypertension (PH). While RV myocardial architectural remodeling has been observed in PH, its effect on RV adaptation is poorly understood. METHODS:Hemodynamic assessments were performed in 2 rodent models of PH. RV free wall myoarchitecture was quantified using generalized Q-space imaging and tractography analyses. Computational models were developed to predict RV wall strains. Data from animal studies were analyzed to determine the correlations between hemodynamic measurements, RV strains, and structural measures. RESULTS:In contrast to the PH rats with severe RV maladaptation, PH rats with mild RV maladaptation showed a decrease in helical range of fiber orientation in the RV free wall (139º versus 97º; P=0.029), preserved global circumferential strain, and exhibited less reduction in right ventricular-pulmonary arterial coupling (0.029 versus 0.017 mm/mm Hg; P=0.037). Helical range correlated positively with coupling (P=0.036) and stroke volume index (P<0.01). Coupling correlated with global circumferential strain (P<0.01) and global radial strain (P<0.01) but not global longitudinal strain. CONCLUSIONS:Data analysis suggests that adaptive RV architectural remodeling could improve RV function in PH. Our findings suggest the need to assess RV architecture within routine screenings of PH patients to improve our understanding of its prognostic and therapeutic significance in PH.

The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1β increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1β also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1β induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1β induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.

BACKGROUND:Atherosclerosis is an arterial vessel wall disease characterized by slow, progressive lipid accumulation, smooth muscle disorganization, and inflammatory infiltration. Atherosclerosis often remains subclinical until extensive inflammatory injury promotes vulnerability of the atherosclerotic plaque to rupture with luminal thrombosis, which can cause the acute event of myocardial infarction or stroke. Current bioimaging techniques are unable to capture the pathognomonic distribution of cellular elements of the plaque and thus cannot accurately define its structural disorganization. METHODS:We applied cardiovascular magnetic resonance spectroscopy (CMRS) and diffusion weighted CMR (DWI) with generalized Q-space imaging (GQI) analysis to architecturally define features of atheroma and correlated these to the microscopic distribution of vascular smooth muscle cells (SMC), immune cells, extracellular matrix (ECM) fibers, thrombus, and cholesteryl esters (CE). We compared rabbits with normal chow diet and cholesterol-fed rabbits with endothelial balloon injury, which accelerates atherosclerosis and produces advanced rupture-prone plaques, in a well-validated rabbit model of human atherosclerosis. RESULTS:Our methods revealed new structural properties of advanced atherosclerosis incorporating SMC and lipid distributions. GQI with tractography portrayed the locations of these components across the atherosclerotic vessel wall and differentiated multi-level organization of normal, pro-inflammatory cellular phenotypes, or thrombus. Moreover, the locations of CE were differentiated from cellular constituents by their higher restrictive diffusion properties, which permitted chemical confirmation of CE by high field voxel-guided CMRS. CONCLUSIONS:GQI with tractography is a new method for atherosclerosis imaging that defines a pathological architectural signature for the atheromatous plaque composed of distributed SMC, ECM, inflammatory cells, and thrombus and lipid. This provides a detailed transmural map of normal and inflamed vessel walls in the setting of atherosclerosis that has not been previously achieved using traditional CMR techniques. Although this is an ex-vivo study, detection of micro and mesoscale level vascular destabilization as enabled by GQI with tractography could increase the accuracy of diagnosis and assessment of treatment outcomes in individuals with atherosclerosis.

Biomechanical relationships involving lingual myoanatomy, contractility, and bolus movement are fundamental properties of human swallowing. To portray the relationship between lingual deformation and bolus flow during swallowing, a weakly one-way solid-fluid finite element model (FEM) was derived employing an elemental mesh aligned to magnetic resonance diffusional tractography (Q-space MRI, QSI) of the human tongue, an arbitrary Lagrangian-Eulerian (ALE) formulation with remeshing to account for the effects of lingual surface (boundary) deformation, an implementation of patterned fiber shortening, and a computational visualization of liquid bolus flow. Representing lingual tissue deformation in terms of its 2D principal Lagrangian strain in the mid-sagittal plane, we demonstrated that the swallow sequence was characterized by initial superior-anterior expansion directed towards the hard palate, followed by sequential, radially directed, contractions of the genioglossus and verticalis to promote lingual rotation (lateral perspective) and propulsive displacement. We specifically assessed local bolus velocity as a function of viscosity (perfect slip conditions) and observed that a low viscosity bolus (5 cP) exhibited maximal displacement, surface spreading and local velocity compared to medium (110 cP, 300 cP) and high (525 cP) viscosity boluses. Analysis of local nodal velocity revealed that all bolus viscosities exhibited a bi-phasic progression, with the low viscosity bolus being the most heterogeneous and fragmented and the high viscosity bolus being the most homogenous and cohesive. Intraoral bolus cohesion was depicted in terms of the distributed velocity gradient, with higher gradients being associated with increased shear rate and bolus fragmentation. Lastly, we made a sensitivity analysis on tongue stiffness and contractility by varying the degree of extracellular matrix (ECM) stiffness through effects on the Mooney-Rivlin derived passive matrix and by varying maximum tetanized isometric stress, and observed that a graded increase of ECM stiffness was associated with reduced bolus spreading, posterior displacement, and surface velocity gradients, whereas a reduction of global contractility resulted in a graded reduction of obtainable accommodation volume, absent bolus spreading, and loss of posterior displacement. We portray a unidirectionally coupled solid-liquid FEM which associates myoarchitecture-based lingual deformation with intra-oral bolus flow, and deduce that local elevation of the velocity gradient correlates with bolus fragmentation, a precondition believed to be associated with aspiration vulnerability during oropharyngeal swallowing.

AbstractInfiltration with inflammatory T-cells and accumulation of cardiac myofibroblasts are hallmarks of cardiac fibrosis and maladaptive remodeling. The origin, identity, and functions of the resident cardiac cells involved in this process are, however, unclear. To determine the identity of cells contained in regions exhibiting fibrosis, mass cytometry profiling was performed using resident human ventricular cardiac fibroblasts and right ventricle autopsy tissues from individuals diagnosed with pulmonary hypertension and SUGEN/hypoxia rats. Results showed that a subpopulation of resident myocardial fibroblasts expresses increased levels of CD4+, a helper T-cell surface marker, in addition to mesenchymal markers in humans and rats. Characterization of the resident cardiac fibroblast subpopulation, both structurally and functionally, using transcriptome and secretome analysis of the secreted cytokines, chemokines, proteins, and metabolites, evidenced that IL-1β induces a phenotypic switch of human cardiac fibroblasts from mesenchymal to CD4+lymphoidal lineagein vitro. RNA sequencing (RNA-seq) analysis of FACS-sorted CD4-expressing cardiac fibroblasts further revealed that the transcriptome of such IL-1β-induced CD4+fibroblast population exhibited classical lymphoidal and stem cell-like signatures. Lastly, reversal of cell clustering, phosphorylation of MAPK p38 and NF-κB p65, and phenotypic switching was achieved with the administration of an IL-1R antagonist. In conclusion, we have identified a subpopulation of cardiac fibroblasts which exhibits structural and functional attributes of both mesenchymal and lymphoid cells which is induced by IL-1β-IL-1R-NFkB pathway for differentiation of cardiac fibroblast cells. These data suggest that cardiac fibroblast transdifferentiation during inflammation may form the basis for maladaptive remodeling during myocardial fibrosis.

Background Infiltration with inflammatory CD4+ T-cells and the accumulation of heterogeneous cardiac myofibroblasts are hallmarks of cardiac fibrosis and remodeling. The origin, identity, states, and functions of the resident cells involved in the transition from adaptive to maladaptive fibrotic remodeling, as well as the pathways of inflammatory regulation are unclear. Methods We performed mass cytometry profiling of resident human ventricular cardiac fibroblasts (hVCF) and determined the identity of cells contained in fibrotic right ventricle autopsy tissues from individuals diagnosed with pulmonary hypertension and tissue from SUGEN/hypoxia rats exhibiting cardiac fibrosis. We further characterized the resident cardiac fibroblast sub-population morphologically, structurally and functionally using transcriptome and secretome analysis of the secreted cytokines, chemokines, proteins, metabolites using milliplex panels, proteomics and metabolomics pipelines. Results Single-cell mass cytometry identified remarkable plasticity of resident human cardiac fibroblasts. We provide evidence of a sub-population of resident cardiac myofibroblasts expressing high levels of CD4+, a helper T-cell surface marker in addition to mesenchymal markers, αSMA and Vimentin in all the human donors. These cardiac cells co-expressing lymphoid CD4+and αSMA+ were localized to the fibrotic regions of the human right ventricular tissue and were a common feature in the interstitial and perivascular lesions of SUGEN/Hypoxia (SuHx) rats. CD3+CD4+ T-cell numbers were higher in the right ventricle compared with the left ventricle of SuHx, as determined by flow cytometry. In vitro , T-cell homing receptors CD44, Interleukin-1 receptor (IL-1R), and CCR2 were upregulated in cardiac fibroblasts in response to IL-1β. Exposure of cardiac fibroblasts to IL-1β led to upregulation of genes regulating extracellular matrix, collagen deposition and inflammation-related genes, and induced secretion of cytokines, chemokines, and metabolites involved in innate and adaptive humoral immune responses. Cell clustering, elevated phosphorylation of MAPK p38 and inflammatory NF-κB p65 and cell phenotype switching upon IL-1β stimulation reverted with the administration of an IL-1R antagonist. Conclusions Our data expand concepts of heterogeneity of resident cardiac fibroblasts and plasticity in response to pro-inflammatory cytokines by the demonstration of a unique subpopulation of cardiac fibroblasts exhibiting attributes of both mesenchymal and lymphoid cells. Exposure of cardiac fibroblasts to the pro-inflammatory cytokine, IL-1β, induces a robust phenotypic response linked to extracellular matrix deposition and up-regulates an immune-associated phenotype linked to expression of immune markers and secretion of immunomodulatory cytokines and chemokines. We also propose that resident cardiac fibroblast transdifferentiation and phenotype switching maybe the key process involved in adaptive to maladaptive remodeling leading to fibrosis and failure. ### Competing Interest Statement The authors have declared no competing interest. * CD4 : Cluster of differentiation αSMA : alpha smooth muscle actin IL-1R : Interleukin-1-receptor CCR2 : C-X-C Motif Chemokine Receptor 2

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N′)-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C∆C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N′-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N′-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.

Fear of the viral syndrome severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) termed COVID-19 (ie, coronavirus disease 2019)1World Health OrganizationNaming the coronavirus disease (COVID-19) and the virus that causes it.https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-itDate accessed: May 1, 2020Google Scholar is real. Government mandates intended to reduce the rate of transmission, such as social distancing (read as physical distancing), community lock-downs, and public masking, are the only options available for containment.2Kai D, Goldstein G-P, Morgunov A, Nangalia V, Rotkirch A. Universal masking is urgent in the COVID-19 pandemic: SEIR and agent based models, empirical validation, policy recommendations. arXiv. 2020, 200413553.Google Scholar, 3Howard J, Huang A, Li Z, et al. Face masks against COVID-19: an evidence review, Preprints. 2020, 2020040203.Google Scholar, 4Wilder-Smith A. Freedman D.O. Isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-nCoV) outbreak.J Travel Med. 2020; 27 (taaa020)Crossref Scopus (1441) Google Scholar This new normal, amid the constant threat of COVID-19, has led to an upheaval in rehabilitation care, forcing us to rethink the manner in which we deliver it. The virus is with us and will likely remain so, even when the more stringent methods of disease mitigation have been lifted. Rehabilitation professionals work physically close with patients, caregivers too. Health care professionals who make a living assessing and treating the oropharynx, nasopharynx, larynx, and upper and lower airways, the anatomical epicenters of the SARS-CoV-2 virus, share the responsibility for constructive clinical engagement. Specific to dysphagia assessment, highly affected geographical regions have limited use of the gold standards—videofluoroscopic swallow study (VFSS) and flexible endoscopic evaluation of swallowing (FEES). Less affected regions have adjusted practice to address safety concerns. Under the current regime, guided by professional societies down to departments of clinicians, VFSS and FEES are considered: (1) aerosol generating procedures5American Speech-Language-Hearing AssociationASHA guidance to SLPs regarding aerosol generating procedures.https://www.asha.org/slp/healthcare/asha-guidance-to-slps-regarding-aerosol-generating-procedures/Date accessed: May 10, 2020Google Scholar, 6Dysphagia Research SocietyCOVID-19 information and resources: risk management of AGPs for dysphagia care.https://www.dysphagiaresearch.org/page/COVID19AGPsDate accessed: May 8, 2020Google Scholar, 7Bolton L, Brady G, Coffeey M, et al. Speech and language therapist-led endoscopic procedures in the COVID-19 pandemic 2020. Available at: https://www.rcslt.org/-/media/docs/Covid/RCSLT-COVID-19-SLT-led-endoscopic-procedure-guidance_FINAL-(2).PDF?la=en&hash=8101575091FE8F1ABA41B4B472387DAFB023A39D. Accessed May 7, 2020.Google Scholar and (2) elective procedures (defined as neither emergent nor urgent for medical care7Bolton L, Brady G, Coffeey M, et al. Speech and language therapist-led endoscopic procedures in the COVID-19 pandemic 2020. Available at: https://www.rcslt.org/-/media/docs/Covid/RCSLT-COVID-19-SLT-led-endoscopic-procedure-guidance_FINAL-(2).PDF?la=en&hash=8101575091FE8F1ABA41B4B472387DAFB023A39D. 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Prevalence, pathophysiology, diagnostic modalities and treatment options for dysphagia in critically ill patients.Am J Phys Med Rehabil. 2020 Apr 16; ([Epub ahead of print])Crossref PubMed Scopus (40) Google Scholar Moreover, if we take the perspective that all patients with a potentially compromised (ie, vulnerable) airway may be carriers of SARS-CoV-2 (ie, person under investigation12Centers for Disease Control and PreventionInformation for health departments on reporting cases of COVID-19.https://www.cdc.gov/coronavirus/2019-ncov/php/reporting-pui.htmlDate accessed: May 1, 2020Google Scholar), determining a safe swallow of foods and liquids may be less relevant than quantifying the degree of airway risk. In this light, VFSS and FEES are both insufficient and unsafe. We are caught in a clinical time warp, assessing patients with little more than clinical examinations. How do we resume evaluations of swallowing and airway protection in this post-COVID-19 world? We could consider risk stratification of airway vulnerability with noninvasive imaging and noninvasive metrics. Assessments could include such swallowing characteristics as laryngeal structure and dynamics, lingual deformation during swallowing, airway compromise during swallowing, and efficiency of swallowing physiology. Among the methods that address these characteristics are noninvasive imaging,13Ekprachayakoon I. Miyamoto J.J. Inoue-Arai M.S. et al.New application of dynamic magnetic resonance imaging for the assessment of deglutitive tongue movement.Prog Orthod. 2018; 19: 45Crossref PubMed Scopus (4) Google Scholar,14Ohkubo M. Scobbie J.M. Tongue shape dynamics in swallowing using sagittal ultrasound.Dysphagia. 2019; 34: 112-118Crossref PubMed Scopus (12) Google Scholar strength or somatosensory testing,15Butler S.G. Stuart A. 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Associations between spontaneous swallowing frequency at admission, dysphagia, and stroke-related outcomes in acute care.Arch Phys Med Rehabil. 2019; 100: 1283-1288Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Still largely being developed and what many might consider not ready for prime time, none of these methods have been substantively tested in the clinical setting. Characterizing pathology across the spectrum of diseases, distinguishing macroscale from microscale aspiration, and quantitative assessment of airway vulnerability and its risk of pneumonia using tools with translatable and reproducible metrics to clinical outcomes are needed—now more than ever. We must embrace noninvasive testing of swallowing and airway safety. Combining a detailed medical history, validated patient-reported symptoms inventory, and cranial nerve examination are a good start, but with variable reliability,38McCullough G.H. Wertz R.T. Rosenbek J.C. Mills R.H. Ross K.B. Ashford J.R. Inter- and intrajudge reliability of a clinical examination of swallowing in adults.Dysphagia. 2000; 15: 58-67Crossref PubMed Scopus (80) Google Scholar but this cannot be all there is. We need to work constructively with industry and regulatory bodies to develop and test inventions for routine, value-based care. Health care, especially rehabilitation, is dynamic. This necessitates continued engagement with third-party payors, including state and federal governments, to welcome and respond to these changes. Skepticism and reluctance need to be quelled when innovation and onboarding must be the ever-present themes. "We've always done it that way" never was an acceptable ideology. Outpatient visits have been severely restricted, redirecting resources to address acute care hospitalization demands. This will continue for some time after the curve has been flattened. In the months and years that follow, when supplies are restored and personnel resume business as usual, we will endeavor to overcome the economic burden of this medical tragedy. Stimulus packages to individuals will not make a dent in the medical bills many thousands of patients face posthospitalization needing rehabilitation. The rehabilitation burden is only at the beginning, severely lagging the onslaught of hospitalizations climbing as high as 31% in the United States.39Koh G.C.-H. Hoenig H. How should the rehabilitation community prepare for 2019-nCoV?.Arch Phys Med Rehabil. 2020; 101: 1068-1071Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 40Grabowski D.C. Joynt Maddox K.E. Postacute care preparedness for COVID-19: thinking ahead.JAMA. 2020 Mar 25; ([Epub ahead of print])Crossref PubMed Scopus (123) Google Scholar, 41Kiekens C. Boldrini P. Andreoli A. et al.Rehabilitation and respiratory management in the acute and early post-acute phase. "Instant paper from the field" on rehabilitation answers to the Covid-19 emergency.Eur J Phys Rehabil Med. 2020 Apr 15; ([Epub ahead of print])Crossref Scopus (128) Google Scholar, 42Johns Hopkins University and MedicineCoronavirus Resource Center.https://coronavirus.jhu.edu/map.htmlDate accessed: May 1, 2020Google Scholar Worse, the economics of rehabilitation are far-reaching, impacting many professions and patients, all with no end in sight.43Lo J. Chan L. Flynn S. A systematic review of the incidence, prevalence, costs, and activity/work limitations of amputation, osteoarthritis, rheumatoid arthritis, back pain, multiple sclerosis, spinal cord injury, stroke, and traumatic brain injury in the United States: a 2019 update.Arch Phys Med Rehabil. 2020 Apr 24; ([Epub ahead of print])PubMed Google Scholar,44Lord R.K. Mayhew C.R. Korupolu R. et al.ICU early physical rehabilitation programs: financial modeling of cost savings.Crit Care Med. 2013; 41: 717-724Crossref PubMed Scopus (153) Google Scholar Strokes, for example, have not stopped since the pandemic began; rather, they have increased.45Helms J. Tacquard C. Severac F. et al.High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.Intensive Care Med. 2020; : 1-10Google Scholar,46Markus H.S. Brainin M. COVID-19 and stroke-a global World Stroke Organization perspective.Int J Stroke. 2020; 15: 361-364Crossref PubMed Scopus (285) Google Scholar Dysphagia is no different,47Patel D.A. Krishnaswami S. Steger E. et al.Economic and survival burden of dysphagia among inpatients in the United States.Dis Esophagus. 2018; 31: 1-7Crossref PubMed Scopus (123) Google Scholar never mind the ongoing threat of airway invasion in the context of weakness from both SARS-CoV-2 and acute care hospitalization. Patients need follow-up, but we must mitigate the challenges of treating patients when physical contact may be harmful for all involved. Creativity and resourcefulness are needed to meet patients' needs. Enter telehealth. Various applications, including electronic medical records systems and video conferencing platforms, are being used to deliver health care, many long before the SARS-CoV-2 outbreak. Remote methods of assessing or treating dysphagia are nearly 20 years old.48Perlman A.L. Witthawaskul W. Real-time remote telefluoroscopic assessment of patients with dysphagia.Dysphagia. 2002; 17: 162-167Crossref PubMed Scopus (33) Google Scholar, 49Malandraki G.A. McCullough G. He X. McWeeny E. Perlmana A.L. Teledynamic evaluation of oropharyngeal swallowing.J Speech Lang Hear Res. 2011; 54: 1497-1505Crossref PubMed Scopus (44) Google Scholar, 50Ciucci M. Jones C.A. Malandraki G.A. Hutcheson K.A. Dysphagia practice in 2035: beyond fluorography, thickener, and electrical stimulation.Semin Speech Lang. 2016; 37: 201-218Crossref PubMed Scopus (24) Google Scholar Such methods may not be standardized or generally implemented in clinical settings due to technological insufficiencies, lack of training, and issues related to billing and reimbursement. Moreover, telehealth may not be a panacea or used for all patient populations.51Nordio S. Innocenti T. Agostini M. Meneghello F. Battel I. The efficacy of telerehabilitation in dysphagic patients: a systematic review.Acta Otorhinolaryngol Ital. 2018; 38: 79-85Crossref PubMed Scopus (16) Google Scholar, 52Weidner K. Lowman J. Telepractice for adult speech-language pathology services: a systematic review.Perspect ASHA Spec Interest Groups. 2020; 5: 326-338Crossref Google Scholar, 53American Speech-Language-Hearing AssociationTelepractice services and coronavirus/COVID-19.https://www.asha.org/Practice/Telepractice-Services-and-Coronavirus/Date accessed: May 10, 2020Google Scholar Despite these apparent limitations, patients are still able to follow-up with providers and at least receive limited care where they would otherwise be refused care until systems for reentry and clinical pathways are more established. At the time of printing, specifically in the United States, Medicare temporarily waived requirements in 42 CFR §484.55(a)(2) and §484.55(b)(3), permitting speech-language pathologists to remotely evaluate and treat speech production and fluency, language comprehension, and voice (CPT 92507-08, 92521-24),54Centers for Medicare and Medicaid ServicesList of telehealth services.https://www.cms.gov/Medicare/Medicare-General-Information/Telehealth/Telehealth-CodesDate accessed: May 10, 2020Google Scholar,55American Speech-Language-Hearing AssociationProviding telehealth services under Medicare during the COVID-19 pandemic.https://www.asha.org/Practice/reimbursement/medicare/Providing-Telehealth-Services-Under-Medicare-During-the-COVID-19-Pandemic/#SLPDate accessed: May 10, 2020Google Scholar yet clinical swallowing evaluations (CPT 92610) and swallowing treatment (CPT 92526) remain not covered.54Centers for Medicare and Medicaid ServicesList of telehealth services.https://www.cms.gov/Medicare/Medicare-General-Information/Telehealth/Telehealth-CodesDate accessed: May 10, 2020Google Scholar,55American Speech-Language-Hearing AssociationProviding telehealth services under Medicare during the COVID-19 pandemic.https://www.asha.org/Practice/reimbursement/medicare/Providing-Telehealth-Services-Under-Medicare-During-the-COVID-19-Pandemic/#SLPDate accessed: May 10, 2020Google Scholar Medicare beneficiaries, 64 million in 2019,56Kaiser Family FoundationMedicare advantage.https://www.kff.org/medicare/fact-sheet/medicare-advantage/Date accessed: May 1, 2020Google Scholar have a forced choice: (1) suffer with dysphagia while hoping for spontaneous recovery and fear the worst-case scenario of being rehospitalized with pneumonia due to impaired airway safety, or (2) pay out-of-pocket for telehealth services that—currently—will not be reimbursed, further straining personal economics and still risk rehospitalization with pneumonia due to impaired airway safety. All of these limitations now can be reconsidered. Wearable technologies allow clinicians to remotely assess minute-to-minute physiological performance (eg, swallowing frequency) or monitor physiochemical components of exhaled air as a metric of aspiration. These technologies for dysphagia are not clinical realities; telehealth is the best we have. In the end, distinguishing between clinical practice and innovation is a false choice. Clinicians are responsible for meeting the challenge of COVID-19 by identifying new methods wherever they exist. Researchers must strive to find clinical relevance to match their innovations. SARS-CoV-2 has dictated that those who manage dysphagia must evolve. And so, we shall. We thank Michael A. Crary, PhD, for his assistance with this editorial.

The investigation of healthy and diseased muscle behavior via in silico analysis requires the modeling of biophysical processes on multiple spatial and temporal scales. Owing to the complexity of the phenomena in question, simultaneous simulations of all the processes across different scales are extremely computationally expensive. Therefore, many multi-scale models utilize simplified phenomenological models at the micro level. However, such models may not be able to predict transient contractile behavior accurately when the deformation is unsteady or non-uniform. To overcome these deficiencies of phenomenological models, we propose a novel multi-scale muscle model in which continuum muscle mechanics are modeled utilizing the finite element method, and the material characteristics of muscle tissues at the microscopic scale are defined by Huxley’s model of muscle contraction. Owing to the specific application of the sliding-filament theory coupled with the kinetic formulation of Gordon’s length-tension relationship, the proposed model can provide more precise simulations of muscle behavior under both isotonic and transient conditions. The proposed model is verified using both benchmark data and real-world examples, and the results are compared to corresponding predictions obtained using the FE-Hill model. Specific implementations of biophysical components at the muscle fiber scale are validated by comparing them to predictions obtained using a spatially explicit molecular model implemented on the MUSICO platform. To enable the execution of two-scale simulations in a reasonable timeframe, we utilize a custom-tailored parallelization platform called Mexie. The ability of the proposed model to describe tissue-scale motor system behavior and the efficiency of its parallel execution are demonstrated through simulations of tongue movement during the propulsive phase of human swallowing. In these simulations the tissue’s complex muscular structure is represented by a 2D finite element mesh. The proposed model provides tools for the scientific investigation of musculoskeletal disorders and facilitates the prospective development of clinical applications for characterizing neuromuscular disorders and monitoring disease progression during therapy.

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25–base pair deletion in intron 32 of MYBPC3 (MYBPC3Δ25bp) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3Δ25bp carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3Δ25bp variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3Δ25bp pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.

Pulmonary arterial hypertension (PAH) is a syndrome diagnosed by increased mean pulmonary artery (PA) pressure and resistance and normal pulmonary capillary wedge pressure. PAH is characterized pathologically by distal pulmonary artery remodeling, increased pulmonary vascular resistance, and plexiform lesions (PLs). Right ventricular fibrosis and hypertrophy, leading to right ventricular failure, are the main determinants of mortality in PAH. Recent work suggests that right ventricular fibrosis results from resident cardiac fibroblast activation and conversion to myofibroblasts, leading to replacement of contractile cardiomyocytes with nondistensible tissue incapable of conductivity or contractility. However, the origins, triggers, and consequences of myofibroblast expansion and its pathophysiological relationship with PAH are unclear. Recent advances indicate that signals generated by adaptive and innate immune cells may play a role in right ventricular fibrosis and remodeling. This review summarizes recent insights into the mechanisms by which adaptive and innate immune signals participate in the transition of cardiac fibroblasts to activated myofibroblasts and highlights the existing gaps of knowledge as relates to the development of right ventricular fibrosis.

Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is essential for normal heart function and protects the heart from ischemia-reperfusion (I/R) injury. It is known that protein kinase-A (PKA)-mediated phosphorylation of cMyBP-C prevents I/R-dependent proteolysis, whereas dephosphorylation of cMyBP-C at PKA sites correlates with its degradation. While sites on cMyBP-C associated with phosphorylation and proteolysis co-localize, the mechanisms that link cMyBP-C phosphorylation and proteolysis during cardioprotection are not well understood. Therefore, we aimed to determine if abrogation of cMyBP-C proteolysis in association with calpain, a calcium-activated protease, confers cardioprotection during I/R injury. Calpain is activated in both human ischemic heart samples and ischemic mouse myocardium where cMyBP-C is dephosphorylated and undergoes proteolysis. Moreover, cMyBP-C is a substrate for calpain proteolysis and cleaved by calpain at residues 272-TSLAGAGRR-280, a domain termed as the calpain-target site (CTS). Cardiac-specific transgenic (Tg) mice in which the CTS motif was ablated were bred into a cMyBP-C null background. These Tg mice were conclusively shown to possess a normal basal structure and function by analysis of histology, electron microscopy, immunofluorescence microscopy, Q-space MRI of tissue architecture, echocardiography, and hemodynamics. However, the genetic ablation of the CTS motif conferred resistance to calpain-mediated proteolysis of cMyBP-C. Following I/R injury, the loss of the CTS reduced infarct size compared to non-transgenic controls. Collectively, these findings demonstrate the physiological significance of calpain-targeted cMyBP-C proteolysis and provide a rationale for studying inhibition of calpain-mediated proteolysis of cMyBP-C as a therapeutic target for cardioprotection.

Editorial FocusThe potential role of neddylation in pre- and postnatal cardiac remodelingSakthivel Sadayappan and Richard J. GilbertSakthivel SadayappanHeart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio and Richard J. GilbertResearch Service, Providence Veterans Affairs Medical Center and Brown University, Providence, Rhode IslandPublished Online:16 Jul 2019https://doi.org/10.1152/ajpheart.00260.2019This is the final version - click for previous versionMoreSectionsPDF (566 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat BIOLOGICAL CONTINUUM OF NEDDYLATION AND DENEDDYLATIONNeddylation is a reversible posttranslational modification involving the ubiquitin-like protein, NEDD8, acting in dynamic balance with enzyme-regulated deneddylation (5). Neddylation is analogous to ubiquitination in that it relies on its own E1 and E2 enzymes and it is involved in diverse cellular processes, such as proliferation, survival, inflammation, and apoptosis. As a result of neddylation, substrate DNA or proteins become either functional or dysfunctional and thereby modulate fundamental processes like transcription, ribosomal biogenesis, subcellular localization of various proteins, protein stability, and targeted proteolysis (6). Similar to ubiquitination, neddylation involves a cascade of NEDD8-associated activating enzyme E1, conjugating enzyme E2, and substrate-specific E3 ligases (4). Ubiquitination and neddylation are mutually inclusive; hence, the two protein modifications can be considered cooperative. For example, the cullin-RING ubiquitin ligase protein complex is modified by neddylation for efficient ubiquitination and plays an essential role in targeting proteins for selective ubiquitin-mediated destruction. Among other neddylation targets identified to date (namely, Mdm2, parkin, ubiquitin, HuR, p53, HIF1α, and Smurf1), HuR, an oncogenic RNA-binding protein, may be modified by NEDD8 to affect cell proliferation and survival. Yet such neddylation of HuR can also prevent its ubiquitination, thereby increasing its stability and nuclear localization (3). With the acknowledgment of the dynamic and complex nature of these reactions, neddylation may have different effects on various cellular targets based on the stage of maturation. Lastly, neddylation may be linked to multiple other diseases, notably cancer, neurodegenerative disorders, and cardiac disease (6). Strikingly, MLN4924 (Pevonedistat), a selective inhibitor of neddylation, has shown promise in cancer treatment (8). While neddylation is a key player in multiple biological processes (Fig. 1), including organogenesis of the heart, little is currently known of its role in the evolution of cardiac morphology and its impact on the development of heart disease.Fig. 1.Schematic illustration demonstrating the expression level of NEDD8 (A) and impact of NEDD8 inhibition (B) on cardiac development. Studies in the literature show that expression of NEDD8 is very high during embryogenesis and early neonatal stage in the heart. However, such expression level decreases at the adult stage (15), which is consistent with increased cardiomyocyte proliferation. When compared with that in the adult stage, inhibition of NEDD8 significantly affects cardiac development at the neonatal stage. The effects of NEDD8 inhibition by MLN4924 are indicated in B. Furthermore, Zou et al. (16) showed that postnatal inhibition predisposed adults to more severe isoproterenol (Iso)-induced cardiomyopathy.Download figureDownload PowerPointDIVERSE CELLULAR TARGETS OF NEDDYLATION AND NEDDYLATION INHIBITIONNEDD8 expresses in diverse organs, such as brain, kidney, colon, spleen, endocrine tissues, lung, skeletal and heart muscles, and adipocytes. Importantly, neddylation and deneddylation play a major role in brain development and function, including neurons and neural progenitor cells. Dysfunction of the ubiquitin-dependent proteolysis pathway may be associated with neurodegenerative diseases, especially in the setting of Alzheimer's disease (2) and cancer. Mechanisms regulating neddylation and deneddylation in vivo depend on covalent binding of NEDD8 substrates via a COOH-terminal glycine on NEDD8 to a lysine of the target protein (10). The direct effects of neddylation include conformational changes that preclude association with other posttranslational modifications and provide a novel binding site to recruit new NEDD8-interacting proteins. Significantly, NEDD8 is highly expressed in cardiac and skeletal muscles and appears in these settings to have a notable role in the regulation of various physiological and pathological conditions (14).STRESS-INDUCED CARDIAC REMODELING ACCENTUATED BY INHIBITION OF NEDDYLATIONIn a recent article published in the American Journal of Physiology-Heart and Circulatory Physiology, Zou et al. (16) propose that in addition to its dominant role in regulating embryonic cardiac development, neddylation may also be important in postnatal cardiac development and the heart's response to injury. This study used a selective neddylation inhibitor, MLN4924, to block neddylation at postnatal (P) days 1, 3, and 5, then assessed cardiac structure and function during the postnatal and adult phases of maturation, and following stress, associated with isoproterenol (Iso) infusion in adult rats. Results from these studies showed that MLN4924-treated neonatal rats developed cardiomyopathy by P7 days, but significantly that inhibition of neddylation in the neonatal phase caused exacerbated pathological cardiac remodeling and dilated cardiomyopathy following Iso infusion in adults.These results affirm that MLN4924 treatment can induce cardiac hypertrophy and enhance pathological remodeling and dysfunction in neonatal rats and predispose to stress-induced heart failure in adults. The study also demonstrated that MLN4924 administration to neonatal rat hearts significantly reduced the mitotic marker phospho-histone H3 and 5-ethynyl-2′-deoxyuridine (EdU)-positive cells. These data suggest that inhibition of neddylation in neonatal hearts prevents cardiomyocyte proliferation, which, in turn, leads to increased heart wt-to-body wt ratio (16). Such an inhibition of neddylation in postnatal days is expected to delay cardiomyocyte proliferation by blocking nonreplicative DNA synthesis, which is essential for maintaining sufficient binucleation of cardiomyocytes in the adult heart after 8 wk of age. Furthermore, inhibition of neddylation up to P14 is expected to interfere with DNA synthesis and cardiomyocyte proliferation. Alternatively, MLN4924 could impair HIF1α signaling (16). Neddylation of cullin 2 promotes HIF1α degradation, which is the key pathway for switching fetal-type glycolytic to adult-type oxidative metabolism in the heart (9). By an inhibition of neddylation, the level of HIF1α could accumulate and reduce oxidative metabolism in the heart.The current findings of Zou et al. (16) support the contention that inhibition of neddylation during postnatal development subsequently predisposes adult hearts to cardiac compromise under stress conditions. As further support of this phenomenon, a recent study from the same group demonstrated that cardiac-specific knockout of NAE1, a subunit of the E1 neddylation-activating enzyme, results in myocardial hypoplasia, ventricular noncompaction, heart failure, and perinatal lethality (15). To validate the necessity and sufficiency of neddylation in neonatal and adult heart development and function, MLN4924 and its targets should be studied using genetically engineered animal models (7). In the aggregate, this study supports the notion that regulation of neddylation, along a continuum of potential effects on cardiac myocyte proliferation, is instrumental during neonatal cardiac development as well as during the process of stress-induced remodeling in adults (16).POSSIBLE TOXICITY ASSOCIATED WITH NEDDYLATION INHIBITION USING MLN4924MLN4924 is a first-in-class selective inhibitor of NEDD8-activating enzyme with a half-maximal inhibitory concentration of (IC50) = 0.004 μM (13). MLN4924 specifically suppresses the growth of human tumors by inhibiting neddylation, which results in the inhibition of apoptotic cell death and cellular senescence. However, MLN4924 has no effect on newly synthesized proteins and ATP-using enzymes, suggesting its specificity to NEDD8-activating enzymes. Mice administered with MLN4924 (30 mg/kg sc) twice a day (with an interval of 12 h) for 3 consecutive days, totaling 6 injections, showed no structural or functional cardiac abnormalities such as cardiac hypertrophy or atrophy (11). Consistently, the results of phase I clinical trials using MLN4924 in patients with relapsed/refractory multiple myeloma or lymphoma showed no cardiac toxicity (12). In contrast, Zou et al. (16) demonstrated that MLN4924 injected (30 mg/kg) via the intraperitoneal route at P1, -3, and -5 in rats resulted in cardiac hypertrophy and dysfunction at P7. The difference between the results of Zou et al. (16) and Reihe et al. (11) is the age of mice versus rats, respectively, at the time of MLN4924 injection. Cullin-3, one of the substrates of NEDD8, regulates vascular smooth muscle and endothelial cells via neddylation to promote angiogenesis and cardiac development. Alternatively, inhibition of neddylation by MLN4924 improves neointimal hyperplasia and promotes apoptosis of vascular smooth muscle cells (1), thus making it possible to further decrease the rate of restenosis after percutaneous coronary intervention. MLN4924 has also been shown to increase autophagic flux by decreasing p62 protein levels in the brain (11), a finding that may contradict other reports that MLN4924 may induce p62 expression and apoptosis in vascular smooth muscle cells.CONCLUSIONSWhile evidence has long suggested the importance in maintaining an appropriate balance of neddylation and deneddylation in the neonatal heart, it is now increasingly clear that the regulation of neddylation is an emerging field in the context of cardiovascular health and disease at all stages of maturation. The regulation of neddylation in the heat is however poorly understood. Therefore, further studies should be undertaken to systematically characterize the impact of selective inhibition of neddylation by cell type and stage of development. Such studies should consider in particular the development of cardiac-specific or organ-specific inhibition of neddylation to selectively treat diseases, while avoiding side effects and toxicity.GRANTSS. Sadayappan has received support from National Institutes of Health Grants R01-HL-130356, R56-HL-139680, R01-AR-067279, R01-HL-105826, and R01-HL-143490; American Heart Association 2019 Institutional Undergraduate Student Grant 19UFEL34380251 and transformation Grant 19TPA34830084); and MyoKardia, Merck and Amgen. R. J. Gilbert has received support from National Institutes of Health Grant R56-HL-139680.DISCLOSURESS. Sadayappan provided consulting and collaborative research studies to the Leducq Foundation, MyoKardia, Merck and Amgen, but such work is unrelated to the content of this manuscript. No other disclosures are reported.AUTHOR CONTRIBUTIONSS.S. conceived and designed research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, and drafted manuscript; S.S. and R.J.G. edited, revised, and approved final version of manuscript.REFERENCES1. Ai TJ, Sun JY, Du LJ, Shi C, Li C, Sun XN, Liu Y, Li L, Xia Z, Jia L, Liu J, Duan SZ. Inhibition of neddylation by MLN4924 improves neointimal hyperplasia and promotes apoptosis of vascular smooth muscle cells through p53 and p62. Cell Death Differ 25: 319–329, 2018. doi:10.1038/cdd.2017.160. Crossref | PubMed | ISI | Google Scholar2. Chen Y, Neve RL, Liu H. Neddylation dysfunction in Alzheimer's disease. J Cell Mol Med 16: 2583–2591, 2012. doi:10.1111/j.1582-4934.2012.01604.x. Crossref | PubMed | ISI | Google Scholar3. 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Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationRelated articlesTransient inhibition of neddylation at neonatal stage evokes reversible cardiomyopathy and predisposes the heart to isoproterenol-induced heart failure 24 May 2019American Journal of Physiology-Heart and Circulatory Physiology More from this issue > Volume 317Issue 2August 2019Pages H276-H278 https://doi.org/10.1152/ajpheart.00260.2019PubMed31274350History Received 1 May 2019 Accepted 3 July 2019 Published online 16 July 2019 Published in print 1 August 2019 Metrics Downloaded 400 times

While it is recognized that the overall resistance of glioblastoma to treatment may be related to intra-tumor patterns of structural heterogeneity, imaging methods to assess such patterns remain rudimentary. Methods: We utilized a generalized Q-space imaging (GQI) algorithm to analyze magnetic resonance imaging (MRI) derived from a rodent model of glioblastoma and 2 clinical datasets to correlate GQI, histology, and survival. Results: In a rodent glioblastoma model, GQI demonstrated a poorly coherent core region, consisting of diffusion tracts < 5 mm, surrounded by a shell of highly coherent diffusion tracts, 6-25 mm. Histologically, the core region possessed a high degree of necrosis, whereas the shell consisted of organized sheets of anaplastic cells with elevated mitotic index. These attributes define tumor architecture as the macroscopic organization of variably aligned tumor cells. Applied to MRI data from The Cancer Imaging Atlas (TCGA), the core-shell diffusion tract-length ratio (c/s ratio) correlated linearly with necrosis, which, in turn, was inversely associated with survival (p = 0.00002). We confirmed in an independent cohort of patients (n = 62) that the c/s ratio correlated inversely with survival (p = 0.0004). Conclusions: The analysis of MR images by GQI affords insight into tumor architectural patterns in glioblastoma that correlate with biological heterogeneity and clinical outcome.

Vibrational spectroscopy is a powerful analytical tool that assesses molecular properties based on spectroscopic signatures. In this study, the effect of gold nanoparticle morphology (spherical vs multi-branched) was assessed for the characterization of a Raman signal (ie, molecular fingerprint) that may be helpful for numerous medical applications. Multibranched gold nanoparticles (MBAuNPs) were fabricated using a green chemistry method which employed the reduction of gold ion solute by 2-[4-(2-hydroxyethyl)-1-piperazyl] ethane sulfonic acid. Two types of reporter dyes, indocyanine (IR820 and IR792) and carbocyanine (DTTC [3,3'-diethylthiatricarbocyanine iodide] and DTDC [3,3'-diethylthiadicarbocyanine iodide]), were functionalized to the surface of the MBAuNPs and stabilized with denatured bovine serum albumin, thus forming the surface-enhanced Raman spectroscopy tag. Fluorescein isothiocyanate-conjugated anti-epidermal growth factor receptor to the surface-enhanced Raman spectroscopy tags and the properties of the resulting conjugates were assessed through determination of the Raman signal. Using the MBAuNP Raman probes synthesized in this manner, we demonstrated that MBAuNP provided significantly more surface-enhanced Raman scattering signal when compared with the associated spherical gold nanoparticle of similar size and concentration. MBAuNP enhancements were retained in the surface-enhanced Raman spectroscopy tags complexed to anti-epidermal growth factor receptor, providing evidence that this could be a useful biological probe for enhanced Raman molecular fingerprinting. Furthermore, while utilizing IR820 as a novel reporter dye linked with MBAuNP, superior Raman signal fingerprint results were obtained. Such results provide significant promise for the use of MBAuNP in the detection of numerous diseases for which biologically specific surface markers exist.

Conventional inhaled NO systems deliver NO by synchronized injection or continuous NO flow in the ventilator circuitry. Such methods can lead to variable concentrations during inspiration that may differ from desired dosing. NO concentrations in these systems are generally monitored through electrochemical methods that are too slow to capture this nuance and potential dosing error. A novel technology that reduces NO2 into NO via low-resistance ascorbic-acid cartridges just prior to inhalation has recently been described. The gas volume of these cartridges may enhance gas mixing and reduce dosing inconsistency throughout inhalation. The impact of the ascorbic-acid cartridge technology on NO concentration during inspiration was characterized through rapid chemiluminescence detection during volume control ventilation, pressure control ventilation, synchronized intermittent mandatory ventilation and continuous positive airway pressure using an in vitro lung model configured to simulate the complete uptake of NO. Two ascorbic acid cartridges in series provided uniform and consistent dosing during inspiration during all modes of ventilation. The use of one cartridge showed variable inspiratory concentration of NO at the largest tidal volumes, whereas the use of no ascorbic acid cartridge led to highly inconsistent NO inspiratory waveforms. The use of ascorbic acid cartridges also decreased breath-to-breath variation in SIMV and CPAP ventilation. The ascorbic-acid cartridges, which are designed to convert NO2 (either as substrate or resulting from NO oxidation during injection) into NO, also provide the benefit of minimizing the variation of inhaled NO concentration during inspiration. It is expected that the implementation of this method will lead to more consistent and predictable dosing. (C) 2016 Elsevier Inc. All rights reserved.