Tele-Operative Low-Cost Robotic Lung Ultrasound Scanning Platform for Triage of COVID-19 Patients.

Novel severe acute respiratory syndrome coronavirus 2 (COVID-19) has become a pandemic of epic proportions, and global response to prepare health systems worldwide is of utmost importance. 2-dimensional (2D) lung ultrasound (LUS) has emerged as a rapid, noninvasive imaging tool for diagnosing COVID-19 infected patients. Concerns surrounding LUS include the disparity of infected patients and healthcare providers, and importantly, the requirement for substantial physical contact between the patient and operator, increasing the risk of transmission. New variants of COVID-19 will continue to emerge; therefore, mitigation of the virus's spread is of paramount importance. A tele-operative robotic ultrasound platform capable of performing LUS in COVID-19 infected patients may be of significant benefit, especially in low- and middle-income countries. The authors address the issues mentioned above surrounding the use of LUS in COVID-19 infected patients and the potential for extension of this technology in a resource-limited environment. Additionally, first-time application, feasibility, and safety were validated in healthy subjects. Preliminary results demonstrate that our platform allows for the successful acquisition and application of robotic LUS in humans.

Anatomical Feature-Based Lung Ultrasound Image Quality Assessment Using Deep Convolutional Neural Network.

Lung ultrasound (LUS) has been used for point-of-care diagnosis of respiratory diseases including COVID-19, with advantages such as low cost, safety, absence of radiation, and portability. The scanning procedure and assessment of LUS are highly operator-dependent, and the appearance of LUS images varies with the probe's position, orientation, and contact force. Karamalis et al. introduced the concept of ultrasound confidence maps based on random walks to assess the ultrasound image quality algorithmically by estimating the per-pixel confidence in the image data. However, these confidence maps do not consider the clinical context of an image, such as anatomical feature visibility and diagnosability. This work proposes a deep convolutional network that detects important anatomical features in an LUS image to quantify its clinical context. This work introduces an Anatomical Feature-based Confidence (AFC) Map, quantifying an LUS image's clinical context based on the visible anatomical features. We developed two U-net models, each segmenting one of the two classes crucial for analyzing an LUS image, namely 1) Bright Features: Pleural and Rib Lines and 2) Dark Features: Rib Shadows. Each model takes the LUS image as input and outputs the segmented regions with confidence values for the corresponding class. The evaluation dataset consists of ultrasound images extracted from videos of two sub-regions of the chest above the anterior axial line from three human subjects. The feature segmentation models achieved an average Dice score of 0.72 on the model's output for the testing data. The average of non-zero confidence values in all the pixels was calculated and compared against the image quality scores. The confidence values were different between different image quality scores. The results demonstrated the relevance of using an AFC Map to quantify the clinical context of an LUS image.

Accuracy of Focused Assessment with Sonography for Trauma (FAST) in Disaster Settings: A Meta-Analysis and Systematic Review.

Focused assessment with sonography for trauma (FAST) has been incorporated into the initial evaluation of trauma for decades. It is an important screening tool in the detection of intra-abdominal fluid. The objective of this study was to perform a systematic review of the use and accuracy of FAST as an imaging tool for blunt abdominal trauma in disaster/mass casualty settings. A systematic review of literature was conducted using key words and search terms. Two independent reviewers screened abstracts to determine inclusion using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS). For studies passing QUADAS, a meta-analysis was performed calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). FAST results were compared with the gold standard, which was a combination of CT scan results, operative findings, and medical records of the clinical course. Initial database screening resulted in 133 articles, of which 21 were selected for QUADAS evaluation. Five studies passed QUADAS and were selected in the final meta-analysis, with a total of 4263 patients. The sensitivity of FAST was 92.1% (87.8-95.6), specificity 98.7% (96.0-99.9), PPV 90.7% (70.0-98.0), and NPV 98.8% (98.1-99.5) for the detection of intra-abdominal injury. In our meta-analysis, FAST was both sensitive and specific in the evaluation of trauma in the disaster setting.

Examiner Position in Ocular Point-of-Care Ultrasound: A Proposed Technique.

BACKGROUND: Ocular point-of-care ultrasound (POCUS) is a fast and safe non-invasive procedure used to evaluate the structural integrity and pathology of the eye. Ocular POCUS can be used for evaluation of posterior chamber and orbital pathology, including retinal detachment, vitreous detachment or hemorrhage, foreign body, lens dislocation, and increased intracranial pressure. DISCUSSION: The purpose of this brief communication is to describe a technique for conducting an ocular POCUS that may in some cases be easier and more comfortable by adjusting the position of the sonographer relative to the patient. CONCLUSIONS: To our knowledge, this proposed technique has not been described in previous literature and may result in greater comfort for both sonographer and patient.

CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection.

Osteoarthritis (OA) pathogenesis is mediated largely through the actions of proteolytic enzymes such as matrix metalloproteinase (MMP) 13. The transcriptional regulator CITED2, which suppresses the expression of MMP13 in chondrocytes, is induced by interleukin (IL)-4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. We tested the hypothesis that CITED2 mediates cross-talk between IL-4 signaling and mechanical loading-induced pathways that result in chondroprotection, at least in part, by downregulating MMP13. IL-4 induced CITED2 gene expression in human chondrocytes in a dose- and time-dependent manner through JAK/STAT signaling. Mechanical loading combined with IL-4 resulted in additive effects on inducing CITED2 expression and downregulating of MMP13 in human chondrocytes in vitro. In vivo, IL-4 gene knockout (KO) mice exhibited reduced basal levels of CITED2 expression in chondrocytes. While moderate treadmill running induced CITED2 expression and reduced MMP13 expression in wild-type mice, these effects were blunted (for CITED2) or abolished (for MMP13) in chondrocytes of IL-4 gene KO mice. Moreover, intra-articular injections of mouse recombinant IL-4 combined with regular cage activity mitigated post-traumatic OA to a greater degree compared to immobilized mice treated with IL-4 alone. These data suggest that using moderate loading to enhance IL-4 may be a potential therapeutic strategy for chondroprotection in OA.

Correction to: Green tea polyphenol treatment is chondroprotective, anti-inflammatory and palliative in a mouse posttraumatic osteoarthritis model.

Following publication of the original article [1], the authors reported an error in Figs. 2C and 5C.

Lung ultrasound compared to chest X-ray for diagnosis of pediatric pneumonia: A meta-analysis.

OBJECTIVE: Although a clinical diagnosis, the standard initial imaging modality for patients with concern for pediatric community acquired pneumonia (pCAP) is a chest x-ray (CXR), which has a relatively high false negative rate, exposes patients to ionizing radiation, and may not be available in resource limited settings. The primary objective of this meta-analysis is to evaluate the accuracy of lung ultrasound (LUS) compared to CXR for the diagnosis of pCAP. METHODS: Data were collected via a systematic review of PubMed, EMBASE, and Web of Science with dates up to August 2017. Keywords and search terms were generated for pneumonia, lung ultrasound, and pediatric population. Two independent investigators screened abstracts for inclusion. PRISMA was used for selecting appropriate studies. QUADAS was applied to these studies to assess quality for inclusion into the meta-analysis. We collected data from included studies and calculated sensitivity, specificity, positive predictive value, and negative predictive values of CXR and LUS for the diagnosis of pCAP. RESULTS: Twelve studies including 1510 patients were selected for data extraction. LUS had a sensitivity of 95.5% (93.6-97.1) and specificity of 95.3% (91.1-98.3). CXR had a sensitivity of 86.8% (83.3-90.0) and specificity of 98.2% (95.7-99.6). Variations between the studies included ultrasound findings diagnostic of pneumonia, study setting (inpatient vs emergency department) and inclusion of CXR in the reference standard for pneumonia. CONCLUSIONS: In our meta-analysis, lung ultrasound had significantly better sensitivity with similar specificity when compared to chest x-ray for the diagnosis of pediatric community acquired pneumonia.

Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling.

Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark), orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling.

Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model.

BACKGROUND: Curcumin has been shown to have chondroprotective potential in vitro. However, its effect on disease and symptom modification in osteoarthritis (OA) is largely unknown. This study aimed to determine whether curcumin could slow progression of OA and relieve OA-related pain in a mouse model of destabilization of the medial meniscus (DMM). METHODS: Expression of selected cartilage degradative-associated genes was evaluated in human primary chondrocytes treated with curcumin and curcumin nanoparticles and assayed by real-time PCR. The mice subjected to DMM surgery were orally administered curcumin or topically administered curcumin nanoparticles for 8 weeks. Cartilage integrity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical staining of cleaved aggrecan and type II collagen, and levels of matrix metalloproteinase (MMP)-13 and ADAMTS5. Synovitis and subchondral bone thickness were scored based on histologic images. OA-associated pain and symptoms were evaluated by von Frey assay, and locomotor behavior including distance traveled and rearing. RESULTS: Both curcumin and nanoparticles encapsulating curcumin suppressed mRNA expression of pro-inflammatory mediators IL-1ß and TNF-α, MMPs 1, 3, and 13, and aggrecanase ADAMTS5, and upregulated the chondroprotective transcriptional regulator CITED2, in primary cultured chondrocytes in the absence or presence of IL-1ß. Oral administration of curcumin significantly reduced OA disease progression, but showed no significant effect on OA pain relief. Curcumin was detected in the infrapatellar fat pad (IPFP) following topical administration of curcumin nanoparticles on the skin of the injured mouse knee. Compared to vehicle-treated controls, topical treatment led to: (1) reduced proteoglycan loss and cartilage erosion and lower OARSI scores, (2) reduced synovitis and subchondral plate thickness, (3) reduced immunochemical staining of type II collagen and aggrecan cleavage epitopes and numbers of chondrocytes positive for MMP-13 and ADAMTS5 in the articular cartilage, and (4) reduced expression of adipokines and pro-inflammatory mediators in the IPFP. In contrast to oral curcumin, topical application of curcumin nanoparticles relieved OA-related pain as indicated by reduced tactile hypersensitivity and improved locomotor behavior. CONCLUSION: This study provides the first evidence that curcumin significantly slows OA disease progression and exerts a palliative effect in an OA mouse model.

Autoimmune response to transthyretin in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatological condition. Although it has been proposed that JIA has an autoimmune component, the autoantigens are still unknown. Using biochemical and proteomic approaches, we identified the molecular chaperone transthyretin (TTR) as an antigenic target for B and T cell immune responses. TTR was eluted from IgG complexes and affinity purified from 3 JIA patients, and a statistically significant increase in TTR autoantibodies was observed in a group of 43 JIA patients. Three cryptic, HLA-DR1-restricted TTR peptides, which induced CD4+ T cell expansion and IFN-γ and TNF-α production in 3 out of 17 analyzed patients, were also identified. Misfolding, aggregation and oxidation of TTR, as observed in the synovial fluid of all JIA patients, enhanced its immunogenicity in HLA-DR1 transgenic mice. Our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and to oxidation and aggregation as a mechanism facilitating TTR autoimmunity.

Assembly and dynamics of the U4/U6 di-snRNP by single-molecule FRET.

In large ribonucleoprotein machines, such as ribosomes and spliceosomes, RNA functions as an assembly scaffold as well as a critical catalytic component. Protein binding to the RNA scaffold can induce structural changes, which in turn modulate subsequent binding of other components. The spliceosomal U4/U6 di-snRNP contains extensively base paired U4 and U6 snRNAs, Snu13, Prp31, Prp3 and Prp4, seven Sm and seven LSm proteins. We have studied successive binding of all protein components to the snRNA duplex during di-snRNP assembly by electrophoretic mobility shift assay and accompanying conformational changes in the U4/U6 RNA 3-way junction by single-molecule FRET. Stems I and II of the duplex were found to co-axially stack in free RNA and function as a rigid scaffold during the entire assembly, but the U4 snRNA 5' stem-loop adopts alternative orientations each stabilized by Prp31 and Prp3/4 binding accounting for altered Prp3/4 binding affinities in presence of Prp31.

Consequences of metabolic and oxidative modifications of cartilage tissue.

A hallmark of chronic metabolic diseases, such as diabetes and metabolic syndrome, and oxidative stress, as occurs in chronic inflammatory and degenerative conditions, is the presence of extensive protein post-translational modifications, including glycation, glycoxidation, carbonylation and nitrosylation. These modifications have been detected on structural cartilage proteins in joints and intervertebral discs, where they are known to affect protein folding, induce protein aggregation and, ultimately, generate microanatomical changes in the proteoglycan-collagen network that surrounds chondrocytes. Many of these modifications have also been shown to promote oxidative cleavage as well as enzymatically-mediated matrix degradation. Overall, a general picture starts to emerge indicating that biochemical changes in proteins constitute an early event that compromises the anatomical organization and viscoelasticity of cartilage, thereby affecting its ability to sustain pressure and, ultimately, impeding its overall bio-performance.

Green tea polyphenol treatment is chondroprotective, anti-inflammatory and palliative in a mouse post-traumatic osteoarthritis model.

INTRODUCTION: Epigallocatechin 3-gallate (EGCG), a polyphenol present in green tea, was shown to exert chondroprotective effects in vitro. In this study, we used a post-traumatic osteoarthritis (OA) mouse model to test whether EGCG could slow the progression of OA and relieve OA-associated pain. METHODS: C57BL/6 mice were subjected to surgical destabilization of the medial meniscus (DMM) or sham surgery. EGCG (25 mg/kg) or vehicle control was administered daily for four or eight weeks by intraperitoneal injection starting on the day of surgery. OA severity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical analysis to detect cleaved aggrecan and type II collagen, and expression of proteolytic enzymes matrix metalloproteinase (MMP)-13 and A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS5). Real-time polymerase chain reaction (PCR) was performed to characterize the expression of genes critical for articular cartilage homeostasis. During the course of the experiments, tactile sensitivity testing (von Frey test) and open field assays were used to evaluate pain behaviors associated with OA, and expression of pain expression markers and inflammatory cytokines in the dorsal root ganglion (DRG) were determined by real-time PCR. RESULTS: Four and eight weeks after DMM surgery, the cartilage in EGCG-treated mice exhibited less Safranin O loss and cartilage erosion, and lower OARSI scores compared to vehicle-treated controls, which was associated with reduced staining for aggrecan and type II collagen cleavage epitopes, and reduced staining for MMP-13 and ADAMTS5 in the articular cartilage. Articular cartilage in the EGCG-treated mice also exhibited reduced levels of MMP-1, -3, -8, -13, ADAMTS5, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α mRNA and elevated gene expression of the MMP regulator Cbp/p300 Interacting Transactivator 2 (CITED2). Compared to vehicle controls, mice treated with EGCG exhibited reduced OA-associated pain, as indicated by higher locomotor behavior (i.e. distance traveled). Moreover, expression of chemokine receptor (CCR2), and pro-inflammatory cytokines IL-1ß and TNF-α in the DRG were significantly reduced to levels similar to sham-operated animals. CONCLUSIONS: This study provides the first evidence in an OA animal model that EGCG significantly slows OA disease progression and exerts a palliative effect.

Physiological and behavioural indices of hostility: an extension of the capacity model to include exposure to affective stress and right lateralized motor stress.

Right hemisphere functional cerebral systems have reliably been associated with sympathetic nervous system arousal and the perception of negative affective events. The goal of the current research was to provide additional support for the capacity model of hostility by examining changes attributable to functional cerebral systems within the right hemisphere using a dual concurrent task paradigm. To incorporate exposure to negative affective and right-lateralized motor stress using this approach, high and low hostile individuals completed a series of grip-strength tasks before and after hearing a recording of angry infant vocalizations. Results supported the capacity model in that high hostile individuals were unable to maintain regulatory control over right hemisphere activation as indicated through increased motor perseveration in the pre- and post-affective stress conditions, heightened systolic blood pressure (SBP) upon exposure to negative emotional sounds, and increased heart rate (HR) following stress. Conversely, low hostile individuals showed improved regulatory control over these regions as evidenced by reduced motor perseveration in the pre- and post-affective stress conditions, maintenance of SBP and reductions in HR following stress. The current data support the capacity model and extend its scope to include exposure to affective and right-lateralized motor stress.

Nutraceuticals: potential for chondroprotection and molecular targeting of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no cure for OA, and no effective treatments which arrest or slow its progression. Current pharmacologic treatments such as analgesics may improve pain relief but do not alter OA disease progression. Prolonged consumption of these drugs can result in severe adverse effects. Given the nature of OA, life-long treatment will likely be required to arrest or slow its progression. Consequently, there is an urgent need for OA disease-modifying therapies which also improve symptoms and are safe for clinical use over long periods of time. Nutraceuticals-food or food products that provide medical or health benefits, including the prevention and/or treatment of a disease-offer not only favorable safety profiles, but may exert disease- and symptom-modification effects in OA. Forty-seven percent of OA patients use alternative medications, including nutraceuticals. This review will overview the efficacy and mechanism of action of commonly used nutraceuticals, discuss recent experimental and clinical data on the effects of select nutraceuticals, such as phytoflavonoids, polyphenols, and bioflavonoids on OA, and highlight their known molecular actions and limitations of their current use. We will conclude with a proposed novel nutraceutical-based molecular targeting strategy for chondroprotection and OA treatment.

Age-related carbonylation of fibrocartilage structural proteins drives tissue degenerative modification.

Aging-related oxidative stress has been linked to degenerative modifications in different organs and tissues. Using redox proteomic analysis and illustrative tandem mass spectrometry mapping, we demonstrate oxidative posttranslational modifications in structural proteins of intervertebral discs (IVDs) isolated from aging mice. Increased protein carbonylation was associated with protein fragmentation and aggregation. Complementing these findings, a significant loss of elasticity and increased stiffness was measured in fibrocartilage from aging mice. Studies using circular dichroism and intrinsic tryptophan fluorescence revealed a significant loss of secondary and tertiary structures of purified collagens following oxidation. Collagen unfolding and oxidation promoted both nonenzymatic and enzymatic degradation. Importantly, induction of oxidative modification in healthy fibrocartilage recapitulated the biochemical and biophysical modifications observed in the aging IVD. Together, these results suggest that protein carbonylation, glycation, and lipoxidation could be early events in promoting IVD degenerative changes.

Peripubertal vitamin D(3) deficiency delays puberty and disrupts the estrous cycle in adult female mice.

The mechanism(s) by which vitamin D(3) regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D(3) deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D(3)) null mice to study the effect of vitamin D(3) deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D(3)-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D(3) deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D(3)-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D(3)-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D(3)-replete diet. Estrous cycles were restored when vitamin D(3)-deficient Cyp27b1 null young adult females were transferred to a vitamin D(3)-replete diet. This study is the first to demonstrate that peripubertal vitamin D(3) sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D(3) is a key regulator of neuroendocrine and ovarian physiology.