Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling.

Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI. Thus, this study aimed to determine if eNAMPT-mediated inflammatory injury is associated with the loss of mitochondrial function. Our data show that eNAMPT disrupted mitochondrial bioenergetics. This was associated with cytoskeleton remodeling and the loss of endothelial barrier integrity. These changes were associated with enhanced mitochondrial fission and blocked when Rho-kinase (ROCK) was inhibited. The increases in mitochondrial fission were also associated with the nitration-mediated activation of the small GTPase activator of ROCK, RhoA. Blocking RhoA nitration decreased eNAMPT-mediated mitochondrial fission and endothelial barrier dysfunction. The increase in fission was linked to a RhoA-ROCK mediated increase in Drp1 (dynamin-related protein 1) at serine(S)616. Another TLR4 agonist, lipopolysaccharide (LPS), also increased mitochondrial fission in a Drp1 and RhoA-ROCK-dependent manner. To validate our findings in vivo, we challenged C57BL/6 mice with eNAMPT in the presence and absence of the Drp1 inhibitor, Mdivi-1. Mdivi-1 treatment protected against eNAMPT-induced lung inflammation, edema, and lung injury. These studies demonstrate that mitochondrial fission-dependent disruption of mitochondrial function is essential in TLR4-mediated inflammatory lung injury and identify a key role for RhoA-ROCK signaling. Reducing mitochondrial fission could be a potential therapeutic strategy to improve ARDS outcomes.

Free Radical-Associated Gene Signature Predicts Survival in Sepsis Patients.

Sepsis continues to overwhelm hospital systems with its high mortality rate and prevalence. A strategy to reduce the strain of sepsis on hospital systems is to develop a diagnostic/prognostic measure that identifies patients who are more susceptible to septic death. Current biomarkers fail to achieve this outcome, as they only have moderate diagnostic power and limited prognostic capabilities. Sepsis disrupts a multitude of pathways in many different organ systems, making the identification of a single powerful biomarker difficult to achieve. However, a common feature of many of these perturbed pathways is the increased generation of reactive oxygen species (ROS), which can alter gene expression, changes in which may precede the clinical manifestation of severe sepsis. Therefore, the aim of this study was to evaluate whether ROS-related circulating molecular signature can be used as a tool to predict sepsis survival. Here we created a ROS-related gene signature and used two Gene Expression Omnibus datasets from whole blood samples of septic patients to generate a 37-gene molecular signature that can predict survival of sepsis patients. Our results indicate that peripheral blood gene expression data can be used to predict the survival of sepsis patients by assessing the gene expression pattern of free radical-associated -related genes in patients, warranting further exploration.

Integrating of analytical techniques with enzyme-mimicking nanomaterials for the fabrication of microfluidic systems for biomedical analysis.

Bioanalysis faces challenges in achieving fast, reliable, and point-of-care (POC) determination methods for timely diagnosis and prognosis of diseases. POC devices often display lower sensitivity compared to laboratory-based methods, limiting their ability to quantify low concentrations of target analytes. To enhance sensitivity, the synthesis of new materials and improvement of the efficiency of the analytical strategies are necessary. Enzyme-mimicking materials have revolutionized the field of the fabrication of new high-throughput sensing devices. The integration of microfluidic chips with analytical techniques offers several benefits, such as easy miniaturization, need for low biological sample volume, etc., while also enhancing the sensitivity of the probe. The use enzyme-like nanomaterials in microfluidic systems can offer portable strategies for real-time and reliable detection of biological agents. Colorimetry and electrochemical methods are commonly utilized in the fabrication of nanozyme-based microfluidic systems. The review summarizes recent developments in enzyme-mimicking materials-integrated microfluidic analytical methods in biomedical analysis and discusses the current challenges, advantages, and potential future directions.

Phytochemical profile, nutritional composition of pomegranate peel and peel extract as a potential source of nutraceutical: A comprehensive review.

The current study focuses on Punica granatum L. (pomegranate) peel and peel extract and their use as functional foods, food additives, or physiologically active constituents in nutraceutical formulations. The pomegranate peel extract is a good source of bioactive substances needed for the biological activity of the fruit, including phenolic acids, minerals, flavonoids (anthocyanins), and hydrolyzable tannins (gallic acid). The macromolecules found in pomegranate peel and peel extract have been recommended as substitutes for synthetic nutraceuticals, food additives, and chemo-preventive agents because of their well-known ethno-medical significance and chemical properties. Moreover, considering the promises for both their health-promoting activities and chemical properties, the dietary and nutraceutical significance of pomegranate peel and pomegranate peel extract appears to be underestimated. The present review article details their nutritional composition, phytochemical profile, food applications, nutraceutical action, and health benefits.

Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis.

OBJECTIVES: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS). METHODS: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate. RESULTS: A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively. CONCLUSION: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.

Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics.

Once thought of in terms of bioenergetics, mitochondria are now widely accepted as both the orchestrator of cellular health and the gatekeeper of cell death. The pulmonary disease field has performed extensive efforts to explore the role of mitochondria in regulating inflammation, cellular metabolism, apoptosis, and oxidative stress. However, a critical component of these processes needs to be more studied: mitochondrial network dynamics. Mitochondria morphologically change in response to their environment to regulate these processes through fusion, fission, and mitophagy. This allows mitochondria to adapt their function to respond to cellular requirements, a critical component in maintaining cellular homeostasis. For that reason, mitochondrial network dynamics can be considered a bridge that brings multiple cellular processes together, revealing a potential pathway for therapeutic intervention. In this review, we discuss the critical modulators of mitochondrial dynamics and how they are affected in pulmonary diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), and pulmonary arterial hypertension (PAH). A dysregulated mitochondrial network plays a crucial role in lung disease pathobiology, and aberrant fission/fusion/mitophagy pathways are druggable processes that warrant further exploration. Thus, we also discuss the candidates for lung disease therapeutics that regulate mitochondrial network dynamics.

Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.

OBJECTIVE: Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown. METHODS: Utilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH. RESULTS: We observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C5-glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential. CONCLUSIONS: Our data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development.

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells.

The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.

Synthesis of a bistriazolyl-phenanthroline-Cu(ii) complex immobilized on nanomagnetic iron oxide as a novel green catalyst for synthesis of imidazoles via annulation reactions.

We designed and prepared a novel N-heterocycle-based nanocatalyst by a post synthetic method, namely the [Fe3O4@DAA-BTrzPhen-Cu(ii)] composite. In this method, bistriazolyl-phenanthroline groups were stepwise synthesized on an Fe3O4 substrate and used as a tetradentate nitrogenous ligand for coordinating to copper ions. The obtained nanocomposite was well characterized using FT-IR, PXRD, TGA, EDAX, ICP-OES, EDX-mapping, SEM, TEM, VSM and BET analyses, which confirm the formation of a thermostable crystalline spherical particle morphology with the particle size in the range of 17 nm to 25 nm and a magnetization value of 42 emu g-1. Also, the catalytic activity of [Fe3O4@DAA-BTrzPhen-Cu(ii)] as a novel and magnetically separable heterogeneous nanocatalyst was evaluated in preparing various tetrasubstituted imidazole derivatives from one-pot four-component condensation of anilines, aldehydes, 1,2-diketones and ammonium acetate, and favorable products were produced with excellent yields. The stability, low Cu leaching, and heterogenous nature of the nanocatalyst were confirmed by hot-filtration and leaching tests. The copper based nanocatalyst could be easily recovered by magnetic field separation and recycled at least 8 times in a row without noticeable loss in its catalytic activity.

Assessment of pain-related behaviors in HIV-1 transgenic rats as a model of HIV-associated chronic pain.

Human immunodeficiency virus-1 (HIV)-associated chronic pain is a debilitating comorbid condition that affects 25-85% of people with HIV. The use of opioids to alleviate pain has given rise to opioid dependency in this cohort. Therefore, there is an urgent need to understand mechanisms and identify novel therapeutics for HIV-associated chronic pain. Several animal models have been developed to study HIV-related comorbidities. HIV-1 transgenic (Tg) rats have been shown to serve as a reliable model that mimic the deficits observed in people with HIV, such as neurological and immune system alterations. However, pain-related behavior in these animals has not been extensively evaluated. In this study, we measured evoked and spontaneous behavior in HIV-1Tg male and female rats. The results indicated that HIV-1Tg rats exhibit similar behavior to those with HIV-1-related neuropathy, specifically, cold sensitivity. Consequently, HIV-1Tg rats can serve as a model of neuropathy to study pain-related mechanisms and therapeutics targeted toward individuals living with HIV-1.

Sex-Based Disparities in Leukocyte Migration and Activation in Response to Inhalation Lung Injury: Role of SDF-1/CXCR4 Signaling.

The aim of the study was to determine whether sex-related differences exist in immune response to inhalation lung injury. C57BL/6 mice were exposed to Cl2 gas (500 ppm for 15, 20, or 30 min). Results showed that male mice have higher rates of mortality and lung injury than females. The binding of the chemokine ligand C-X-C motif chemokine 12 (CXCL12), also called stromal-derived-factor-1 (SDF-1), to the C-X-C chemokine receptor type 4 (CXCR4) on lung cells promotes the migration of leukocytes from circulation to lungs. Therefore, the hypothesis was that elevated SDF-1/CXCR4 signaling mediates exaggerated immune response in males. Plasma, blood leukocytes, and lung cells were collected from mice post-Cl2 exposure. Plasma levels of SDF-1 and peripheral levels of CXCR4 in lung cells were higher in male vs. female mice post-Cl2 exposure. Myeloperoxidase (MPO) and elastase activity was significantly increased in leukocytes of male mice exposed to Cl2. Lung cells were then ex vivo treated with SDF-1 (100 ng/mL) in the presence or absence of the CXCR4 inhibitor, AMD3100 (100 nM). SDF-1 significantly increased migration, MPO, and elastase activity in cells obtained from male vs. female mice post-Cl2 exposure. AMD3100 attenuated these effects, suggesting that differential SDF-1/CXCR4 signaling may be responsible for sex-based disparities in the immune response to inhalation lung injury.

Heme-Induced Macrophage Phenotype Switching and Impaired Endogenous Opioid Homeostasis Correlate with Chronic Widespread Pain in HIV.

Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs ß-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens ß-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low ß-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced ß-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased ß-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV.

High Heme and Low Heme Oxygenase-1 Are Associated with Mast Cell Activation/Degranulation in HIV-Induced Chronic Widespread Pain.

An overwhelming number of people with HIV (PWH) experience chronic widespread pain (CWP) throughout their lifetimes. Previously, we demonstrated that PWH with CWP have increased hemolysis and attenuated heme oxygenase 1 (HO-1) levels. HO-1 degrades reactive, cell-free heme into antioxidants like biliverdin and carbon monoxide (CO). We found that high heme or low HO-1 caused hyperalgesia in animals, likely through multiple mechanisms. In this study, we hypothesized that high heme or low HO-1 caused mast cell activation/degranulation, resulting in the release of pain mediators like histamine and bradykinin. PWH who self-report CWP were recruited from the University of Alabama at Birmingham HIV clinic. Animal models included HO-1-/- mice and hemolytic mice, where C57BL/6 mice were injected intraperitoneally with phenylhydrazine hydrochloride (PHZ). Results demonstrated that plasma histamine and bradykinin were elevated in PWH with CWP. These pain mediators were also high in HO-1-/- mice and in hemolytic mice. Both in vivo and in vitro (RBL-2H3 mast cells), heme-induced mast cell degranulation was inhibited by treatment with CORM-A1, a CO donor. CORM-A1 also attenuated mechanical and thermal (cold) allodynia in hemolytic mice. Together, the data suggest that mast cell activation secondary to high heme or low HO-1 seen in cells and animals correlates with elevated plasma levels of heme, histamine, and bradykinin in PWH with CWP.

NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury.

In acute lung injury (ALI), the NF-κB-mediated downregulation of Sox18 gene expression leads to the disruption of the pulmonary endothelial barrier. Previous studies have suggested that the action of NF-κB as a transcriptional repressor also requires the action of class I histone deacetylases (HDACs). Thus, the purpose of this study was to investigate and further delineate the mechanism of Sox18 repression during lipopolysaccharide (LPS) induced ALI. Using selective inhibitors and specific siRNA-driven depletion of HDACs 1-3 in human lung microvascular endothelial cells (HLMVEC) we were able to demonstrate a critical role for HDACs 1 and 2 in the LPS-mediated repression of Sox18 gene expression and the loss of endothelial monolayer integrity. Moreover, our data demonstrate that HDAC1 associates with a transcription-repressive complex within the NF-κB-binding site of Sox18 promoter. Further, we were able to show that the selective inhibitor of HDAC1, tacedinaline, significantly reduced the endothelial permeability and injury associated with LPS challenge in the mouse lung. Taken together, our data demonstrate, for the first time, that transcription repressors HDACs 1 and 2 are involved in pathological mechanism of ALI and can be considered as therapeutic targets.

A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome.

BACKGROUND AND OBJECTIVES: Defibrotide is approved to treat severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after haematopoietic cell transplantation in patients aged > 1 month in the European Union and for VOD/SOS with renal/pulmonary dysfunction post-haematopoietic cell transplantation in the United States. This meta-analysis estimated the incidence and risk of VOD/SOS after intravenous defibrotide prophylaxis using the published literature. METHODS: PubMed, Embase and Web of Science were searched through 30 November 2021 for defibrotide studies in VOD/SOS "prevention" or "prophylaxis," excluding phase I studies, case reports, studies with fewer than ten patients and reviews. RESULTS: The search identified 733 records; 24 met inclusion criteria, of which 20 (N = 3005) evaluated intravenous defibrotide for VOD/SOS prophylaxis. Overall VOD/SOS incidence with intravenous defibrotide was 5%, with incidences of 5% in adults and 8% in paediatric patients. In eight studies with data on intravenous defibrotide prophylaxis vs controls (e.g. heparin, no prophylaxis), VOD/SOS incidence in controls was 16%. The risk ratio for developing VOD/SOS with defibrotide prophylaxis vs controls was 0.30 (95% confidence interval 0.12-0.71; p = 0.006). CONCLUSIONS: This analysis suggests a low incidence of VOD/SOS following intravenous defibrotide prophylaxis, regardless of age group, and a lower relative risk for VOD/SOS with defibrotide prophylaxis vs controls in patient populations at high risk of VOD/SOS.

Symptomatic Coracoclavicular Joint - A Case Report of an Important but Lesser known Differential Diagnosis of Shoulder Pain.

Introduction: Actual coracoclavicular (CC) joint is a rare finding and usually incidental. It is mostly asymptomatic, but few cases have been reported in which there was associated shoulder pain and even brachial plexus neuralgia. It is not to be confused with CC ligament which is a well-known anatomical entity. Case Report: Here, we present a case of symptomatic CC joint treated at our hospital. A 50-year-old man presented to the outdoor patient department of our hospital with a history of acute on chronic pain in the left shoulder. The pain used to be dull/aching, occurring after some activity and usually relieved on rest. On local examination, mild tenderness was present around the coracoid process. The pain was aggravated on flexion and external rotation of the shoulder. X-ray of the shoulder revealed the presence of a CC joint. It was confirmed by non-contrast computed tomography of the shoulder. Ultrasound-guided injection of local anesthetic and steroid was given in the CC joint, providing instant pain relief to the patient. At 1-year follow-up, the patient is asymptomatic and continuing his daily routine activities. Conclusion: Although CC Joint is a rare entity, its role in causing symptoms is unrefutable. Conservative treatment should be tried before surgical excision. More awareness regarding this joint and its pathology is required for identification and diagnosis.

Serum biomarkers for prediction of mortality in patients with COVID-19.

BACKGROUND: There is limited information regarding the role of biomarker levels at predicting mortality in patients with the coronavirus disease (COVID-19) pandemic. The purpose of this study is to determine the differences in serum biomarker levels in adults with COVID-19 who survived hospitalization from those who did not. METHODS: A comprehensive search was completed on PubMed, EMBASE and Cochrane libraries to identify studies of interest. Endpoints of interest were blood counts, hepatic function test, acute phase reactants, cytokines and cardiac biomarkers. RESULTS: A total of 10 studies with 1584 patients were included in the pooled analyses. Biomarkers that were noted to be significantly higher in those who died from coronavirus disease included: white blood cell count, neutrophil count, C-reactive protein, high sensitivity C-reactive protein, procalcitonin, ferritin, D-dimer, interleukin-6, lactate dehydrogenase, creatine kinase, prothrombin time, aspartate aminotransferase, alanine aminotransferase, total bilirubin and creatinine. Lymphocyte count, platelet count and albumin were significantly lower in patients who died. CONCLUSION: This pooled analysis of 10 studies including 1584 patients identified significant differences in biomarkers on admission in patients who survived from those who did not. Further research is needed to develop risk stratification models to help with judicious use of limited health-care resources.

Subcutaneouscardiac Rhythm Monitors: A Comprehensive Review.

Subcutaneous loop recorders (SCRMs) are subcutaneous electronic devices which have revolutionized the field of arrhythmia detection. They have become increasingly appealing due to advances such as miniaturization of device, longer battery life, bluetooth capabilities and relatively simple implantation technique without the need for complex surgical suites. They can be implanted in the office, patient bedside without the need to go to the operating room. One of the most common indications for their implantation is detection of atrial fibrillation (AF) after a cryptogenic stroke. They have also been utilized for assessing the success of rhythm control strategies such post pulmonary venous isolation. More recently studies have assessed the utility of SCRMs for detecting silent AF in at risk populations such as patients with sleep apnea or those on hemodialysis. In this paper, we review the evolution of SCRMs, the clinical studies assessing their value for different indications, their role incurrent clinical practice and future avenues in the era of smart wearable devices like apple watch etc.

Shear-induced mixing of granular materials featuring broad granule size distributions.

Granular flows during a shear-induced mixing process are studied using discrete element methods. The aim is to understand the underlying elementary mechanisms of transition from unmixed to mixed phases for a granular material featuring a broad distribution of particles, which we investigate systematically by varying the strain rate and system size. Here the strain rate varies over four orders of magnitude and the system size varies from ten thousand to more than a million granules. A strain rate-dependent transition from quasistatic to purely inertial flow is observed. At the macroscopic scale, the contact stresses drop due to the formation of shear-induced instabilities that serves as an onset of granular flows and initiates mixing between the granules. The stress-drop displays a profound system size dependence. At the granular scale, mixing dynamics are correlated with the formation of shear bands, which result in significantly different timescales of mixing, especially for those regions that are close to the system walls and the bulk. Overall, our results reveal that although the transient dynamics display a generic behavior, these have a significant finite-size effect. In contrast, macroscopic behaviors at steady states have negligible system size dependence.

Dislocations of the elbow - An instructional review.

Dislocations of the elbow require recognition of the injury pattern followed by adequate treatment to allow early mobilisation. Not every injury requires surgery but if surgery is undertaken all structures providing stability should be addressed, including fractures, medial and lateral ligament insertion and the radial head. The current concepts of biomechanical modelling are addressed and surgical implications discussed.