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Abstract Background Despite calls for regionalizing pancreatic cancer (PC) care to high-volume centers (HVCs), many patients with PC elect to receive therapy closer to their home or at multiple institutions. In the context of cross-institutional PC care, the challenges associated with coordinating care are poorly understood. Methods In this qualitative study we conducted semi-structured interviews with oncology clinicians from a HVC (n = 9) and community-based hospitals (n = 11) to assess their perspectives related to coordinating the care of and treating PC patients across their respective institutions. Interviews were transcribed, coded, and analyzed using deductive and inductive approaches to identify themes related to cross-institutional coordination challenges and to note improvement opportunities. Results Clinicians identified challenges associated with closed-loop communication due, in part, to not having access to a shared electronic health record. Challenges with patient co-management were attributed to patients receiving inconsistent recommendations from different clinicians. To address these challenges, participants suggested several improvement opportunities such as building rapport with clinicians across institutions and updating tumor board processes. The opportunity to update tumor board processes was reportedly multi-dimensional and could involve: (1) designating a tumor board coordinator; (2) documenting and disseminating tumor board recommendations; and (3) using teleconferencing to facilitate community-based clinician engagement during tumor board meetings. Conclusions In light of communication barriers and challenges associated with patient co-management, enabling the development of relationships among PC clinicians and improving the practices of multidisciplinary tumor boards could potentially foster cross-institutional coordination. Research examining how multidisciplinary tumor board coordinators and teleconferencing platforms could enhance cross-institutional communication and thereby improve patient outcomes is warranted.

Abstract Xanthine oxidase (XO) is an enzyme that converts hypoxanthine into xanthine and xanthine into uric acid, which is then eliminated by the kidneys. Serum XO has been linked to diabetes, hypertension, liver dysfunction, and cardiovascular diseases. However, limited information exists on the relationship between serum XO activity and MetS. This study aimed to analyze the relationship between XO activity and metabolic syndrome (MetS) and its components in an adult population group in Bangladesh A total of 601 participants aged ≥18 years were included in the study. MetS was defined based on the criteria set by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Serum XO activity was measured using the enzyme-linked immunosorbent assay (ELISA), while other biochemical parameters were measured using colorimetric methods. The relationship between serum XO and MetS levels was determined through multivariate logistic regression analysis. Serum XO activity was found to be significantly higher in females (6.17 ± 3.77 U/L) as compared to males (4.00 ± 2.77 U/L) (p

Earth pressure balance machine (EPBM) operation is sensitive to the properties of the excavated soil due to the requirements of proper soil conditioning and maintenance of necessary chamber pressure. However, soil properties are invariably only available at a limited number of borehole explorations and soil samplings conducted during the subsoil investigation. Thus, it is crucial to identify properties of the tunnel excavation face, such as clay-sand mixed conditions, grain size distributions, and clogging potential along the whole alignment beside the few borehole locations to attain optimally efficient EPBM operation. Therefore, this paper presents the development of machine learning prediction models (i.e., classifiers and regressors) to estimate the properties of the tunnel excavation face using EPBM operational data collected during the tunneling operation as input features. Geotechnical data collected from boreholes and soil samples can be used to validate prediction models and calibrate them. To develop such models, the Northgate Link Extension (N125) tunneling project, constructed in Seattle, Washington, the USA, is used to capture and identify the true ground conditions. The results indicate successful prediction performances by the models, providing indication that EPBM parameters are crucial pointers of the tunnel excavation face properties to help attain optimally efficient EPBM operation.

Abstract Background Stem cell-derived extracellular vesicles (EVs) are an emerging class of therapeutics with excellent biocompatibility, bioactivity and pro-regenerative capacity. One of the potential targets for EV-based medicines are cardiovascular diseases (CVD). In this work we used EVs derived from human induced pluripotent stem cells (hiPSCs; hiPS-EVs) cultured under different oxygen concentrations (21, 5 and 3% O2) to dissect the molecular mechanisms responsible for cardioprotection. Methods EVs were isolated by ultrafiltration combined with size exclusion chromatography (UF + SEC), followed by characterization by nanoparticle tracking analysis, atomic force microscopy (AFM) and Western blot methods. Liquid chromatography and tandem mass spectrometry coupled with bioinformatic analyses were used to identify differentially enriched proteins in various oxygen conditions. We directly compared the cardioprotective effects of these EVs in an oxygen-glucose deprivation/reoxygenation (OGD/R) model of cardiomyocyte (CM) injury. Using advanced molecular biology, fluorescence microscopy, atomic force spectroscopy and bioinformatics techniques, we investigated intracellular signaling pathways involved in the regulation of cell survival, apoptosis and antioxidant response. The direct effect of EVs on NRF2-regulated signaling was evaluated in CMs following NRF2 inhibition with ML385. Results We demonstrate that hiPS-EVs derived from physiological hypoxia at 5% O2 (EV-H5) exert enhanced cytoprotective function towards damaged CMs compared to EVs derived from other tested oxygen conditions (normoxia; EV-N and hypoxia 3% O2; EV-H3). This resulted from higher phosphorylation rates of Akt kinase in the recipient cells after transfer, modulation of AMPK activity and reduced apoptosis. Furthermore, we provide direct evidence for improved calcium signaling and sustained contractility in CMs treated with EV-H5 using AFM measurements. Mechanistically, our mass spectrometry and bioinformatics analyses revealed differentially enriched proteins in EV-H5 associated with the antioxidant pathway regulated by NRF2. In this regard, EV-H5 increased the nuclear translocation of NRF2 protein and enhanced its transcription in CMs upon OGD/R. In contrast, inhibition of NRF2 with ML385 abolished the protective effect of EVs on CMs. Conclusions In this work, we demonstrate a superior cardioprotective function of EV-H5 compared to EV-N and EV-H3. Such EVs were most effective in restoring redox balance in stressed CMs, preserving their contractile function and preventing cell death. Our data support the potential use of hiPS-EVs derived from physiological hypoxia, as cell-free therapeutics with regenerative properties for the treatment of cardiac diseases.

Dengue infection is a mosquito borne arboviral disease of the tropics. It has a wide spectrum of presentation from flu-like illness to lethal hemorrhagic fever. Neurological manifestations are rare in dengue and can be due to neurotropic effect, immune mediated, or due to systemic complication. We hereby present a case report of a 21-year-old male presenting to us with acute pure motor quadriparesis due to hypokalemia caused by dengue fever.

IntroductionElectronic referral (e-referral) to quitlines helps connect tobacco-using patients to free, evidence-based cessation counseling. Little has been published about the real-world implementation of e-referrals across U.S. health systems, their maintenance over time, and the outcomes of e-referred patients.Aims and methodsBeginning in 2014, the University of California (UC)-wide project called UC Quits scaled up quitline e-referrals and related modifications to clinical workflows from one to five UC health systems. Implementation strategies were used to increase site readiness. Maintenance was supported through ongoing monitoring and quality improvement programs. Data on e-referred patients (n = 20 709) and quitline callers (n = 197 377) were collected from April 2014 to March 2021. Analyses of referral trends and cessation outcomes were conducted in 2021-2022.ResultsOf 20 709 patients referred, the quitline contacted 47.1%, 20.6% completed intake, 15.2% requested counseling, and 10.9% received it. In the 1.5-year implementation phase, 1813 patients were referred. In the 5.5-year maintenance phase, volume was sustained, with 3436 referrals annually on average. Among referred patients completing intake (n = 4264), 46.2% were nonwhite, 58.8% had Medicaid, 58.7% had a chronic disease, and 48.8% had a behavioral health condition. In a sample randomly selected for follow-up, e-referred patients were as likely as general quitline callers to attempt quitting (68.5% vs. 71.4%; p = .23), quit for 30 days (28.3% vs. 26.9%; p = .52), and quit for 6 months (13.6% vs. 13.9%; p = .88).ConclusionsWith a whole-systems approach, quitline e-referrals can be established and sustained across inpatient and outpatient settings with diverse patient populations. Cessation outcomes were similar to those of general quitline callers.ImplicationsThis study supports the broad implementation of tobacco quitline e-referrals in health care. To the best of our knowledge, no other paper has described the implementation of e-referrals across multiple U.S. health systems or how they were sustained over time. Modifying electronic health records systems and clinical workflows to enable and encourage e-referrals, if implemented and maintained appropriately, can be expected to improve patient care, make it easier for clinicians to support patients in quitting, increase the proportion of patients using evidence-based treatment, provide data to assess progress on quality goals, and help meet reporting requirements for tobacco screening and prevention.

Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.

Abstract Background Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infections in children worldwide. The highest incidence of severe disease is in the first 6 months of life, with infants born preterm at greatest risk for severe RSV infections. The licensure of new RSV therapeutics (a long-acting monoclonal antibody and a maternal vaccine) in Europe, USA, UK and most recently in Australia, has driven the need for strategic decision making on the implementation of RSV immunisation programs. Data driven approaches, considering the local RSV epidemiology, are critical to advise on the optimal use of these therapeutics for effective RSV control. Methods We developed a dynamic compartmental model of RSV transmission fitted to individually-linked population-based laboratory, perinatal and hospitalisation data for 2000–2012 from metropolitan Western Australia (WA), stratified by age and prior exposure. We account for the differential risk of RSV-hospitalisation in full-term and preterm infants (defined as

An increasing amount of molecular imaging studies are ordered each year for an oncologic population that continues to expand and increase in age. The importance of these studies in dictating further care for oncologic patients underscores the necessity of differentiating benign from malignant findings, particularly for a population in whom incidental findings are common. The aim of this review is to provide pictorial examples of benign musculoskeletal pathologies which may be found on molecular imaging and which may be mistaken for malignant processes. Imaging examples are provided in the form of radiographs, bone scintigraphy, computed tomography, and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scans. Special attention is paid to specific features that help narrow the differential diagnosis and distinguish benign from malignant processes, with the goal of avoiding unnecessary invasive procedures.

Background: Many conditions we now call body-focused repetitive behaviors (BFRBs) have been subject to research for several decades, most notably trichotillomania and skin picking. However, the American Psychiatric Association did not combine these conditions into a single category, body-focused repetitive behavior disorders (BFRBDs), until the fifth edition of the DSM (2013). Several aspects of the disorder remain uncertain and controversial. For example, ongoing debate surrounds which specific conditions fall under this diagnostic category and how to best differentiate BFRBs from conditions such as nonsuicidal self-injury (NSSI). The current article presents results from a survey of experts' opinions on diagnostic criteria, with the goal of refining the diagnostic criteria. Method: We contacted experts on BFRB via various sources and invited them to complete an online survey on the phenomenology, classification, and differential diagnosis of BFRB. We also inquired about possible alternative syndrome labels (e.g., body-focused habit). Results: Data from the final sample of 50 experts demonstrates that most experts agree with the present classification of BFRB/BFRBD as an obsessive-compulsive and related disorder and recommend retaining the labels BFRB or BFRBD. The experts considered the following conditions BFRB, with an agreement of over 60%: trichotillomania, skin picking, dermatophagia, nail biting, and lip-cheek biting. Mixed results emerged for awake bruxism and thumb sucking in adults. Only a minority regarded night bruxism and knuckle cracking as BFRB. To differentiate BFRB from NSSI, the experts noted that the motive behind the urge (self-harm/injury versus release of tension) should be considered. Analyses of a sub-sample of experts with at least six years of clinical and/or research experience yielded results compatible with those of the entire sample. Discussion: The survey supports the usefulness of the BFRBD diagnostic entity. However, some criteria require further refinement. Future editions of the DSM should more explicitly delineate which conditions qualify as BFRB. Furthermore, it is important to give more attention to the primary motivation behind BFRB to distinguish it from NSSI and potentially from stereotypic movement behavior.

ObjectivesThe distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD.MethodsCross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept.ResultsAfter adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p

PurposeTo assess changes in retinopathy of prematurity (ROP) diagnosis in single and serial retinal images.DesignCohort study.ParticipantsCases of ROP recruited from the Imaging and Informatics in Retinopathy of Prematurity (i-ROP) consortium evaluated by 7 graders.MethodsSeven ophthalmologists reviewed both single and 3 consecutive serial retinal images from 15 cases with ROP, and severity was assigned as plus, preplus, or none. Imaging data were acquired during routine ROP screening from 2011 to 2015, and a reference standard diagnosis was established for each image. A secondary analysis was performed using the i-ROP deep learning system to assign a vascular severity score (VSS) to each image, ranging from 1 to 9, with 9 being the most severe disease. This score has been previously demonstrated to correlate with the International Classification of ROP. Mean plus disease severity was calculated by averaging 14 labels per image in serial and single images to decrease noise.Main outcome measuresGrading severity of ROP as defined by plus, preplus, or no ROP.ResultsAssessment of serial retinal images changed the grading severity for > 50% of the graders, although there was wide variability. Cohen's kappa ranged from 0.29 to 1.0, which showed a wide range of agreement from slight to perfect by each grader. Changes in the grading of serial retinal images were noted more commonly in cases of preplus disease. The mean severity in cases with a diagnosis of plus disease and no disease did not change between single and serial images. The ROP VSS demonstrated good correlation with the range of expert classifications of plus disease and overall agreement with the mode class (P = 0.001). The VSS correlated with mean plus disease severity by expert diagnosis (correlation coefficient, 0.89). The more aggressive graders tended to be influenced by serial images to increase the severity of their grading. The VSS also demonstrated agreement with disease progression across serial images, which progressed to preplus and plus disease.ConclusionsClinicians demonstrated variability in ROP diagnosis when presented with both single and serial images. The use of deep learning as a quantitative assessment of plus disease has the potential to standardize ROP diagnosis and treatment.

Summary: The efficacy of T cell therapies in treating solid tumors is limited by poor in vivo persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable ex vivo activation. Herein, we present a 10-day kinetic profile of T cells subjected to fluid shear stress (FSS) ex vivo, with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). This study represents the first characterization of the dynamic response of primary T cells to FSS. Collectively, our findings underscore the critical role of mechanosensitive ion channel-mediated mechanobiological signaling in T cell activation and fitness, enabling the development of strategies to address the current challenges associated with poor immunotherapy outcomes.

Poland was one of the countries that was hit by the COVID-19 pandemic in 2020, and its government imposed restrictions to combat the spreading of the virus. The Internet and social media became outlets for people's reactions to the events that unfolded, including the lockdown. A part of this reaction came in the form of creating and sharing memes -- an expression of digital participatory culture. This paper aims to analyze how COVID-19 was communicated and narrated through Internet memes and how they presented the pandemic and actors responsible for fighting it. 1,763 memes from six media platforms were analyzed using content analysis with framing elements and a comparative narrative analysis. The results show that the memes provided a form of commentary on the situation experienced by Poles. The most common category of memes was "bans and orders", involving restrictions that were often criticized and ridiculed as pointless. The main characters within the memes were ordinary citizens, often portrayed in a comedic way as careless in regards to the virus and violating the restrictions. They were also presented as victims of the police and the government. Furthermore, the people responsible for fighting the pandemic were portrayed as incompetent and imposing needlessly severe restrictions and penalties for not abiding by them.

Members of the lesbian, gay, bisexual, and transgender + (LGBT+) undergraduate student community are at heightened risk for a variety of health and mental health challenges due to unsupportive environments which may include home, school, and society. However, research underscores the importance of mentors, mentorship, and other social supports upon the mental health of LGBT+ youth, especially when navigating discriminatory experiences. An online survey was conducted among LGBT+ undergraduate college students within one mid-sized university located in the Midwest to assess experiences with discrimination, perceptions of mentoring, and the beneficial components of mentoring programs. 289 LGBT+ undergraduate students (65.7% cisgender female, 47.8% ages 19-20, 51.2% bisexual) responded with 71.6% of participants reporting no current LGBT+ mentor. 56.4% either agreed or strongly agreed that acceptance of the LGBT+ community could be improved at the university. Discussion centers upon the importance of mentoring programs for LGBT+ undergraduate students to provide support and create a more affirming college experience.

OBJECTIVES: There is limited information on the characteristics of older adults with bipolar disorder (OABD) treated with lithium, along with safety concerns about its use by older adults. The aim of the present study is to describe the demographic and clinical characteristics of OABD receiving lithium therapy, using data from the Global Ageing & Geriatric Experiments in Bipolar Disorder (GAGE-BD). EXPERIMENTAL PROCEDURES: Cross-sectional analysis of the GAGE-BD dataset to determine differences and similarities between lithium users and non-users. We analysed data from 986 participants aged 50 years or older (mean age 63.5 years; 57.5% females) from 12 study sites. Two subgroups (Lithium; Non-lithium) were defined according to the current prescription of lithium. We compared several outcomes between these groups, controlling for age, gender, and study site. RESULTS: OABD treated with lithium had lower scores on depression rating scales and were less likely to be categorised as with moderate or severe depression. There was a lower proportion of lithium users than non-users among those with evidence of rapid cycling and non-bipolar psychiatric diagnoses. Assessment of global cognitive state and functionality indicated better performance among lithium users. The current use of antipsychotics was less frequent among lithium users, who also reported fewer cardiovascular comorbidities than non-users. CONCLUSION: We found several potentially relevant differences in the clinical profile of OABD treated with lithium compared with those treated with other mood stabilisers. However, the interpretation of the present results must take into account the methodological limitations inherent to the cross-sectional approach and data harmonisation.

ObjectiveTo investigate the use of near-infrared (NIR) imaging as a tool for outpatient clinicians to quickly and accurately assess for maxillary sinusitis and to characterize its accuracy compared to computerized tomography (CT) scan.MethodsIn a prospective investigational study, NIR and CT images from 65 patients who presented to a tertiary care rhinology clinic were compared to determine the sensitivity and specificity of NIR as an imaging modality.ResultsThe sensitivity and specificity of NIR imaging in distinguishing normal versus maxillary sinus disease was found to be 90% and 84%, normal versus mild maxillary sinus disease to be 76% and 91%, and mild versus severe maxillary sinus disease to be 96% and 81%, respectively. The average pixel intensity was also calculated and compared to the modified Lund-Mackay scores from CT scans to assess the ability of NIR imaging to stratify the severity of maxillary sinus disease. Average pixel intensity over a region of interest was significantly different (P < .001) between normal, mild, and severe disease, as well as when comparing normal versus mild (P < .001, 95% CI 42.22-105.39), normal versus severe (P < .001, 95% CI 119.43-174.14), and mild versus severe (P < .001, 95% CI 41.39-104.56) maxillary sinus disease.ConclusionBased on this data, NIR shows promise as a tool for identifying patients with potential maxillary sinus disease as well as providing information on severity of disease that may guide administration of appropriate treatments.

We use correspondence analysis to look at the changing nature of political debates in the Canadian House of Commons concerning immigration over a five-decade period. Using data drawn from the Linked Parliamentary Data (LiPaD) project we assess the way in which immigration policy and issues are discussed by different political parties from September of 1968 to June of 2019. We look at debates in five of the longest Prime Ministers' mandates. In doing so, we trace changes in both emphasis and rhetoric by political party. We find that party political views on immigration became more polarized with the breakup of the Progressive Conservative party in the early 1990s. Liberal party views moved toward to the left of the spectrum while the Reform/Alliance/Conservative Party of Canada parties moved toward the right and became increasingly entrenched until 2015. After that, the Conservatives and the Liberals moved closer to the centre. The New Democratic Party was the most consistent in its views over time, focusing on issues of humanitarianism as well as broad policy issues. Nous utilisons l'analyse des correspondances pour examiner la nature changeante des debats politiques a la Chambre des communes du Canada concernant l'immigration sur une periode de cinq decennies. En utilisant des donnees tirees du projet Linked Parliamentary Data (LiPaD), nous evaluons la facon dont la politique et les questions d'immigration sont discutees par les differents partis politiques de septembre 1968 a juin 2019. Nous examinons les debats au cours de cinq des plus longs mandats de Premier ministre. Ce faisant, nous retracons l'evolution de l'accent et de la rhetorique par parti politique. Nous constatons que les opinions politiques des partis sur l'immigration sont devenues plus polarisees avec l'eclatement du Parti progressiste-conservateur au debut des annees 1990. Les opinions des partis liberaux se sont rapprochees de la gauche du spectre, tandis que les partis Reforme / Alliance / Parti conservateur du Canada se sont rapproches de la droite et sont devenus de plus en plus enracines jusqu'en 2015. Par la suite, les conservateurs et les liberaux se sont rapproches du centre. Le Nouveau Parti Democratique a ete le plus coherent dans ses opinions au fil du temps, se concentrant sur les questions humanitaires ainsi que sur les questions politiques generales., INTRODUCTION We analyze five decades of Canadian parliamentary debates (1968-2019) on immigration to trace patterns across time and parties using correspondence analysis. Our work differs from traditional political discourse analysis [...]

Abstract Mesenchymal stem cells/stromal cells (MSCs)-derived extracellular vesicles (EVs) mediate pro-regenerative effects in damaged ischemic tissues by regulating angiogenesis. MSCs-EVs modulate functions of cells including endogenous mature cells, progenitors and stem cells, resulting in restoration of blood flow. However, the mechanisms underlying such MSC-EV activity still remain poorly understood. The present study analyzes biological effects of bone marrow (BM) MSC-EVs on endothelial cells (ECs) in ischemic tissues both in in vitro and in vivo conditions and elucidates the molecular mechanisms underlying the tissue repair. MSC-EVs were isolated from murine BM-derived MSCs and their morphological, antigenic and molecular composition regarding protein and microRNA levels were evaluated to examine their properties. Global proteomic analysis demonstrated the presence in MSC-EVs of proteins regulating pro-regenerative pathways, including integrin α5 (Itgα5) and neuropilin-1 (NRP1) involved in lymphangiogenesis. MSC-EVs were also enriched in microRNAs regulating angiogenesis, TGF-β signaling and processes guiding cellular adhesion and interactions with extracellular matrix. The functional effects of MSC-EVs on capillary ECs in vitro included the increase of capillary-like tube formation and cytoprotection under normal and inflammatory conditions by inhibiting apoptosis. Notably, MSC-EVs enhanced also capillary-like tube formation of lymphatic ECs, which may be regulated by Itgα5 and NRP1. Moreover, in a mouse model of critical hind limb ischemia, MSC-EVs increased the recovery of blood flow in ischemic muscle tissue, which was accompanied with increased vascular density in vivo. This pro-angiogenic effect was associated with an increase in nitric oxide (NO) production via endothelial NO-synthase activation in ischemic muscles. Interestingly, MSC-EVs enhanced lymphangiogenesis, which has never been reported before. The study provides evidence on pro-angiogenic and novel pro-lymphangiogenic role of MSC-EVs on ECs in ischemic tissue mediated by their protein and miRNA molecular cargos. The results highlight Itgα5 and NRP1 carried by MSC-EVs as potential therapeutic targets to boost lymphangiogenesis. Graphical Abstract