bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of pre-course preparation using a serious smartphone game on advanced life support knowledge and skills -A randomized controlled trial
Authors: Kotruchin P , Phungoen P , Mitsungnern T
Published: November 2020

Background

Over the past several years, gamified learning has been growing in popularity in various medical educational contexts including cardiopulmonary resuscitation (CPR) training. Furthermore, prior work in Basic Life Support (BLS) training has demonstrated the benefits of serious games as a method for pre-training among medical students. However, there is little evidence to support these benefits with regard to Advanced Life Support (ALS) training

Objective

We compare the effects of a brief pre-course ALS preparation course using a serious smartphone game on students' knowledge, skills, and perceptions in this area with those of conventional ALS training alone.

Methods

A serious game (Resus Days) was developed by a Thai physician based on global ALS clinical practice guidelines. Fifth-year medical students were enrolled and randomized to either a game group or a control group. Participants in both groups attended a traditional ALS lecture, but the game group was assigned to play Resus Days for 1 hour before attending the lecture and as wished after that. All students underwent conventional ALS training, and their abilities were evaluated using multiple choice questions and with hands-on practice on a mannequin. Subjects' attitudes and perceptions about the game were evaluated using a questionnaire.

Results

A total of 105 students participated in the study and were randomly assigned to either the game group (n=52) or the control group (n=53). Students in the game group performed better on the ALS algorithm knowledge posttest than those in the control group (17.22±1.93 vs 16.60±1.97, P=0.01; adjusted mean difference [AMD] 0.93, 95% CI 0.21–1.66;). The game group's pass rate on the skill test was also higher, but not to a statistically significant extent (79% vs 66%, P=0.09; adjusted odds ratio [AOR] 2.22, 95% CI 0.89–5.51). Students also indicated high satisfaction with the game (9.02±1.11 out of 10).

Conclusions

Engaging in game-based preparation prior to an ALS training course resulted in greater medical students' algorithm knowledge scores than attending the course alone.

A screen shot of Resus Days

Funding Acknowledgement

Type of funding source: None
First clinical experience with the wearable cardiac rhythm long-term monitoring cardioskin device
Authors: Guedeney P , Silvain J , Hidden-Lucet F , Maupain C , Dinanian S , Waintraub X , Gandjbakhch E , Montalescot G
Published: November 2020

Background

There are only limited options for long-term cardiac monitoring devices readily available in clinical practice for outpatients. Holter monitoring devices are limited by the uncomfort of wires and patches, the small number of leads for analysis, the quality of recordings or the monitoring duration while insertable cardiac monitors are costly and exposed to potential local complication.

Purpose

To describe a single center experience with a novel wearable device for cardiac rhythm monitoring.

Methods

The Cardioskin™ system is a patch-free, wire-free, wearable device with rechargeable batteries that provides a high quality 15-lead electrocardiogram monitoring over 1 month (Figure 1). Data are sent using a mobile application downloaded in the patient smartphone to a central Corelab where they can be interpreted by an expert and/or the prescribing physician. An alarm signal is readily available within the Cardioskin™ device, to allow patients to indicate the presence of symptoms. In this single center retrospective registry, we provide a first report of the use of this novel device in real world practice, with indication and duration of cardiac monitoring left at the physicans “discretion”.

Results

From January 2019 to December 2019, the Cardioskin™ system was prescribed in 60 patients for an overall median duration of 26.5 (14–32) days. The mean age of the patients was 45±12.2 years and 24 (40%) were male. Indications for cardiac monitoring were post-Stroke, palpitation, syncope and cardiomyopathy assessment in 56%, 30%, 7% and 7% of the cases, respectively. A sustained (>30 seconds) supraventricular tachycardia was detected in 4 cases, including one case of atrial fibrillation, two case of atrial tachycardia and on case of junctional tachycardia. Unsustained ventricular tachycardia and atrial fibrillation burst were detected in another 2 cases (Figure 1). There was no reported case of skin irritation by the Cardioskin™ system or abrupt interruption of the monitoring by the patients.

Conclusion

The Cardioskin™ system is a novel, discreet and comfortable cardiac rhythm wearable long-term monitoring device which can be used in clinical practice for broad diagnostic indications.

Figure 1. Cardioskin system

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): ACTION coeur
Detection of ST changes by a smartphone-based electrocardiographic monitoring system in patients with ST elevated myocardial infarction
Authors: De La Torre Hernandez J.M , Aritz Gil Ongay A , Borderias Villaroel T , Gonzalez Lizarbe S , Veiga Fernandez G , Catoya Villa S , De Tapia Majado B , Lozano Gonzalez M , Molina San Quirico M , Serrano Lozano D , Cabrera Rubio I , Sanchez Cena J , Garcia Camarero T , Zueco J
Published: November 2020

Background

Recent technological advances have led to several novel electrocardiographic monitoring devices appearing on the market. The pocket sized Kardia Mobile is a monitoring device that requires the patient to trigger the ECG recording through a smartphone-based application. This system is generally aimed to detect alterations in cardiac rhythm and its potential for detection of ST changes remains largely unknown.

Purpose

This study sought to assess the diagnostic sensitivity of the Kardia Mobile system for detection of ST changes in patients with ST elevated myocardial infarction (STEMI).

Methods

Patients admitted with diagnosis of STEMI according to current universal standard definition were consecutively included. Recordings with Kardia were obtained in leads I, II and anterior precordial (prec). All anonymized recordings were submitted for review to a single cardiologist blinded to the 12 leads ECG findings and to all clinical data. A Kardia recording was considered positive if any significant elevation or depression of ST segment was observed.

Results

A total of 102 consecutive patients were included (age 60.6±11.4 years, 27% females, weight 78.6±17.4 kg) admitted with diagnosis of STEMI after a median of 165 (IQR 120–367) minutes of chest pain. STEMI was anterior-lateral in 48% and inferior-posterior in 52%. Values of sensitivity for each lead and for combination of leads are shown in Table for all STEMI and separately for anterior and inferior locations. ST changes in all leads consisted mostly in depression (70–78%). Poor quality recording rates were 8% for lead I, 1% for lead II and 3% for lead prec.

Conclusions

The Kardia Mobile system with single lead use shows a modest sensitivity for detection of ST changes (mostly depression) in STEMI patients. However, the combination of two leads (particularly I+prec or II+prec) or three leads shows a very high sensitivity for both anterior and inferior STEMI.

Funding Acknowledgement

Type of funding source: None
Improved prediction of cardiac, limb and bleeding events in patients with coronary and peripheral arterial disease using machine learning models and artificial intelligence
Authors: Steffel J , Kloss S , Roohi Sefidmazgi N , Chevreux B , Fox K.A.A
Published: November 2020

Background

Coronary artery disease (CAD) and peripheral arterial disease (PAD) represent a significant burden in patients with cardiovascular disease (CVD). However, current antithrombotic therapies are inconsistently used because of clinical concerns about selecting patients with optimal benefit versus risk.

Purpose

We aimed to determine whether complex data engineering, multi-layered machine learning and artificial intelligence could be used to derive and test an improved risk stratification tool to support clinical decision making among CAD/PAD patients at risk of thrombotic events.

Methods

We conducted a retrospective cohort study using claims data from the US Optum Clinformatics dataset, derived from Jan 1, 2010 to Dec 31, 2018. Predictive modeling analytics, including multi-label logistic regression, cox-regression and machine learning techniques (Random Forests and Gradient Boosting Machines) were used to calculate individual patient risks for Major Adverse Cardiac Events (MACE), Major Adverse Limb Events (MALE) and Major Bleeding (MB) events for 1-year and 5-year predictions. To translate findings from black box models into interpretable results, explainable artificial intelligence (AI) techniques based on Shapley additive explanations (SHAP) were applied.

Results

The study cohort consisted of 1,842 million patients with a diagnosis of CAD (mean age: 71±11) and 1,557 million patients with a diagnosis of PAD (mean age: 74±10). 1,017 million patients had a diagnosis of both. Annual event rates for MACE, MALE and Major Bleeding events were 3.5%, 0.7% and 1.6%. 865 variables were extracted from the patient history, including demographics, diagnoses, procedures and prescriptions. For all outcomes, the gradient boosting machines outperformed all other statistical models, including risk scores like CHA2DS2VASc and REACH. The AUCs for the 1-year prediction were 0.75 for MACE, 0.88 for MALE and 0.76 for MB, respectively. For a standard risk score-based approach AUCs were 0.67 for both MACE and Major Bleeding, there was no risk score available for MALE. Linear regression models using all 865 variables showed slightly inferior results compared to the machine learning methods (AUCs: 0.74 for MACE, 0.84 for MALE and 0.75 for MB, respectively).

Conclusion

Our study showed that in a very heterogeneous patient population, machine learning techniques can outperform existing risk scores as well as linear models when assessing individual patient risks. Machine learning and artificial intelligence can be used to shape and evolve evidence generation for personalized healthcare and digital health solutions and support HCPs and payers in understanding most relevant prognostic factors that are associated with patient outcomes.

Figure 1

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): Bayer AG
Effect of immortal time bias on the association between atrial fibrillation ablation and incident stroke: a meta-analysis
Authors: Samuel M , Khairy P
Published: November 2020

Background/Introduction

In the era of big data and large observational studies, identification and prevention of immortal time bias (ITB) is essential to attain unbiased effect estimates. Immortal time refers to a period of follow-up in a cohort when the outcome cannot occur. Typically, it results when the exposure is initiated after the start of follow-up. The misclassification of person-time results in a systematic overestimation of the treatment effect. ITB is a common methodological issue in epidemiology studies. We sought to assess the presence and magnitude of bias due to ITB in observational studies evaluating the effectiveness of catheter ablation (CA) for atrial fibrillation.

Purpose

To compare the association between CA and stroke in 1) observational studies that controlled for ITB, 2) observational studies that did not address ITB, and 3) randomized controlled trials (RCT).

Methods

The PUBMED database was screened from inception to January 15, 2020 for publications with the following string of search terms: (“ablation” or “catheter ablation” or “pulmonary vein isolation”) and “atrial fibrillation” and (“stroke” or “thromboembolism”). Observational studies and RCTs comparing CA to medical therapy were eligible. Studies were excluded if: 1) evaluation of the association was limited to a subgroup of AF patients, 2) cryoablation was performed, 3) strokes were not reported, and 4) HRs or 95% CI were not presented. Information on study characteristics, HRs, and the potential for ITB was extracted. Subsequently, articles were classified based on the type of study and whether ITB was addressed. For each group of articles, HRs were logarithmically transformed and pooled using the random effects model.

Results

A total of 10 observational studies and 1 randomized controlled trial were included in the present analysis. Of the 10 observational studies, only 2 studies were designed to prevent ITB. The pooled HR for observational studies without ITB prevention showed a statistically significant reduction in risk of stroke (HR 0.66 (95% CI 0.58–0.74); I2=27.3%) in CA patients compared to non-CA patients. However, pooling the two observational studies that prevented ITB indicated no difference in the incidence of stroke [HR 0.75 (95% CI 0.49–1.02); I2=4.5%] among patients with and without CA, a finding similar to CABANA trial [HR 0.42 (95% CI 0.11–1.21)].

Conclusion

It is important to evaluate the effectiveness of procedures and medications using observational data to determine if the results from RCTs translate to the real-world. However, careful consideration needs to be taken in the design phase to avoid ITB and produce effect estimates that more accurately represent the true association between treatment and outcomes. Examples of design methods to prevent ITB include the use of a time-varying covariate or matching on pre-treatment exposure time.

Funding Acknowledgement

Type of funding source: None
Genome-wide association study identifies 18 new susceptibility variants loci associated with Brugada Syndrome
Authors: Barc J , Trados R , Glinge C , Simonet F , Chiang D , Jouni M , Jurgens S , The Brugada Syndrome Genetic Consortium B.R.S , Tanck M , Dina C , Probst V , Wilde A , Redon R , Schott J.J , Bezzina C
Published: November 2020

The Brugada Syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads and is associated with an increased risk of sudden cardiac death. The disorder was initially described as a monogenic primary cardiac electrical disease. However, mutations in SCN5A, encoding the cardiac sodium channel (NaV1.5), which is the major gene associated with the disorder are found in only around 20% of cases and are associated with low penetrance. Furthermore many cases did not display familial aggregation. Based on a previous GWAS conducted on 312 BrS patients and the discovery of the unexpected strong effect of 3 common variants, we proposed that the BrS may comprise a more complex inheritance model. We conducted a genome-wide association study on 2820 individuals with BrS and 10001 ancestry-matched controls to uncover additional genetic loci that modulate susceptibility to BrS, to characterize further the BrS genetic architecture and to uncover new molecular mechanisms.

We identified 21 susceptibility variants that passed the genome-wide statistical significance threshold (P<5.10–8), of which 18 were novel. Eight were located at the SCN5A-SCN10A locus, illustrating the central role of NaV1.5 in the disease. Interestingly, 9 occur in the vicinity of genes known to play a crucial role in cardiac development (HEY2, TBX20, GATA4, ZFPM2, WT1, TBX5, IRX3, IRX5) and / or control cardiac ion channel expression. Of note, 2 others signals occurred in the vicinity of microtubule / cytoskeleton associated proteins (MAPRE2 and MYO18B). Through studies in zebrafish and in human iPSC-derived cardiomyocytes, we demonstrate a role of MAPRE2 on NaV1.5 function.

We identified 18 new susceptibility variants associated with BrS and uncovered a new pathophysiological molecular mechanism underlying BrS susceptibility. We provided further support for a complex genetic architecture underlying susceptibility for the disorder.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): H2020 - Marie Sklodowska Curie IF grant, Rising star grant from the Pays de la Loire regional council
Intense cardiac-targeted small extracellular vesicles-mediated delivery of RAGE siRNA attenuates inflammation in rat myocarditis model
Authors: Kim H , Mun D , Kang J , Yun N , Joung B
Published: November 2020

Background

Despite advances in the field and new therapeutics being developed, heart disease remains the leading cause of mortality worldwide. Small extracellular vesicles (sEV) are 30–150 nm in diameter and ferry RNA and proteins to cells. sEV are a natural carrier of many signaling molecules and play an important role in heart disease. However, the high probability of off-target effects associated with these carriers is a major barrier to translation into clinical application.

Purpose

Our aim was to evaluate whether sEVs engineered to express potent cardiac targeting peptides (CTPs) could deliver siRNA to the heart and exert a therapeutic effect.

Methods

We use vectors encoding LAMP2B (sEV) or CTP-LAMP2B (PsEV) into HEK 293 cells expressing. sEVs were purified from culture media of HEK 293 cells by serial centrifugation followed by tangential flow filtration (TFF) system. sEV and PsEV were loaded with siRNAs by Exo-Fect™ exosome transfection reagent, and were treated into H9C2 rat cardiomyocyte. TNF-alpha were then added to the cells to induce inflammation. And sEVs were intravenously injected into myocarditis rat. Inflammation factors of in vitro and in vivo inflammation model were identified by western blot. Echocardiographic examination was also performed in rat.

Results

The successful development of PsEVs was analyzed by Western blot and TEM. We observed a 4 fold increase from that of the previously developed sEVs in H9C2 cells and a 200% increase in cardiac-specific delivery without toxicity in rat model. AGE is involved in proinflammatory/pro-apoptotic processes. To block RAGE, we loaded RAGE siRNA (siRAGE) in sEV that had high expression of PsEV. Characteristics of sEVs were maintained despite siRNA load.In inflammatory cell models and rat disease models, PsEV-treated groups significantly reduced molecular levels associated with inflammatory responses such as RAGE, IL-6, TNF-alpha, COX2, HMGB1, and p-p65 / p65.

Conclusions

Our results suggest that PsEV can potentially serve as a treatment delivery vehicle for heart disease.

Scheme

Funding Acknowledgement

Type of funding source: None
Novel regulation of cardiac branched-chain amino acid metabolism through AMP deaminase: a possible therapeutic target for diabetic cardiomyopathy
Authors: Ogawa T , Kouzu H , Tatekoshi Y , Osanami A , Oshima H , Mizuno M , Kuno A , Igaki Y , Sugawara H , Fujita Y , Sato T , Yano T , Tannno M , Miki T , Miura T
Published: November 2020

Background

Dysregulation of branched-chain amino acid (BCAA) metabolism has been shown to be associated with type 2 diabetes mellitus (T2DM) and heart failure. BCAA reportedly protects cells from fatty acid-induced mitochondrial injury via sequestration of fatty acids in intracellular lipid droplets from mitochondria. We previously reported that up-regulation of AMP deaminase 3 (AMPD3) impairs cardiac energetics in T2DM hearts, and AMPD3 was recently shown to participate in regulation of amino acid metabolism in skeletal muscle.

Purpose

We hypothesized that AMPD3 regulates cardiac amino acid metabolism by interaction with branched-chain α-ketoacid dehydrogenase (BCKDH) complex and that cardioprotective effect of sodium glucose cotransporter 2 inhibitors is mediated by modification of BCAA metabolism in diabetic cardiomyocytes.

Methods and results

Proteomic analyses of immunoprecipitates with an anti-AMPD3 antibody in rat hearts revealed that AMPD3 interacted with the E1α component of BCKDH complex. Whereas BCKDH has been reported to localize in mitochondria matrix as a rate-limiting enzyme for BCAA catabolism, immunoblotting using subcellular fractions revealed that BCKDH E1α is present in cytosol and endoplasmic reticulum as well. AMPD3-BCKDH E1α interaction was decreased by 68% in T2DM rats (OLETF) compared to that in control rats (LETO), and significant accumulation of BCAAs was observed in OLETF hearts (317±30 vs. 213±16 nmol/g). Survival rate at 48 hours after myocardial infarction (MI) was significantly lower in OLETF than in LETO (40% vs 84%). Empagliflozin treatment (10 mg/kg/day, 14 days) before MI improved the survival rate in OLETF to 70%, increased BCAAs as the top of 92 detected metabolites (791±187 nmol/g) and significantly preserved tissue ATP in the non-MI remote region. Electron microscopy showed a significantly higher prevalence of myocardium lipid droplets in OLETF, which was further increased by empagliflozin.

Conclusions

Results of the present analyses support the hypotheses that conversion of BCAA-derived branched-chain α-ketoacid to branched-chain acyl-CoA is suppressed by reduced AMPD3-BCKDH interaction in the myocardium of T2DM and that empagliflozin induces compensation of the dysregulated cardiac BCAA metabolism by augmentation of BCAA influx and promotion of fatty acid sequestration in intracellular lipid droplets.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Boehringer Ingelheim
CRISPR-Cas9-based gene editing of human mesenchymal stromal cells to improve the outcome of cell therapy
Authors: Schary Y , Brzezinski R.Y , Teper-Shaihov O , Naftali-Shani N , Leor J
Published: November 2020

Background

The environment of the failing and infarcted myocardium drives resident and transplanted mesenchymal stromal cells (MSCs) toward a pro-inflammatory phenotype, thus restricting their survival and their reparative effects in a mechanism mediated by toll-like receptor 4 (TLR4). Hence, new approaches are needed to improve the efficacy of cell therapy for heart failure. CRISPR is a promising tool for genome editing, which raises the hope for therapeutic genome editing in the clinic.

Purpose

We aimed to provide a new strategy to enhance MSC-based cell therapy to improve cardiac remodeling and function. We hypothesized that ex vivo knockout (KO) of the human TLR4 gene by CRISPR would switch human-cardiac MSCs (hMSCs) to an anti-inflammatory, reparative phenotype that could prevent remodeling of the left ventricle after myocardial infarction (Fig. 1A).

Methods and results

We achieved up to 68% (out of 4x105 cells, R2=0.93) success rate in editing the genome of primary cardiac hMSCs taken from patients with ischemic heart disease. The deletion of TLR4 in hMSCs significantly reduced the secretion of inflammatory and extracellular-matrix (ECM) proteins, compared with unedited hMSCs, by protein mass spectrometry (Fig. 1B) and by multiplex ELISA (Fig. 1C). Additionally, edited cells secreted significantly more extracellular vesicles (EVs) than unedited hMScs (Fig. 1D, p<0.001). These EVs from edited hMSCs stimulated faster migration of hMSCs in a “wound healing” assay (p<0.001).

Conclusions

We show, for the first time, that CRISPR-based deletion of the TLR4 gene in hMSCs inhibits inflammatory and ECM protein secretion and facilitates a reparative response by hMSCs in vitro. This precise and efficient ex vivo gene editing could provide a newly engineered cell line to improve the outcome of hMSC-based cell therapy.

Figure 1

Funding Acknowledgement

Type of funding source: Public hospital(s). Main funding source(s): The Foundation in Memory of Seymour Fefer, Sheba Medical Center
The selective late sodium current inhibitor eleclazine reduces atrial fibrillation dominant frequency and facilitates the suppression of arrhythmia in HL-1 cells
Authors: Del Canto Serrano I , Gomez-Cid L , De La Nava A.S , Guillem M.S , Fernandez-Santos M.E , Climent A.M , Atienza F , Fernandez-Aviles F , Chorro F.J
Published: November 2020

Background

The cardiac late sodium current (INaL) has been increasingly implicated in the initiation of atrial fibrillation (AF). In fact, it has been reported that the augmentation of INaL in pathophysiological conditions prolongs repolarization and facilitates the appearance of afterdepolarizations, which can act as triggers of arrhythmic activity. Eleclazine is a novel selective inhibitor of INaL and is undergoing clinical testing for the treatment of cardiac arrhythmias.

Purpose

The aim of this study was to investigate the effects of eleclazine on spectral characteristics of atrial fibrillation in cultured atrial myocyte monolayer in order to assess whether this inhibitor could protect against cardiac arrhythmias.

Methods

Confluent HL-1 murine atrial myocyte monolayer with spontaneous fibrillatory activity was cultured in 1.5 cm diameter petri dishes (n=10). A high-resolution optical mapping system was used to record fibrillatory activity under basal conditions (without drug), and under eleclazine at increasing concentrations (1, 3 and 5 μM). Power spectra of optical signals were estimated by using Welch periodogram and dominant frequency (frequency with the largest peak in the spectrum between 0.05 and 30 Hz) was determined. The incidence of spontaneous defibrillation was analyzed under control and drug conditions. An ANOVA and a chi-squared test were used. Significance was reached when p<0.05.

Results

Eleclazine at 1, 3 and 5 μM significantly decreased dominant frequency with respect to basal conditions (basal: 4.74±1.31 Hz; 1μM: 3.59±1.17 Hz, p<0.001; 3μM: 3.19±0.64 Hz, p<0.01; 5μM: 2.58±0.40 Hz, p<0.01). The magnitude of drug-induced decrease in AF activation frequency was enhanced by increasing concentrations (1μM: 27%, 3μM: 42%; 5μM: 46%; p<0.05). After the analysis of optical signals, we observed that the incidence of spontaneous defibrillation in atrial monolayers was significantly greater under eleclazine 5μM action than under control conditions (chi-square=5.00, p=0.025). In fact, under the action of eleclazine 5μM, fibrillatory activity was suppressed in 4 of the 10 monolayers, phenomenon that did not occur in any case of control situation.

Conclusions

Selective late INa inhibition with eleclazine reduced dominant frequency of atrial fibrillation and facilitates the termination of arrhythmia in cultured atrial myocyte monolayer.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Ministerio de Innovaciόn y Ciencia, Spain; Generalitat Valenciana, Spain
A unique proteomic signature of extracellular vesicles derived from mesenchymal stromal cells of epicardial fat from patients with and without ischemic heart disease
Authors: Brzezinski R.Y , Tepper-Shaihov O , Naftali-Shani N , Zuroff E , Volvovitch D , Amunts S , Ram E , Sternik L , Raanani E , Grossman E , Leor J
Published: November 2020

Background

Mesenchymal stromal cells (MSCs) have been implicated in the development and progression of myocardial diseases. However, the role of extracellular vesicles (EVs) secreted from human MSCs (hMSCs) of epicardial fat (eFat) in the pathogenesis of ischemic heart disease (IHD) has never been studied.

Purpose

We sought to characterize EVs from eFat-hMSCs of patients with and without IHD.

Methods

We collected eFat specimens from 12 patients with (n=7) and without (n=5) IHD who underwent open heart surgery. We isolated and cultured hMSCs by enzymatic digestion and adherence to plastic. EVs were separated from the culture media by differential ultra-centrifugation. We assessed EV size and structure by electron microscopy and nanoparticle tracking analysis. Finally, we evaluated the proteomic profile of EVs from ischemic and non-ischemic patients by mass spectrometry.

Results

eFat-hMSCs from ischemic patients, secreted higher amounts of small EVs (size range of 70–200 nm) compared with non-ischemic controls (Figure 1A+B). Proteomic analysis revealed over 1,000 proteins inside isolated EVs. We identified 13 proteins that were significantly differentially expressed between patients with and without IHD, including apolipoprotein E, transforming growth factor-β and collagen α-1 (Figure 1C). We performed an enrichment analysis which showed that EVs from eFat-hMSCs from ischemic patients encapsulated functional protein networks associated with immune activation. Unlike IHD patients, EVs from non-ischemic patients carried functional protein networks that regulate angiogenesis.

Conclusions

eFat-hMSCs of patients with IHD secrete higher amounts of small EVs with a unique proteomic signature related to immune activation. EVs derived from eFat-hMSCs should be further studied for their potential role in the initiation and progression of cardiovascular diseases, such as coronary artery disease, heart failure and arrhythmias.

Figure 1

Funding Acknowledgement

Type of funding source: None
SIRT5 deficiency enhances the proliferative and therapeutic capacities of adipose-derived mesenchymal stem cell via metabolic switching
Authors: Ou T , Yang W , Li W , Lu Y , Dong Z , Sun A , Ge J
Published: November 2020

Background

Mesenchymal stem/stromal cells (MSCs) render potential therapies for multiple ischemic diseases. However, in vitro expansion of MSCs before application leads to a metabolic switch from glycolysis to oxidative phosphorylation, drastically impairing their proliferative and therapeutic capacities.

Purpose

Here we aim to identify the role of SIRT5, a master metabolic regulator, in culture expansion of adipose-derived MSCs (ADMSCs).

Methods

SIRT5 deficiencyADMSCs was obtained from Sirt5−/− mice and their metabolic pattern and proliferation capacity were tested during in vitro expansion. Hind limb ischemic model was established to evaluated the therapeutic function of Sirt5−/−ADMSCs.

Results

SIRT5 protein level was upregulated in ADMCSs undergoing culture expansion. Sirt5−/−ADMSCs during in vitro expansion exhibited higher proliferation rate, delayed senescence and enhanced antioxidant capacity. SIRT5 deficiency induced hypersuccinylation of metabolic-related proteins, leading to attenuated mitochondrial respiration with elevated glycolysis and pentose phosphate pathway. Furthermore, lowering succinylation level by glycine treatment reversed the altered metabolism and enhanced proliferation of Sirt5−/−ADMSCs. In mice hind limb ischemic model, SIRT5−/−ADMSCs treatment achieved better blood flow recovery and angiogenesis compared to WT ADMSCs treatment.

Conclusion

We reveal that SIRT5 is a key regulator of ADMSCs undergoing in vitro culture. Ablation of SIRT5 leads to reversed metabolic pattern, enhanced proliferative capacity and improved therapeutic outcomes. Our data provide a potential target for enhancing MSC functional properties during bio-manufacturing in future MSC therapy. Such work may not only benefit MSC cell therapy, but could extent to a wide variety of other stem cells that share similar metabolic pattern.

Graphic Abstract

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Major Research Plan of the National Natural Science Foundation of China. National Science Fund for Distinguished Young Scholars.
Cardiac recovery following left ventricular assist device therapy: experience of complete device explantation including ventricular patch plasty
Authors: Gyoten Takayuki , Rojas Sebastian V , Fox Henrik , Hata Masatoshi , Deutsch Marcus-André , Schramm René , Gummert Jan F , Morshuis Michiel
Published: November 2020

OBJECTIVES

Myocardial recovery is a rare phenomenon in left ventricular assist device (LVAD) therapy. Surgical LVAD removal is associated with the risk of cardiac failure, and the individual evaluation of sufficient myocardial recovery is crucial. Thus, complete device explantation is not consistently performed to minimize perioperative risk. However, the remaining ventricular assist device components bear significant risks of infection or thrombosis. Therefore, we developed this study to evaluate a complete LVAD explantation protocol.

METHODS

All patients in our institution who had an LVAD explanted were enrolled in the study. Explant surgery involved removal of the driveline, pump housing, sewing ring and outflow graft. The ventricular wall was reconstructed by double patch plasty. Our analysis focused on surgical and postoperative outcome parameters, including all-cause mortality and major adverse cardiac and cerebrovascular events.

RESULTS

A total of 12 patients (HVAD, n = 5; HeartMate II, n = 3; HeartMate 3, n = 4) had myocardial recovery and qualified for our LVAD explantation study protocol [median age: 40 years, interquartile range (IQR) 33–52 years; 50% men]. Primary heart failure aetiology: myocarditis (n = 5), dilated cardiomyopathy (n = 4), toxic cardiomyopathy (n = 2) and valvular heart failure (n = 1). The median average duration on LVAD was 10 months (25–75%: IQR 8.5–30 months). The median left ventricular ejection fraction was 15% (IQR 13–18%) at LVAD implantation and 50% (IQR 45–50%) before LVAD explantation (P = 0.0025).The 30-day survival was 100%. The 1-year survival was 91.7%. All patients were discharged after a median 13 days (IQR 10–18 days) postoperatively. No patient had major adverse cardiac and cerebrovascular events. The New York Heart Association functional class remained consistent during the follow-up period (median New York Heart Association functional class: II, IQR II–II class) including preservation of ventricular function.

CONCLUSIONS

Complete LVAD explantation with ventricular patch plasty is feasible and has consistent long-term results.
Enacting a queer pedagogy in the composition classroom
Authors: Buyserie Beth , Ramírez Ricardo
Published: November 2020

Adopting a queer pedagogy in composition classes that include diverse student populations can play an important role in promoting conversations on diversity and equity in the classroom. Under this approach, teachers and students are invited to question the connections between language, the body, power, and ethnicity, thus analysing how our language practices denote unique perceptions of the world. In this article, we intend to connect queer composition theory and pedagogies to a research experience to account for how teachers and students construct embodied and meaningful interactions in the composition class when they explore alternative queer forms of thinking and writing. To accomplish this goal, we foreground the work of queer composition scholars who question how our everyday language and writing practices shape our perception of other individuals and challenge us to consider how we mutually care for and respect each other’s language practices and raced bodies within our pedagogies.
Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome
Authors: Frustaci Andrea , Alfarano Maria , Verardo Romina , Agrati Chiara , Casetti Rita , Miraldi Fabio , Galea Nicola , Letizia Claudio , Chimenti Cristina
Published: November 2020

Aims 

Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.

Methods and results 

Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.

Conclusion 

Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.
A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans
Authors: Abohashem Shady , Osborne Michael T , Dar Tawseef , Naddaf Nicki , Abbasi Taimur , Ghoneem Ahmed , Radfar Azar , Patrich Tomas , Oberfeld Blake , Tung Brian , Fayad Zahi A , Rajagopalan Sanjay , Tawakol Ahmed
Published: November 2020

Aims 

Air pollution [i.e. particulate matter with diameter <2.5 μm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE.

Methods and results 

Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual’s home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE.

Conclusions 

Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.
Interaction among endophytic bacteria, sweet sorghum (Sorghum bicolor) cultivars and chemical nitrogen fertilization
Authors: Heijo Gabriela , Taulé Cecilia , Mareque Cintia , Stefanello Adriano , Souza Emanuel M , Battistoni Federico
Published: November 2020

The application of new agricultural technologies to attain sustainable production systems is necessary. The use of plant growth-promoting bacteria to improve plant growth and health has been studied for decades. This work aimed to isolate diazotrophic endophytic bacteria associated with sweet sorghum plants and study the interaction of their inoculation in combination with chemical N-fertilization on different sorghum cultivars. A bacterial collection of 181 isolates was constructed and characterized in vitro and in vivo. From that, the strains Enterobacter sp. UYSB89 and Kosakonia sp. UYSB139 were nifH+, produce IAA, defined as true endophytes and able to promote growth of two sweet sorghum under greenhouse conditions. The evaluated cultivars responded differentially to bacterial inoculation, the nitrogen fertilization doses and their interaction. Thus, plant growth is a multifactorial consequence of the interrelation between crop practices and the plant genotypes. This knowledge is a valuable factor in terms of understanding plant–bacteria endophyte interactions to preserve environmental sustainability during the implementation of agronomic practices.
Nanopore Amplicon Sequencing Reveals Molecular Convergence and Local Adaptation of Rhodopsin in Great Lakes Salmonids
Authors: Eaton Katherine M , Bernal Moisés A , Backenstose Nathan J C , Yule Daniel L , Krabbenhoft Trevor J
Published: November 2020

Local adaptation can drive diversification of closely related species across environmental gradients and promote convergence of distantly related taxa that experience similar conditions. We examined a potential case of adaptation to novel visual environments in a species flock (Great Lakes salmonids, genus Coregonus) using a new amplicon genotyping protocol on the Oxford Nanopore Flongle and MinION. We sequenced five visual opsin genes for individuals of Coregonus artedi, Coregonus hoyi, Coregonus kiyi, and Coregonus zenithicus. Comparisons revealed species-specific differences in a key spectral tuning amino acid in rhodopsin (Tyr261Phe substitution), suggesting local adaptation of C. kiyi to the blue-shifted depths of Lake Superior. Ancestral state reconstruction demonstrates that parallel evolution and “toggling” at this amino acid residue has occurred several times across the fish tree of life, resulting in identical changes to the visual systems of distantly related taxa across replicated environmental gradients. Our results suggest that ecological differences and local adaptation to distinct visual environments are strong drivers of both evolutionary parallelism and diversification.
Lessons learnt from the field: a qualitative evaluation of adolescent experiences of a universal mental health education program
Authors: Johnson C L , Hart L M , Rossetto A , Morgan A J , Jorm A F
Published: November 2020

teen Mental Health First Aid (teenMHFA) is a school-based mental health program that trains adolescents to support peers who are experiencing mental health problems or crises. The program has been evaluated for adolescents aged 15–18 years as part of a randomized controlled trial, however qualitative feedback from students on their perceptions of the program is yet to be explored. The current study describes the perspectives of students who took part in the trial. Feedback on the perceived strengths and weaknesses of the program was provided by 979 Year 10 students (M = 15.82 years, female = 43.94%, English as a first language = 72.77%) at four government funded public schools in Melbourne, Australia via online surveys. A content and thematic analysis was performed on the data using a six-step process. Students generally found the program relevant and they connected with the visual material, personal stories and interactive activities. Suggestions for improvements included encouraging active student participation in classroom discussion and providing opportunities to practice skills. School-based mental health education can benefit from input from stakeholder perspectives, particularly when designing mental health content for delivery by external trainers.
Systematic Review of Design Guidelines for Full-Body Interactive Games
Authors: Subramanian Sruti , Skjæret-Maroni Nina , Dahl Yngve
Published: November 2020

This paper provides a systematic review of research articles published between 2010 and mid-2018 that have offered design guidelines for full-body interactive games for recreational purposes and physical exercise. From an initial 3562 retrieved database references, 22 articles were found to meet our predefined criteria and were included in the final review. The review of 22 articles resulted in the extraction of 107 design guidelines, which were grouped in 12 different categories: movement elicitation, mapping of movement, explicit movement guidance, player representation and game world, attention, feedback on player performance, player agency and customization, exertion, safety, universal design and social aspects. While the current body of guidelines was found to cover multiple aspects pertaining to the design of full-body interactive games, the conducted review also revealed a number of overarching concerns regarding the present state. Specifically, these concerns relate to (i) the hedonic–utilitarian divide in movement-related design guidelines of relevant literature, (ii) the lack of common structure for specifying guidelines, (iii) the lack of systematic development of guidelines, (iv) the issues related to the validity of the existing guidelines and (v) the limited focus on tangible interfaces in the present state of the art. In conclusion, the current review paints a somewhat questionable picture of the present state of the corpus of design guidelines for full-body games, with relatively large differences in the quality of the guidelines proposed in the individual articles and a lack of reference to already existing guidelines. In the longer run, these quality issues risk watering out the original meaning of the term design guideline and reducing the potential value design guidelines can offer in development of full-body interactive games.
Case report: multiple gastrointestinal stroma tumors in the background of neurofibromatosis type 1
Authors: Beck Tim N , Brown Kevin , Lapinski James , Gurajala Ram K , Karamlou Kasra , Augustin Toms
Published: November 2020

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies of the gastrointestinal tract. GISTs can occur in the background of neurofibromatosis 1 (NF-1), where chemotherapeutic treatment is not optimal and surgical intervention is the only management option. In this case report, we present a case involving a 61-year-old gentleman with NF-1. The patient presented with acute blood loss anemia that was initially controlled with embolization of a hyper-vascular mass abutting the distal jejunum. The patient was taken to the operating room for excision of the mass. All macroscopic disease was excised and the pathology noted GISTs. Surgical decision making is not clearly delineated in the literature for GISTs in patients with NF-1, where targeted therapy is not a treatment option. Resection of all disease should be considered, since NF-1 associated GISTs generally do not have harbor mutations that can be targeted.
Cultivating Student Engagement and Connectedness
Authors: Pinzone Christopher , Reschly Amy L.
Published: November 2020

Student engagement and school connectedness are interrelated and overlapping concepts that are essential to promoting positive youth development and well-being for students, families, and teachers. Affective engagement is reflected in students’ relationships with their peers, teachers, and the school environment, which are related to important outcomes like achievement, school completion, and postsecondary success. These relationships have long been viewed as being important or essential to the academic and behavioral success of students. Intervention research conducted from early childhood through adolescence suggests that affective engagement can be altered through different approaches with different targets; this includes student mentoring, teacher training and feedback, brief cognitive interventions, and grade-level or schoolwide programming. Teachers’ and students’ affective engagement will continue to be an important area for research and intervention.