bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular inflammasomes as novel endogenous danger signals that exert pro-inflammatory signaling on vascular cells
Authors: Schaeffer K , Uhlmann L , Behzadi A , Boeckel J.N , Pelegrin P , Wagner U , Rossner S , Laufs U , Gaul S
Published: November 2020

Background and aims

As part of the innate immune response, NLRP3 inflammasomes are involved in the process of sterile inflammation, IL-1β release and are key mediators of inflammation-related vascular diseases, such as atherosclerosis. Recent data showed the existence of extracellular inflammasomes released from monocytes during pyroptotic cell death. Their biological function in the vascular system is still not known. Here, we established a method to detect extracellular inflammasomes and tested the hypothesis that extracellular NLRP3 inflammasomes can be internalized by vascular cells, such as macrophages, endothelial cells and coronary smooth muscle cells and induce pro-inflammatory signaling.

Methods and result

Stimulation of THP1 monocytes and of isolated primary human monocytes with Lipopolysaccharide and Nigericin activated the NLRP3 inflammasome and induced pyroptosis and the release of inflammasome complexes. Extracellular inflammasomes were isolated from cell-free supernatant and identified as inflammasome complexes (oligomers) by immunoblot. For functional characterization, isolated fluorescent-labeled NLRP3 inflammasome complexes were shown to be internalized by THP1 macrophages (19.7±9.7% pos. cells), primary endothelial cells (HUVEC: 9.0±2.3% pos. cells, coronary artery endothelial cells: 11.0% ± 2.3% pos. cells) and coronary smooth muscle cells (42.8±9.9% pos.cells) using immunofluorescence staining, Z-stacks and imaging flow cytometric analysis. Extracellular NLRP3 inflammasomes (eNLRP3) induced pro-inflammatory signaling in macrophages by increasing IL1b and Tnfa gene expression (3.0- fold) as well as IL-1β release (con: 1.9 pg/ml vs. eNLRP3: 191.0 pg/ml). In coronary smooth muscle cells, treatment with extracellular inflammasomes increased endogenous Nlrp3 and IL1b gene expression as well as upregulation of Cell adhesion molecule 1 (Cadm1). Coronary artery endothelial cells showed also increased protein level of surface adhesion marker Intercellular Adhesion Molecule 1 (ICAM1).

Conclusion

Upon canonical NLRP3 inflammasome activation, mononuclear cells release inflammasome complexes into the extracellular space. Macrophages, endothelial cells and smooth muscle cells are able to internalize these extracellular inflammasome complexes that exert pro-inflammatory effects. These findings support the concept that cell-free NLRP3 inflammasomes act as extracellular signal molecules triggering pro-atherogenic signaling mechanisms in vascular cells.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): Leipzig University, Medical Faculty
Has the time come to integrate genetic risk scores into clinical practice?
Authors: Moniz Mendonca F.V , Mendonca M.I , Pereira A , Monteiro J , Sousa J , Santos M , Temtem M , Sousa A.C , Henriques E , Freitas S , Freitas A.I , Freitas D , Reis P
Published: November 2020

Background

The risk for Coronary Artery Disease (CAD) is determined by both genetic and environmental factors, as well as by the interaction between them. It is estimated that genetic factors could account for 40% to 55% of the existing variability among the population (inheritability). Therefore, some authors have advised that it is time we integrated genetic risk scores into clinical practice.

Aim

The aim of this study was to evaluate the magnitude of the association between an additive genetic risk score (aGRS) and CAD based on the cumulative number of risk alleles in these variants, and to estimate whether their use is valuable in clinical practice.

Methods

A case-control study was performed in a Portuguese population. We enrolled 3120 participants, of whom 1687 were CAD patients and 1433 were normal controls. Controls were paired to cases with respect to gender and age. 33 genetic variants known to be associated with CAD were selected, and an aGRS was calculated for each individual. The aGRS was further subdivided into deciles groups, in order to estimate the CAD risk in each decile, defined by the number of risk alleles. The magnitude of the risk (odds ratio) was calculated for each group by multiple logistic regression using the 5th decile as the reference group (median). In order to evaluate the ability of the aGRS to discriminate susceptibility to CAD, two genetic models were performed, the first with traditional risk factors (TRF) and second with TRF plus aGRS. The AUC of the two ROC curves was calculated.

Results

A higher prevalence of cases over controls became apparent from the 6th decile of the aGRS, reflecting the higher number of risk alleles present (see figure). The difference in CAD risk was only significant from the 6th decile, increasing gradually until the 10th decile. The odds ratio (OR) for the last decile related to 5th decile (median) was 1.87 (95% CI:1.36–2.56; p<0.0001). The first model yielded an AUC=0.738 (95% CI:0.720–0.755) and the second model was slightly more discriminative for CAD risk (AUC=0.748; 95% CI:0.730–0.765). The DeLong test was significant (p=0.0002).

Conclusion

Adding an aGRS to the non-genetic risk factors resulted in a modest improvement in the ability to discriminate the risk of CAD. Such improvement, even if statistically significant, does not appear to be of real value in clinical practice yet. We anticipate that with the development of further knowledge about different SNPs and their complex interactions, and with the inclusion of rare genetic variants, genetic risk scores will be better suited for use in a clinical setting.

Funding Acknowledgement

Type of funding source: None
Endothelial-specific Ablation of Non-nuclear Estrogen Receptor alpha Signaling Deteriorates Vascular Remodelling Response
Authors: Liu P.Y , Fukuma N , Hiroi Y , Ueda K , Kariya T , Numata G , Adachi Y , Toyoda M , Li Y , Noma K , Toko H , Kanai Y , Takimoto E , Liao J.K , Komuro I
Published: November 2020

Background and introduction

The difference in cardiovascular disease risk between age-matched women and men narrows as transition through menopause in observational studies. Estrogen exerts complex physiological effects via its non-nuclear and nuclear actions. Experimental studies have shown that endothelial estrogen receptors mediate vasoprotection via endothelial nitric oxide production, reendothelialization, and atherosclerosis. Prior studies in vitro addressed estrogen's effects on endothelial cells and vascular smooth muscle cells, leading to vasoprotection. However, the in vivo evidences are lacking for beneficial effects of endothelium non-nuclear ERα signaling on vascular remodelling in response to injury.

Purpose

This study aims to clarify the impact of endothelial ERα non-nuclear signaling in the vasoprotection, using a novel mouse model lacking tissue-specific ERα non-nuclear signaling.

Methods

We identified the amino acids of ERα which were responsible for its binding to p85α subunit of phosphatidylinositol 3-kinase in vitro. We generated a novel mouse model in which non-nuclear signaling of ERα was ablated in endothelial cells by crossing Tie2-Cre transgenic mice with floxed ERα mutants (RR259/260AA) in which p85α and ERα interaction was disrupted.

Results

In endothelial cells isolated from ERαKI/KITie2 cre/+ animals, E2 failed to induce phosphorylation of Akt, confirming the absence of ERα non-nuclear signaling. Baseline characteristics at 8 to 12 weeks of age were undistinguishable between the genotypes, including body weight, systolic blood pressure, uterine weight and echocardiographic fractional shortening. We then assessed how vascular remodelling process was impacted in a carotid artery wire injury model. Histological analyses with Elastica van Gieson staining two weeks after injury revealed that estrogen dependent suppression of remodelling response (intima to medial ratio) was abolished in ERαki/kiTie2cre/+mice (P=0.0004). Masson's Trichrome staining showed that in the presence of E2 fibrosis was significantly higher in ERαki/kiTie2cre/+ mice than ERαki/kiTie2cre/− mice (P=0.0015).

Conclusions

We generated a novel mouse model for tissue-specific ablation of ERα non-nuclear signaling by interfering ERα-PI3K interaction. Our results demonstrate that the pivotal role for ERα non-nuclear signaling of endothelial cells in carotid arterial protection following injury with its minimal impact on baseline cardiovascular phenotype.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Japan Heart Foundation Research Grant, SENSHIN Medical Research Foundation
A novel whole blood coagulometer for NOAC testing
Authors: Bakhru S , Jiang X , Chen L , Wang Y , Osmani D , Mootoo D , Ansell J , Zappe S
Published: November 2020

Background

While use of the non-vitamin K antagonist oral anticoagulants (NOACs) does not currently require routine coagulation monitoring, this can be highly desirable in at-risk patients, including those suffering major trauma or having to undergo emergency surgery, especially when a NOAC reversal agent is used. However, a point-of-care (PoC) device for the rapid measurement of clotting times in patients on NOACs is currently not available.

Purpose

To characterize the sensitivity of a novel PoC coagulometer to NOAC-induced anticoagulation, as well as quantify instrument precision, via venous whole blood samples freshly spiked with rivaroxaban, apixaban and edoxaban.

Methods

This study was conducted using healthy volunteers with normal coagulation lab values, including PT/INR and aPTT, confirmed via laboratory testing. Whole blood samples from two volunteers per NOAC were spiked with either 0 (sham), 75, 150, or 300 ng/mL of rivaroxaban, apixaban or edoxaban, in randomized order, each day for five days of testing. Each day, each spiked sample was run on five PoC coagulometers simultaneously for replicate measurement.

Results

PoC coagulometer clotting times exhibited a high degree of linearity spanning the measuring range, with R2 values approaching 1, and high sensitivity across NOAC concentrations tested (i.e. each concentration was statistically significantly different from the others), as well as a high level of precision across the five days of testing. Furthermore, the PoC coagulometer yielded notably low %CVs at each concentration tested, for each subject and anticoagulant, ranging from approximately 3–7% (Fig. 1, rivaroxaban and apixaban data from individual subjects shown).

Conclusions

These results suggest that this PoC coagulometer could be a valuable tool to assess the pharmacodynamic effects of the NOACs in emergency and other settings. The PoC coagulometer yields results within minutes at a patient's bedside, requiring only a drop of whole blood.

Figure 1

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): Perosphere Technologies Inc.
Heparin is more effective than apixaban in inhibiting in vitro contact activated coagulation
Authors: Engelen M.M , Van Laer C , Jacquemin M , Vandenbriele C , Peerlinck K , Verhamme P , Vanassche T
Published: November 2020

Introduction

Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors.

Purpose

To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation.

Methods

Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed.

Results

With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH.

Conclusion

UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway.

Thrombin generation curves

Funding Acknowledgement

Type of funding source: None
Deficiency of the purinergic receptor P2X4 limits atherosclerosis in mice
Authors: Koenig S , Peikert A , Merz J , Rofa K , Schaefer I , Dimanski D , Karnbrock L , Von Garlen S , Aleid R , Bulatova K , Hoppe N , Bode C , Zirlik A , Stachon P
Published: November 2020

Introduction

Extracellular nucleotides like ATP promote inflammation as danger signals in various chronic diseases via purinergic receptors. In our previous work we identified P2X4 expression in murine atherosclerotic lesions. Therefore, we hypothesized a contribution of the ATP-P2X4 axis to vascular inflammation in atherosclerosis.

Methods

To investigate the functional role of P2X4 in atherogenesis, wild-type LDL-receptor deficient mice (LDLR−/−) and P2X4-deficient LDLR−/− mice (P2X4−/−LDLR−/−) were fed a high cholesterol diet for 16 weeks. Plaque progression in aortic arches was monitored by echography at intervals of 4 weeks, and leukocyte subsets in blood samples were analysed by flow cytometry. Atherosclerotic lesions were then assessed histologically in aortic root, arch, and abdominal aorta. In order to assess leukocyte recruitment, intravital microscopy was performed after injection of ATP in P2X4−/− or wildtype mice (WT). Regarding transferability to human disease, atherosclerotic plaque from carotid endarterectomy has been stained immunohistochemically for P2X4-receptor expression.

Results

After 16 weeks, P2X4-deficient mice showed significantly reduced atherosclerotic lesions in the aortic root (n=40, LDLR−/−: 0.47 mm2, P2X4−/−LDLR−/−: 0.39 mm2, p=0.04). Ly6C- monocyte count in peripheral blood was higher in P2X4−/−LDLR−/− (n=32, LDLR−/−: 241/μl, P2X4−/−LDLR−/−: 542/μl, p=0.0088), shifting the balance to a more anti-inflammatory subset. Memory-cell generation of CD4-T-cells is significantly higher in knockout-mice, suggesting an involvement of T-helper cells (n=25, LDLR−/−: 27%, P2X4−/−LDLR−/−: 46%, p=0.0003). Peritoneally injected ATP induced leukocyte rolling in WT, but not in P2X4-deficient mice. In human carotid arteries, atherosclerotic plaque shows higher staining for P2X4−/− receptor than not diseased areas.

Conclusion

P2X4-deficiency enhances anti-inflammatory leukocytes in peripheral blood and reduces atherosclerosis. Therefore, blocking the ATP-P2X4 axis may prevent leukocyte recruitment to atherosclerotic lesions and could present a potential new target for anti-atherogenic therapy.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by a research grant of the German Research Foundation (DFG) to Peter Stachon. Sebastian König was supported by a research grant of the German Cardiac Society (DGK)
Modification of histone 3 lysine 27 (H3K27) trimethylation in EZH2 and JMJD3 deficient T cells attenuates atherosclerosis through polarization towards anti-inflammatory phenotypes
Authors: Lacy M , Nitz K , Janjic A , Wu Y , Venkatasubramani A , Imhof A , Enard W , Weber C , De Winther M , Atzler D , Lutgens E
Published: November 2020

Background

The trimethylation status of Histone 3 Lysine 27 (H3K27), which is regulated by the methylating enzyme Enchancer of zeste homolog 2 (EZH2) and the demethylating enzyme Jumonji domain containing 3 (JMJD3), is a critical epigenetic signature for the differentiation and polarization of T cells. During atherogenesis, T cells initiate and propagate lesion formation through imbalanced polarization of T helper (Th) cells leading to the accumulation of pro-atherogenic T cell subsets, including Th1, that exacerbate inflammation.

Purpose

We hypothesize that T-cell EZH2 and JMJD3 may contribute to inflammation and atherosclerotic plaque formation through opposing polarization of T helper cells.

Methods

We generated transgenic mice with either Ezh2 or Jmjd3 flanked by loxP-sites that were sensitive to Cre-mediated inactivation. Mice were backcrossed to apolipoprotein E (ApoE−/−) mice expressing Cre in T cells (Cd4Cretg) to generate hypercholesterolemic Ezh2fl/fl-Cd4Cre-ApoE−/− (Ezh2fl/fl) and Jmjd3fl/fl-Cd4Cre-ApoE−/− (Jmjd3fl/fl) mice. Following a 6 week high fat diet, the immune status and atherosclerotic progression of the mice were assessed by histology, flow cytometry, and RNA sequencing.

Results

Mass spectrometry of histones isolated from CD4+ T cells confirmed a decrease in H3K27 trimethylation in Ezh2fl/fl mice and an increase in Jmjd3fl/fl mice (p=0.0002 and p=0.01, respectively). In the aortic root, both Ezh2fl/fl and Jmjd3fl/fl mice developed significantly less atherosclerosis (p=0.001 and p=0.0006, respectively). A shift from naive T cells to effectors was observed in the lymph nodes and spleens in both models (p<0.0001 for all). Flow cytometric analysis revealed a systemic accumulation of Th2 in Ezh2fl/flmice (p<0.0001), which was corroborated by a 2.75 log2 fold change of IL-4 expression (padj<0.0001) (RNA-sequencing) in CD4+ T cells as well as elevated IL-4 plasma concentrations (p=0.04). Ingenuity pathway analysis revealed the canonical Th1 pathway was inhibited in Ezh2fl/fl mice. In Jmjd3fl/fl mice, flow cytometric analysis revealed a 2 fold increase of Foxp3-expressing T regulatory (Treg) cells in the blood (p=0.005), lymph nodes (p<0.0001), and spleen (p<0.0001).

Conclusions

Our data demonstrate deficiency of either EZH2 or JMJD3 strongly reduce lesion progression in atherosclerosis through polarization of T cells towards anti-atherogenic Th2 or Treg populations, respectively. Targeting T-cell H3K27 trimethylation may be a promising candidate for further investigation to treat atherosclerosis.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG)
Anthracyclines and regional myocardial damage in breast cancer patients. A multicentre study from the Working Group on Drug Cardiotoxicity and Cardioprotection, Italian Society of Cardiology (SIC)
Authors: Zito Concetta , Manganaro Roberta , Cusmà Piccione Maurizio , Madonna Rosalinda , Monte Ines , Novo Giuseppina , Mercurio Valentina , Longobardo Luca , Cadeddu Dessalvi Christian , Deidda Martino , Pagliaro Pasquale , Spallarossa Paolo , Costantino Rossella , Santarpia Mariacarmela , Altavilla Giuseppe , Carerj Scipione , Tocchetti Carlo Gabriele
Published: November 2020

Aims

In breast cancer (BC) patients treated with anthracyclines-based therapies, we aim at assessing whether adjuvant drugs impact cardiac function differently and whether their cardiotoxicity has a regional pattern.

Methods and results

In a multicentre study, 146 BC patients (56 ± 11 years) were prospectively enrolled and divided into three groups according to the received treatments: AC/EC-Group (doxorubicin or epirubicin + cyclophosphamide), AC/EC/Tax-Group (AC/EC + taxanes), FEC/Tax-Group (fluorouracil + EC + taxanes). Fifty-six patients of the total cohort also received trastuzumab. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were calculated before starting chemotherapy (T0), at 3 months (T3), at 6 (T6), and 12 months (T12). A ≥10% drop of EF, while remaining within the normal range, was reached at T6 in 25.3% of patients from the whole cohort with an early decrease only in FEC/Tax-Group (P = 0.04). A ≥15% GLS reduction was observed in many more (61.6%) patients. GLS decreased early both in the whole population (P < 0.001) and in the subgroups. The FEC-Tax Group showed the worst GLS at T6. Trastuzumab further worsened GLS at T12 (P = 0.031). A significant reduction of GLS was observed in all LV segments and was more relevant in the anterior septum and apex.

Conclusions

The decrease of GLS is more precocious and pronounced in BC patients who received FEC + taxanes. Cardiac function further worsens after 6 months of adjuvant trastuzumab. All LV segments are damaged, with the anterior septum and the apex showing the greatest impairments.
Trajectories, bifurcations, and pseudo-time in large clinical datasets: applications to myocardial infarction and diabetes data
Authors: Golovenkin Sergey E , Bac Jonathan , Chervov Alexander , Mirkes Evgeny M , Orlova Yuliya V , Barillot Emmanuel , Gorban Alexander N , Zinovyev Andrei
Published: November 2020

Background

Large observational clinical datasets are becoming increasingly available for mining associations between various disease traits and administered therapy. These datasets can be considered as representations of the landscape of all possible disease conditions, in which a concrete disease state develops through stereotypical routes, characterized by “points of no return" and “final states" (such as lethal or recovery states). Extracting this information directly from the data remains challenging, especially in the case of synchronic (with a short-term follow-up) observations.

Results

Here we suggest a semi-supervised methodology for the analysis of large clinical datasets, characterized by mixed data types and missing values, through modeling the geometrical data structure as a bouquet of bifurcating clinical trajectories. The methodology is based on application of elastic principal graphs, which can address simultaneously the tasks of dimensionality reduction, data visualization, clustering, feature selection, and quantifying the geodesic distances (pseudo-time) in partially ordered sequences of observations. The methodology allows a patient to be positioned on a particular clinical trajectory (pathological scenario) and the degree of progression along it to be characterized with a qualitative estimate of the uncertainty of the prognosis. We developed a tool ClinTrajan for clinical trajectory analysis implemented in the Python programming language. We test the methodology in 2 large publicly available datasets: myocardial infarction complications and readmission of diabetic patients data.

Conclusions

Our pseudo-time quantification-based approach makes it possible to apply the methods developed for dynamical disease phenotyping and illness trajectory analysis (diachronic data analysis) to synchronic observational data.
Testing for Endogeneity of Covid-19 Patient Assignments
Authors: Gourieroux C , Djogbenou A , Jasiak J
Published: November 2020

A considerable number of individuals infected by COVID-19 died in self-isolation. This paper uses a graphical inference method to examine if patients were endogenously assigned to self-isolation during the early phase of COVID-19 epidemic in Ontario. The endogeneity of patient assignment is evaluated from a dependence measure revealing relationships between patients’ characteristics and their location at the time of death. We test for absence of assignment endogeneity in daily samples and study the dynamic of endogeneity. This methodology is applied to patients’ characteristics, such as age, gender, location of the diagnosing health unit, presence of symptoms, and underlying health conditions.
Case review of severe acute radiation syndrome from whole body exposure: concepts of radiation-induced multi-organ dysfunction and failure
Authors: Tanigawa Koichi
Published: November 2020

Acute radiation syndrome (ARS) due to whole body exposure (WBE) presents various clinical pictures, occasionally leading to fatal consequences. In this report, the literature providing details of the clinical course of severe ARS owing to WBE is reviewed and the lessons learned from recent accidents are discussed, to better prepare for another radiological event. Studies investigating radiological accidents that provided details of medical care for severe ARS were searched in official reports from the International Atomic Energy Agency and through the databases of PubMed, Medline, CiNii and Google Scholar and reviewed. Four fatal cases of severe ARS due to WBE in Soreq 1990 and Nesvizh 1992, and two cases in JCO Tokaimura 1999 were reviewed. A common set of medical interventions was carried out, that put a focus on medical management assuming the occurrence of hematopoietic disorders. However, clinicians were faced with a mixture of chronic hematological and non-hematological events including persistent gastrointestinal disorders, gradual and progressive skin disorders, liver and renal dysfunction and respiratory failure. Clinical pictures following high-dose WBE have become more complicated as treatment modalities improve. To address these issues, a concept of severe ARS due to WBE has been proposed with respect to radiation-induced multi-organ dysfunction syndrome (RI-MODS) and failure (RI-MOF). These patients need to be managed at institutions where multidisciplinary, resource-intensive therapy can be provided.
Re-assessing the role of the fecalith in acute appendicitis in adults: case report, case series and literature review
Authors: Tran Nguyen , Emuakhagbon Valerie-Sue , Baker Bradford T , Huerta Sergio
Published: November 2020

Appendicitis in adults is thought to occur because of luminal obstruction from a fecalith. We present a unique case of a patient who had her entire appendiceal lumen occupied by a fecalith (5.0 cm long) but had no appendicitis. We reviewed the records of 257 veterans who underwent surgical intervention at our institution for the management of acute appendicitis. Fecaliths occurred in 15.6% of patients. At laparotomy, 20.6% had a perforated appendix; pathology showed fecaliths in 20.8% of specimens. A review of the literature inclusive of 25 series showed fecaliths in 33.3% of patients with a normal appendix, 23.5% of patients with acute appendicitis and 24.9% with perforated appendicitis. These data show that appendicitis is not a common cause of fecalith obstruction in adults.
Separatrix divergence of stellar streams in galactic potentials
Authors: Yavetz Tomer D , Johnston Kathryn V , Pearson Sarah , Price-Whelan Adrian M , Weinberg Martin D
Published: November 2020

Flattened axisymmetric galactic potentials are known to host minor orbit families surrounding orbits with commensurable frequencies. The behaviour of orbits that belong to these orbit families is fundamentally different than that of typical orbits with non-commensurable frequencies. We investigate the evolution of stellar streams on orbits near the boundaries between orbit families (separatrices) in a flattened axisymmetric potential. We demonstrate that the separatrix divides these streams into two groups of stars that belong to two different orbit families, and that as a result, these streams diffuse more rapidly than streams that evolve elsewhere in the potential. We utilize Hamiltonian perturbation theory to estimate both the time-scale of this effect and the likelihood of a stream evolving close enough to a separatrix to be affected by it. We analyse two prior reports of stream-fanning in simulations with triaxial potentials, and conclude that at least one of them is caused by separatrix divergence. These results lay the foundation for a method of mapping the orbit families of galactic potentials using the morphology of stellar streams. Comparing these predictions with the currently known distribution of streams in the Milky Way presents a new way of constraining the shape of our Galaxy’s potential and distribution of dark matter.
Incidence and Impact of Persistent Viremia on SVR Rates in Patients Receiving Direct-Acting Antiviral Therapy
Authors: Carver Alicia B , Zuckerman Autumn D , DeClercq Joshua , Choi Leena , Chastain Cody A
Published: November 2020

Rates of persistent viremia (PV) while on direct-acting antiviral therapy were low (5.7%) in a real-world cohort of 983 patients. High sustained virologic response rates were achieved both in patients with PV (92.9%) and those with rapid virologic response (96.5%), without significant differences.
A functional module states framework reveals cell states for drug and target prediction
Authors: Qin Guangrong , Knijnenburg Theo , Gibbs David , Moser Russell , Monnat Raymond J. , Kemp Christopher , Shmulevich Ilya
Published: November 2020

Cells are complex systems in which many functions are performed by different genetically-defined and encoded functional modules. To systematically understand how these modules respond to drug or genetic perturbations, we developed a Functional Module States framework. Using this framework, we 1) defined the drug induced transcriptional state space for breast cancer cell lines using large public gene expression datasets, and revealed that the transcriptional states are associated with drug concentration and drug targets; 2) identified potential targetable vulnerabilities through integrative analysis of transcriptional states after drug treatment and gene knockdown associated cancer dependency; and 3) used functional module states to predict transcriptional state-dependent drug sensitivity and built prediction models using the functional module states for drug response. This approach demonstrates a similar prediction performance as do approaches using high dimensional gene expression values, with the added advantage of more clearly revealing biologically relevant transcriptional states and key regulators.
ProteoSushi: a software tool to biologically annotate and quantify modification-specific, peptide-centric proteomics datasets
Authors: Seymour Robert W. , van der Post Sjoerd , Mooradian Arshag D. , Held Jason M.
Published: November 2020

Large-scale proteomic profiling of protein post-translational modifications has provided important insights into the regulation of cell signaling and disease. These modification-specific proteomics workflows nearly universally enrich modified peptides prior to mass spectrometry analysis, but protein-centric proteomic software tools have many limitations evaluating and interpreting these peptide-centric datasets. We therefore developed ProteoSushi, a software tool tailored to the analysis of each modified site in peptide-centric proteomic datasets that is compatible with any post-translational modification or chemical label. ProteoSushi uses a unique approach to assign identified peptides to shared proteins and genes, minimizing redundancy by prioritizing shared assignments based on UniProt annotation score and optional user-supplied protein/gene lists. ProteoSushi simplifies quantitation by summing or averaging intensities, merging overlapping peptide charge states, missed cleavages, peptide spectral matches, and variable modifications into a single value for each modified site. ProteoSushi annotates each PTM site with the most up-to-date biological information available from UniProt, such as functional roles or known modifications, the protein domain in which the site resides, the protein’s subcellular location and function and more. ProteoSushi has a graphical user interface for ease of use. ProteoSushi’s flexibility and combination of features streamlines peptide-centric data processing and knowledge mining of large modification-specific proteomics datasets.
Th17 cells provide direct protective effects that limit stomach parasite burden following orogastric mucosalTrypanosoma cruziinfection
Authors: Cai Catherine W. , Eickhoff Christopher S. , Meza Krystal A. , Blase Jennifer R. , Audette Rebecca E. , Chan David H. , Bockerstett Kevin A. , DiPaolo Richard J. , Hoft Daniel F.
Published: November 2020

Trypanosoma cruziis the intracellular parasite of Chagas disease, a chronic condition characterized by cardiac and gastrointestinal morbidity. Protective immunity requires CD4+ T cells, and Th1 cells and IFN-γ are important players in host defense. More recently, Th17 cells and IL-17 have been shown to exert protective functions in systemicT. cruziinfection. However, it remains unclear whether Th17 cells and IL-17A protect against mucosal infection, which is an important cause of human outbreaks. We found that IL-17RA knock-out (KO) mice are highly susceptible to orogastric infection, indicating an important function for this cytokine in mucosal immunity toT. cruzi. To investigate the specific role of Th17 cells for mucosal immunity, we reconstituted RAG1 KO mice withT. cruzi-specificT cell receptor transgenic Th17 cells prior to orogastricT. cruzichallenges. We found that Th17 cells provided protection against gastric mucosalT. cruziinfection, indicated by significantly lower stomach parasite burdens.In vitromacrophage infection assays revealed that protection by Th17 cells is reversed with IL-17A neutralization or loss of macrophage NADPH oxidase activity. Consistent with this,in vivo, mice lacking functional NADPH oxidase were not protected by Th17 cell transfer. These data are the first report that Th17 cells protect against mucosalT. cruziinfection, and identify a novel protective mechanism involving the induction of NADPH oxidase activity in macrophages by IL-17A. These studies provide important insights for Chagas vaccine development, and more broadly, increase our understanding of the diverse roles of Th17 cells in host defense.
The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans
Authors: Zhou Xin , Vachon Camille , Cizeron Mélissa , Romatif Océane , Bülow Hannes E. , Jospin Maëlle , Bessereau Jean-Louis
Published: November 2020

The extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan inC. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.
Hippocampal Asymmetry of Regional Development and Structural Covariance in Preterm Neonates
Authors: Ge Xinting , Qiao Yuchuan , Yuan Shiyu , Jiang Wenjuan , Liu Mengting
Published: November 2020

Premature birth is associated with high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, the putative role of hippocampus dysfunction remains poorly understood in preterm neonates. Particularly, hemispherical asymmetry of the hippocampus has been well-noted, either structurally or functionally. How the preterm birth impairs the hippocampal development, and to what extent the hippocampus was impaired by preterm birth asymmetrical has not been well studied. In this study, we compared regional and local hippocampal development in term born neonates (n=361) and prematurely born infants at term-born equivalent age on MRI studies (n = 53) using T2 MRI images collected from the Developing Human Connectome Project (dHCP); We compared 1) volumetric growth; 2) shape development in the hippocampal hemispheres using Laplace–Beltrami eigen-projection and boundary deformation between the two groups; and 3) structural covariance between hippocampal vertices and the cortical thickness in cerebral cortex regions. We demonstrated that premature infants have smaller volume for the right hippocampi, while no difference was observed for the left hippocampi. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared to full-term peers, while an accelerated hippocampal thickness growth rate was found in left hippocampus only. Structural covariance analysis demonstrated that in premature infants, the structural covariance between hippocampi and limbic lobe were severely impaired compared to healthy term neonates only in left hemisphere. These data suggest that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure, with high degree of asymmetry. These findings suggested that the hippocampus shows high degree of vulnerability, particularly asymmetrical vulnerability or plasticity, in preterm neonates at the term-born equivalent age compared to full-term healthy controls.
Characterization of the Percival detector with soft X-rays
Authors: Marras Alessandro , Correa Jonathan , Lange Sabine , Vardanyan Vahagn , Gerhardt Tim , Kuhn Manuela , Krivan Frantisek , Shevyakov Igor , Zimmer Manfred , Hoesch Moritz , Bagschik Kai , Scholz Frank , Guerrini Nicola , Marsh Ben , Sedgwick Iain , Cautero Giuseppe , Giuressi Dario , Iztok Gregori , Menk Ralf H. , Scarcia Martin , Stebel Luigi , Nicholls Tim , Nichols William , Pedersen Ulrik K. , Shikhaliev Polad , Tartoni Nicola , Hyun HyoJung , Kim SeongHan , Kim KyungSook , Rah SeungYu , Dawiec Arkadiusz , Orsini Fabienne , Pinaroli Giovanni , Greer Alan , Aplin Steve , Jewell April D. , Jones Todd J. , Nikzad Shouleh , Hoenk Michael E. , Okrent Frank , Graafsma Heinz , Wunderer Cornelia B.
Published: November 2020

In this paper the back-side-illuminated Percival 2-Megapixel (P2M) detector is presented, along with its characterization by means of optical and X-ray photons. For the first time, the response of the system to soft X-rays (250 eV to 1 keV) is presented. The main performance parameters of the first detector are measured, assessing the capabilities in terms of noise, dynamic range and single-photon discrimination capability. Present limitations and coming improvements are discussed.
HR at the top table
Authors: Mayo Andrew
Published: November 2020

Purpose

The purpose of this paper is to examine the aspiration of Human Resources (HR) professionals to “be at the top table”; what that means; and how such professionals can become highly valued members of business teams.

Design/methodology/approach

The paper discusses what is meant by “top table” and the ambitions of HR professionals to be there. It looks at the prevalence of HR in top teams; how professionals are prepared for senior roles; and it provides a model for effective top team membership.

Findings

The paper discusses the statistics of HR directors in top teams and concludes it should be no surprise that HR is not frequently represented on main boards. It makes the case nevertheless for HR to be on executive teams and finds about two-thirds of major companies recognise this. This paper describes a model of three key functional roles for the top team member and analyses the contributions that can be made.

Practical implications

The practical applications relate to the development of HR professionals and to the expectations that team leaders – such as Chief Executive Officers – should have from the HR team member.

Originality/value

This paper is based mostly on the writing, models and experience of the author but draws on relevant research papers.
Development of a structural model based on ISM for analysis of barriers to integration of leanwith industry 4.0
Authors: R Vigneshvaran , Vinodh S.
Published: November 2020

Purpose

To develop a structural model based on Interpretive Structural Modelling (ISM) approach to analyse the barriers to integration of Lean with Industry 4.0.

Design/methodology/approach

Integrated lean and I4.0 is essential for optimising customer value, rapid product design and redesign to comply with customer demand on time. Also, manufacturing processes to be made more flexible, intelligent and agile. In this context, integrated lean and Industry 4.0 barriers were identified and an ISM approach is employed to identify hierarchical structure of barriers and analysed.

Findings

The result obtained reflects that barriers “increasing competitive pressure”, “lack of long-term vision”, “lack of management support”, “lack of capital fund” are found to be the important barriers that affect the integration of lean and I4.0.

Research limitations/implications

In the present study, 16 barriers are analysed. In future, additional barriers could be included.

Practical implications

The driving and dependence power of barriers were analysed from ISM model and it provided guidance for practitioners to concentrate on barriers for integrating lean and I4.0.

Originality/value

The idea of developing structural model for analysis of barriers to integration of lean with I4.0 is the original contribution.
Numerical modeling on varying patch repair size of cracked beam using engineered cementitious composites
Authors: Cahyati Martyana Dwi , Huang Wei-Hsing , Hsu Hsieh-Lung
Published: November 2020

Purpose

This study aims to investigate the size effect of the patched repairing material applied to the cracked beam.

Design/methodology/approach

Numerical analysis was conducted on a simply supported cracked beam with a dimension of 200 × 25 × 15 cm using ABAQUS software. The behavior of concrete and engineered cementitious composites (ECC) in the simulation are described as concrete damage plasticity model. Linear elastic-plastic model was used to represent the behavior of rebar steel. The type of patching consisted of the varying ratio of lengths and depths, including patching length to total length ratios of 0.2, 0.3 and 0.4, and patching depth to total depth ratios of 0.2, 0.3, 0.4 and 0.5.

Findings

Results show that variations in the patching length and depth ratios affect the maximum flexural load, stiffness and ductility of the repaired beam. It was also found that repairing the cracked beam by using ECC provides higher flexural load of the beam than the use of conventional concrete, owing to the superior tensile strength of ECC.

Originality/value

ECC is the cementitious-based mortar that contains the special selected poly vinyl alcohol fiber having high tensile strength. ECC has been known to exhibit high ductility, high tensile strength and improve durability performance. Thus, ECC is suitable as repairing material for patching cracked beam. By investigating the size of the patched repairing material applied to the cracked beam, the structural performance of repairing beam and the effectiveness of the various patching size were achieved.
Substituting inpatient rehabilitation beds for home‐based multidisciplinary rehabilitation: A qualitative study of patient perceptions
Authors: Kimmel Lara A. , Burge Angela , Watterson Dina , Wolters Catherine , Holland Anne , Reed Melanie , Hunter Peter , Brookes Belinda , Lee Victoria , Leong Ronald
Published: November 2020

Objective

To understand the patients’ perspectives of the pilot Better at Home program in order to inform the development of bed substitution rehabilitation services.

Methods

Prospective qualitative study using semi‐structured interviews undertaken 3‐6 months following program participation was performed. Interviews were transcribed and themes developed by two independent researchers.

Results

Nineteen participants (14 females) were interviewed. Major themes found included high satisfaction with the service and a high regard for the importance of communication both within the team and with the patients. Patients had inconsistent views on the provision of services with some feeling that the program was not specific to their needs, whilst others felt it was focused and flexible. Involvement in decision‐making for referral to the service was also not always fully understood.

Conclusion

This study provides important information that can be utilised in the development of any bed substitution home‐based model of care.
Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus
Authors: Wang Zhangyang , Zhang Yiying , Hu Fan , Ding Jing , Wang Xin
Published: November 2020

Idiopathic normal pressure hydrocephalus (iNPH), the most common type of adult‐onset hydrocephalus, is a potentially reversible neuropsychiatric entity characterized by dilated ventricles, cognitive deficit, gait apraxia, and urinary incontinence. Despite its relatively typical imaging features and clinical symptoms, the pathogenesis and pathophysiology of iNPH remain unclear. In this review, we summarize current pathogenetic conceptions of iNPH and its pathophysiological features that lead to neurological deficits. The common consensus is that ventriculomegaly resulting from cerebrospinal fluid (CSF) dynamics could initiate a vicious cycle of neurological damages in iNPH. Pathophysiological factors including hypoperfusion, glymphatic impairment, disturbance of metabolism, astrogliosis, neuroinflammation, and blood‐brain barrier disruption jointly cause white matter and gray matter lesions, and eventually lead to various iNPH symptoms. Also, we review the current treatment options and discuss the prospective treatment strategies for iNPH. CSF diversion with ventriculoperitoneal or lumboperitonealshunts remains as the standard therapy, while its complications prompt attempts to refine shunt insertion and develop new therapeutic procedures. Recent progress on advanced biomaterials and improved understanding of pathogenesis offers new avenues to treat iNPH.