bluuebunny/crossref_metadata_2025 huggingface dataset:
Iliac artery deformation during EVAR
Authors: Koutouzi Giasemi , Pfister Marcus , Breininger Katharina , Hellström Mikael , Roos Håkan , Falkenberg Mårten
Published: March 2019

Objectives

To quantify the deformation of the common iliac artery caused by stiff guide wires and delivery systems during abdominal endovascular aortic repair (EVAR).

Methods

Twenty-two patients treated with abdominal EVAR were included. The following three image data-sets were acquired for each patient: (1) a preoperative computed tomography angiography (CTA), (2) an intraoperative contrast-enhanced cone beam CT (CBCT) obtained after the main trunk of the bifurcated stent graft was released and both iliac limbs were engaged with stiff guide wires, and (3) the first postoperative CTA. These data-sets were merged and compared in an image analysis work station. The length and the tortuosity index of the common iliac artery, the Euclidian displacement of the aortic and the iliac bifurcations, and the optimal C-arm angulation for projection of the iliac bifurcation were computed.

Results

The common iliac artery was on average 6.4 mm shorter ( p < 0.001) and tortuosity index was lower ( p = 0.003) in the intraoperative images compared to preoperative. Some of the foreshortening was reversed postoperatively, remaining mean length difference was 2.9 mm ( p = 0.007) compared to preoperative. Intraoperatively, the aortic bifurcation was mostly displaced in a cranial direction (100%) and the iliac bifurcation in a ventral direction (93%). The optimal lateral C-arm angulation for projection of the iliac bifurcation changed. Anterior contralateral angle increased from median 42° (IQR, 27–63) in the preoperative CTA to 62 (49–74) in the intraoperative CBCT ( p = 0.02). Optimal cranio-caudal angulation did not change.

Conclusion

Stiff guide wires and delivery systems cause significant deformation of the common iliac arteries during EVAR. The aortic bifurcation is more cranial, the common iliac arteries are shorter, and optimal C-arm angulation is more contralateral oblique when the iliac limbs are to be deployed compared to baseline measurements from preoperative CTA. This affects image fusion accuracy and stent graft selection.
Long-term results of the heparin-bonded Viabahn stent graft in femoropopliteal TASC C and D lesions with a covered stent length of minimum 25 cm
Authors: Uhl C , Dadras A , Reichmann F , Betz T , Zorger N , Toepel I , Steinbauer M
Published: March 2019

Background

Heparin-bonded covered stent grafts (Viabahn) are used to treat femoropopliteal long-segment arteriosclerotic lesions. The aim of this study was to evaluate the long-term outcome of Viabahn grafts with a covered stent length of minimum 25 cm.

Methods

We conducted a retrospective analysis of patients receiving a heparin-bonded stent graft in our clinic who met the length criteria between July 2010 and March 2018. Primary endpoints were patency rates, limb salvage and survival after five years. Secondary endpoint was the 30-day outcome including early complications.

Results

A total of 62 patients (45 male, median age 70.5 years) were included. The median arteriosclerotic lesion length was 25 cm (22.0–41.3 cm), the minimum covered stent length was 25 cm (25–46 cm). All lesions were TASC C and D lesions. The 30-day mortality was 0%, an early stent graft occlusion occurred in 8.1%. A major amputation was performed in 1.6%. Primary patency, primary assisted patency, secondary patency, limb salvage and survival were 38.5%, 45.7%, 52.4%, 92.8% and 68.9% after five years. Distal stent graft end below the femoral condyles and critical limb ischemia was associated with a significant decreased survival. The diameter of the stent had no influence on the outcome.

Conclusion

The Viabahn stent graft for long segment arteriosclerotic lesions is a feasible treatment with adequate long-term results.
Analysis of multimodal Bayesian nonparametric autoregressive hidden Markov models for process monitoring in robotic contact tasks
Authors: Wu Hongmin , Guan Yisheng , Rojas Juan
Published: March 2019

Robot introspection aids robots to understand what they do and how they do it. Previous robot introspection techniques have often used parametric hidden Markov models or supervised learning techniques, implying that the number of hidden states or classes is defined a priori and fixed through the entire modeling process. Fixed parameterizations limit the modeling power of a process to properly encode the data. Furthermore, first-order Markov models are limited in their ability to model complex data sequences that represent highly dynamic behaviors as they assume observations are conditionally independent given the state. In this work, we contribute a Bayesian nonparametric autoregressive Hidden Markov model for the monitoring of robot contact tasks, which are characterized by complex dynamical data that are hard to model. We used a nonparametric prior that endows our hidden Markov models with an unbounded number of hidden states for a given robot skill (or subtask). We use a hierarchical Dirichlet stochastic process prior to learn an hidden Markov model with a switching vector autoregressive observation model of wrench signatures and end-effector pose for the manipulation contact tasks. The proposed scheme monitors both nominal skill execution and anomalous behaviors. Two contact tasks are used to measure the effectiveness of our approach: (i) a traditional pick-and-place task composed of four skills and (ii) a cantilever snap assembly task (also composed of four skills). The modeling performance or our approach was compared with other methods, and classification accuracy measures were computed for skill and anomaly identification. The hierarchical Dirichlet stochastic process prior to learn an hidden Markov model with a switching vector autoregressive observation model was shown to have excellent process monitoring performance with higher identification rates and monitoring ability.
Comprehensive assessment of disability post-stroke using the newly developed miFUNCTION scale
Authors: Zerna Charlotte , Burley Tyler , Green Theresa L , Dukelow Sean P , Demchuk Andrew M , Hill Michael D
Published: March 2019

Background and Purpose

The modified Rankin Scale (mRS) is the most widely used primary outcome measure in acute stroke trials. However, substantial interobserver variability impairs outcome assessment as well as reduces power of clinical trials. Guided by the International Classification of Functioning, Disability and Health, we developed a comprehensive, hierarchical assessment tool (miFUNCTION) to address the shortcomings of the modified Rankin Scale and deliver a more thorough understanding of disability following stroke.

Methods

The initial construct validity of miFUNCTION was established in a pilot study of patients at an outpatient stroke prevention clinic that had been diagnosed with stroke within 60 days. To further assess criterion validity, miFUNCTION was compared against the modified Rankin Scale and other outcome measures within the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial. Logistic regression analysis with miFUNCTION as an outcome was used to demonstrate the beneficial effect of endovascular treatment.

Results

The pilot study showed moderate inter-observer agreement (k = 0.585, p < 0.005) but near perfect correlation between miFUNCTION and modified Rankin Scale (ρ = 0.821, p < 0.05). The correlation of miFUNCTION and modified Rankin Scale was near perfect again in the ESCAPE trial (ρ = 0.944). Effect size of the multivariable models using modified Rankin Scale (adjusted odds ratio: 3.45, 95% confidence interval: 2.05–5.78) and miFUNCTION (adjusted odds ratio: 3.32, 95% confidence interval: 1.99–5.55) as an outcome measure for the ESCAPE trial patients was similar.

Conclusions

miFUNCTION is strongly associated with the degree of disability following stroke both in an outpatient setting and a clinical trial. Further work remains to assess sensitivity to change and to improve the inter-observer reliability of the scale.
Pulsed immune reconstitution therapy in multiple sclerosis
Authors: Sorensen Per Soelberg , Sellebjerg Finn
Published: March 2019

Whereas drugs used for maintenance/escalation therapy do not maintain their beneficial effect after cessation of therapy, some new highly effective therapies can show prolonged treatment effects after a short treatment course. Such therapies have been named pulsed immune reconstitution therapies or pulsed immunosuppressive therapies, and typical representatives are alemtuzumab and cladribine. Autologous haematopoietic stem cell transplantation could be considered as the strongest immune reconstitution therapy. Both alemtuzumab and cladribine induce depletion of lymphocytes, and a common mechanism of action is preferential depletion of class-switched and unswitched memory B-cells. Whereas CD-19+ B-lymphocytes repopulate within 6 months, CD4+ T-cells repopulate at a slower rate, taking 1–2 years to reach the lower level of normal. In general, the depletion of lymphocytes is more profound and the repletion of T-cells is slower after alemtuzumab than after cladribine treatment. Both drugs have a strong effect on relapses and magnetic resonance imaging (MRI) activity, and reduce disability worsening. The therapeutic effect is maintained beyond the period of active treatment in a large proportion of patients, which is best documented for alemtuzumab. Adverse effects include reactivation of latent infections such as tuberculosis and risk of herpes zoster. The main disadvantage in alemtuzumab-treated patients is the risk of secondary immune-mediated disorders. Pulsed immune reconstitution therapy is an option as initial therapy in relapsing-remitting multiple sclerosis patients with high disease activity and in patients on treatment with another disease-modifying therapy with significant relapse and/or MRI activity.
Predictors of organizational resilience by factorial analysis
Authors: Morales Salvador Noriega , Martínez Luis Raúl , Gómez Jesús Andrés Hernández , López Roberto Romero , Torres-Argüelles Vianey
Published: March 2019

The global economy is characterized by a progressive complexity, uncertainty, and volatility, which exert intense pressures to organizations and confronts them, with increasing frequency, to disruptive and unexpected events. In such environments, some organizations develop a resilience profile to increase the capacity to anticipate, adapt, and recover equilibrium or even, gain a new advantage position after the disruption. In this research, the factors of organizational resilience (OR) are identified and a structural equations model is developed. The article discusses the theoretical background and the literature of the resilience factors, and proposes their classification, which is used for the development of a questionnaire for the determination of the relative importance of the factors in several industrial sectors. The internal consistency of the questionnaire was validated with the Cronbach’s α coefficient and was applied to a sample of 159 manufacturing companies of the twin plant “maquiladora” industry of Ciudad Juarez, México, using a convenience sampling method. The key driver factors related to the development of OR are identified employing a partial least squares structural equation modeling approach, also is developed a structural model as a predictor of OR and its effectiveness, covering the description of the proposed model. By hypotheses tests, it is verified that resilient leadership explains the role of variables related to the development of OR, having a high influence in the organizational culture and in the capacity to organize and manage operations, being these three contributors, the drivers of the adaptation capacity that has a direct relation to the development of resilience.
Asian Sand Dust Regulates IL-32 Production in Airway Epithelial Cells: Inhibitory Effect of Glucocorticoids
Authors: Shin Jae-Min , Kim Hwee-Jin , Park Joo-Hoo , Hwang You Jin , Lee Heung-Man
Published: March 2019

Purpose

Epidemiologic studies have reported that Asian sand dust (ASD) is associated with chronic inflammatory diseases of the respiratory system. Glucocorticoids (GCs) have potent anti-inflammatory properties. The aims of this study were to evaluate the effects of GCs on ASD-induced interleukin-32 (IL-32) expression and to identify the underlying signaling pathways in airway epithelial cells.

Methods

A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cytotoxicity in A549 and human primary nasal epithelial cells. Expression levels of IL-32 messenger RNA and protein were measured by Western blot, real-time polymerase chain reaction, ELISA, and immunofluorescence staining. Signaling pathways were analyzed using specific inhibitors of Akt, MAPK, or NF- κB. The effects of GCs on the expression of ASD-induced IL-32 were confirmed with ex vivo organ cultures of the nasal interior turbinate.

Results

ASD (0–400 ng/mL) had no significant cytotoxic effects in A549 cells and human primary nasal epithelial cells. Expression levels of IL-32 were dose-dependently upregulated by ASD treatment in A549 cells. ASD induced phosphorylation of Akt, MAPK, and NF-κB, whereas GCs and specific inhibitors of Akt, MAPK, and NF-κB downregulated these activations and the expression of IL-32. These findings were further confirmed in human primary nasal epithelial cells and ex vivo organ cultures of the nasal interior turbinate.

Conclusions

GCs have an inhibitory effect on ASD-induced IL-32 expression via the Akt, MAPK, and NF- κB signaling pathways in airway epithelial cells.
Vegetarian or gluten‐free diets in patients with inflammatory bowel disease are associated with lower psychological well‐being and a different gut microbiota, but no beneficial effects on the course of the disease
Authors: Schreiner Philipp , Yilmaz Bahtiyar , Rossel Jean-Benoît , Franc Yannick , Misselwitz Benjamin , Scharl Michael , Zeitz Jonas , Frei Pascal , Greuter Thomas , Vavricka Stephan R , Pittet Valérie , Siebenhüner Alexander , Juillerat Pascal , von Känel Roland , Macpherson Andrew J , Rogler Gerhard , Biedermann Luc ,   Swiss IBD Cohort Study Group
Published: March 2019

Background

Many inflammatory bowel disease (IBD) patients follow a restrictive diet due to perceived positive effects on their symptoms. We assessed the prevalence of vegetarian (VD) and gluten‐free diets (GFDs) in IBD patients, the reasons for following such a diet, and whether nutrition has an impact on disease activity and microbiota composition.

Methods

We included 1254 patients from the Swiss Inflammatory Bowel Disease Cohort Study with prospective acquisition of clinical data and psychosocial, disease‐related and lifestyle factors between 2006 and 2015. Dietary habits were assessed through a self‐report questionnaire. In 92 patients, we analysed intestinal mucosa‐associated microbial composition using high‐throughput sequencing.

Results

Overall, 4.1% (n = 52) of the patients reported following a VD and 4.7% (n = 54) a GFD. No differences regarding disease activity, fistula, hospitalization or surgery rates were observed. Patients on a VD or GFD had significantly higher levels of post‐traumatic stress symptoms. Furthermore, GFD patients had significantly higher anxiety and depression symptom levels. The gut microbiota composition in IBD patients following a VD or GFD was significantly different compared to that of omnivores.

Conclusions

Although we did not identify a relevant impact of a specific diet on the course of the disease, there was a significant association with lower psychological well‐being in VD and GFD patients.
Shrinking and shouting: the political revolt of the declining middle in times of employment polarization
Authors: Kurer Thomas , Palier Bruno
Published: March 2019

Automation, digitalization and smart software fundamentally reshape the employment structure of post-industrial societies. The share of routine jobs is constantly shrinking while non-routine jobs at both ends of the skill distribution tend to grow. We contend that the existing political science literature has not sufficiently connected the distributive implications of technological change with contemporary political disruptions. The fact that disadvantages are strongly concentrated among blue- and white-collar routine workers in the lower middle class is of crucial importance. Routine workers are a large and electorally relevant group with all the necessary means for political participation. Increasingly bleak prospects in the labor markets of tomorrow create a demand for social, cultural, and economic protectionism. Socially conservative parties in general and right-wing populist parties in particular have recognized the electoral potential of disaffected routine workers and skillfully address and acknowledge their anxieties. We conclude that a lower middle class no longer protected from the vagaries of economic modernization is a potential electoral game changer.
Did State Responses to Automation Matter for Voters?
Authors: Gingrich Jane
Published: March 2019

This paper asks whether early responses to de-industrialization and automation shaped how those affected negatively by technological change responded politically. It begins by examining patterns of compensation, outlining cross-national differences in the use of passive early retirement benefits, the expansion of public services, and regulation of the labor market. It then pools 20 waves of the International Social Survey Programme, and examines party choices across groups of workers. It finds that those exposed to technological change are both more likely to vote for the mainstream left and right populists. Differences in compensation have a limited direct or indirect effect. Where spending and labor market regulation does matter, it heightens both left and right-populist voting among affected groups.
Expression and clinical significance of the receptors of the EGF family in oral squamous cell carcinomas
Authors: Dissanayake Upul
Published: March 2019

Objective:

To examine the immunohistochemical expression of four members of the type 1 growth factor receptor family in oral squamous cell carcinomas (OSCCs) and to correlate with clinical outcomes.

Materials and methods:

Sixty OSCCs from a patient cohort in Sri Lanka were included in the study. Five sections from each carcinoma were immunostained with antibodies to epidermal growth factor receptor (EGFR)/c-erbB-1, c-erbB-2/HER-2/neu, c-erbB-3/HER-3 and c-erbB-4/HER-4. Two clones were used to stain for c-erbB-2/HER-2/neu. Semiquantitative analysis of immunoreactivity was carried out by scoring the intensity of expression and proportions of positively stained cells. A logistic regression analysis was performed to examine positive expression against overall survival.

Results:

There was heterogenous expression of the four receptors, positivity ranging from 26% to 60%. Co-expression of all four markers was observed only in 1–3% of the tumours. Both membranous and cytoplasmic expressions were observed, EGFR showing predominantly membranous expression and c-erbB-2 showing only cytoplasmic staining. In logistic regression analysis, none of the growth factor receptors were significantly predictive of overall survival.

Conclusion:

Type 1 growth factor receptors are highly expressed in oral carcinomas, EGFR being the predominant marker.
Simple methods for estimating confidence levels, or tentative probabilities, for hypotheses instead of p values
Authors: Wood Michael
Published: March 2019

In many fields of research, null hypothesis significance tests and p values are the accepted way of assessing the degree of certainty with which research results can be extrapolated beyond the sample studied. However, there are very serious concerns about the suitability of p values for this purpose. An alternative approach is to cite confidence intervals for a statistic of interest, but this does not directly tell readers how certain a hypothesis is. Here, I suggest how the framework used for confidence intervals could easily be extended to derive confidence levels, or “tentative probabilities,” for hypotheses. I also outline four quick methods for estimating these. This allows researchers to state their confidence in a hypothesis as a direct probability, instead of circuitously by p values referring to a hypothetical null hypothesis—which is usually not even stated explicitly. The inevitable difficulties of statistical inference mean that these probabilities can only be tentative, but probabilities are the natural way to express uncertainties, so, arguably, researchers using statistical methods have an obligation to estimate how probable their hypotheses are by the best available method. Otherwise, misinterpretations will fill the void.
Integrating Chiropractic Care Into the Treatment of Migraine Headaches in a Tertiary Care Hospital: A Case Series
Authors: Bernstein Carolyn , Wayne Peter M , Rist Pamela M , Osypiuk Kamila , Hernandez Audrey , Kowalski Matthew
Published: March 2019

This case series illustrates an integrated model of care for migraine that combines standard neurological care with chiropractic treatment. For each patient, we describe the rationale for referral, diagnosis by both the neurologist and chiropractor, the coordinated care plan, communication between the neurologist and chiropractor based on direct face-to-face “hallway” interaction, medical notes, team meetings, and clinical outcomes. Findings are evaluated within the broader context of the multicause nature of migraine and the impact of integrative chiropractic. Suggestions for future areas of research evaluating integrative approaches are discussed.
Development of the Person–Family Fit Construct: An Extension of Person–Environment Fit into the Family Domain
Authors: Padmasiri M. K. Dinithi , Kailasapathy Pavithra , Jayawardana A. K. L.
Published: March 2019

This article defines a person’s environment as a combination of work and family environments by extending the person–environment fit theory to include the family domain. The study extends the person–environment fit construct by including person–job fit, person–organization fit, person–group fit, person–supervisor fit (all in work environment) and person–family fit (family environment). In the two studies that were carried using operational-level employees from various industries, we empirically develop a scale for the new concept person–family fit, validated person–family fit scale and the person–environment fit construct. This study makes several theoretical contributions including defining person–family fit construct, developing a scale to measure the same and confirming its inclusion into the person–environment fit construct. Managerial implications are provided to ensure person–job fit, person–group fit, person–supervisor fit and person–family fit in the working environment.
Implementing a New Common Rule Requirement for Informed Consent: A Randomized Trial on Adult Asthma Patients
Authors: Yu Michael , Fischhoff Baruch , Krishnamurti Tamar
Published: March 2019

Objectives. To determine how the format of a clinical trial informed consent document can affect participants’ retention of enrollment-relevant information. Background. Recent changes to the US Federal Common Rule require informed consent documents for clinical trials to be concise and start with the information most relevant for enrollment decisions. However, there is limited guidance on how to identify this information or evaluate its impact. Design. Participants with a self-reported asthma diagnosis were randomized to one of five versions of the informed consent document for a clinical trial of an injectable asthma product: the original, full-length document; a concise version, removing information identified by asthma patients in an earlier study as not relevant to their enrollment decisions; an interactive version, where participants self-navigated to the information they chose; a reordered version, moving up information deemed more relevant for enrollment in an earlier study; and a highlights version, following the suggested revised Common Rule structure, starting with a summary of enrollment-relevant information based on patient ratings. Knowledge acquisition was evaluated with a knowledge test, with submeasures for information that had high and low relevance for enrollment decisions. Results. Participants who saw the highlights (“Common Rule”) version were more likely to answer questions about high enrollment-relevant information correctly than were participants who saw the full-length version (65% v 59%, P = 0.0105). Participants who saw the other revised versions did not perform significantly differently from the full-length version. Conclusions. An informed consent document designed to implement revised US Federal Common Rule requirements performed better than other designs, in terms of readers retaining information relevant for clinical trial enrollment, as characterized by potential trial participants in a separate study.
National electrocardiographic mapping by telemedicine for diagnosis and prevention of cardiological pathologies in Paraguay
Authors: Galván Pedro , Rivas Ronald , Portillo Juan , Mazzoleni Julio , Hilario Enrique , Ortellado José
Published: March 2019

Introduction:

Telemedicine tools offer multiple advantages to achieve an epidemiological screening of communities in rural settings countrywide. However, evidence on the cardiological pathology surveillance in these communities is limited. The feasibility of telemedicine as an electrocardiographic (EKG) mapping tool for the diagnosis and prevention of cardiological pathologies in Paraguay was investigated.

Methods:

A descriptive study was conducted in 60 telediagnostic centers countrywide in Paraguay to evaluate the feasibility of telemedicine as an EKG mapping tool for the diagnosis and prevention of cardiological pathologies over a period of 5 years from 2014 to 2018. The adherence rate was determined comparing yearly scheduled visits versus fulfilled visits at the telemedicine platform.

Results:

During the study, 246,217 remote EKG diagnoses were performed in 60 hospitals using telemedicine. The patients were 19.4% children/adolescents and 80.6% adults. The results of EKG tests in the children/adolescent group were 79.4% normal and 20.6% abnormal. The most frequent abnormal heart rhythms observed were sinusal bradicardia (10.6%), sinusal tachycardia (3.2%), and unspecified arrhythmia (2.8%). In the adult group, the results were 66.3% normal and 33.7% abnormal. The most frequent abnormal heart rhythms in this group were sinusal bradicardia (11.2%), blockade of the right branch (4.8%), and left ventricular hypertrophy (4.7%). The most frequent cardiovascular risk factors observed were the association of hypertension and obesity (40%), hypertension and diabetes (20%), and hypertension and dyslipidemia (19%). During the test period (2014–2018), the average rate of patient adherence to the prevention program was 2.26 for each 1000 diagnosis.

Conclusion:

These results demonstrate the feasibility of telemedicine as an EKG mapping tool for the diagnosis and prevention of cardiological pathologies in low-resource countries, thus enhancing cardiovascular disease surveillance and optimizing human and financial resources.
Complementary Therapies as a Strategy to Reduce Stress and Stimulate Immunity of Women With Breast Cancer
Authors: Abrahão Camila Aparecida , Bomfim Emiliana , Lopes-Júnior Luís Carlos , Pereira-da-Silva Gabriela
Published: March 2019

The stress associated with cancer development leads to disturbances in the hypothalamic-pituitary-adrenal axis and suppresses important facets of the immune response. The use of complementary therapies in the treatment of women with breast cancer has demonstrated therapeutic benefits that entail improvements in the patients’ quality of life. The objective of this article is to present evidence on the use of complementary therapies as a stress reduction strategy and on its stimulating effects on the immune system of women with breast cancer. This is a reflexive updating article that will support the health professionals’ understanding on the use of complementary therapies in breast cancer care. The use of complementary therapies in the treatment of women with breast cancer has significantly improved these subjects’ stress, depression, fatigue, anxiety, and, consequently, their quality of life, as well as their immune response, which is mainly illustrated by the increased number and cytotoxic activity of natural killer cells. Clinicians, health professionals, and patients need to be cautious about using complementary therapies and fully understand the real benefits and risks associated with each therapy. Little or no supporting evidence is available to clarify the effects on the immune system of women with breast cancer, and the consequent therapeutic benefits obtained through the use of these practices.
Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia
Authors: Ghia Emanuela M. , Rassenti Laura Z. , Neuberg Donna S. , Blanco Alejandro , Yousif Fouad , Smith Erin N. , McPherson John D. , Hudson Thomas J. ,   the HALT Pan-Leukemia Gene Panel Consortium, Harismendy Olivier , Frazer Kelly A. , Kipps Thomas J.
Published: March 2019

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.
Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program
Authors: Mack Ethan A. , Stein Sarah J. , Rome Kelly S. , Xu Lanwei , Wertheim Gerald B. , Melo Rossana C. N. , Pear Warren S.
Published: March 2019

Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage–specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein α (C/EBPα) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.
Cleavage of anti-PF4/heparin IgG by a bacterial protease and potential benefit in heparin-induced thrombocytopenia
Authors: Kizlik-Masson Claire , Deveuve Quentin , Zhou Yuhang , Vayne Caroline , Thibault Gilles , McKenzie Steven E. , Pouplard Claire , Loyau Stéphane , Gruel Yves , Rollin Jérôme
Published: March 2019

Heparin-induced thrombocytopenia (HIT) is due to immunoglobulin G (IgG) antibodies, which bind platelet factor 4 (PF4) modified by polyanions, such as heparin (H). IgG/PF4/polyanion complexes directly activate platelets via Fc gamma type 2 receptor A (FcγRIIA) receptors. A bacterial protease, IgG-degrading enzyme of Streptococcus pyogenes (IdeS), cleaves the hinge region of heavy-chain IgG, abolishing its ability to bind FcγR, including FcγRIIA. We evaluated whether cleavage of anti-PF4/H IgG by IdeS could suppress the pathogenicity of HIT antibodies. IdeS quickly cleaved purified 5B9, a monoclonal chimeric anti-PF4/H IgG1, which led to the formation of single cleaved 5B9 (sc5B9), without any reduction in binding ability to the PF4/H complex. However, as compared with uncleaved 5B9, the affinity of sc5B9 for platelet FcγRIIA was greatly reduced, and sc5B9 was also unable to induce heparin-dependent platelet activation. In addition, incubating IdeS in whole blood containing 5B9 or HIT plasma samples led to cleavage of anti-PF4/H antibodies, which fully abolished the ability to induce heparin-dependent platelet aggregation and tissue factor messenger RNA synthesis by monocytes. Also, when whole blood was perfused in von Willebrand factor–coated microfluidic channels, platelet aggregation and fibrin formation induced by 5B9 with heparin was strongly reduced after IdeS treatment. Finally, IdeS prevented thrombocytopenia and hypercoagulability induced by 5B9 with heparin in transgenic mice expressing human PF4 and FcγRIIA receptors. In conclusion, cleavage of anti-PF4/H IgG by IdeS abolishes heparin-dependent cellular activation induced by HIT antibodies. IdeS injection could be a potential treatment of patients with severe HIT.
HLA-DRB3*01:01 exhibits a dose-dependent impact on HPA-1a antibody levels in HPA-1a–immunized women
Authors: Kjeldsen-Kragh Jens , Titze Thomas L. , Lie Benedicte Alexandra , Vaage John T. , Kjær Mette
Published: March 2019

HLA-DRB3*01:01 is a predisposing factor for human platelet antigen 1a (HPA-1a) immunization, which is responsible for most cases of fetal and neonatal alloimmune thrombocytopenia. The aim of this study was to investigate if the HLA-DRB3*01:01 allele imposes a dose-dependent effect on anti-HPA-1a levels and neonatal platelet counts. One hundred and thirty HPA-1a–immunized women were divided into 3 groups: HLA-DRB3*01:01 negative, HLA-DRB3*01:01 hemizygous or heterozygous, and HLA-DRB3*01:01 homozygous. The dose of the HLA-DRB3*01:01 allele was determined by sequencing exon 2 of the HLA-DRB3 gene followed by HLA-DRB3 and HLA-DRB1 typing of selected samples. Anti-HPA-1a levels at time of delivery and neonatal platelet counts were compared among groups. There was a significant dose-dependent effect of the HLA-DRB3*01:01 allele on anti-HPA-1a levels (global P value [Pglobal] = .0032). Median (range) anti-HPA-1a levels were 1.5 IU/mL (0.0-19.0 IU/mL), 21.1 IU/mL (0.0-1967 IU/mL), and 43.7 IU/mL (1.0-980 IU/mL) in women with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. There was also a significant, but opposite, dose-dependent effect of the mother’s HLA-DRB3*01:01 allele on the platelet count of the newborn (Pglobal = .0155). Median (range) neonatal platelet counts were 241 × 109/L (59 × 109/L to 393 × 109/L), 107 × 109/L (4 × 109/L to 387 × 109/L) and 32 × 109/L (4 × 109/L to 352 × 109/L) for newborns of mothers with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. Thus, the HLA-DRB3*01:01 allele exhibits a dose-dependent impact on maternal anti-HPA-1a levels in HPA-1a–immunized women.
Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension
Authors: Mair Kirsty M. , Harvey Katie Y. , Henry Alasdair D. , Hillyard Dianne Z. , Nilsen Margaret , MacLean Margaret R.
Published: March 2019

Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension in male and female obese mice.

We depleted endogenous oestrogen in leptin-deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS).

ob/obmice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated pulmonary hypertension in maleob/obmice. Intra-thoracic fat fromob/obmice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress, effects that are attenuated by both ANA and TMS.

Obesity can induce pulmonary hypertension and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.
RETRACTED ARTICLE: Investigation of molecular biomarker candidates for diagnosis and prognosis of chronic periodontitis by bioinformatics analysis of pooled microarray gene expression datasets in Gene Expression Omnibus (GEO)
Authors: Suzuki Asami , Horie Tetsuro , Numabe Yukihiro
Published: March 2019

Background

Chronic periodontitis (CP) is a multifactorial inflammatory disease. For the diagnosis of CP, it is necessary to investigate molecular biomarkers and the biological pathway of CP. Although analysis of mRNA expression profiling with microarray is useful to elucidate pathological mechanisms of multifactorial diseases, it is expensive. Therefore, we utilized pooled microarray gene expression data on the basis of data sharing to reduce hybridization costs and compensate for insufficient mRNA sampling. The aim of the present study was to identify molecular biomarker candidates and biological pathways of CP using pooled datasets in the Gene Expression Omnibus (GEO) database.

Methods

Three pooled transcriptomic datasets (GSE10334, GSE16134, and GSE23586) of gingival tissue with CP in the GEO database were analyzed for differentially expressed genes (DEGs) using GEO2R, functional analysis and biological pathways with the Database of Annotation Visualization and Integrated Discovery database, Protein-Protein Interaction (PPI) network and hub gene with the Search Tool for the Retrieval of Interaction Genes database, and biomarker candidates for diagnosis and prognosis and upstream regulators of dominant biomarker candidates with the Ingenuity Pathway Analysis database.

Results

We shared pooled microarray datasets in the GEO database. One hundred and twenty-three common DEGs were found in gingival tissue with CP, including 81 upregulated genes and 42 downregulated genes. Upregulated genes in Gene Ontology were significantly enriched in immune responses, and those in the Kyoto Encyclopedia of Genes and Genomes pathway were significantly enriched in the cytokine-cytokine receptor interaction pathway, cell adhesion molecules, and hematopoietic cell lineage. From the PPI network, the 12 nodes with the highest degree were screened as hub genes. Additionally, six biomarker candidates for CP diagnosis and prognosis were screened.

Conclusions

We identified several potential biomarkers for CP diagnosis and prognosis (e.g., CSF3, CXCL12, IL1B, MS4A1, PECAM1, and TAGLN) and upstream regulators of biomarker candidates for CP diagnosis (TNF and TGF2). We also confirmed key genes of CP pathogenesis such as CD19, IL8, CD79A, FCGR3B, SELL, CSF3, IL1B, FCGR2B, CXCL12, C3, CD53, and IL10RA. To our knowledge, this is the first report to reveal associations of CD53, CD79A, MS4A1, PECAM1, and TAGLN with CP.
Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case–control study
Authors: Gourgari Evgenia , Ma Junfeng , Playford Martin P. , Mehta Nehal N. , Goldman Radoslav , Remaley Alan T. , Gordon Scott M.
Published: March 2019

Background

Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.

Methods

This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification.

Results

Samples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P < 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P < 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin.

Conclusions

Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM.

Trial registrationNCT02275091
Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study
Authors: Nambozi Michael , Tinto Halidou , Mwapasa Victor , Tagbor Harry , Kabuya Jean-Bertin Bukasa , Hachizovu Sebastian , Traoré Maminata , Valea Innocent , Tahita Marc Christian , Ampofo Gifty , Buyze Jozefien , Ravinetto Raffaella , Arango Diana , Thriemer Kamala , Mulenga Modest , van Geertruyden Jean-Pierre , D’Alessandro Umberto
Published: March 2019

Background

The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant’s health.

Methods

Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether–lumefantrine (AL), amodiaquine–artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin–piperaquine (DHA–PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday.

Results

Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found.

Conclusions

Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings.

Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423
Characterization of the microstructural features and the rust layers of an archaeological iron sword in the Egyptian Museum in Cairo (380–500 A.D.)
Authors: Salem Yussri , Oudbashi Omid , Eid Doaa
Published: March 2019

In this paper, a sword is investigated from a collection of archaeological iron swords displayed in the Egyptian Museum from the civilization centered on Ballana and Qustul in Egyptian Nubia (380–600 A.D.). A range of metallographic analytical techniques have been used to characterize the sword’s metallic structure and its rust crust. The results revealed that the sword was made of low-carbon steel and corrosion products formed on the surface are iron sulfate, iron oxides/hydroxides including goethite, maghemite, magnetite, lepidocrocite, akaganeite and ferric chloride. The investigation also revealed that the rust crust constituted of two corrosion layers: a dense layer and a transformed medium. Crystals of soil minerals were clearly observed in the outer corrosion layer. Moreover, several microstructural features were detected, indicating the stage of deterioration and the features of metallurgy of this sword. Furthermore, the obtained results have been used to select appropriate conservation procedures for preventing degradation in the future and ensuring its reliable restoration.