bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical Options for the Refractive Correction of Keratoconus: Myth or Reality
Authors: Fernández-Vega-Cueto L. , Romano V. , Zaldivar R. , Gordillo C. H. , Aiello F. , Madrid-Costa D. , Alfonso J. F.
Published: December 2017

Keratoconus provides a decrease of quality of life to the patients who suffer from it. The treatment used as well as the method to correct the refractive error of these patients may influence on the impact of the disease on their quality of life. The purpose of this review is to describe the evidence about the conservative surgical treatment for keratoconus aiming to therapeutic and refractive effect. The visual rehabilitation for keratoconic corneas requires addressing three concerns: halting the ectatic process, improving corneal shape, and minimizing the residual refractive error. Cross-linking can halt the disease progression, intrastromal corneal ring segments can improve the corneal shape and hence the visual quality and reduce the refractive error, PRK can correct mild-moderate refractive error, and intraocular lenses can correct from low to high refractive error associated with keratoconus. Any of these surgical options can be performed alone or combined with the other techniques depending on what the case requires. Although it could be considered that the surgical option for the refracto-therapeutic treatment of the keratoconus is a reality, controlled, randomized studies with larger cohorts and longer follow-up periods are needed to determine which refractive procedure and/or sequence are most suitable for each case.
Sinus Floor Elevation with Modified Crestal Approach and Single Loaded Short Implants: A Case Report with 4 Years of Follow-Up
Authors: Perelli Michele , Abundo Roberto , Corrente Giuseppe , Saccone Carlo , Arduino Paolo G.
Published: December 2017

Tooth extraction is usually followed by bone reduction. In the maxillary posterior region, this remodelling combined with sinus pneumatisation and periodontal defects may lead to a reduced basal bone height available for implant placement. Sinus floor elevation can be performed with different surgical techniques. Crestal approach has demonstrated to be effective, less invasive, and associated with a reduced morbidity. This article reports a modified sinus floor elevation by means of rotary, noncutting instruments, addition of xenograft, and 2 short-threaded implant placements. The aim of the study was to evaluate the implant’s success and intrasinus radiographical bone gain after 4 years of functional loading. The premolar implant site presented a starting basal bone height of 6 mm, while the molar site was of 2 mm. In the first surgical step, sinus floor elevation was performed mesially and the implant was inserted, and distally only sinus floor elevation was performed. After 6 months, the mesial implant was uncovered and the second implant was inserted; 4 months later, the second fixture was uncovered, and both fixtures were loaded with single provisional screw-retained crowns and later with single screw-retained porcelain fused to metal crowns. Implants integrated successfully, and crestal bone remodelling did not exceed the smooth collar. Bone gain was 3 mm for the mesial implant and more than 5 mm for the distal one.
Associated Factors and Outcome of Uterine Rupture at Suhul General Hospital, Shire Town, North West Tigray, Ethiopia 2016: A Case-Control Study
Authors: Marie Bereka Tefera , Mulat Aweke Amlaku , Eshetie Wondie Tewodrose
Published: December 2017

Background. Uterine rupture is tearing of the uterine wall during pregnancy or delivery. It may extend to partial or whole thickness of the uterine wall. It is usually a case where obstetric care is poor. In extensive damage, death of the baby and sometimes even maternal death are evident.Objective. This study assesses associated factors and outcome of uterine rupture at Suhul General Hospital, Tigray Region, Ethiopia, 2016.Methodology. A case-control study was conducted by review of data from September 2012 to August 2016. A total of 336 samples were studied after calculating by EPI-INFO using proportion of multiparity (53%) and ratio of 1 : 2 for cases and controls, respectively. Analysis was done using SPSS version 20. Bivariate and multivariate logistic regression was applied withp<0.05.Result. ANC, grand multiparity, malpresentation, and obstructed labor had association, but previous cesarean delivery was not significant. Perinatal mortality was 105 (93%) versus 13 (5.8%) in cases and controls, respectively. Anemia was highest for both groups (53.7% versus 32.1%).Conclusion. Majority of uterine rupture is attributed to prolonged or obstructed labor. Cases of uterine rupture had prompt management preventing maternal mortality, but burden of perinatal death is still high.
A Coupled Pseudospectral‐Differential Quadrature Method for a Class of Hyperbolic Telegraph Equations
Authors: Wang Fangzong , Wang Yong
Published: December 2017

Pseudospectral methods and differential quadrature methods are two kinds of important meshless methods, both of which have been widely used in scientific and engineering calculation. The Lagrange interpolation polynomials are used as the trial function of the two methods, and the same distribution of grid points is used. This paper points out that the differential quadrature method is a special form of the pseudospectral method. On the basis of the above, a coupled pseudospectral‐differential quadrature method (PSDQM) is proposed to solve a class of hyperbolic telegraph equations. Theoretical analysis and numerical tests show that the new method has spectral precision convergence in spatial domain and has A‐stability in time domain. And it is suitable for solving multidimensional telegraph equations.
Granulocyte-Monocyte Apheresis in Steroid-Dependent, Azathioprine-Intolerant/Resistant Moderate Ulcerative Colitis: A Prospective Multicenter Study
Authors: Imperiali Gianni , Amato Arnaldo , Terpin Maria Maddalena , Beverina Ivo , Bortoli Aurora , Devani Massimo , Viganò Chiara , Study Group on IBD (GSMII)
Published: December 2017

Background. Granulocyte-monocyte apheresis has been proposed for the treatment of ulcerative colitis, although it is limited by costs and variability of results. Aim. To assess effectiveness of granulocyte-monocyte apheresis in patients with steroid-dependent, azathioprine-intolerant/resistant moderate ulcerative colitis. Methods. Consecutive patients fulfilling inclusion criteria were prospectively enrolled, treated by apheresis, and followed up for 12 months. The primary end point of the study was steroid-free clinical remission at 12 months, with no need for biologic therapy or surgery. Results. From January to December 2013, 33 patients were enrolled. After one year of follow-up, 12 (36%) patients had clinical remission, were steroid-free, and had no need for biological therapy or surgery; 3 (9%) cases showed a clinical response (but not clinical remission). Moreover, 12 (36%) patients required biologic therapy, 4 (12%) underwent colectomy, and in the other 2 (6%) a reduction, but not withdrawal, of steroid dose was achieved. Conclusions. Our study shows that a standard course of granulocyte-monocyte apheresis is associated with a 36% steroid-free clinical remission in patients with steroid-dependent, azathioprine-intolerant or resistant moderate ulcerative colitis. Apheresis might represent an alternative to biologic therapy or surgery in this specific subgroup of patients. This trial is registered with Clinicaltrial.gov NCT03189888.
New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome
Authors: Wilson Leah J. , Linley Adam , Hammond Dean E. , Hood Fiona E. , Coulson Judy M. , MacEwan David J. , Ross Sarah J. , Slupsky Joseph R. , Smith Paul D. , Eyers Patrick A. , Prior Ian A.
Published: December 2017

The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. Cancer Res; 78(1); 15–29. ©2017 AACR.
“Future-Proofing” Blood Processing for Measurement of Circulating miRNAs in Samples from Biobanks and Prospective Clinical Trials
Authors: Murray Matthew J. , Watson Hannah L. , Ward Dawn , Bailey Shivani , Ferraresso Marta , Nicholson James C. , Gnanapragasam Vincent J. , Thomas Benjamin , Scarpini Cinzia G. , Coleman Nicholas
Published: December 2017

Background: Quantifying circulating nucleic acids is an important new approach to cancer diagnosis/monitoring.

Methods: We compared the suitability of serum versus plasma for measuring miRNAs using qRT-PCR and assessed how preanalytic variables that can affect circulating tumor DNA (ctDNA) quantification in plasma also influence miRNA levels.

Results: Across 62 blood-derived specimens, plasma samples in EDTA, Streck-DNA, and Streck-RNA tubes showed significantly higher Ct values for multiple housekeeping miRNAs, compared with serum samples. For the EDTA-plasma tubes, this difference was only seen when including the high-speed centrifugation protocol used to optimize ctDNA extraction. In plasma samples derived from blood stored at room temperature for up to 14 days (conditions that typically apply to samples processed for biobanking), levels of endogenous housekeeping miRNAs gradually increased, in parallel with the hemolysis marker hsa-miR-451a, consistent with release from blood cells/platelets. It was necessary to normalize levels of the housekeeping miRNAs to those of hsa-miR-451a, to obtain the stable values needed for referencing test miRNA levels.

Conclusions: Our data indicate that plasma samples prepared for ctDNA extraction are suboptimal for miRNA quantification and require the incorporation of multiple data normalization steps. For prospective studies designed to measure both miRNAs and ctDNA, the most suitable approach would be to obtain both serum (for miRNAs) and plasma (for ctDNA). If only plasma can be collected, we recommend an initial low-speed centrifugation step, followed by aliquoting the supernatant into parallel samples, one for direct miRNA quantification, and the other for a further high-speed centrifugation step to optimize ctDNA retrieval.

Impact: These recommendations will help “future-proof” clinical studies in which quantification of circulating miRNAs is a component. Cancer Epidemiol Biomarkers Prev; 27(2); 208–18. ©2017 AACR.
Association of Pancreatic Cancer Susceptibility Variants with Risk of Breast Cancer in Women of European and African Ancestry
Authors: Wang Shengfeng , Zheng Yonglan , Ogundiran Temidayo O. , Ojengbede Oladosu , Zheng Wei , Nathanson Katherine L. , Nemesure Barbara , Ambs Stefan , Olopade Olufunmilayo I. , Huo Dezheng
Published: December 2017

Background: Pancreatic cancer mutation signatures closely resemble breast cancer, suggesting that both cancers may have common predisposition mechanisms that may include commonly inherited SNPs.

Methods: We examined 23 genetic variants known to be associated with pancreatic cancer as breast cancer risk factors in the Root genome-wide association study (GWAS; 1,657 cases and 2,029 controls of African diaspora) and GAME-ON/DRIVE GWAS (16,003 cases and 41,335 controls of European ancestry).

Results: None of the pancreatic cancer susceptibility variants were individually associated with breast cancer risk after adjustment for multiple testing (at α = 0.002) in the two populations. In Root GWAS, a change by one SD in the polygenic risk score (PRS) was not significantly associated with breast cancer. In addition, we did not observe a trend in the relationship between PRS percentiles and breast cancer risk.

Conclusions: The association between reported pancreatic cancer genetic susceptibility variants and breast cancer development in women of African or European ancestry is likely weak, if it does exist.

Impact: Known GWAS-derived susceptibility variants of pancreatic cancer do not explain its shared genetic etiology with breast cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 116–8. ©2017 AACR.
Novel Targeting of Transcription and Metabolism in Glioblastoma
Authors: Su Yu-Ting , Chen Robert , Wang Herui , Song Hua , Zhang Qi , Chen Li-Yuan , Lappin Hallie , Vasconcelos Gabriel , Lita Adrian , Maric Dragan , Li Aiguo , Celiku Orieta , Zhang Wei , Meetze Kristan , Estok Thomas , Larion Mioara , Abu-Asab Mones , Zhuang Zhengping , Yang Chunzhang , Gilbert Mark R. , Wu Jing
Published: December 2017

Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients.

Experimental Design: To investigate TG02, an agent with known penetration of the blood–brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays.

Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue.

Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial. Clin Cancer Res; 24(5); 1124–37. ©2017 AACR.
RegisPt: Registry of Registries in Portugal – Design, Data Model, and Functionalities
Authors: Laires Pedro , Barros Vitor
Published: December 2017

Introduction: The number and quality of existing patient registries are not known in Portugal. In order to improve the knowledge regarding this issue, an interactive tool (RegisPt) was developed to identify and characterize all available patient registries in our country. This article aims to describe the RegisPt design, data model, and due functionalities. Methods: RegisPt was developed in Microsoft Office Access 2010 and all variables definitions were done according to standardized international classifications. A review of the available literature and web resources was performed in order to identify all relevant patient registries. Results: The RegisPt platform is divided into 5 core modules containing comprehensive information from each patient registry (general data, registry design, characterization, effectiveness, and publications). Effectiveness is of utmost importance for health technology assessment and is divided into 2 sections: the exposure (health care service, pharmaceutical drugs, and medical devices) and the outcomes (safety, clinical, and economic). The RegisPt platform allows adding and editing registries as well as consulting all available registries in an interactive and user-friendly way, using a preferred query (e.g., registry name, institution, and therapeutic area). About 50 patient registries were identified and characterized in Portugal in accordance with the patient registry definition of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Discussion: The RegisPt is a first step to better understand and use the available resources for health research in Portugal. RegisPt can promote collaboration between researchers and registry owners and encourage the efficient use of resources and may improve the access to registries. This project may also be useful to identify therapeutic areas still lacking patient registries and to optimize existing ones in the country, by comparing registry design, quality, and functional strategies. In the future, this valuable platform may be particularly relevant for researchers and authorities aiming to carry out health technology assessment.
Iron Nutriture of the Fetus, Neonate, Infant, and Child
Authors: Cerami Carla
Published: December 2017

Iron is a key nutrient and is essential for the developing fetus, neonate, infant, and child. Iron requirements are high during early stages of life because it is critically important for the production of new red blood cells and muscle cells as well as brain development. Neonates, infants, and children obtain iron from dietary sources including breast milk (lactoferrin) and heme- and non-heme-containing foods. Iron deficiency (ID) is the most common micronutrient deficiency in children and pregnant women worldwide. ID and iron deficiency anemia (IDA) can affect growth and energy levels as well as motor and cognitive performance in the developing child. The fetus is completely dependent on maternal iron crossing through the placenta and, although it is generally well protected against deficiency at birth, ID in mothers can increase the risk of ID and IDA in their children as early as 4 months. This review will discuss the uses of iron, iron requirements, and the sources of iron from conception through childhood. In addition, it will describe the prevalence and clinical manifestations of ID and IDA in children and discuss recommendations for iron supplementation of children and pregnant women.
Hearing Impairment, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Cohort Studies
Authors: Wei Jingkai , Hu Yirui , Zhang Li , Hao Qiang , Yang Ruowei , Lu Haidong , Zhang Xuan , Chandrasekar Eeshwar K.
Published: December 2017

Background: To estimate a pooled association between hearing impairment and risk of mild cognitive impairment and dementia. Methods: PubMed, Embase, and Web of Science were searched for prospective cohort studies that examined the association between hearing impairment and risk of mild cognitive impairment and/or dementia. Random-effects models were fitted to estimate the summary risk ratios (RRs) and 95% confidence interval (CIs), which represents the pooled association between hearing impairment with risk of mild cognitive impairment and dementia, compared to subjects free of hearing impairment. Results: Four studies on hearing impairment with mild cognitive impairment and 7 studies on hearing impairment with dementia were included in the meta-analysis. A total of 15,521 subjects were studied with follow-up periods between 2 and 16.8 years. Hearing impairment was associated with a greater risk of mild cognitive impairment (RR = 1.30, 95% CI: 1.12, 1.51) and dementia (RR = 2.39, 95% CI: 1.58, 3.61). Conclusions: The meta-analysis showed that hearing impairment is associated with a higher risk of mild cognitive impairment and dementia among older adults.
Renal PGC1α May Be Associated with Recovery after Delayed Graft Function
Authors: Drury Erika R. , Zsengeller Zsuzsanna K. , Stillman Isaac E. , Khankin Eliyahu V. , Pavlakis Martha , Parikh Samir M.
Published: December 2017

Background: Delayed renal graft function (DGF) contributes to the determination of length of hospitalization, risk of acute rejection, and graft loss. Existing tools aid the diagnosis of specific DGF etiologies such as antibody-mediated rejection, but markers of recovery have been elusive. The peroxisome proliferator gamma co-activator-1-alpha (PGC1α) is highly expressed in the renal tubule, regulates mitochondrial biogenesis, and promotes recovery from experimental acute kidney injury. Objectives: We aimed to determine the association between renal allograft PGC1α expression and recovery from delayed graft function. Methods: We retrospectively analyzed patients undergoing renal transplantation at a single center from January 1, 2008 to June 30, 2014. PGC1α expression was assessed by immunostaining and ultrastructural characteristics by transmission electron microscopy. Of 34 patients who underwent renal biopsy for DGF within 30 days of transplant, 21 were included for analysis. Results: Low PGC1α expression was associated with a significantly longer time on dialysis after transplant (median of 35.5 vs. 16 days, p < 0.05) and a significantly higher serum creatinine (sCr) at 4 weeks after transplantation among those who discontinued dialysis (5 vs. 1.65 mg/dL, p < 0.0001). Low PGC1α expression was not associated with higher sCr at 12 weeks after transplantation. Ultrastructural characteristics including apical membrane blebbing and necrotic luminal debris were not informative regarding clinical outcomes. Conclusions: These data suggest that higher PGC1α expression is associated with faster and more complete recovery from DGF. Mitochondrial biogenesis may be a therapeutic target for DGF. Larger studies are needed to validate these findings.
Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage
Authors: Zhu Chengjun , Shen Hua , Zhu Lingjun , Zhao Feng , Shu Yongqian
Published: December 2017

Background: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression.
Refinement of Mouse Protocols for the Study of Platelet Thromboembolic Responses In Vivo
Authors: Rauzi Francesca , Smyth Erica , Emerson Michael
Published: December 2017

Mouse models of thromboembolism are frequently used to investigate platelet function in vivo and, according to European Union (EU) legislation, must be conducted in the context of replacement, refinement and reduction. We have previously developed a refined real-time mouse model of thromboembolism as an alternative to models of thromboembolic mortality which inflict considerable pain and suffering. Real-time monitoring involves infusion of radiolabelled platelets into the circulation of anaesthetized mice, and platelet aggregation is measured as increases in platelet-associated counts in the pulmonary vasculature following injection of platelet agonists. This gives a definitive data set on the tissue localization and extent of platelet activation. We developed an additional, more simplistic alternative to mortality models based on blood microsampling which entails the measurement of circulating platelet counts following agonist stimulation. Blood microsamples were collected from the tail vein of anaesthetized mice at three different time points leading to a reduction in animal numbers. Platelet counts significantly dropped 1 minute after stimulation with collagen or thrombin and were restored over 10 minutes. These results correlate with those obtained via real-time monitoring and were confirmed by immunohistochemistry. Pre-treatment of mice with aspirin significantly inhibited the decrease in platelet counts following collagen. These data suggest that blood microsampling may be implemented as a simplistic refined alternative to mortality models of thromboembolism when specialized monitoring equipment, or use of radioactive isotopes for real-time monitoring, which remains the ‘gold standard’, is not feasible. Microsampling refines and reduces animal procedures in compliance with current EU legislation.
Enrichment of Circulating Endothelial Cells by CD34 Microbeads Followed by Enumeration Using Flow Cytometry
Authors: Burylo Artur , de Weger Vincent , Stuurman Frederik , Beijnen Jos , Schellens Jan
Published: December 2017

Background Circulating endothelial cells (CECs) are a potential biomarker of angiogenesis. CECs increase in numbers after vessel injury. Higher CEC numbers are reported in cancer patients. Most methods for CEC detection and enumeration rely on flow cytometry (FCM); however, there is no agreement on CEC phenotype and the detection method to be used. This leads to uncertainty about the clinical applicability and variation between studies on CEC numbers reported.

Objective To develop a selective and accurate method for CEC enumeration in peripheral blood by enrichment, followed by FCM in healthy volunteers (HV) and cancer patients.

Methods Samples were enriched using CD34 microbeads, stained with nuclear dye and anti-CD14, CD15, CD45, CD34 and CD146 antibodies. Putative CECs were examined for Weibel–Palade bodies (WPBs) using anti–von Willebrand factor (vWF) antibody and fluorescence microscopy. Linear range of detection (R
2), recovery and precision (coefficient of variation percentage [CV%]) were defined in three experiments by spiking a known number (range 12–12,800 CECs/4 mL) of surrogate endothelial cells in peripheral blood. Sample storage was determined at –80°C for up to 2 months.

Results Sorted CECs showed vWF in the WPBs. The relationship between spiked and detected surrogate cells was R
2 = 1.0, recovery of 94.0 to 101.4% and CV% of 1.0 to 18.4%. Recovery ± standard deviation (within-run days 1, 2 and 3) were, respectively, 102.5% ± 8.2, 97.8% ± 4.6, 99.1% ± 7.7, and after 2 months 94.3% ± 15.3. The median CECs/mL in patients was 24.1 versus 14.4 in HVs.

Conclusion This method for selective, sensitive and reliable CEC analysis by FCM allows for investigation of CECs as a biomarker in clinical research.
Myeloperoxidase Is a Negative Regulator of Phospholipid-Dependent Coagulation
Authors: Beckmann Lennart , Dicke Christina , Spath Brigitte , Lehr Carina , Sievers Bianca , Klinke Anna , Baldus Stephan , Rudolph Volker , Langer Florian
Published: December 2017

Myeloperoxidase (MPO) is a cationic heme enzyme stored in neutrophilic polymorphonuclear leukocytes (PMNs) that has recently been implicated in inflammatory cell signaling and tissue damage. Although PMNs play a critical role in both innate immunity and vascular thrombosis, no previous study has systematically investigated the effect of MPO on blood coagulation. Here, we show that PMN-derived MPO inhibits the procoagulant activity (PCA) of lipidated recombinant human tissue factor (rhTF) in a time- and concentration-dependent manner that involves, but is not entirely dependent on the enzyme's catalytic activity. Similarly, MPO together with its substrate, H2O2, inhibited the PCA of plasma microvesicles isolated from lipopolysaccharide (LPS)-stimulated whole blood, an effect additive to that of a function blocking TF antibody. Treatment of whole blood with LPS or phorbol-myristate-acetate dramatically increased MPO plasma levels, and co-incubation with 4-ABAH, a specific MPO inhibitor, significantly enhanced the PCA in plasma supernatants. MPO and MPO/H2O2 also inhibited the PCA of activated platelets and purified phospholipids (PLs), suggesting that modulation of negatively charged PLs, i.e., phosphatidylserine, rather than direct interference with the TF/FVIIa initiation complex was involved. Consistently, pretreatment of activated platelets with MPO or MPO/H2O2 attenuated the subsequent binding of lactadherin, which specifically recognizes procoagulant PS on cell membranes. Finally, endogenously released MPO regulated the PCA of THP1 cells in an autocrine manner dependent on the binding to CD11b/CD18 integrins. Collectively, these findings indicate that MPO is a negative regulator of PL-dependent coagulation and suggest a more complex role of activated PMNs in haemostasis and thrombosis.
Diagnostic Accuracy of a Novel Chromogenic Direct Thrombin Inhibitor Assay: Clinical Experiences for Dabigatran Monitoring
Authors: Poli Sven , Härtig Florian , Spencer Charlotte , Ebner Matthias , Birschmann Ingvild , Kuhn Joachim , Faix Susanne , Ziemann Ulf , Häring Hans-Ulrich , Lehmann Rainer , Peter Andreas , Hörber Sebastian
Published: December 2017

Background Direct oral anticoagulants (DOACs) are increasingly replacing vitamin K antagonists (VKA) for clinical indications requiring long-term oral anticoagulation. In contrast to VKA, treatment with DOAC including dabigatran—the only direct thrombin inhibitor amongst them—does not require therapeutic drug monitoring. However, in case of treatment complications (e.g., major haemorrhage) and conditions requiring urgent surgery or thrombolytic therapy, information about actual DOAC plasma levels is needed to guide treatment decisions. Due to short reagent stability, limited accuracy at low dabigatran levels and high heparin sensitivity, the applicability of the widely used Hemoclot thrombin inhibitor (HTI) coagulation assay is limited in the emergency setting.

Methods Dabigatran concentrations of 288 citrated plasma samples taken from 48 dabigatran-treated patients with drug concentrations of up to 300 ng/mL were measured with the chromogenic anti-IIa Biophen direct thrombin inhibitor (BDTI) assay and results compared with HTI using ultra performance liquid chromatography—tandem mass spectrometry as the reference method for measuring dabigatran plasma concentrations.

Results BDTI results showed a very strong correlation with dabigatran concentrations (r = 0.965, p < 0.0001) as well as a low intra- and inter-assay variation of <5%. Compared with HTI, BDTI provides an improved on-board reagent stability of 72 hours, rapid turnaround times comparable to routine coagulation assays, high accuracy at low drug levels and reduced heparin sensitivity.

Conclusion The BDTI is an ideal coagulation assay for the around-the-clock determination of dabigatran plasma levels in clinical routine including emergency situations.
Outpatient Management in Patients with Venous Thromboembolism with Edoxaban: A Post Hoc Analysis of the Hokusai-VTE Study
Authors: Medina Andria , Raskob Gary , Ageno Walter , Cohen Alexander , Brekelmans Marjolein , Chen Cathy , Grosso Michael , Mercuri Michele , Segers Annelise , Verhamme Peter , Vanassche Thomas , Wells Philip , Lin Min , Winters Shannon , Weitz Jeffrey , Büller Harry
Published: December 2017

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.
Rapidly growing abdominopelvic mass - to be or not to be, not all we see is what it seems
Authors: Veríssimo Renata Sofia Fernandes Teixeira , Aidos Joana Mafalda , Sousa Ana Isabel , Martins Nuno Francisco Nogueira
Published: December 2017

The finding of a pelvic mass is often a source of great concern to our patients. Establishing the correct diagnosis and accurately staging these tumors is mandatory, but sometimes difficult, as abdominal masses may prove to be benign or malignant and have different etiologies. We describe a patient with a rapidly growing abdominal mass with weight loss and other accompanying symptoms, that together with the exams performed, posed a genuine diagnostic challenge to the team. Only after surgery the authors reached the definitive diagnosis of leiomyoma. Still waters run deep.
New observations of frog and lizard predation by wandering and orb-weaver spiders in Costa Rica
Authors: Folt Brian , Lapinski Witold
Published: December 2017

Studies have suggested that predation by spiders may be an important force regulating life history in neotropical frogs and lizards, but detailed descriptions of predator-prey relationships are few. Here we describe novel observations where spiders contributed to the mortality of frogs and lizards in northeastern Costa Rica, and we corrected or clarified three identification errors of spiders from the literature. The most frequently observed predators were wandering spiders (Ctenidae), which seem to be generalist predators on frogs and lizards. An orb-weaver spider (Araneidae) also contributed to frog mortality, likely after the frog became entangled in the spider’s web. More detailed studies are needed to elucidate the role that spider predation contributes to frog and lizard demography in neotropical forests.
2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis
Authors: Weitz Jeffrey I. , Fredenburgh James C.
Published: December 2017

The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI–deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development.
Age of First Arrhythmic Event in Brugada Syndrome
Authors: Milman Anat , Andorin Antoine , Gourraud Jean-Baptiste , Sacher Frederic , Mabo Philippe , Kim Sung-Hwan , Maeda Shingo , Takahashi Yoshihide , Kamakura Tsukasa , Aiba Takeshi , Conte Giulio , Juang Jimmy J.M. , Leshem Eran , Rahkovich Michael , Hochstadt Aviram , Mizusawa Yuka , Postema Pieter G. , Arbelo Elena , Huang Zhengrong , Denjoy Isabelle , Giustetto Carla , Wijeyeratne Yanushi D. , Napolitano Carlo , Michowitz Yoav , Brugada Ramon , Casado-Arroyo Ruben , Champagne Jean , Calo Leonardo , Sarquella-Brugada Georgia , Tfelt-Hansen Jacob , Priori Silvia G. , Takagi Masahiko , Veltmann Christian , Delise Pietro , Corrado Domenico , Behr Elijah R. , Gaita Fiorenzo , Yan Gan-Xin , Brugada Josep , Leenhardt Antoine , Wilde Arthur A.M. , Brugada Pedro , Kusano Kengo F. , Hirao Kenzo , Nam Gi-Byoung , Probst Vincent , Belhassen Bernard
Published: December 2017

Background

Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE.

Methods and Results

A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter–defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27–84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years;
P
<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (
P
=0.003). Whites and Asians exhibited their AE at the same median age (43 years).

Conclusions

SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE.
Geographical Variations in Blood Pressure Level and Seasonality in Hemodialysis Patients
Authors: Duranton Flore , Kramer Anneke , Szwarc Ilan , Bieber Brian , Gayrard Nathalie , Jover Bernard , Vetromile Fernando , Massy Ziad A. , Combe Christian , Tentori Francesca , Jager Kitty J. , Servel Marie-Françoise , Argilés Àngel
Published: December 2017

Seasons and climate influence the regulation of blood pressure (BP) in the general population and in hemodialysis patients. It is unknown whether this phenomenon varies across the world. Our objective was to estimate BP seasonality in hemodialysis patients from different geographical locations. Patients from 7 European countries (Spain, Italy, France, Belgium, Germany, United Kingdom, and Sweden) participating in the DOPPS (Dialysis Outcomes and Practice Patterns Study) on years 2005 to 2011 were studied. Factors influencing pre- and postdialysis systolic BP and diastolic BP levels were analyzed by mixed models. There were 9655 patients (median age, 68; 59% male) from 263 facilities, seen every 4 months during a median duration of 1.3 years. Pre- and postdialysis systolic BP increased by a mean estimate of 5.1 mm Hg (95% confidence interval [CI], 3.7–6.4 mm Hg) and 4.4 mm Hg (95% CI, 2.9–5.9 mm Hg) for each 10° increase in latitude (1111 km to the North). In the longitudinal analysis, predialysis systolic BP was lower in summer and higher in winter (difference, 1.7 mm Hg; 95% CI, 1.3–2.2 mm Hg), with greater differences in southern locations (
P
interaction
=0.04). Predialysis systolic BP was inversely associated with outdoor temperature (−0.8 mm Hg/7.2°C; 95% CI, −1.0 to −0.5 mm Hg/7.2°C), with steeper slopes in southern locations (
P
interaction
=0.005). Results were similar for predialysis diastolic BP. In conclusion, there is a geographical and seasonal gradient of BP in European hemodialysis patients. There is a need to consider these effects when evaluating and treating BP in this population and potentially in others.
Effect of Plant Protein on Blood Lipids: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Li Siying S. , Blanco Mejia Sonia , Lytvyn Lyubov , Stewart Sarah E. , Viguiliouk Effie , Ha Vanessa , de Souza Russell J. , Leiter Lawrence A. , Kendall Cyril W. C. , Jenkins David J. A. , Sievenpiper John L.
Published: December 2017

Background

There is a heightened interest in plant‐based diets for cardiovascular disease prevention. Although plant protein is thought to mediate such prevention through modifying blood lipids, the effect of plant protein in specific substitution for animal protein on blood lipids remains unclear. To assess the effect of this substitution on established lipid targets for cardiovascular risk reduction, we conducted a systematic review and meta‐analysis of randomized controlled trials using the Grading of Recommendations Assessment, Development, and Evaluation system.

Methods and Results

MEDLINE
,
EMBASE
, and the Cochrane Registry were searched through September 9, 2017. We included randomized controlled trials of ≥3 weeks comparing the effect of plant protein in substitution for animal protein on low‐density lipoprotein cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. Two independent reviewers extracted relevant data and assessed risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences with 95% confidence intervals. Heterogeneity was assessed (Cochran Q statistic) and quantified (I
2
statistic). The overall quality (certainty) of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. One‐hundred twelve randomized controlled trials met the eligibility criteria. Plant protein in substitution for animal protein decreased low‐density lipoprotein cholesterol by 0.16 mmol/L (95% confidence interval, −0.20 to −0.12 mmol/L;
P
<0.00001; I
2
=55%; moderate‐quality evidence), non–high‐density lipoprotein cholesterol by 0.18 mmol/L (95% confidence interval, −0.22 to −0.14 mmol/L;
P
<0.00001; I
2
=52%; moderate‐quality evidence), and apolipoprotein B by 0.05 g/L (95% confidence interval, −0.06 to −0.03 g/L;
P
<0.00001; I
2
=30%; moderate‐quality evidence).

Conclusions

Substitution of plant protein for animal protein decreases the established lipid targets low‐density lipoprotein cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. More high‐quality randomized trials are needed to improve our estimates.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
02037321.
Description of a new species of Liocheles Sundevall, 1833 (Hormuridae) from India
Authors: MIRZA ZEESHAN A.
Published: December 2017

Scorpions of the genus Liocheles Sundevall, 1833 are widespread in forests of the Indo-Pacific region; however, its species diversity is poorly resolved. A new species of the genus Liocheles is herein described from northeast India after examination of freshly collected specimens and available museum material. The new species, Liocheles schalleri sp. nov., occurs in the Indo-Burma biodiversity hotspot, a region that has been poorly explored for its arachnid diversity.
Variability and Clustering of Midlatitude Summertime Convection: Testing the Craig and Cohen Theory in a Convection-Permitting Ensemble with Stochastic Boundary Layer Perturbations
Authors: Rasp Stephan , Selz Tobias , Craig George C.
Published: December 2017

The statistical theory of convective variability developed by Craig and Cohen in 2006 has provided a promising foundation for the design of stochastic parameterizations. The simplifying assumptions of this theory, however, were made with tropical equilibrium convection in mind. This study investigates the predictions of the statistical theory in real-weather case studies of nonequilibrium summertime convection over land. For this purpose, a convection-permitting ensemble is used in which all members share the same large-scale weather conditions but the convection is displaced using stochastic boundary layer perturbations. The results show that the standard deviation of the domain-integrated mass flux is proportional to the square root of its mean over a wide range of scales. This confirms the general applicability and scale adaptivity of the Craig and Cohen theory for complex weather. However, clouds tend to cluster on scales of around 100 km, particularly in the morning and evening. This strongly impacts the theoretical predictions of the variability, which does not include clustering. Furthermore, the mass flux per cloud closely follows an exponential distribution if all clouds are considered together and if overlapping cloud objects are separated. The nonseparated cloud mass flux distribution resembles a power law. These findings support the use of the theory for stochastic parameterizations but also highlight areas for improvement.