bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inconclusive Evidence That Age Predicts a Prolonged or Chronic Course of Acute Rhinosinusitis in Adults: A Systematic Review of the Evidence Base
Authors: Broeder Timo P. , Grooteman Karina V. , Overdijkink Sanne B. , Selhorst Christel E. , Kaper Nina M. , Grolman Wilko , van der Heijden Geert J. M. G. 
Published: December 2013

ObjectiveTo review the evidence whether the risk for a prolonged or chronic course increases with age in adult patients with acute rhinosinusitis.Data SourcesPubMed, EMBASE, and the Cochrane Library.Review MethodsA comprehensive literature search was performed on March 24, 2013, and articles were screened and selected using predefined inclusion and exclusion criteria. Articles reporting studies on age as a predictor for the course in patients with acute rhinosinusitis were included. For included articles, the design of reported studies was assessed for directness of evidence and risk of bias. We aimed to extract hazard ratios for age as a continuous variable.ResultsOut of 13,382 unique publications, 3 articles with moderate risk of bias were included, with a maximum follow‐up period of 30 days. The reported hazard ratios for recovery at 10, 15, and 30 days are 1.0 (95% confidence interval, 0.9‐1.1) for age as a continuous variable, 0.86 (0.66‐1.11) for age dichotomized at 38 years, and 0.58 (0.40‐0.84) for age dichotomized for an increase with 20 years, respectively.Conclusion and RecommendationThere is no evidence that age increases the risk for chronic rhinosinusitis in adult patients with acute rhinosinusitis. The literature is inconclusive that age increases the risk for a prolonged course of acute rhinosinusitis and, therefore, does not provide grounds for different management according to age of patients. As such, patients can be managed according to clinical practice guidelines with expectant observation and symptomatic treatment.
Tracheal Reconstruction in a Canine Model
Authors: Wood Megan W. , Murphy Sean V. , Feng Xin , Wright S. Carter 
Published: December 2013

ObjectiveTracheal reconstruction using a stem cell–based engineered trachea has recently shown promise. Our goal is to achieve a single‐stage stem cell–based tracheal replacement.Study DesignProspective feasibility study.SettingWake Forest Institute of Regenerative Medicine.Subjects and MethodsFive healthy male beagles were implanted with a 2.5‐cm segment of decellularized trachea. A sixth animal, planned for the control arm, died of anesthetic complications prior to tracheal implantation. The remaining 5 beagles were divided into 2 study arms: 4 had adipose‐derived stem cells coating the lumen of the donor trachea, and a control animal had the trachea implanted cell free. The donor tracheas were obtained from previously sacrificed size‐matched canines and decellularized. The adipose tissue was harvested from a recipient animal and the trachea prepared, seeded, and then implanted, all in one operation. Adipose stem cells were labeled fluorescently.ResultsFive of 6 planned surgical procedures were completed successfully. All required sacrifice for airway distress at approximately 1 week postoperatively. All tracheal grafts were found to be malacic and compromised.ConclusionIn a canine model using a decellularized tracheal scaffold and adipose stem cells, the postoperative inflammatory response and evidence of rejection was minimal. However, all scaffolds exhibited breakdown, compromising the animals’ airways, necessitating euthanasia earlier than planned. For future study, a similar animal model using a single‐stage approach with a more robust scaffold may allow for greater survival and stem cell differentiation.
Thrombosis: tangled up in NETs
Authors: Martinod Kimberly , Wagner Denisa D. 
Published: December 2013

AbstractThe contributions by blood cells to pathological venous thrombosis were only recently appreciated. Both platelets and neutrophils are now recognized as crucial for thrombus initiation and progression. Here we review the most recent findings regarding the role of neutrophil extracellular traps (NETs) in thrombosis. We describe the biological process of NET formation (NETosis) and how the extracellular release of DNA and protein components of NETs, such as histones and serine proteases, contributes to coagulation and platelet aggregation. Animal models have unveiled conditions in which NETs form and their relation to thrombogenesis. Genetically engineered mice enable further elucidation of the pathways contributing to NETosis at the molecular level. Peptidylarginine deiminase 4, an enzyme that mediates chromatin decondensation, was identified to regulate both NETosis and pathological thrombosis. A growing body of evidence reveals that NETs also form in human thrombosis and that NET biomarkers in plasma reflect disease activity. The cell biology of NETosis is still being actively characterized and may provide novel insights for the design of specific inhibitory therapeutics. After a review of the relevant literature, we propose new ways to approach thrombolysis and suggest potential prophylactic and therapeutic agents for thrombosis.
Comparative analysis of genome sequences from four strains of the Buchnera aphidicola Mp endosymbion of the green peach aphid, Myzus persicae
Authors: Jiang Zhijie , Jones Derek H , Khuri Sawsan , Tsinoremas Nicholas F , Wyss Tania , Jander Georg , Wilson Alex C C 
Published: December 2013

Abstract

Background

Myzus persicae, the green peach aphid, is a polyphagous herbivore that feeds from hundreds of species of mostly dicot crop plants. Like other phloem-feeding aphids, M. persicae rely on the endosymbiotic bacterium, Buchnera aphidicola (Buchnera Mp), for biosynthesis of essential amino acids and other nutrients that are not sufficiently abundant in their phloem sap diet. Tobacco-specialized M. persicae are typically red and somewhat distinct from other lineages of this species. To determine whether the endosymbiotic bacteria of M. persicae could play a role in tobacco adaptation, we sequenced the Buchnera Mp genomes from two tobacco-adapted and two non-tobacco M. persicae lineages.

Results
With a genome size of 643.5 kb and 579 predicted genes, Buchnera Mp is the largest Buchnera genome sequenced to date. No differences in gene content were found between the four sequenced Buchnera Mp strains. Compared to Buchnera APS from the well-studied pea aphid, Acyrthosiphon pisum, Buchnera Mp has 21 additional genes. These include genes encoding five enzymes required for biosynthesis of the modified nucleoside queosine, the heme pathway enzyme uroporphyrinogen III synthase, and asparaginase. Asparaginase, which is also encoded by the genome of the aphid host, may allow Buchnera Mp to synthesize essential amino acids from asparagine, a relatively abundant phloem amino acid.

Conclusions
Together our results indicate that the obligate intracellular symbiont Buchnera aphidicola does not contribute to the adaptation of Myzus persicae to feeding on tobacco.
Cost Sharing and Adherence to Tyrosine Kinase Inhibitors for Patients With Chronic Myeloid Leukemia
Authors: Dusetzina Stacie B. , Winn Aaron N. , Abel Gregory A. , Huskamp Haiden A. , Keating Nancy L. 
Published: December 2013

Purpose The introduction of imatinib, a tyrosine kinase inhibitor (TKI), has greatly increased survival for patients with chronic myeloid leukemia (CML). Conversely, nonadherence to imatinib and other TKIs undoubtedly results in disease progression and treatment resistance. We examined trends in imatinib expenditures from 2002 to 2011 and assessed the association between copayment requirements for imatinib and TKI adherence. Patients and Methods We used MarketScan health plan claims from 2002 to 2011 to identify adults (age 18 to 64 years) with CML who initiated imatinib therapy between January 1, 2002, and June 30, 2011, and had insurance coverage for at least 3 months before through 6 months after initiation (N = 1,541). Primary outcomes were TKI discontinuation and nonadherence. The primary independent variable was out-of-pocket cost for a 30-day supply of imatinib. By using a propensity-score weighted sample, we estimated the risk of discontinuation and nonadherence for patients with higher (top quartile) versus lower copayments. Results Monthly copayments for imatinib averaged $108; median copayments were $30 (range, $0 to $4,792). Mean total monthly expenditures for imatinib nearly doubled between 2002 and 2011, from $2,798 to $4,892. Approximately 17% of patients with higher copayments and 10% with lower copayments discontinued TKIs during the first 180 days following initiation (adjusted risk ratio [aRR], 1.70; 95% CI, 1.30 to 2.22). Similarly, patients with higher copayments were 42% more likely to be nonadherent (aRR, 1.42; 95% CI, 1.19 to 1.69). Conclusion Patients with higher copayments are more likely to discontinue or be nonadherent to TKIs. Given the importance of these therapies for patients with CML, our data suggest a critical need to reduce patient costs for these therapies.
Identification of a Novel SHP-2 Protein Tyrosine Phosphatase Inhibitor
Authors: Ju Anna , Seo Huiyun , Kim Heemun , Park Byoung Chul , Park Sung Goo , Kim Jeong Hoon , Choi Hyung-Kyoon , Min Kyung Hoon , Cho Sayeon 
Published: December 2013

Abstract
The Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) is a nonreceptor protein tyrosine phosphatase (PTP) involved in extracellular-regulated kinase (ERK) activation. Recent studies have shown that gain-of-function mutations in SHP-2 are associated with several diseases, including LEOPARD syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. In this study, we identified the novel SHP-2 inhibitor 3-(1-benzimidazolylmethyl)-6-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (MLS-001). SHP-2 activity was inhibited by MLS-001, whereas other types of PTPs, namely ACP1, CDC25A, DUSP3, DUSP14, DUSP18, DUSP22, DUSP23, DUSP26, and SSH3, were not. Furthermore, TCPTP and SHP-1 that are closely related to SHP-2 were not inhibited by the inhibitor. Kinetic studies with MLS-001 and SHP-2 revealed a competitive inhibition. The SHP-2 expressing cells treated with MLS-001 demonstrated reduced SHP-2 phosphatase activity, thereby suggesting that MLS-001 effectively passes through cell membranes. In addition, MLS-001 reduced SHP-2-mediated phosphorylation in the activation loop of ERK in cells. Therefore, MLS-001 could be a lead compound for developing a potent SHP-2 inhibitor.
Multigenic Natural Variation UnderliesCaenorhabditis elegansOlfactory Preference for the Bacterial PathogenSerratia marcescens
Authors: Glater Elizabeth E , Rockman Matthew V , Bargmann Cornelia I 
Published: December 2013

AbstractThe nematode Caenorhabditis elegans can use olfaction to discriminate among different kinds of bacteria, its major food source. We asked how natural genetic variation contributes to choice behavior, focusing on differences in olfactory preference behavior between two wild-type C. elegans strains. The laboratory strain N2 strongly prefers the odor of Serratia marcescens, a soil bacterium that is pathogenic to C. elegans, to the odor of Escherichia coli, a commonly used laboratory food source. The divergent Hawaiian strain CB4856 has a weaker attraction to Serratia than the N2 strain, and this behavioral difference has a complex genetic basis. At least three quantitative trait loci (QTLs) from the CB4856 Hawaii strain (HW) with large effect sizes lead to reduced Serratia preference when introgressed into an N2 genetic background. These loci interact and have epistatic interactions with at least two antagonistic QTLs from HW that increase Serratia preference. The complex genetic architecture of this C. elegans trait is reminiscent of the architecture of mammalian metabolic and behavioral traits.
Why Breeding Values Estimated Using Familial Data Should Not Be Used for Genome-Wide Association Studies
Authors: Ekine Chinyere C , Rowe Suzanne J , Bishop Stephen C , de Koning Dirk-Jan 
Published: December 2013

Abstract
In animal breeding, the genetic potential of an animal is summarized as its estimated breeding value, which is derived from its own performance as well as the performance of related individuals. Here, we illustrate why estimated breeding values are not suitable as a phenotype for genome-wide association studies. We simulated human-type and pig-type pedigrees with a range of quantitative trait loci (QTL) effects (0.5–3% of phenotypic variance) and heritabilities (0.3−0.8). We analyzed 1000 replicates of each scenario with four models: (a) a full mixed model including a polygenic effect, (b) a regression analysis using the residual of a mixed model as a trait score (so called GRAMMAR approach), (c) a regression analysis using the estimated breeding value as a trait score, and (d) a regression analysis that uses the raw phenotype as a trait score. We show that using breeding values as a trait score gives very high false-positive rates (up 14% in human pedigrees and &gt;60% in pig pedigrees). Simulations based on a real pedigree show that additional generations of pedigree increase the type I error. Including the family relationship as a random effect provides the greatest power to detect QTL while controlling for type I error at the desired level and providing the most accurate estimates of the QTL effect. Both the use of residuals and the use of breeding values result in deflated estimates of the QTL effect. We derive the contributions of QTL effects to the breeding value and residual and show how this affects the estimates.
Identification of Suppressors ofmbk-2/DYRKby Whole-Genome Sequencing
Authors: Wang Yuemeng , Wang Jennifer T , Rasoloson Dominique , Stitzel Michael L , O’ Connell Kevin F , Smith Harold E , Seydoux Geraldine 
Published: December 2013

AbstractScreening for suppressor mutations is a powerful method to isolate genes that function in a common pathway or process. Because suppressor mutations often do not have phenotypes on their own, cloning of suppressor loci can be challenging. A method combining whole-genome sequencing (WGS) and single nucleotide polymorphism (SNP) mapping (WGS/SNP mapping) was developed to identify mutations with visible phenotypes in C. elegans. We show here that WGS/SNP mapping is an efficient method to map suppressor mutations without the need for previous phenotypic characterization. Using RNA-mediated interference to test candidate loci identified by WGS/SNP mapping, we identified 10 extragenic and six intragenic suppressors of mbk-2, a DYRK family kinase required for the transition from oocyte to zygote. Remarkably, seven suppressors are mutations in cell-cycle regulators that extend the timing of the oocyte-to-zygote transition.
Extensive Use of RNA-Binding Proteins inDrosophilaSensory Neuron Dendrite Morphogenesis
Authors: Olesnicky Eugenia C , Killian Darrell J , Garcia Evelyn , Morton Mary C , Rathjen Alan R , Sola Ismail E , Gavis Elizabeth R 
Published: December 2013

AbstractThe large number of RNA-binding proteins and translation factors encoded in the Drosophila and other metazoan genomes predicts widespread use of post-transcriptional regulation in cellular and developmental processes. Previous studies identified roles for several RNA-binding proteins in dendrite branching morphogenesis of Drosophila larval sensory neurons. To determine the larger contribution of post-transcriptional gene regulation to neuronal morphogenesis, we conducted an RNA interference screen to identify additional Drosophila proteins annotated as either RNA-binding proteins or translation factors that function in producing the complex dendritic trees of larval class IV dendritic arborization neurons. We identified 88 genes encoding such proteins whose knockdown resulted in aberrant dendritic morphology, including alterations in dendritic branch number, branch length, field size, and patterning of the dendritic tree. In particular, splicing and translation initiation factors were associated with distinct and characteristic phenotypes, suggesting that different morphogenetic events are best controlled at specific steps in post-transcriptional messenger RNA metabolism. Many of the factors identified in the screen have been implicated in controlling the subcellular distributions and translation of maternal messenger RNAs; thus, common post-transcriptional regulatory strategies may be used in neurogenesis and in the generation of asymmetry in the female germline and embryo.
Accuracy of Early DMSA Scan for VUR in Young Children With Febrile UTI
Authors: Zhang Xin , Xu Hong , Zhou Lijun , Cao Qi , Shen Qian , Sun Li , Fang Xiaoyan , Guo Wei , Zhai Yihui , Rao Jia , Pa Mier , Zhao Ruifang , Bi Yunli 
Published: December 2013

OBJECTIVE:
To evaluate the accuracy of an acute 99mTc-dimercaptosuccinic acid (DMSA) scan in predicting dilating vesicoureteral reflux (VUR) among young children with a febrile urinary tract infection (UTI).

METHODS:
The medical records of children (≤2 years of age), presenting with febrile UTI between January 2000 and December 2011, were retrospectively reviewed.

RESULTS:
A total of 523 children were included in this study, of whom 397 children (75.9%) had abnormal DMSA results and 178 children (34.0%) were identified as VUR on micturating cystourethrography (MCU). Among all the patients, the number of children with dilating VUR was 151 (28.9%). The rate of abnormal results on DMSA for the dilating VUR group was significantly higher than the rates for the non-VUR and low-grade VUR groups (P &lt; .01). In the &lt;6 months age group and ≥6 months age group, the sensitivities of DMSA in predicting dilating VUR were 96.15% and 100.0%, respectively, the negative predictive values were 97.26% and 100.0%, respectively, and the negative likelihood ratios were 0.0911 and 0.0000, respectively.

CONCLUSION:
For children ≤2 years of age with a febrile UTI, an acute DMSA scan is valuable in the exclusion of dilating VUR. The likelihood of the presence of dilating VUR on MCU is rather low when the result of DMSA is negative. DMSA should be conducted to assess the need for an MCU.
Pneumococcal Antibody Levels in Children With PID Receiving Immunoglobulin
Authors: Tuerlinckx David , Florkin Benoit , Ferster Alina , De Schutter Iris , Chantrain Christophe , Haerynck Filomeen , Philippet Pierre , Strengers Paul , Laub Ruth 
Published: December 2013

OBJECTIVES:Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization.METHODS:Patients received 7 consecutive IVIG infusions. Total IgG and PnPsAb levels were determined on plasma samples obtained before and after infusion.RESULTS:Twenty-two children with PID were treated with IVIG (mean weekly dose: 0.10 g/kg). The mean trough and peak levels of total IgG were 7.77 and 13.93 g/L, respectively. Trough and peak geometric mean concentrations and distribution curves differed between serotypes and showed wide dispersion (0.17–7.96 µg/mL). In patients (89%–100%), antibodies against most serotypes reached trough levels ≥0.2 µg/mL, a threshold considered protective against invasive pneumococcal infection. For several serotypes, trough levels reached ≥1.0 to 1.3 µg/mL, the level found in adults. Trough geometric mean concentrations correlated well with the PnPsAb contents of the IVIG product.CONCLUSIONS:In IVIG-treated children with PID, protective PnPsAb levels for most pathogenic serotypes were obtained. A correlation was observed between PnPsAb levels in patients and in the IVIG product. This offers the potential to improve infection prevention by adapting the IVIG product and dose according to epidemiology.
Stratification of Risk of Early-Onset Sepsis in Newborns ≥34 Weeks’ Gestation
Authors: Escobar Gabriel J. , Puopolo Karen M. , Wi Soora , Turk Benjamin J. , Kuzniewicz Michael W. , Walsh Eileen M. , Newman Thomas B. , Zupancic John , Lieberman Ellice , Draper David 
Published: December 2013

OBJECTIVE:
To define a quantitative stratification algorithm for the risk of early-onset sepsis (EOS) in newborns ≥34 weeks’ gestation.

METHODS:
We conducted a retrospective nested case-control study that used split validation. Data collected on each infant included sepsis risk at birth based on objective maternal factors, demographics, specific clinical milestones, and vital signs during the first 24 hours after birth. Using a combination of recursive partitioning and logistic regression, we developed a risk classification scheme for EOS on the derivation dataset. This scheme was then applied to the validation dataset.

RESULTS:
Using a base population of 608 014 live births ≥34 weeks’ gestation at 14 hospitals between 1993 and 2007, we identified all 350 EOS cases &lt;72 hours of age and frequency matched them by hospital and year of birth to 1063 controls. Using maternal and neonatal data, we defined a risk stratification scheme that divided the neonatal population into 3 groups: treat empirically (4.1% of all live births, 60.8% of all EOS cases, sepsis incidence of 8.4/1000 live births), observe and evaluate (11.1% of births, 23.4% of cases, 1.2/1000), and continued observation (84.8% of births, 15.7% of cases, incidence 0.11/1000).

CONCLUSIONS:
It is possible to combine objective maternal data with evolving objective neonatal clinical findings to define more efficient strategies for the evaluation and treatment of EOS in term and late preterm infants. Judicious application of our scheme could result in decreased antibiotic treatment in 80 000 to 240 000 US newborns each year.
B Cells Promote Induction of Experimental Autoimmune Encephalomyelitis by Facilitating Reactivation of T Cells in the Central Nervous System
Authors: Pierson Emily R. , Stromnes Ingunn M. , Goverman Joan M. 
Published: December 2013

Abstract
The efficacy of rituximab treatment in multiple sclerosis has renewed interest in the role of B cells in CNS autoimmunity. In this study, we show that B cells are the predominant MHC class II+ subset in the naive CNS in mice, and they constitutively express proinflammatory cytokines. Incidence of experimental autoimmune encephalomyelitis induced by adoptive transfer was significantly reduced in C3HeB/Fej μMT (B cell–deficient) mice, suggesting an important role for CNS B cells in initiating inflammatory responses. Initial T cell infiltration of the CNS occurred normally in μMT mice; however, lack of production of T cell cytokines and other immune mediators indicated impaired T cell reactivation. Subsequent recruitment of immune cells from the periphery driven by this initial T cell reactivation did not occur in μMT mice. B cells required exogenous IL-1β to reactivate Th17 but not Th1 cells in vitro. Similarly, reactivation of Th1 cells infiltrating the CNS was selectively impaired compared with Th17 cells in μMT mice, causing an increased Th17/Th1 ratio in the CNS at experimental autoimmune encephalomyelitis onset and enhanced brain inflammation. These studies reveal an important role for B cells within the CNS in reactivating T cells and influencing the clinical manifestation of disease.