bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pediatric Eating Assessment Tool
Authors: Thoyre Suzanne M. , Pados Britt F. , Park Jinhee , Estrem Hayley , McComish Cara , Hodges Eric A.
Published: September 2017

Objectives:

The Pediatric Eating Assessment Tool (PediEAT) is a parent‐report instrument developed to assess symptoms of feeding problems in children aged 6 months to 7 years. The purpose of this study was to identify the factor structure of the PediEAT and test its psychometric properties, including internal consistency reliability, temporal stability, and construct validity.

Methods:

Participants included 567 parents of children aged 6 months to 7 years. Fifty‐four percent of the sample had parent report of a diagnosed feeding problem or feeding concerns. Exploratory factor‐analysis techniques were used to remove redundant or non‐endorsed items and identify the factor structure of the instrument. Construct validity was examined with 466 parents completing the Mealtime Behavior Questionnaire as a criterion standard. Known‐groups validation was used to compare PediEAT scores between children with and without diagnosed feeding problems. Temporal stability of the PediEAT was examined with 97 parents repeating the PediEAT after 2 weeks.

Results:

Principal components factor analysis with varimax rotation supported a 4‐factor model accounting for 39.4% of the total variance. The 4 subscales (Physiologic Symptoms, Problematic Mealtime Behaviors, Selective/Restrictive Eating, Oral Processing) demonstrated acceptable internal consistencies (coefficient alphas: 0.92, 0.91, 0.83, 0.83; respectively). Construct validity was supported in 2 ways. The PediEAT correlated with the Mealtime Behavior Questionnaire (r = 0.77, P < 0.001) and total score and subscale scores were significantly different between children with and without diagnosed feeding problem (P < 0.001). Temporal stability was demonstrated through test‐retest reliability (r = 0.95, P < 0.001).

Conclusions:

Strong psychometric properties support the use of the PediEAT in research and clinical practice.
High Rate of Febrile Seizures in Japanese Children With Occult Bacteremia
Authors: Kamidani Satoshi , Shoji Kensuke , Ogawa Eiki , Funaki Takanori , Mishina Hiroki , Miyairi Isao
Published: September 2017

Objectives

Fever of 39°C or higher and a white blood cell (WBC) count of 15,000/μL or greater are known predictors of occult bacteremia (OB). However, because of a decreasing prevalence of OB, WBC counts have become poor predictors of OB in populations of routinely immunized children. Thus, we aim to evaluate the clinical characteristics of OB in Japanese children and identify potential risk factors for OB.

Methods

We conducted an observational study of children aged 3 to 36 months old with positive blood cultures for Streptococcus pneumoniae or Haemophilus influenzae at an emergency department in a tertiary care children's hospital between April 2002 and December 2015. Patients with significant underlying diseases, a proven source of infection, or toxic appearance, were excluded.

Results

Positive blood cultures were recorded in 231 patients; of these, 110 were included in the study (S. pneumoniae, n = 102; H. influenzae, n = 8). Median age was 16 (3–34) months. Patients had a high median body temperature of 39.2 (interquartile range, 38.6–39.9) °C and median WBC of 21,120 (interquartile range, 16,408–24,242)/μL. A high rate of febrile seizures (58 patients, 53%) was observed, with complex febrile seizures accounting for 43% of the episodes. Frequency of febrile seizures was positively associated with age (P = 0.001).

Conclusions

Our study revealed a high rate of children presenting with febrile seizures, especially complex seizures, among children with OB in Japan. A further study is necessary to evaluate the role of febrile seizures as a predictor for OB.
Management of Croup in the Emergency Department
Authors: Bagwell Taylor , Hollingsworth Amanda , Thompson Tonya , Abramo Thomas , Huckabee Mary , Chang Di , Crawley Leroy , Robbins James M.
Published: September 2017

Objectives

Croup occasionally requires medical intervention for respiratory distress. Mainstays of treatment are corticosteroids and nebulized epinephrine. Diagnosis and assessment of severity remain clinical. Safety of discharge from an emergency department (ED) after treatment with corticosteroids and 1 nebulized epinephrine has been established. No evidence exists regarding risk associated with discharge after multidose nebulized epinephrine. Many patients requiring multidose nebulized epinephrine are reflexively admitted. The purpose of this study was to provide a descriptive analysis of the current management of croup, specifically patients requiring multidose nebulized epinephrine.

Methods

The Pediatric Health Information System was used to extract information on patients diagnosed with croup age 0 to 11 years, evaluated in pediatric EDs from 2004 to 2014, who received corticosteroids and at least 1 nebulized epinephrine. We retrospectively assessed patients requiring multidose nebulized epinephrine, evaluating risk of return for additional care associated with discharges and reviewing admissions for markers of disease severity.

Results

A total of 95,403 patients were identified. Those requiring corticosteroids and multidose nebulized epinephrine (N = 8084) were less likely to return for further care if discharged from the ED (5.4% return single dose, 0.8% return multidose: P < 0.0001) and were admitted at a higher rate (10.7% admission single dose, 70.5% admission multidose: P < 0.0001). Of those admitted, only 31.7% received more than 2 treatments.

Conclusions

Patients requiring single-dose nebulized epinephrine are managed differently than those requiring multidose nebulized epinephrine. There is likely a role for multidose nebulized epinephrine in the outpatient management of croup. A prospective study is needed.
Implications of Increased Weight Status for the Occurrence of Fall-Induced Intracranial Hemorrhage in Children Aged 4 Years or Younger
Authors: Kim Jung Heon , Kwon Jae Hyun , Lee Jong Seung , Ryu Jeong-Min , Lim Kyoung Soo , Kim Won Young
Published: September 2017

Objectives

The aim of this study was to investigate the association between increased weight status (IWS), a weight for age/sex at greater than the 95th percentile, and fall-induced intracranial hemorrhage (ICH) in children aged 4 years or younger.

Methods

In 7072 children aged 4 years or younger with head injury who visited a tertiary care hospital emergency department in Korea from 2013 through 2015, the presence of fall-induced ICH was reviewed. The association between IWS and ICH was investigated by multivariable logistic regression. We retrospectively validated the Pediatric Emergency Care Applied Research Network rule alone and in combination with IWS for predicting ICH.

Results

Of 7072 children, 547 (7.7%) underwent computed tomography, of whom 451 (6.4%) were enrolled. Of these, 41 (9.1%; estimated event rate, 0.6%) had ICHs, and 26 (5.8%) had IWS. Increased weight status was more common in the children with ICH (P = 0.023). The association between IWS and ICH remained significant after adjustment (odds ratio, 5.24; 95% confidence interval [CI], 1.49–18.46; P = 0.010). The validation of the rule in combination with IWS showed no significant increases in a sensitivity (92.7% [95% CI, 80.1%–98.5%] to 95.7% [95% CI, 83.5%–99.4%]) and negative predictive value (98.2% [95% CI, 94.7%–99.4%] to 98.8% [95% CI, 95.4%–99.8%]).

Conclusions

Increased weight status is associated with fall-induced ICH in children aged 4 years or younger. Information on weight status could be potentially helpful in predicting ICH in young children with fall-induced head injury.
Closed Digital Artery Injury in Children
Authors: Bougie Emilie , Cugno Sabrina
Published: September 2017

Closed digital artery injury is a very rare phenomenon, even more so in children, with only 5 cases reported in the literature. We report a case of closed digital arterial interruption in a child after crush injury to the left hand. We further discuss possible etiologies and describe adequate management as found in the pertinent literature. Digital arterial injury should be suspected even in closed hand trauma because a delay in recognition may lead to devastating consequences.
Emergency Department Utilization by Native American Children
Authors: Zook Heather G. , Kharbanda Anupam B. , Puumala Susan E. , Burgess Katherine A. , Pickner Wyatt , Payne Nathaniel R.
Published: September 2017

Objectives

The aims of this study were to determine differences in emergency department (ED) use by Native American (NA) children in rural and urban settings and identify factors associated with frequent ED visits.

Methods

This cross-sectional, cohort study examined visits to 6 EDs: 2 rural, 2 midsize urban, and 2 large urban EDs from June 2011 to May 2012. Univariate and multiple regression analyses were conducted. Frequent ED visitors had more than 4 visits in the study period.

Results

We studied 8294 NA visits (5275 patients) and 44,503 white visits (33,945 patients). Rural EDs had a higher proportion of NA patients, those below 200% of the income poverty level, and those who traveled more than 10 miles from their residence to attend the ED (all P < 0.05) compared with midsize and urban EDs. Native American patients had a high proportion of mental health diagnoses compared with whites (4.9% vs 1.9%, P < 0.001). Frequent ED visitors had greater odds of NA race, age younger than 1 year, public insurance, female sex, residence within less than 5 miles from the ED, and chronic disease.

Conclusions

Native American children seem to have greater challenges compared with whites obtaining care in rural areas. Native American children were more likely to be frequent ED visitors, despite having to travel farther from their residence to the ED. Native American children visiting rural and midsize urban EDs had a much higher prevalence of mental health problems than whites. Additional efforts to provide both medical and mental health services to rural NA are urgently needed.
Validity of Accelerometry to Measure Physical Activity Intensity in Children With an Acquired Brain Injury
Authors: Baque Emmah , Sakzewski Leanne , Trost Stewart G. , Boyd Roslyn N. , Barber Lee
Published: September 2017

Purpose:

To evaluate the validity of the ActiGraph accelerometer (AG) to differentiate between standardized, physical activity tasks using oxygen consumption (

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2) as the criterion measure in children and adolescents with an acquired brain injury; to determine vector magnitude activity intensity cut-points; to compare performance of cut-points to previously published cut-points.

Methods:

Twenty-seven children performed standardized walking and stepping activities wearing a portable indirect calorimeter, AG, and heart rate monitor. Differences in

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2 and AG vector magnitude activity counts were measured during activities. Receiver operating characteristic curves were determined for intensity cut-points.

Results:

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2 and AG activity counts significantly increased as walking speed increased. Discrimination of the newly derived cut-points was excellent and demonstrated greater agreement compared with the previously published cut-points.

Conclusion:

Output from accelerometers can differentiate physical activity intensity in children with an acquired brain injury. Future studies can apply these cut-points to evaluate physical activity performance.
Efficacy of Noninvasive Brain Stimulation on Unilateral Neglect After Stroke
Authors: Fan Jingjing , Li Yi , Yang Yonghong , Qu Yun , Li Shasha
Published: September 2017

Objective

Unilateral neglect (UN) is a common debilitating consequence of stroke. This review focused on the effect of noninvasive brain stimulation (NIBS) techniques in the recovery of UN in poststroke patients.

Methods

Relevant databases were comprehensively searched, including Cochrane Central Register of Controlled Trials, Medline, Embase, the Web of Knowledge, and relevant websites. All randomized controlled trials were identified which used NIBS for poststroke UN. The methodological quality and risk of bias were systematically evaluated.

Results

Twelve studies were included, and 11 randomized controlled trials were made further meta-analysis. Participants who were randomized to active transcranial direct current stimulation (effect size [ES], −0.51; 95% confidence interval [CI], −1.02 to −0.01; P = 0.04) and repetitive transcranial magnetic stimulation (ES, −1.76; 95% CI, −2.40 to −1.12; P < 0.00001) decreased UN severity after intervention compared with the control group. Nonsignificant pooled effect size presented for continuous theta burst stimulation results (ES, −0.77; 95% CI, −1.90 to 0.37; P = 0.18). No participants experienced serious adverse events.

Conclusions

This review found evidence for the efficacy of repetitive transcranial magnetic stimulation in the remediation of poststroke UN, but the efficacy of transcranial direct current stimulation and continuous theta burst stimulation was uncertain. Large-sample randomized controlled clinical trials are needed to understand effects of NIBS on poststroke UN.
Endoscopic Removal of Displaced Sagittal Intracapsular Condylar Fracture
Authors: Trento Guilherme dos Santos , Gorla Luis Fernando de Oliveira , Rodrigues Marcos Marques , Pereira-Filho Valfrido Antônio
Published: September 2017

Fractures involving the mandibular condyle are among the most common fractures of facial bones and still generate great discussion concerning therapeutic issues. Several factors have influence on the decision of treatment management of these fractures. In some patients, even when there is displacement of fractured fragments, the choice for conservative treatment is made. However, the removal of the condyle fragment may be required. In the oral surgery scope, endoscopy is a procedure used in many areas, and can be helpful to improve the visualization of surgical sites with difficult access. The endoscopic surgery brings benefits to patient such as no scar or minimal scar, lower risk to nerve damage, and decreased of surgical trauma and bleeding. In addition, according to surgeon experience, the surgery may become more dynamic. The aim of this study is to present an endoscopic technique associated with a transoral approach to remove a displaced sagittal intracapsular condyle fragment. Furthermore, to expose the advantages and benefits of this technique as well as the satisfactory results achieved.
Role of M2 Macrophages in Sepsis-Induced Acute Kidney Injury
Authors: Li Xing , Mu Genhua , Song Chunmei , Zhou Liangliang , He Lei , Jin Qin , Lu Zhongqian
Published: September 2017

Background:

Sepsis is a major cause of acute kidney injury (AKI), with high rates of morbidity and mortality. M2 macrophages have been shown to play important roles in the secretion of anti-inflammatory and tissue repair mediators. In this study, we investigate the role of M2 macrophages in sepsis-induced AKI by depleting these cells in vivo through the systemic administration of liposomal clodronate (LC).

Methods:

Male Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham surgery. Biochemical and histological renal damage was assessed. Macrophage infiltration and M2 macrophage depletion were assessed by immunohistochemistry. RT-PCR was used to investigate the expression of the inducible nitric oxide synthase (iNOS), arginase 1 (Arg-1), and found in inflammatory zone 1 (FIZZ1) mRNAs. Western blots were performed to assay the tissue levels of interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α).

Results:

M2 macrophages were obviously detected 72 h after sepsis-induced AKI. Kidney injury was more severe, renal function was decreased, and blood creatinine and blood urea nitrogen (BUN) levels were higher after M2 macrophage depletion. M2 macrophage depletion significantly inhibited the proliferation of tubular cells. M2 macrophage depletion also downregulated IL-10 expression and increased TNF-α secretion during sepsis-induced AKI.

Conclusions:

M2 macrophages attenuate sepsis-induced AKI, presumably by upregulating IL-10 expression and suppressing TNF-α secretion.
Comparing 3-Dimensional Ultrasound to 3-Dimensional Magnetic Resonance Imaging in the Detection of Levator Ani Defects
Authors: Calderwood Camille S. , Thurmond Amy , Holland Amanda , Osmundsen Blake , Gregory W. Thomas
Published: September 2017

Objective

The aim of this study was to compare the detection of levator ani defects (LAD) between 3-dimensional (3D) ultrasound (US) and 3D magnetic resonance imaging (MRI).

Methods

This is a secondary analysis of the Pelvic Floor Nerve Injury Following Childbirth Study. Nulliparous women underwent a standardized protocol of pelvic floor evaluations between January 2008 and December 2013, prior to pregnancy (V1) and at 2 points postpartum: 6 weeks (V2) and 6 months (V3). Those women who underwent a high-resolution 3D MRI pelvic floor sequence were selected. Comparisons were made to concomitantly acquired 3D perineal US. Eight tomographic slices were examined in the axial plane, each side independently scored with 0 (no defect) or 1 (defect). A similar tomographic approach was applied to the MRI. For both MRI and US, the right and left sides were each scored. A total score of 0 to 8 was given to each side. A dichotomous variable “complete LAD” was defined. Cohen κ was used as a measurement of agreement of complete LAD between MRI and US. Kendall τ b was used to correlate total scores.

Results

On the right side, 80 (90%) of 89 pairs were in agreement (concordant in the diagnosis or not of a “defect”). On the left side, 72 (81%) of 89 pairs were in agreement. Correlations (Cohen κ) of complete LAD were 0.65 (P < 0.001) on the right and 0.37 (P < 0.001) on the left. Correlations of total scores were 0.47 (P < 0.001) on the right and 0.41 (P < 0.001) on the left.

Conclusions

Moderate agreement was found between 3D US and 3D MRI LAD detection. More LADs and discordance were seen on the left.
When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome
Authors: Carrel Laura , Brown Carolyn J.
Published: September 2017

A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation.

This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
Mechanistic insights in X-chromosome inactivation
Authors: Lu Zhipeng , Carter Ava C. , Chang Howard Y.
Published: September 2017

X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing gene dosage between XY males and XX females in eutherian mammals. A long non-coding RNA (lncRNA), XIST, and its associated proteins orchestrate this multi-step process, resulting in the inheritable silencing of one of the two X-chromosomes in females. The XIST RNA is large and complex, exemplifying the unique challenges associated with the structural and functional analysis of lncRNAs. Recent technological advances in the analysis of macromolecular structure and interactions have enabled us to systematically dissect the XIST ribonucleoprotein complex, which is larger than the ribosome, and its place of action, the inactive X-chromosome. These studies shed light on key mechanisms of XCI, such as XIST coating of the X-chromosome, recruitment of DNA, RNA and histone modification enzymes, and compaction and compartmentalization of the inactive X. Here, we summarize recent studies on XCI, highlight the critical contributions of new technologies and propose a unifying model for XIST function in XCI where modular domains serve as the structural and functional units in both lncRNA–protein complexes and DNA–protein complexes in chromatin.

This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
XISTRNA: a window into the broader role of RNA in nuclear chromosome architecture
Authors: Creamer K. M. , Lawrence J. B.
Published: September 2017

XISTRNA triggers the transformation of an active X chromosome into a condensed, inactive Barr body and therefore provides a unique window into transitions of higher-order chromosome architecture. Despite recent progress, howXISTRNA localizes and interacts with the X chromosome remains poorly understood. Genetic engineering ofXISTinto a trisomic autosome demonstrates remarkable capacity ofXISTRNA to localize and comprehensively silence that autosome. Thus,XISTdoes not require X chromosome-specific sequences but operates on mechanisms available genome-wide. Prior results suggestedXISTlocalization is controlled by attachment to the insoluble nuclear scaffold. Our recent work affirms that scaffold attachment factor A (SAF-A) is involved in anchoringXIST, but argues against the view that SAF-A provides a unimolecular bridge between RNA and the chromosome. Rather, we suggest that a complex meshwork of architectural proteins interact withXISTRNA. Parallel work studying the territory of actively transcribed chromosomes suggests that repeat-rich RNA ‘coats’ euchromatin and may impact chromosome architecture in a manner opposite ofXIST. A model is discussed whereby RNA may not just recruit histone modifications, but more directly impact higher-order chromatin condensation via interaction with architectural proteins of the nucleus.

This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
Regulation of X-chromosome dosage compensation in human: mechanisms and model systems
Authors: Sahakyan Anna , Plath Kathrin , Rougeulle Claire
Published: September 2017

The human blastocyst forms 5 days after one of the smallest human cells (the sperm) fertilizes one of the largest human cells (the egg). Depending on the sex-chromosome contribution from the sperm, the resulting embryo will either be female, with two X chromosomes (XX), or male, with an X and a Y chromosome (XY). In early development, one of the major differences between XX female and XY male embryos is the conserved process of X-chromosome inactivation (XCI), which compensates gene expression of the two female X chromosomes to match the dosage of the single X chromosome of males. Most of our understanding of the pre-XCI state and XCI establishment is based on mouse studies, but recent evidence from human pre-implantation embryo research suggests that many of the molecular steps defined in the mouse are not conserved in human. Here, we will discuss recent advances in understanding the control of X-chromosome dosage compensation in early human embryonic development and compare it to that of the mouse.

This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
What makes the maternal X chromosome resistant to undergoing imprinted X inactivation?
Authors: Sado Takashi
Published: September 2017

In the mouse, while either X chromosome is chosen for inactivation in a random fashion in the embryonic tissue, the paternally derived X chromosome is preferentially inactivated in the extraembryonic tissues. It has been shown that the maternal X chromosome is imprinted so as not to undergo inactivation in the extraembryonic tissues. X-linked noncodingXistRNA becomes upregulated on the X chromosome that is to be inactivated. An antisense noncoding RNA,Tsix, which occurs at theXistlocus and has been shown to negatively regulateXistexpression in cis, is imprinted to be expressed from the maternal X in the extraembryonic tissues. AlthoughTsixappears to be responsible for the imprint laid on the maternal X, those who disagree with this idea would point out the fact thatTsixhas not yet been expressed from the maternal X whenXistbecomes upregulated on the paternal but not the maternal X at the onset of imprinted X-inactivation in preimplantation embryos. Recent studies have demonstrated, however, that there is a prominent difference in the chromatin structure at theXistlocus depending on the parental origin, which I suggest might account for the repression of maternalXistin the absence of maternalTsixat the preimplantation stages.

This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
Visualization of the lymphocytic choriomeningitis mammarenavirus (LCMV) genome reveals the early endosome as a possible site for genome replication and viral particle  pre-assembly
Authors: King Benjamin R. , Kellner Samuel , Eisenhauer Philip L. , Bruce Emily A. , Ziegler Christopher M. , Zenklusen Daniel , Botten Jason William
Published: September 2017

We report a fluorescence in situ hybridization (FISH) assay that allows the visualization of lymphocytic choriomeningitis mammarenavirus (LCMV) genomic RNAs in individual cells. We show that viral S segment genomic and antigenomic RNA, along with viral nucleoprotein, colocalize in subcellular structures we presume to be viral replication factories. These viral RNA structures are highly dynamic during acute infection, with the many small foci seen early coalescing into larger perinuclear foci later in infection. These late-forming perinuclear viral RNA aggregates are located near the cellular microtubule organizing centre and colocalize with the early endosomal marker Rab5c and the viral glycoprotein in a proportion of infected cells. We propose that the virus is using the surface of a cellular membrane-bound organelle as a site for the pre-assembly of viral components, including genomic RNA and viral glycoprotein, prior to their transport to the plasma membrane, where new particles will bud.
Sensory neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering
Authors: Krols Michiel , Detry Sammy , Asselbergh Bob , Almeida-Souza Leonardo , Kremer Anna , Lippens Saskia , Rycke Riet de , Winter Vicky De , Müller Franz-Josef , Kurth Ingo , McMahon Harvey T. , Savvides Savvas N. , Timmerman Vincent , Janssens Sophie
Published: September 2017

The ER is a complex network of sheets and tubules that is continuously being remodeled. The relevance of this membrane dynamics is underscored by the fact that mutations in Atlastins (ATL), the ER fusion proteins in mammals, cause neurodegeneration. How defects in this process disrupt neuronal homeostasis is largely unknown. Here we show by EM volume reconstruction of transfected cells, neurons and patient fibroblasts that the HSAN-causing ATL3 mutants promote aberrant ER tethering hallmarked by bundles of laterally attached ER tubules.In vitro, these mutants cause excessive liposome tethering, recapitulating the results in cells. Moreover, ATL3 variants retain their dimerization-dependent GTPase activity, but are unable to promote membrane fusion, suggesting a defect on an intermediate step of the ATL3 functional cycle. Our data therefore show that the effects of ATL3 mutations on ER network organization stretch beyond a loss of fusion, shedding a new light on neuropathies caused by atlastin defects.
Dual-trait pleiotropic analysis in highly stratified natural populations using genome-wide association summary statistics
Authors: Feng Xiao , Zan Yanjun , Ning Zheng , Xu Weilin , Wan Qianhui , Zeng Dongyu , Zeng Ziyi , Liu Yang , Shen Xia
Published: September 2017

Genome-wide association analysis is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset ofArabidopsis thaliana. We demonstrate the efficiency of double-phenotype analysisto uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, acommon allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate geneAT1G11560that potentially causes this association. Further analysis indicates that this locusis co-selected with flowering-time-related genes. The discovered pleiotropic genotypephenotype map provides new insights into understanding the genetic correlation of complex traits.
Natural changes in light interact with circadian regulation at promoters to control gene expression in cyanobacteria
Authors: Piechura Joseph R. , Amarnath Kapil , O’Shea Erin K.
Published: September 2017

The circadian clock interacts with other regulatory pathways to tune physiology to predictable daily changes and unexpected environmental fluctuations. However, the complexity of circadian clocks in higher organisms has prevented a clear understanding of how natural environmental conditions affect circadian clocks and their physiological outputs. Here, we dissect the interaction between circadian regulation and responses to fluctuating light in the cyanobacteriumSynechococcus elongatus. We demonstrate that natural changes in light intensity substantially affect the expression of hundreds of circadian-clock-controlled genes, many of which are involved in key steps in metabolism. These changes in expression arise from control of RNA polymerase recruitment to promoters by circadian and light-responsive regulation of a network of transcription factors including RpaA and RpaB. Using phenomenological modeling constrained by our data, we reveal simple principles that underlie the small number of stereotyped responses of dusk circadian genes to changes in light.
Reprogramming, oscillations and transdifferentiation in epigenetic landscapes
Authors: Kaity Bivash , Sarkar Ratan , Chakrabarti Buddhapriya , Mitra Mithun K.
Published: September 2017

Waddington’s epigenetic landscape provides a phenomenological understanding of the cell differentiation pathways from the pluripotent to mature lineage-committed cell lines. In light of recent successes in the reverse programming process there has been significant interest in quantifying the underlying landscape picture through the mathematics of gene regulatory networks. We investigate the role of time delays arising from multistep chemical reactions and epigenetic rearrangement on the cell differentiation landscape for a realistic two-gene regulatory network, consisting of selfpromoting and mutually inhibiting genes. Our work provides the first theoretical basis of the transdifferentiation process in the presence of delays, where one differentiated cell type can transition to another directly without passing through the undifferentiated state. Additionally, the interplay of time-delayed feedback and a time dependent chemical drive leads to long-lived oscillatory states in appropriate parameter regimes. This work emphasizes the important role played by time-delayed feedback loops in gene regulatory circuits and provides a framework for the characterization of epigenetic landscapes.
7′-Nitro-6′-phenyl-1′,6′,7′,7a′-tetrahydro-spiro[indeno[1,2-b]quinoxaline-11,5′-pyrrolo[1,2-c][1,3]thiazole]
Authors: Muthuselvi C. , Muthu M. , Athimoolam S. , Ravikumar B. , Pandiarajan S. , Krishnakumar R. V.
Published: September 2017

In the title compound, C26H20N4O2S, the thiazole and pyrrolidine rings adopt envelope conformations with the respective flap atoms being the N atom and the nitro-bearing C atom. The phenyl and indenoquinoxaline planes are oriented at an angle of 66.72 (1)° to each other. The molecular structure features two intramolecular interactions,viz. C—H...N and C—H...O. In the crystal, the molecules are connected through C—H...N and C—H...O interactions, forming ring motifs [twoR21(7),R22(14),R22(22) andR22(16)]. These ring motifs are connected through aC(9) motif chain.
Lactose crystallisation in concentrated whey: the influence of vat type
Authors: Simeão Moisés , DA Silva Cleuber R , Stephani Rodrigo , de Oliveira Luiz Fernando C , Schuck Pierre , de Carvalho Antônio F , Perrone Ítalo T
Published: September 2017

This work aimed to describe the rate of lactose crystallisation in concentrated whey carried out using two different crystallisers, utilising central or lateral stirring. The lactose crystallisation rate differed between treatments, showing high values with use of the central stirrer. Under the experimental conditions, after 4 h of crystallisation, in neither of the vats was 70% lactose crystallisation achieved. With the standardised conditions applied in this study, with soluble solids, time, and stirring and rate cooling being constant, it was possible to verify the influence of the vat type on the rate of lactose crystallisation.
Differential protein‐coding gene and long noncoding RNA expression in smoking‐related lung squamous cell carcinoma
Authors: Li Shicheng , Sun Xiao , Miao Shuncheng , Liu Jia , Jiao Wenjie
Published: September 2017

Background

Cigarette smoking is one of the greatest preventable risk factors for developing cancer, and most cases of lung squamous cell carcinoma (lung SCC) are associated with smoking. The pathogenesis mechanism of tumor progress is unclear. This study aimed to identify biomarkers in smoking‐related lung cancer, including protein‐coding gene, long noncoding RNA, and transcription factors.

Methods

We selected and obtained messenger RNA microarray datasets and clinical data from the Gene Expression Omnibus database to identify gene expression altered by cigarette smoking. Integrated bioinformatic analysis was used to clarify biological functions of the identified genes, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, the construction of a protein–protein interaction network, transcription factor, and statistical analyses. Subsequent quantitative real‐time PCR was utilized to verify these bioinformatic analyses.

Results

Five hundred and ninety‐eight differentially expressed genes and 21 long noncoding RNA were identified in smoking‐related lung SCC. GO and KEGG pathway analysis showed that identified genes were enriched in the cancer‐related functions and pathways. The protein–protein interaction network revealed seven hub genes identified in lung SCC. Several transcription factors and their binding sites were predicted. The results of real‐time quantitative PCR revealed that AURKA and BIRC5 were significantly upregulated and LINC00094 was downregulated in the tumor tissues of smoking patients. Further statistical analysis indicated that dysregulation of AURKA, BIRC5, and LINC00094 indicated poor prognosis in lung SCC.

Conclusion

Protein‐coding genes AURKA, BIRC5, and LINC00094 could be biomarkers or therapeutic targets for smoking‐related lung SCC.
Alternative Markers of Performance in Simulation: Where We Are and Where We Need To Go
Authors: Willemsen‐Dunlap Ann M. , Binstadt Emily S. , Nguyen Michael C. , Elliott Nicole C. , Cheney Alan R. , Stevens Ronald H. , Dooley‐Hash Suzanne
Published: September 2017

This article on alternative markers of performance in simulation is the product of a session held during the 2017 Academic Emergency Medicine Consensus Conference “Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes.” There is a dearth of research on the use of performance markers other than checklists, holistic ratings, and behaviorally anchored rating scales in the simulation environment. Through literature review, group discussion, and consultation with experts prior to the conference, the working group defined five topics for discussion: 1) establishing a working definition for alternative markers of performance, 2) defining goals for using alternative performance markers, 3) implications for measurement when using alternative markers, identifying practical concerns related to the use of alternative performance markers, and 5) identifying potential for alternative markers of performance to validate simulation scenarios. Five research propositions also emerged and are summarized.
Primary thromboprophylaxis (PTP) in ambulatory patients with lung cancer receiving chemotherapy: A systematic review and meta‐analysis of randomized controlled trials (RCTs)
Authors: Thein Kyaw Zin , Yeung Sai‐Ching J. , Oo Thein Hlaing
Published: September 2017

Background

Thromboembolism (TE) is a leading cause of death in cancer patients. Primary thromboprophylaxis (PTP) in ambulatory cancer patients receiving chemotherapy has been debated and considered to potentially improve survival by reducing TE occurrence.

Objective

We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) in ambulatory lung cancer (LC) patients on chemotherapy to determine the benefit and risk of PTP with low‐molecular‐weight heparins (LMWHs).

Method

A literature search using MEDLINE and EMBASE databases was performed through June 2016. RCTs with venous thromboembolism (VTE) reduction as primary or secondary endpoints were included. Mantel–Haenszel method was used to estimate the pooled event risk ratio as well as pooled absolute risk difference with 95% confidence interval (CI).

Result

A total of 4315 LC patients from six studies were available for analysis. PTP lasted for 4 to 6 months. The venous thromboembolism (VTE) incidence was 4.0% and 7.9% in LMWH and control groups, respectively (risk ratio, 0.510 (95% CI, 0.397–0.654, P < 0.001). The absolute risk difference in VTE was −0.039 (95% CI, −0.053 to −0.025, P < 0.001), with an estimated number needed to treat (NNT) of 25 to prevent one VTE event. The pooled risk ratio for major bleeding was 1.468 (95% CI, 0.785–2.746, P = 0.229). The pooled risk ratio for overall survival was statistically nonsignificant at 1.020 (95% CI, 0.938–1.109, P = 0.648).

Conclusion

Routine PTP for ambulatory LC patients receiving chemotherapy is not recommended and further studies are necessary to define a subset of ambulatory LC patients receiving chemotherapy who may benefit from PTP.
Distinct peripheral vs mucosal T‐cell phenotypes in chlamydia‐infected women
Authors: Ogendi Brian M. O. , Bakshi Rakesh K. , Sabbaj Steffanie , Brown LaDraka' , Lee Jeannette Y. , Kapil Richa , Geisler William M.
Published: September 2017

Problem

Differences in circulating (peripheral) and mucosal T‐cell phenotypes in chlamydia‐infected women remain largely unknown.

Method of study

Thirteen paired mononuclear cell specimens from blood and cervicovaginal lavages collected from chlamydia‐infected women were stained and analyzed using ten‐color cell surface flow cytometry for T‐cell distribution, activation status, homing, and T helper (Th)‐associated chemokine receptors (CKRs).

Results

A higher proportion of genital mucosal T‐cells were activated (CD38+HLA‐DR+) and expressed CCR5 and Th1‐associated CKR CXCR3+CCR5+ compared to peripheral T‐cells, but a lower proportion of mucosal T‐cells expressed homing CKR CCR7, Th‐2 associated CKR CCR4, and CXCR3+CCR4+ for both T‐cell subsets.

Conclusion

T‐cell phenotypes differed in the peripheral vs genital mucosa compartments in chlamydia‐infected women. As chlamydia infects mucosal epithelial cells, the finding of a higher frequency of activated T‐cells and Th‐1 phenotypes in the mucosa likely reflects an adaptive immune response to infection.
Informing Aerial Total Counts with Demographic Models: Population Growth of Serengeti Elephants Not Explained Purely by Demography
Authors: Morrison Thomas A. , Estes Anna B. , Mduma Simon A.R. , Maliti Honori T. , Frederick Howard , Kija Hamza , Mwita Machoke , Sinclair A.R.E. , Kohi Edward M.
Published: September 2017

Conservation management is strongly shaped by the interpretation of population trends. In the Serengeti ecosystem, Tanzania, aerial total counts indicate a striking increase in elephant abundance compared to all previous censuses. We developed a simple age‐structured population model to guide interpretation of this reported increase, focusing on three possible causes: (1) in situ population growth, (2) immigration from Kenya, and (3) differences in counting methodologies over time. No single cause, nor the combination of two causes, adequately explained the observed population growth. Under the assumptions of maximum in situ growth and detection bias of 12.7% in previous censuses, conservative estimates of immigration from Kenya were between 250 and 1,450 individuals. Our results highlight the value of considering demography when drawing conclusions about the causes of population trends. The issues we illustrate apply to other species that have undergone dramatic changes in abundance, as well as many elephant populations.
Liraglutide and cardiovascular outcomes in adults with overweight or obesity: Apost hoc analysis from SCALE randomized controlled trials
Authors: Davies M. J. , Aronne L. J. , Caterson I. D. , Thomsen A. B. , Jacobsen P. B. , Marso S. P. ,   on behalf of the Satiety and Clinical Adiposity – Liraglutide Evidence in individuals with and without diabetes (SCALE) study groups
Published: September 2017

The cardiovascular safety of liraglutide, a glucagon‐like peptide‐1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double‐blind, placebo‐controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time‐to‐event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person‐years) compared to 10 participants in the comparators group (3.65 events/1000 person‐years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17‐1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis.
A biologically inspired neurocomputational model for audiovisual integration and causal inference
Authors: Cuppini Cristiano , Shams Ladan , Magosso Elisa , Ursino Mauro
Published: September 2017

Recently, experimental and theoretical research has focused on the brain's abilities to extract information from a noisy sensory environment and how cross‐modal inputs are processed to solve the causal inference problem to provide the best estimate of external events. Despite the empirical evidence suggesting that the nervous system uses a statistically optimal and probabilistic approach in addressing these problems, little is known about the brain's architecture needed to implement these computations. The aim of this work was to realize a mathematical model, based on physiologically plausible hypotheses, to analyze the neural mechanisms underlying multisensory perception and causal inference. The model consists of three layers topologically organized: two encode auditory and visual stimuli, separately, and are reciprocally connected via excitatory synapses and send excitatory connections to the third downstream layer. This synaptic organization realizes two mechanisms of cross‐modal interactions: the first is responsible for the sensory representation of the external stimuli, while the second solves the causal inference problem. We tested the network by comparing its results to behavioral data reported in the literature. Among others, the network can account for the ventriloquism illusion, the pattern of sensory bias and the percept of unity as a function of the spatial auditory–visual distance, and the dependence of the auditory error on the causal inference. Finally, simulations results are consistent with probability matching as the perceptual strategy used in auditory–visual spatial localization tasks, agreeing with the behavioral data. The model makes untested predictions that can be investigated in future behavioral experiments.
Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population‐based cohort
Authors: Aaberg Kari Modalsli , Surén Pål , Søraas Camilla Lund , Bakken Inger Johanne , Lossius Morten I. , Stoltenberg Camilla , Chin Richard
Published: September 2017

Objective

The study provides updated information about the distribution of seizures, epilepsies, and etiologies of epilepsy in the general child population, and compares the old and new classification systems from the International League Against Epilepsy (ILAE).

Methods

The study platform was the Norwegian Mother and Child Cohort Study. Cases of epilepsy were identified through registry linkages and sequential parental questionnaires. Epilepsy diagnoses were validated using a standardized protocol, and seizures, epilepsies, and etiologies were classified according to the old (ILAE 1981/1989) and new (ILAE 2017) classifications. Information was collected through medical record reviews and/or parental telephone interviews.

Results

The study population included 112,744 children aged 3–13 years at the end of follow‐up on December 31, 2012. Of these, there were 606 children with epilepsy (CWE). Distribution of seizure types varied by age of onset. Multiple seizure types were common with early onset. Focal epilepsies were the most common, occurring in 317 per 100,000 children in the study population and in 59% of CWE. Generalized epilepsies were found in 190 per 100,000 (35% of CWE). CWE with onset during the first 2 years of life had an even distribution of focal and generalized epilepsies, whereas focal epilepsies became dominant at later ages of onset. A definite cause of epilepsy had been demonstrated in 33% of CWE. The ILAE 1989 classification allowed for a broad syndrome category in 93% of CWE and a defined epileptic syndrome in 37%. With the ILAE 2017 classification, 41% of CWE had a defined epileptic syndrome and 63% had either a defined syndrome or structural–metabolic etiology.

Significance

The distribution of seizures and epilepsies is strongly dependent on age of onset. Despite diagnostic advances, the causes of epilepsy are still unknown in two‐thirds of CWE. The ILAE 2017 classifications allow for a higher precision of diagnoses, but at the expense of leaving more epilepsies classifiable only at the mode of onset level.