bluuebunny/crossref_metadata_2025 huggingface dataset:
Palkhi: a moving sacred town.
Authors: Shinde K. A.
Published: June 2018

This chapter begins with an overview of the Dnyaneshwar palkhi (a pilgrimage procession in Maharashtra), looking at its meaning and history, as well as its organization. The chapter then looks at how the palkhi is akin to a sacred moving town, where normally regular or mundane space becomes, at least temporarily, sacred space. Finally, the chapter addresses a number of issues arising from the rise in popularity of the palkhi, including environment and sanitation issues and the social problems that arise as traditional stopping places along the pilgrimage route are changing because of the need for larger spaces to accommodate more pilgrims.
Pilgrimage and identity along the mormon trail.
Authors: Olsen D. H. , Hill B. J.
Published: June 2018

This chapter examines the historical and present development of the Mormon Trail in the USA. After giving a brief history of The Church of Jesus Christ of Latter-day Saints and its move to modern-day Utah, the chapter looks at the present development and use of the Mormon Trail, including stakeholder, environmental and economic development concerns. The chapter then looks more in-depth at the importance of the Mormon Trail in the development of Latter-day Saint identity and historical consciousness.
Assisted interventions involving animals, humans and the environment.
Authors: Pinillos R. G.
Published: June 2018

This book chapter discusses the One Welfare framework which describes those activities involving animals, humans and the environment that involve a need for support, rehabilitation and managed animal rehoming programmes. It highlights and encourages forms of such work that take into consideration the benefits for all the parties involved.
Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43
Authors: Kam Chen Yuan , Dubash Adi D. , Magistrati Elisa , Polo Simona , Satchell Karla J.F. , Sheikh Farah , Lampe Paul D. , Green Kathleen J.
Published: June 2018

Desmoplakin (DP) is an obligate component of desmosomes, intercellular adhesive junctions that maintain the integrity of the epidermis and myocardium. Mutations in DP can cause cardiac and cutaneous disease, including arrhythmogenic cardiomyopathy (ACM), an inherited disorder that frequently results in deadly arrhythmias. Conduction defects in ACM are linked to the remodeling and functional interference with Cx43-based gap junctions that electrically and chemically couple cells. How DP loss impairs gap junctions is poorly understood. We show that DP prevents lysosomal-mediated degradation of Cx43. DP loss triggered robust activation of ERK1/2–MAPK and increased phosphorylation of S279/282 of Cx43, which signals clathrin-mediated internalization and subsequent lysosomal degradation of Cx43. RNA sequencing revealed Ras-GTPases as candidates for the aberrant activation of ERK1/2 upon loss of DP. Using a novel Ras inhibitor, Ras/Rap1-specific peptidase (RRSP), or K-Ras knockdown, we demonstrate restoration of Cx43 in DP-deficient cardiomyocytes. Collectively, our results reveal a novel mechanism for the regulation of the Cx43 life cycle by DP in cardiocutaneous models.
Time-resolved transcriptomics in neural stem cells identifies a v-ATPase/Notch regulatory loop
Authors: Wissel Sebastian , Harzer Heike , Bonnay François , Burkard Thomas R. , Neumüller Ralph A. , Knoblich Juergen A.
Published: June 2018

Drosophila melanogaster neural stem cells (neuroblasts [NBs]) divide asymmetrically by differentially segregating protein determinants into their daughter cells. Although the machinery for asymmetric protein segregation is well understood, the events that reprogram one of the two daughter cells toward terminal differentiation are less clear. In this study, we use time-resolved transcriptional profiling to identify the earliest transcriptional differences between the daughter cells on their way toward distinct fates. By screening for coregulated protein complexes, we identify vacuolar-type H+–ATPase (v-ATPase) among the first and most significantly down-regulated complexes in differentiating daughter cells. We show that v-ATPase is essential for NB growth and persistent activity of the Notch signaling pathway. Our data suggest that v-ATPase and Notch form a regulatory loop that acts in multiple stem cell lineages both during nervous system development and in the adult gut. We provide a unique resource for investigating neural stem cell biology and demonstrate that cell fate changes can be induced by transcriptional regulation of basic, cell-essential pathways.
All four subunits of HCN2 channels contribute to the activation gating in an additive but intricate manner
Authors: Sunkara Mallikarjuna Rao , Schwabe Tina , Ehrlich Gunter , Kusch Jana , Benndorf Klaus
Published: June 2018

Hyperpolarization-activated cyclic nucleotide–modulated (HCN) channels are tetramers that elicit electrical rhythmicity in specialized brain neurons and cardiomyocytes. The channels are dually activated by voltage and binding of cyclic adenosine monophosphate (cAMP) to their four cyclic nucleotide-binding domains (CNBDs). Here we analyze the effects of cAMP binding to different concatemers of HCN2 channel subunits, each having a defined number of functional CNBDs. We show that each liganded CNBD promotes channel activation in an additive manner and that, in the special case of two functional CNBDs, functionality does not depend on the arrangement of the subunits. Correspondingly, the reverse process of deactivation is slowed by progressive liganding, but only if four and three ligands as well as two ligands in trans position (opposite to each other) are bound. In contrast, two ligands bound in cis positions (adjacent to each other) and a single bound ligand do not affect channel deactivation. These results support an activation mechanism in which each single liganded CNBD causes a turning momentum on the tetrameric ring-like structure formed by all four CNBDs and that at least two liganded subunits in trans positions are required to maintain activation.
Agricultural Water Allocation under Uncertainty: Redistribution of Water Shortage Risk
Authors: Li Man , Xu Wenchao , Zhu Tingju
Published: June 2018

This article develops an economic model to analyze how the risk of water shortages affects farmers’ land irrigation decision and how the priority‐based water sharing arrangement redistributes such a risk among farms with different water rights priorities. The analysis brings together an array of comprehensive data files on irrigation rights, water supplies, and agricultural land use from eastern Idaho. Results indicate that a more left‐skewed distribution of streamflow significantly discourages land irrigation among farmers except the most senior rights holders. The priority‐based water sharing arrangement redistributes the macroscale risk of water shortages and thus exposes farmers of different water rights priorities to heterogeneous levels of risk: senior water rights holders are affected the least and such a risk is instead passed mostly on to junior water rights holders. The role of water rights in risk redistribution is more significant when the probability distribution of water shortage risk is asymmetric rather than symmetric. The historical development pattern of water rights influences how the priority of water rights takes effect on land irrigation decision.
NeoDTI: neural integration of neighbor information from a heterogeneous network for discovering new drug–target interactions
Authors: Wan Fangping , Hong Lixiang , Xiao An , Jiang Tao , Zeng Jianyang
Published: June 2018

Motivation

Accurately predicting drug–target interactions (DTIs) in silico can guide the drug discovery process and thus facilitate drug development. Computational approaches for DTI prediction that adopt the systems biology perspective generally exploit the rationale that the properties of drugs and targets can be characterized by their functional roles in biological networks.

Results

Inspired by recent advance of information passing and aggregation techniques that generalize the convolution neural networks to mine large-scale graph data and greatly improve the performance of many network-related prediction tasks, we develop a new nonlinear end-to-end learning model, called NeoDTI, that integrates diverse information from heterogeneous network data and automatically learns topology-preserving representations of drugs and targets to facilitate DTI prediction. The substantial prediction performance improvement over other state-of-the-art DTI prediction methods as well as several novel predicted DTIs with evidence supports from previous studies have demonstrated the superior predictive power of NeoDTI. In addition, NeoDTI is robust against a wide range of choices of hyperparameters and is ready to integrate more drug and target related information (e.g. compound–protein binding affinity data). All these results suggest that NeoDTI can offer a powerful and robust tool for drug development and drug repositioning.

Availability and implementation

The source code and data used in NeoDTI are available at: https://github.com/FangpingWan/NeoDTI.

Supplementary information

Supplementary data are available at Bioinformatics online.
lordFAST: sensitive and Fast Alignment Search Tool for LOng noisy Read sequencing Data
Authors: Haghshenas Ehsan , Sahinalp S Cenk , Hach Faraz
Published: June 2018

Motivation

Recent advances in genomics and precision medicine have been made possible through the application of high throughput sequencing (HTS) to large collections of human genomes. Although HTS technologies have proven their use in cataloging human genome variation, computational analysis of the data they generate is still far from being perfect. The main limitation of Illumina and other popular sequencing technologies is their short read length relative to the lengths of (common) genomic repeats. Newer (single molecule sequencing – SMS) technologies such as Pacific Biosciences and Oxford Nanopore are producing longer reads, making it theoretically possible to overcome the difficulties imposed by repeat regions. Unfortunately, because of their high sequencing error rate, reads generated by these technologies are very difficult to work with and cannot be used in many of the standard downstream analysis pipelines. Note that it is not only difficult to find the correct mapping locations of such reads in a reference genome, but also to establish their correct alignment so as to differentiate sequencing errors from real genomic variants. Furthermore, especially since newer SMS instruments provide higher throughput, mapping and alignment need to be performed much faster than before, maintaining high sensitivity.

Results

We introduce lordFAST, a novel long-read mapper that is specifically designed to align reads generated by PacBio and potentially other SMS technologies to a reference. lordFAST not only has higher sensitivity than the available alternatives, it is also among the fastest and has a very low memory footprint.

Availability and implementation

lordFAST is implemented in C++ and supports multi-threading. The source code of lordFAST is available at https://github.com/vpc-ccg/lordfast.

Supplementary information

Supplementary data are available at Bioinformatics online.
emeraLD: rapid linkage disequilibrium estimation with massive datasets
Authors: Quick Corbin , Fuchsberger Christian , Taliun Daniel , Abecasis Gonçalo , Boehnke Michael , Kang Hyun Min
Published: June 2018

Estimating linkage disequilibrium (LD) is essential for a wide range of summary statistics-based association methods for genome-wide association studies. Large genetic datasets, e.g. the TOPMed WGS project and UK Biobank, enable more accurate and comprehensive LD estimates, but increase the computational burden of LD estimation. Here, we describe emeraLD (Efficient Methods for Estimation and Random Access of LD), a computational tool that leverages sparsity and haplotype structure to estimate LD up to 2 orders of magnitude faster than current tools.

Availability and implementation

emeraLD is implemented in C++, and is open source under GPLv3. Source code and documentation are freely available at http://github.com/statgen/emeraLD.

Supplementary information

Supplementary data are available at Bioinformatics online.
A maximum likelihood approach to power calculations for stepped wedge designs of binary outcomes
Authors: Zhou Xin , Liao Xiaomei , Kunz Lauren M , Normand Sharon-Lise T , Wang Molin , Spiegelman Donna
Published: June 2018

In stepped wedge designs (SWD), clusters are randomized to the time period during which new patients will receive the intervention under study in a sequential rollout over time. By the study’s end, patients at all clusters receive the intervention, eliminating ethical concerns related to withholding potentially efficacious treatments. This is a practical option in many large-scale public health implementation settings. Little statistical theory for these designs exists for binary outcomes. To address this, we utilized a maximum likelihood approach and developed numerical methods to determine the asymptotic power of the SWD for binary outcomes. We studied how the power of a SWD for detecting risk differences varies as a function of the number of clusters, cluster size, the baseline risk, the intervention effect, the intra-cluster correlation coefficient, and the time effect. We studied the robustness of power to the assumed form of the distribution of the cluster random effects, as well as how power is affected by variable cluster size. % SWD power is sensitive to neither, in contrast to the parallel cluster randomized design which is highly sensitive to variable cluster size. We also found that the approximate weighted least square approach of Hussey and Hughes (2007, Design and analysis of stepped wedge cluster randomized trials. Contemporary Clinical Trials 28, 182–191) for binary outcomes under-estimates the power in some regions of the parameter spaces, and over-estimates it in others. The new method was applied to the design of a large-scale intervention program on post-partum intra-uterine device insertion services for preventing unintended pregnancy in the first 1.5 years following childbirth in Tanzania, where it was found that the previously available method under-estimated the power.
Causal inference in continuous time: an example on prostate cancer therapy
Authors: Ryalen Pål Christie , Stensrud Mats Julius , Fosså Sophie , Røysland Kjetil
Published: June 2018

In marginal structural models (MSMs), time is traditionally treated as a discrete parameter. In survival analysis on the other hand, we study processes that develop in continuous time. Therefore, Røysland (2011. A martingale approach to continuous-time marginal structural models. Bernoulli 17, 895–915) developed the continuous-time MSMs, along with continuous-time weights. The continuous-time weights are conceptually similar to the inverse probability weights that are used in discrete time MSMs. Here, we demonstrate that continuous-time MSMs may be used in practice. First, we briefly describe the causal model assumptions using counting process notation, and we suggest how causal effect estimates can be derived by calculating continuous-time weights. Then, we describe how additive hazard models can be used to find such effect estimates. Finally, we apply this strategy to compare medium to long-term differences between the two prostate cancer treatments radical prostatectomy and radiation therapy, using data from the Norwegian Cancer Registry. In contrast to the results of a naive analysis, we find that the marginal cumulative incidence of treatment failure is similar between the strategies, accounting for the competing risk of other death.
Emerging from the reds, greens and stripped screws: a communal healing process
Authors: van der Watt Phia
Published: June 2018

The article posits that the field of community development does not adequately engage with intergenerational communal wounding. A family support programme, developed in vulnerable communities in South Africa, was used as case study to investigate the feasibility of healing within community development. The articulation of a clear storyline to guide the process was identified as critical. The programme’s storyline unfolded in four episodes: facing the past (reds and greens); exploring current manifestations thereof (labels, secrets, obscured desires and projections); naming debilitating problems (the screws) to elicit a yearning for healing and action and creating new life stories. Reflection and mirroring through group work were identified as critical elements in this approach. The study concludes that while participants originally accepted the (false) messages/images resulting from oppression and discrimination uncritically, a more authentic self gradually emerged, which directed transformative action (underscoring the Freirean concept of conscientisation). The study invites further debate/research on issues, such as personal healing within group context; the dilemma of risk-and-failure; the slow nature of healing versus organisational demands; and the balance between promises for material improvement and healing. The study shows that communal healing work is both feasible and critically needed within the community development context and offers a practical way to realise this.
Synaptic Mechanisms for Bandwidth Tuning in Awake Mouse Primary Auditory Cortex
Authors: Li Haifu , Liang Feixue , Zhong Wen , Yan Linqing , Mesik Lucas , Xiao Zhongju , Tao Huizhong W , Zhang Li I
Published: June 2018

Spatial size tuning in the visual cortex has been considered as an important neuronal functional property for sensory perception. However, an analogous mechanism in the auditory system has remained controversial. In the present study, cell-attached recordings in the primary auditory cortex (A1) of awake mice revealed that excitatory neurons can be categorized into three types according to their bandwidth tuning profiles in response to band-passed noise (BPN) stimuli: nonmonotonic (NM), flat, and monotonic, with the latter two considered as non-tuned for bandwidth. The prevalence of bandwidth-tuned (i.e., NM) neurons increases significantly from layer 4 to layer 2/3. With sequential cell-attached and whole-cell voltage-clamp recordings from the same neurons, we found that the bandwidth preference of excitatory neurons is largely determined by the excitatory synaptic input they receive, and that the bandwidth selectivity is further enhanced by flatly tuned inhibition observed in all cells. The latter can be attributed at least partially to the flat tuning of parvalbumin inhibitory neurons. The tuning of auditory cortical neurons for bandwidth of BPN may contribute to the processing of complex sounds.
The structure of a recent nova shell as observed by ALMA
Authors: Diaz Marcos P , Abraham Zulema , Ribeiro Valério A R M , Beaklini Pedro P B , Takeda Larissa
Published: June 2018

High resolution ALMA observations of the recent (2.52 yr old) shell of Nova V5668 Sgr (2015) show a highly structured ionized gas distribution with small (1015 cm) clumps. These are the smallest structures ever observed in the remnant of a stellar thermonuclear explosion. No extended contiguous emission could be found above the 2.5σ level in our data, while the peak hydrogen densities in the clumps reach 106 cm−3. The millimetre continuum image suggests that large scale structures previously distinguished in other recent nova shells may result from the distribution of bright unresolved condensations.
Arabic Dialectology
Authors: Behnstedt Peter , Woidich Manfred
Published: June 2018

Geographically, Arabic is one of the most widespread languages of the world, and Arabic dialects are spoken in an unbroken expanse from western Iran to Mauritania and Morocco and from Oman to northeastern Nigeria, albeit with vast uninhabited or scarcely inhabited areas and deserts in between. It is not easy to give the exact number of speakers, estimates from 1999 (i.e., from eighteen years ago) count 206 million L1 speakers, a figure which today seems too low rather than too high.1 This geographical range is marked by extreme dialectal differences in all fields of phonology, grammar, and lexicon, at times to the extent that different varieties are mutually unintelligible.
The Hostile Media Effect
Authors: Feldman Lauren
Published: June 2018

The “hostile media effect” occurs when opposing partisans perceive identical news coverage of a controversial issue as biased against their own side. This is a robust phenomenon, which has been empirically demonstrated in numerous experimental and observational studies across a variety of issue contexts and has been shown to have important consequences for democratic society. This chapter reviews the literature on the hostile media effect with an eye toward the theoretical explanations for it, its relationship to other psychological processes, and its broader implications for perceived public opinion, news consumption patterns, attitudes toward democratic institutions, and political discourse and participation. Particular attention is paid to how the hostile media phenomenon can help explain the public’s eroding trust in the news media and the recent polarization among news audiences. The chapter concludes with several suggestions for future research.
Online News Consumption in the United States and Ideological Extremism
Authors: Winneg Kenneth M. , Butler Daniel M. , Golde Saar , Miller Darwin W. , Nie Norman H.
Published: June 2018

In an earlier study, the authors found evidence that supported a framework predicting that consumers of Internet news sources held more extreme political views and were interested in more diverse political issues than those who solely consume mainstream television news using data covering the period April 2000 to June 2007. In this essay, they test whether the same patterns hold using data from the 2008 National Annenberg Election Survey online panel conducted during the 2008 presidential election cycle. The authors combine insights from theories of selective media exposure from political communication and social psychology with economic theories of differentiated products markets to develop a theoretical framework for understanding how the Internet continues to impact the U.S. political news market. The driving force behind this framework is the dramatically lower cost of production for Internet news sources relative to traditional television news.
Theories and Effects of Political Humor
Authors: Young Dannagal G.
Published: June 2018

As both an art form and a mode of persuasive discourse, the use of political humor dates back to ancient Greece and Rome. For centuries politicians, citizens, and elites have marveled at and even feared its powerful—and magical—influence on public opinion. By reflecting on various approaches to the study of political humor’s content, audience, and impact, this chapter offers scholars multiple ways to consider the effects of political humor on individuals and society. It culminates with a consideration of the latest advances in the study of political humor and humor theory and poses challenges to those in the field to better explicate micro-level processes that incorporate structural elements of the text and characteristics of the audience.
Theories of Media Bias
Authors: Lichter S. Robert
Published: June 2018

Ideological or partisan media bias is widely debated despite disagreement about its meaning, measurement, and impact. The assumption that news should be objective is itself the object of considerable debate. Assertions of a conservative or establishment bias in the news often draw on critical theory, which argues that news preserves the hegemony of society’s ruling interests. Assertions of liberal bias draw on surveys of journalists’ attitudes and content analyses of news coverage. This case has recently been bolstered by economic modeling. However, numerous content analytic studies have failed to find a liberal bias. This has led to efforts to explain public perceptions of liberal bias in terms of cognitive psychology and elite manipulation. Other explanations include structural biases and media negativism. Internet-driven changes in journalism, including an increase in partisan news, may force a rethinking of the entire debate or even render it irrelevant.
Public and Elite Perceptions of News Media in Politics
Authors: Tsfati Yariv
Published: June 2018

This chapter provides an overview of the research on individual’s perceptions about and attitudes toward the news media. It discusses research on trust in media, hostile media perceptions, and perceptions of media influence, also known as third person perceptions. All three perceptions are shaped by both cognitive and self-enhancement mechanisms and all have important political consequences. The chapter argues that perceptions about the news media among the elite have largely been ignored by scholars but are consequential in shaping the political world. When politicians perceive that media are powerful, they react by initiating coverage and cooperating with the requests of journalists. When a certain issue is expected to receive substantial media attention, politicians react by initiating legislation or discussion about that topic. Thus, politicians’ perceptions of media the may be at the heart of a decades-long process of mediatization of politics.
The IMMUNE-ASSOCIATED NUCLEOTIDE-BINDING 9 Protein Is a Regulator of Basal Immunity in Arabidopsis thaliana
Authors: Wang Yuanzheng , Li Yansha , Rosas-Diaz Tabata , Caceres-Moreno Carlos , Lozano-Duran Rosa , Macho Alberto P.
Published: June 2018

A robust regulation of plant immune responses requires a multitude of positive and negative regulators that act in concert. The immune-associated nucleotide-binding (IAN) gene family members are associated with immunity in different organisms, although no characterization of their function has been carried out to date in plants. In this work, we analyzed the expression patterns of IAN genes and found that IAN9 is repressed upon pathogen infection or treatment with immune elicitors. IAN9 encodes a plasma membrane-localized protein that genetically behaves as a negative regulator of immunity. A novel ian9 mutant generated by CRISPR/Cas9 shows increased resistance to Pseudomonas syringae, while transgenic plants overexpressing IAN9 show a slight increase in susceptibility. In vivo immunoprecipitation of IAN9-green fluorescent protein followed by mass spectrometry analysis revealed that IAN9 associates with a previously uncharacterized C3HC4-type RING-finger domain-containing protein that we named IAN9-associated protein 1 (IAP1), which also acts as a negative regulator of basal immunity. Interestingly, neither ian9 or iap1 mutant plants show any obvious developmental phenotype, suggesting that they display enhanced inducible immunity rather than constitutive immune responses. Because both IAN9 and IAP1 have orthologs in important crop species, they could be suitable targets to generate plants more resistant to diseases caused by bacterial pathogens without yield penalty.
Classic SRY‐box protein SOX7 functions as a tumor suppressor regulating WNT signaling and is methylated in renal cell carcinoma
Authors: Wang Lu , Fan Yu , Zhang Lian , Li Lili , Kuang Guanyu , Luo Cheng , Li Chen , Xiang Tingxiu , Tao Qian , Zhang Qian , Ying Jianming
Published: June 2018

SOX7 (SRY‐related high mobility group box 7), a high mobility group protein, is reported to be down‐regulated in several cancer types, which indicates an important role in tumorigenesis; however, its biologic role in renal cell carcinoma (RCC) pathogenesis remains unknown. We studied the alterations and functions of SOX7 in RCC. We detected its broad expression in multiple human normal tissues, including kidney, but frequent down‐regulation in RCC cell lines and primary tumors. Promoter CpG methylation seems to directly mediate SOX7 silencing in RCC cells, which could be reversed by demethylation treatment. SOX7 methylation was detected in primary RCC tumors, but rarely in normal kidney tissues. Restoration of SOX7 in silenced 786‐O and A498 RCC cell lines inhibited their cell growth by inducing G0/G1 arrest, whereas SOX7 knockdown promoted RCC cell proliferation. We also found that SOX7 silencing resulted in the activation of WNT signaling and the induction of epithelial to mesenchymal transition. In conclusion, the current study demonstrates that SOX7 is frequently inactivated by promoter CpG methylation in RCC and functions as a tumor suppressor by regulating WNT signaling.—Wang, L., Fan, Y., Zhang, L., Li, L., Kuang, G., Luo, C., Li, C., Xiang, T., Tao, Q., Zhang, Q., Ying, J. Classic SRY‐box protein SOX7 functions as a tumor suppressor regulating WNT signaling and is methylated in renal cell carcinoma. FASEB J. 33, 254–263 (2019). www.fasebj.org
Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Muscedere John , Maslove David M. , Boyd J. Gordon , O’Callaghan Nicole , Sibley Stephanie , Reynolds Steven , Albert Martin , Hall Richard , Jiang Xuran , Day Andrew G. , Jones Gwyneth , Lamontagne Francois
Published: June 2018

Objective:

To obtain preliminary evidence for the efficacy of lactoferrin as a preventative measure for nosocomial infections and inform the conduct of a definitive study.

Design:

Phase 2, multicenter, randomized, double-blind, placebo-controlled study.

Setting:

Medical-surgical ICUs.

Patients:

Adult, critically ill patients receiving invasive mechanical ventilation.

Interventions:

Randomized, eligible, consenting patients expected to require invasive mechanical ventilation more than 48 hours received lactoferrin both enterally and via an oral swab or a placebo of sterile water for up to 28 days.

Measurements and Main Results:

Of the 214 patients who were randomized, 212 received at least one dose of the intervention and were analyzed (107 lactoferrin and 105 placebo). Protocol adherence was 87.5%. Patients receiving lactoferrin were older (mean [sd], 66.3 [13.5] vs 62.5 [16.2] yr), had a higher Acute Physiology and Chronic Health Evaluation II score (26.8 [7.8] vs 23.5 [7.9]), and need for vasopressors (79% vs 70%). Antibiotic-free days (17.3 [9.0] vs 18.5 [7.1]; p = 0.91) and nosocomial infections (0.3 [0.7] vs 0.4 [0.6] per patient; p = 0.48) did not differ between lactoferrin and placebo groups, respectively. Clinical outcomes for lactoferrin versus placebo were as follows: ICU length of stay (14.5 [18.0] vs 15.0 [37.3] d; p = 0.82), hospital length of stay (25.0 [25.9] vs 28.1 [44.6] d; p = 0.57), hospital mortality (41.1% vs 30.5%; p = 0.11), and 90-day mortality (44.9% vs 32.4%; p = 0.06). Biomarker levels did not differ between the groups.

Conclusions:

Lactoferrin did not improve the primary outcome of antibiotic-free days, nor any of the secondary outcomes. Our data do not support the conduct of a larger phase 3 trial.
Long-Term Outcomes of Women With Recurrent Vulvovaginal Candidiasis After a Course of Maintenance Antifungal Therapy
Authors: Crouss Tess , Sobel Jack D. , Smith Katharine , Nyirjesy Paul
Published: June 2018

Objectives

Data about long-term clinical outcome after a course of maintenance fluconazole in those with recurrent vulvovaginal candidiasis (RVVC) is lacking. We aimed to determine the rate of recurrence at a minimum of 6 months after completion of maintenance therapy.

Methods

A retrospective analysis of women with Candida albicans RVVC from January 2008 to January 2017 was performed using chart review to obtain information about recurrence after maintenance therapy. Patients were considered resolved if they had no further episodes of candidiasis, sporadic with less than 3 episodes yearly and ongoing with greater than 3 episodes yearly.

Results

Approximately 1,672 patients with C. albicans vaginal isolates were identified. Of these, 201 met the criteria for RVVC. The mean age was 40.4 years; 151 (77.4%) were white, 133 (66.2%) had comorbid vulvar conditions, and 76 (37.8%) had a risk factor for vulvovaginal candidiasis. One hundred twenty complete charts were further analyzed. The mean length of follow-up after discontinuing maintenance therapy was 39.9 months. After the initial course, 23 (19.2%), 21 (17.5%), and 76 (63.3%) were resolved, sporadic and ongoing, respectively. Risk factors, comorbid vulvar conditions, obesity, menopause status, and length of therapy were not associated with relapse. Age 40 or older was associated with relapse (p = .018). Of the 201 total patients with RVVC, 22 (10.9%) of patients self-reported at least 1 adverse event. The most common was gastrointestinal symptoms (8 [4%]).

Conclusions

Although RVVC can be controlled, relapse is common after an initial course of maintenance fluconazole. Ongoing maintenance remains the most effective treatment option.
Evaluating the Efficacy and Use of Vein Visualization Equipment Among Clinical Nurses in an Intermediate Care Environment
Authors: Kanipe William , Shobe Kellie , Li Yin , Kime Mary , Smith-Miller Cheryl A.
Published: June 2018

This study compared traditional short peripheral catheter (SPC) insertion methods with 2 vein visualization equipment models among a general patient population on a surgical step-down unit based on first-attempt success rates and the time required to achieve catheter insertion. The experiences of clinical nurses using the ultrasound and vein visualization equipment were also explored. No significant statistical differences were found between the insertion methods, based on 90 unique SPC insertion attempts. However, nurses reported that using the vein visualization equipment informed patient care, facilitated communication among members of the health care team, and facilitated second SPC insertion attempts. Nursing staff also used the equipment more often after the study concluded.
Pressure Ulcer Rate in Multidisciplinary Hospital Units After Multifactorial Intervention: A Stepped-Wedge, Cluster Randomized Controlled Trial
Authors: Jafary Mohamadreza , Adibi Hossin , Shayanfard Kamran , Zohdi Mehri , Godarzi Zahra , Yaseri Mehdi , Najafpour Zhila
Published: June 2018

Objectives

This study was conducted to measure the effectiveness of interventions in decreasing the rates of pressure ulcer in a general hospital setting.

Methods

Sixteen units in a general hospitals in Iran participated in this stepped-wedge, cluster randomized controlled trial during a 45-week study period. This trial has a one-sided crossover design from control to intervention. The units were randomly assigned fulfilling entry criteria. After the approval by the governing board of hospital, the manipulative intervention, in addition to usual care, was implemented on patients with a Braden criterion of 14 or less. The primary outcome was ulcer specification (grade and location of ulcer), and the secondary outcome was the length of hospital stay.

Results

A total of 18,900 patients were admitted during the 45-week study period in the study units, of whom approximately 20% (3846 patients) were identified as high risk according to the items of Braden scale criteria during the admission assessment by nurses. The highest rate of PUs (80%) was in grade 2, and 16% of patients had grade 3 and 4 PUs. The ulcers of the skin overlying the sacrum and hip areas were the most common sites in the patients under study. The rates of PU in the control, training, and intervention phases were 5.49 (4.72–6.34), 5.68 (3.82–8.15), and 4.62 (3.87–5.47), respectively, per 1000 patient-days.

Conclusions

The multifaceted intervention proposed by the present study has succeeded in reducing rate of pressure ulcer. Multifaceted programs based on training are appropriate ways to provide essential information to patients and their caregivers, which result in improvement of their participation in therapeutic process. We recommend hospitals to use these findings as a quality improvement plan for decreasing the rate of pressure ulcer.
Pulmonary Emphysema Quantification on Ultra–Low-Dose Computed Tomography Using Model-Based Iterative Reconstruction With or Without Lung Setting
Authors: Hata Akinori , Yanagawa Masahiro , Kikuchi Noriko , Honda Osamu , Tomiyama Noriyuki
Published: June 2018

Objectives

To evaluate the influence of model-based iterative reconstruction (MBIR) with lung setting and conventional setting on pulmonary emphysema quantification by ultra–low-dose computed tomography (ULDCT) compared with standard-dose CT (SDCT).

Methods

Forty-five patients who underwent ULDCT (0.18 ± 0.02 mSv) and SDCT (6.66 ± 2.69 mSv) were analyzed in this retrospective study. Images were reconstructed using filtered back projection (FBP) with smooth and sharp kernels and MBIR with conventional and lung settings. Extent of emphysema was evaluated using fully automated software. Correlation between ULDCT and SDCT was assessed by interclass correlation coefficiency (ICC) and Bland-Altman analysis.

Results

Excellent correlation was seen between MBIR with conventional setting on ULDCT and FBP with smooth kernel on SDCT (ICC, 0.97; bias, −0.31%) and between MBIR with lung setting on ULDCT and FBP with sharp kernel on SDCT (ICC, 0.82; bias, −2.10%).

Conclusion

Model-based iterative reconstruction improved the agreement between ULDCT and SDCT on emphysema quantification.
Intrahepatic Splenosis: Incidental Liver Lesion after Splenectomy
Authors: Varghese Jerrin , Bergson Jill , Yaipen Omar
Published: June 2018

We describe the case of a 50-year-old man with history of remote splenectomy who underwent routine lung cancer screening chest computed tomography and was incidentally found to have a liver lesion. Dedicated liver protocol computed tomography demonstrated “archiform” enhancement pattern in the arterial phase and homogenous filling-in enhancement on portal venous and delayed phases. Multiple other smaller enhancing intraperitoneal lesions were also found. These findings along with history of splenectomy confirmed a diagnosis of intrahepatic and intraperitoneal splenosis and helped avoid biopsy. Intrahepatic splenules can be challenging to diagnose owing to its unusual location and similarity in appearance to a liver neoplasm or metastasis. However, careful evaluation of enhancement pattern and review of medical history can lead to an accurate diagnosis and avoidance of invasive biopsy.
Improvement in Liver Transplant Outcomes From Older Donors
Authors: Gao Qimeng , Mulvihill Michael S. , Scheuermann Uwe , Davis Robert P. , Yerxa John , Yerokun Babatunde A. , Hartwig Matthew G. , Sudan Debra L. , Knechtle Stuart J. , Barbas Andrew S.
Published: June 2018

Objective:

To investigate trends in long-term graft and patient outcomes following liver transplantation using grafts from donors ≥60 years old.

Summary Background Data:

The scarcity of donor livers has led to increased utilization of organs from donors ≥60 years old. However, few studies have examined how long-term transplant outcomes from older donors have evolved over time.

Methods:

The OPTN/UNOS database was queried for all first-time isolated adult liver transplants. We identified 14,796 adult liver transplant using donors ≧60-year-old suitable for analysis from 1990 to 2014. Cohorts were then developed based on 5-year intervals of transplant date. Kaplan–Meier analysis was used to compare graft and patient survival for recipients from older donor across each 5-year era.

Results:

Utilization of donor grafts ≥60 years old increased steadily for the first 15 years of the study, but has leveled off over the last 10 years. Comparison of the earliest and latest eras in the study was notable for an increase in median recipient age (51 vs. 59, P < 0.001) and reduction in median cold ischemic time (10 vs. 6 h, P = 0.001). Unadjusted 5-year graft and patient survival has improved significantly over time (P < 0.0001). More importantly, the discrepancy in survival between older and younger grafts has narrowed substantially over time (P < 0.0001).

Conclusions:

This study demonstrates significant improvement in transplant outcomes with donor grafts ≥60-years old and supports increased but judicious use of extended criteria donors liver grafts. Improved patient selection and reduction in cold ischemia time appear to be contributing factors.
Cryo-EM structure of an amyloid fibril from systemic amyloidosis
Authors: Liberta Falk , Loerch Sarah , Rennegarbe Matthies , Schierhorn Angelika , Westermark Per , Westermark Gunilla T. , Grigorieff Nikolaus , Fändrich Marcus , Schmidt Matthias
Published: June 2018

Systemic AA amyloidosis is a worldwide occurring disease of humans and animals that arises from the misfolding of serum amyloid A protein. To provide insights into the molecular basis of this disease we used electron cryo-microscopy and determined the structure of anex vivoamyloid fibril purified from AA amyloidotic mice at 3.0 Å resolution. The fibril consists of C-terminally truncated serum amyloid A protein arranged into a compactly folded all-β conformation. The structure identifies the protein N-terminus as central for the assembly of this fibril and provides a mechanism for its prion-like replication. Our data further explain how amino acid substitutions within the tightly packed fibril core can lead to amyloid resistancein vivo.
Scuphr: A probabilistic framework for cell lineage tree reconstruction
Authors: Koptagel Hazal , Jun Seong-Hwan , Hård Joanna , Lagergren Jens
Published: June 2018

Cell lineage tree reconstruction methods are developed for various tasks, such as investigating the development, differentiation, and cancer progression. Single-cell sequencing technologies enable more thorough analysis with higher resolution. We present Scuphr, a distance-based cell lineage tree reconstruction method using bulk and single-cell DNA sequencing data from healthy tissues. Common challenges of single-cell DNA sequencing, such as allelic dropouts and amplification errors, are included in Scuphr. Scuphr computes the distance between cell pairs and reconstructs the lineage tree using the neighbor-joining algorithm. With its embarrassingly parallel design, Scuphr can do faster analysis than the state-of-the-art methods while obtaining better accuracy. The method’s robustness is investigated using various synthetic datasets and a biological dataset of 18 cells.

Author summary

Cell lineage tree reconstruction carries a significant potential for studies of development and medicine. The lineage tree reconstruction task is especially challenging for cells taken from healthy tissue due to the scarcity of mutations. In addition, the single-cell whole-genome sequencing technology introduces artifacts such as amplification errors, allelic dropouts, and sequencing errors. We propose Scuphr, a probabilistic framework to reconstruct cell lineage trees. We designed Scuphr for single-cell DNA sequencing data; it accounts for technological artifacts in its graphical model and uses germline heterozygous sites to improve its accuracy. Scuphr is embarrassingly parallel; the speed of the computational analysis is inversely proportional to the number of available computational nodes. We demonstrated that Scuphr is fast, robust, and more accurate than the state-of-the-art method with the synthetic data experiments. Moreover, in the biological data experiment, we showed Scuphr successfully identifies different clones and further obtains more support on closely related cells within clones.
Multiple Functional Neurosteroid Binding Sites on GABAAReceptors
Authors: Chen Zi-Wei , Bracamontes John R. , Budelier Melissa M. , Germann Allison L. , Shin Daniel J. , Kathiresan Krishnan , Qian Ming-Xing , Manion Brad , Cheng Wayland W. L. , Reichert David E. , Akk Gustav , Covey Douglas F. , Evers Alex S.
Published: June 2018

Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While GABAAreceptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill-defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry, we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3GABAAreceptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1and β3subunits, adjacent to the extracellular domains. An intersubunit site in the interface between the β3(+) and α1(-) subunits of the GABAAreceptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAAreceptors. Electrophysiological studies based on these predictions indicate that both the α1intrasubunit and β3-α1intersubunit sites are critical for neurosteroid action.
Contributions of Low- and High-Frequency Sensorineural Hearing Deficits to Speech Intelligibility in Noise
Authors: Verhulst Sarah , Warzybok Anna
Published: June 2018

The degree to which supra-threshold hearing deficits affect speech recognition in noise is poorly understood. To clarify the role of hearing sensitivity in different stimulus frequency ranges, and to test the contribution of low- and high-pass speech information to broadband speech recognition, we collected speech reception threshold (SRTs) for low-pass (LP < 1.5 kHz), high-pass (HP > 1.6 kHz) and broadband (BB) speech-in-noise stimuli in 34 listeners. Two noise types with similar long-term spectra were considered: stationary (SSN) and temporally modulated noise (ICRA5-250). Irrespective of the tested listener group (i.e., young normal-hearing, older normal- or impaired-hearing), the BB SRT performance was strongly related to the LP SRT. The encoding of LP speech information was different for SSN and ICRA5-250 noise but similar for HP speech, suggesting a single noise-type invariant coding mechanism for HP speech. Masking release was observed for all filtered conditions and related to the ICRA5-250 SRT. Lastly, the role of hearing sensitivity to the SRT was studied using the speech intelligibility index (SII), which failed to predict the SRTs for the filtered speech conditions and for the older normal-hearing listeners. This suggests that supra-threshold hearing deficits are important contributors to the SRT of older normal-hearing listeners.