bluuebunny/crossref_metadata_2025 huggingface dataset:
Bayesian inference of distributed time delay in transcriptional and translational regulation
Authors: Choi Boseung , Cheng Yu-Yu , Cinar Selahattin , Ott William , Bennett Matthew R , Josić Krešimir , Kim Jae Kyoung
Published: July 2019

Motivation

Advances in experimental and imaging techniques have allowed for unprecedented insights into the dynamical processes within individual cells. However, many facets of intracellular dynamics remain hidden, or can be measured only indirectly. This makes it challenging to reconstruct the regulatory networks that govern the biochemical processes underlying various cell functions. Current estimation techniques for inferring reaction rates frequently rely on marginalization over unobserved processes and states. Even in simple systems this approach can be computationally challenging, and can lead to large uncertainties and lack of robustness in parameter estimates. Therefore we will require alternative approaches to efficiently uncover the interactions in complex biochemical networks.

Results

We propose a Bayesian inference framework based on replacing uninteresting or unobserved reactions with time delays. Although the resulting models are non-Markovian, recent results on stochastic systems with random delays allow us to rigorously obtain expressions for the likelihoods of model parameters. In turn, this allows us to extend MCMC methods to efficiently estimate reaction rates, and delay distribution parameters, from single-cell assays. We illustrate the advantages, and potential pitfalls, of the approach using a birth–death model with both synthetic and experimental data, and show that we can robustly infer model parameters using a relatively small number of measurements. We demonstrate how to do so even when only the relative molecule count within the cell is measured, as in the case of fluorescence microscopy.

Availability and implementation

Accompanying code in R is available at https://github.com/cbskust/DDE_BD.

Supplementary information

Supplementary data are available at Bioinformatics online.
amplimap: a versatile tool to process and analyze targeted NGS data
Authors: Koelling Nils , Bernkopf Marie , Calpena Eduardo , Maher Geoffrey J , Miller Kerry A , Ralph Hannah K , Goriely Anne , Wilkie Andrew O M
Published: July 2019

amplimap is a command-line tool to automate the processing and analysis of data from targeted next-generation sequencing experiments with PCR-based amplicons or capture-based enrichment systems. From raw sequencing reads, amplimap generates output such as read alignments, annotated variant calls, target coverage statistics and variant allele counts and frequencies for each target base pair. In addition to its focus on user-friendliness and reproducibility, amplimap supports advanced features such as consensus base calling for read families based on unique molecular identifiers and filtering false positive variant calls caused by amplification of off-target loci.

Availability and implementation

amplimap is available as a free Python package under the open-source Apache 2.0 License. Documentation, source code and installation instructions are available at https://github.com/koelling/amplimap.
MPRAscore: robust and non-parametric analysis of massively parallel reporter assays
Authors: Niroula Abhishek , Ajore Ram , Nilsson Björn
Published: July 2019

Motivation

Massively parallel reporter assays (MPRA) enable systematic screening of DNA sequence variants for effects on transcriptional activity. However, convenient analysis tools are still needed.

Results

We introduce MPRAscore, a novel tool to infer allele-specific effects on transcription from MPRA data. MPRAscore uses a weighted, variance-regularized method to calculate variant effect sizes robustly, and a permutation approach to test for significance without assuming normality or independence.

Availability and implementation

Source code (C++), precompiled binaries and data used in the paper at https://github.com/abhisheknrl/MPRAscore and https://www.ncbi.nlm.nih.gov/bioproject/PRJNA554195.

Supplementary information

Supplementary data are available at Bioinformatics online.
DeepGOPlus: improved protein function prediction from sequence
Authors: Kulmanov Maxat , Hoehndorf Robert
Published: July 2019

Motivation

Protein function prediction is one of the major tasks of bioinformatics that can help in wide range of biological problems such as understanding disease mechanisms or finding drug targets. Many methods are available for predicting protein functions from sequence based features, protein–protein interaction networks, protein structure or literature. However, other than sequence, most of the features are difficult to obtain or not available for many proteins thereby limiting their scope. Furthermore, the performance of sequence-based function prediction methods is often lower than methods that incorporate multiple features and predicting protein functions may require a lot of time.

Results

We developed a novel method for predicting protein functions from sequence alone which combines deep convolutional neural network (CNN) model with sequence similarity based predictions. Our CNN model scans the sequence for motifs which are predictive for protein functions and combines this with functions of similar proteins (if available). We evaluate the performance of DeepGOPlus using the CAFA3 evaluation measures and achieve an Fmax of 0.390, 0.557 and 0.614 for BPO, MFO and CCO evaluations, respectively. These results would have made DeepGOPlus one of the three best predictors in CCO and the second best performing method in the BPO and MFO evaluations. We also compare DeepGOPlus with state-of-the-art methods such as DeepText2GO and GOLabeler on another dataset. DeepGOPlus can annotate around 40 protein sequences per second on common hardware, thereby making fast and accurate function predictions available for a wide range of proteins.

Availability and implementation

http://deepgoplus.bio2vec.net/ .

Supplementary information

Supplementary data are available at Bioinformatics online.
Shifts to multiple optima underlie climatic niche evolution in New World phyllostomid bats
Authors: Varzinczak Luiz H , Moura Mauricio O , Passos Fernando C
Published: July 2019

Climate underlies species distribution patterns, especially in species where climate limits distributions, such as the phyllostomid bats, which are mostly restricted to the New World tropics. The evolutionary dynamics that shaped phyllostomid climatic niches remain unclear, and a broad phylogenetic perspective is required to uncover their patterns. We used geographical distributions and evolutionary relationships of 130 species, climate data and phylogenetic comparative methods to uncover dynamics of phyllostomid climatic niche evolution. Diversification of climatic niches began early in phyllostomid evolution (~34 Mya), with most changes taking place ~20 Mya. Although most of these bats were found in tropical regions, shifts towards different evolutionary optima were common. Shifts were mostly towards temperate climates, reflecting complexities in phyllostomid evolution highlighted by the probable role of species-specific adaptations to cope with these climates, the influence of palaeoclimatic events, and biogeographical effects related to the evolution and dispersal of clades in the New World. Our results broaden our understanding of the relationships between phyllostomid bats and climate, filling an important gap in knowledge and suggesting a complex evolution in their occupation of the climatic niche space.
Optimal management of gestational diabetes
Authors: Egan Aoife M , Dunne Fidelma P
Published: July 2019

Background

Gestational diabetes mellitus (GDM) is highly prevalent and has both short- and long-term implications for mother and infant.

Sources of data

Literature search using PubMed with keywords ‘Gestational diabetes’ and ‘diabetes in pregnancy’ together with published papers known to the authors.

Areas of agreement

The cornerstone of management is medical nutrition therapy with regular self-monitoring of capillary blood glucose levels and intensification of therapy if glycaemic goals are not achieved. Post-partum, annual assessment for type 2 diabetes is recommended.

Areas of controversy

Diagnostic criteria and new biomarkers for GDM and the clinical and economic benefits of treating women with milder levels of glucose intolerance during pregnancy.

Growing points

Women with GDM are a heterogeneous group with varying degrees of insulin resistance and beta cell dysfunction.

Areas timely for developing research

Development of alternative diagnostic markers and application of novel technologies for GDM management.
Hip scores: A current concept review
Authors: Longo Umile Giuseppe , Ciuffreda Mauro , Candela Vincenzo , Berton Alessandra , Maffulli Nicola , Denaro Vincenzo
Published: July 2019

Introduction

During the past decades, several rating scales have been developed to assess the functional status of patients with hip pain.

Source of data

A search in Medline, PubMed, Cochrane and CINAHL was performedusing combinations of the following‘hip’, ‘scoring system’, ‘scale’, ‘scores’, ‘outcome assessment’, ‘arthroplasty’, ‘arthroscopy’ and ‘clinical evaluation’.

Areas of agreement

A total 16 scoring systems are currently available for the evaluation of the hip.

Areas of controversy

Two types of questionnaires are available: physician-rated and patient-rated questionnaires.

Growing points

Each hip score consists of different domains. Interpreting these domains becomes sometimes difficult, because, even though they can be common to more than one scoring system, each stresses them in a different way.

Areas timely for developing research

Although many scoring systems have been used to evaluate hip function, we are still far from a single outcome evaluation system which is reliable, valid and sensitive.
Delving deeper into the phylogenetics of the herbaceous bamboos (Poaceae, Bambusoideae, Olyreae): evaluation of generic boundaries within the Parodiolyra/Raddiella clade uncovers a new genus
Authors: Oliveira Iasmin L C , Matos Andreza O , Silva Christian , Carvalho Maria Luiza S , Tyrrell Christopher D , Clark Lynn G , Oliveira R Patrícia
Published: July 2019

The present study aims to expand the knowledge of phylogenetic relationships in Olyrinae, a subtribe of herbaceous bamboos (Poaceae: Bambusoideae: Olyreae). Our focus is on Parodiolyra and Raddiella, two historically related genera that, with their sister Diandrolyra, form one of the four main lineages in the subtribe. Previous phylogenetic analyses suggested that Parodiolyra is not monophyletic, but its taxonomic boundaries and its relationship with Raddiella remain uncertain due to low sampling. We increased the taxon sampling and sequenced five regions of the nuclear and plastid genomes for this lineage and other representatives of Olyreae. We used maximum parsimony, maximum likelihood, Bayesian inference and coalescence analysis. Our results corroborate the paraphyly of Parodiolyra, with P. micrantha sister to a clade including the remaining Parodiolyra and Raddiella. All remaining Parodiolyra form a well-supported clade, but Raddiella had conflicting resolutions, being either monophyletic or not. Thus, based on phylogenetic and morphological evidence, we here recircumscribe Parodiolyra, transferring P. micrantha and P. colombiensis to the new genus Taquara (described here). Regarding Raddiella, sampling is still not comprehensive and does not allow a decision on to its taxonomic status to be made at this time. Inclusion of other phreatophytic species may be crucial to resolve the problem of conflicting topologies.
Connectivity profile of thalamic deep brain stimulation to effectively treat essential tremor
Authors: Al-Fatly Bassam , Ewert Siobhan , Kübler Dorothee , Kroneberg Daniel , Horn Andreas , Kühn Andrea A
Published: July 2019

Al-Fatly et al. establish predictive connectivity maps of deep brain stimulation in essential tremor. They demonstrate that electrode connectivity to tremor-associated brain areas can predict postoperative improvement and that these maps can be somatotopically segregated according to the tremor-affected body parts.
PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury
Authors: Takahata Keisuke , Kimura Yasuyuki , Sahara Naruhiko , Koga Shunsuke , Shimada Hitoshi , Ichise Masanori , Saito Fumie , Moriguchi Sho , Kitamura Soichiro , Kubota Manabu , Umeda Satoshi , Niwa Fumitoshi , Mizushima Jin , Morimoto Yoko , Funayama Michitaka , Tabuchi Hajime , Bieniek Kevin F , Kawamura Kazunori , Zhang Ming-Rong , Dickson Dennis W , Mimura Masaru , Kato Motoichiro , Suhara Tetsuya , Higuchi Makoto
Published: July 2019

Is tau load associated with long-term outcomes of TBI? By using PET to assess tau deposits in patients with chronic TBI, Takahata et al. reveal elevated tau load compared to age-matched controls, and show that the abundance of tau in white matter is associated with late-onset neuropsychiatric symptoms.
CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Authors: Mancuso Renzo , Fryatt Gemma , Cleal Madeleine , Obst Juliane , Pipi Elena , Monzón-Sandoval Jimena , Ribe Elena , Winchester Laura , Webber Caleb , Nevado Alejo , Jacobs Tom , Austin Nigel , Theunis Clara , Grauwen Karolien , Daniela Ruiz Eva , Mudher Amrit , Vicente-Rodriguez Marta , Parker Christine A , Simmons Camilla , Cash Diana , Richardson Jill ,   NIMA Consortium, Bullmore Edward T , Bhatti Junaid , Chamberlain Samuel J , Correia Marta M , Crofts Anna L , Dickinson Amber , Foster Andrew C , Kitzbichler Manfred G , Knight Clare , Lynall Mary-Ellen , Maurice Christina , O'Donnell Ciara , Pointon Linda J , Hyslop Peter St George , Turner Lorinda , Vertes Petra , Widmer Barry , Williams Guy B , Morgan B Paul , Leckey Claire A , Morgan Angharad R , O'Hagan Caroline , Touchard Samuel , Cavanagh Jonathan , Deith Catherine , Farmer Scott , McClean John , McColl Alison , McPherson Andrew , Scouller Paul , Sutherland Murray , Boddeke H W G M (Erik) , Richardson Jill C , Khan Shahid , Murphy Phil , Parker Christine A , Patel Jai , Jones Declan , de Boer Peter , Kemp John , Drevets Wayne C , Nye Jeffrey S , Wittenberg Gayle , Isaac John , Bhattacharya Anindya , Carruthers Nick , Kolb Hartmuth , Pariante Carmine M , Turkheimer Federico , Barker Gareth J , Byrom Heidi , Cash Diana , Cattaneo Annamaria , Gee Antony , Hastings Caitlin , Mariani Nicole , McLaughlin Anna , Mondelli Valeria , Nettis Maria , Nikkheslat Naghmeh , Randall Karen , Sheridan Hannah , Simmons Camilla , Singh Nisha , Loo Victoria Van , Vicente-Rodriguez Marta , Wood Tobias C , Worrell Courtney , Zajkowska Zuzanna , Plath Niels , Egebjerg Jan , Eriksson Hans , Gastambide Francois , Adams Karen Husted , Jeggo Ross , Thomsen Christian , Pederson Jan Torleif , Campbell Brian , Möller Thomas , Nelson Bob , Zorn Stevin , O'Connor Jason , Attenburrow Mary Jane , Baird Alison , Benjamin Jithen , Clare Stuart , Cowen Philip , Huang I-Shu (Dante) , Hurley Samuel , Jones Helen , Lovestone Simon , Mada Francisca , Nevado-Holgado Alejo , Oladejo Akintayo , Ribe Elena , Smith Katy , Vyas Anviti , Hughes Zoe , Balice-Gordon Rita , Duerr James , Piro Justin R , Sporn Jonathan , Hugh Perry (PI V , Cleal Madeleine , Fryatt Gemma , Gomez-Nicola Diego , Mancuso Renzo , Reynolds Richard , Harrison Neil A , Cercignani Mara , Clarke Charlotte L , Hoskins Elizabeth , Kohn Charmaine , Murray Rosemary , Wilcock Lauren , Wlazly Dominika , Mount Howard , Jones Declan N C , Lovestone Simon , Gómez-Nicola Diego , Perry V Hugh
Published: July 2019

Microglia have been implicated in amyloid beta-induced neuropathology, but their role in tau-induced neurodegeneration remains unclear. Mancuso et al. report that blockade of microglial proliferation by CSF1R inhibitor JNJ-40346527 modifies brain inflammation and ameliorates disease progression in P301S tauopathy mice. CSF1R inhibition may have therapeutic potential in tau-mediated neurodegenerative diseases.
#MeToo and the Politics of Collective Healing: Emotional Connection as Contestation
Authors: Page Allison , Arcy Jacquelyn
Published: July 2019

Participants in the #MeToo movement on Twitter expressed emotions like rage, pain, and solidarity in their personal accounts of sexual violence. This article explores the digital circulation of these affects and considers how the outpouring of tweets about sexual harassment and abuse contribute to a feminist politics centered on collective healing. The particular emotions expressed in the #MeToo Twitter archive subvert the logics of quantification and visibility that undergird popular feminism and the attention economy, and produce an affective excess that works toward movement founder Tarana Burke's original project of “mass healing.” At a moment wherein popular feminism emphasizes individual empowerment and consumption, and carceral feminism relies on criminalization and incarceration, the #MeToo movement's focus on shared emotions represents the potential for a feminist politics rooted in collective support and restorative justice.
Dendritic Localization and Exocytosis of NAAG in the Rat Hippocampus
Authors: Nordengen K , Morland C , Slusher B S , Gundersen V
Published: July 2019

While a lot is known about classical, anterograde neurotransmission, less is known about the mechanisms and molecules involved in retrograde neurotransmission. Our hypothesis is that N-acetylaspartylglutamate (NAAG), the most abundant dipeptide in the brain, may act as a retrograde transmitter in the brain. NAAG was predominantly localized in dendritic compartments of glutamatergic synapses in the intact hippocampus, where it was present in close proximity to synaptic-like vesicles. In acute hippocampal slices, NAAG was depleted from postsynaptic dendritic elements during neuronal stimulation induced by depolarizing concentrations of potassium or by exposure to glutamate receptor (GluR) agonists. The depletion was completely blocked by botulinum toxin B and strictly dependent on extracellular calcium, indicating exocytotic release. In contrast, there were low levels of NAAG and no effect by depolarization or GluR agonists in presynaptic glutamatergic terminals or GABAergic pre- and postsynaptic elements. Together these data suggest a possible role for NAAG as a retrograde signaling molecule at glutamatergic synapses via exocytotic release.
Long-Lasting Somatic Modifications of Convergent Dendritic Inputs in Hippocampal Neurons
Authors: Yang Xin , Bao Yifei , Xu Jindong , Gong Ru , Zhang Nan , Cai Lei , Xia Mingmei , Wang Jingjing , Lu Wei
Published: July 2019

Integrated neural inputs from different dendrites converge at the soma for action potential generation. However, it is unclear how the convergent dendritic inputs interact at the soma and whether they can be further modified there. We report here an entirely new plasticity rule in hippocampal neurons in which repetitive pairing of subthreshold excitatory inputs from proximal apical and basal dendrites at a precise interval induces persistent bidirectional modifications of the two dendritic inputs. Strikingly, the modification of the dendritic inputs specially occurs at soma in the absence of somatic action potential and requires activation of somatic N-methyl-D-aspartate receptors (NMDARs). Once induced, the somatic modification can also be observed in other unpaired dendritic inputs upon their arrival at the soma. We further reveal that the soma can employ an active mechanism to potentiate the dendritic inputs by promoting sustained activation of somatic NMDARs and subsequent down-regulating of the fast inactivating A-type potassium current (IA) at the soma. Thus, the input-timing–dependent somatic plasticity we uncovered here is in sharp contrast to conventional forms of synaptic plasticity that occur at the dendrites and is important to somatic action potential generation.
High Angular Resolution Diffusion MRI Reveals Conserved and Deviant Programs in the Paths that Guide Human Cortical Circuitry
Authors: Charvet Christine J , Das Avilash , Song Jae W , Tindal-Burgess Deselyn J , Kabaria Priya , Dai Guangping , Kane Tara , Takahashi Emi
Published: July 2019

Diffusion magnetic resonance (MR) tractography represents a novel opportunity to investigate conserved and deviant developmental programs between humans and other species such as mice. To that end, we acquired high angular resolution diffusion MR scans of mice [embryonic day (E) 10.5 to postnatal week 4] and human brains [gestational week (GW) 17–30] at successive stages of fetal development to investigate potential evolutionary changes in radial organization and emerging pathways between humans and mice. We compare radial glial development as well as commissural development (e.g., corpus callosum), primarily because our findings can be integrated with previous work. We also compare corpus callosal growth trajectories across primates (i.e., humans and rhesus macaques) and rodents (i.e., mice). One major finding is that the developing cortex of humans is predominated by pathways likely associated with a radial glial organization at GW 17–20, which is not as evident in age-matched mice (E 16.5, 17.5). Another finding is that, early in development, the corpus callosum follows a similar developmental timetable in primates (i.e., macaques and humans) as in mice. However, the corpus callosum grows for an extended period of time in primates compared with rodents. Taken together, these findings highlight deviant developmental programs underlying the emergence of cortical pathways in the human brain.
Stimulation of mGluR1/5 Improves Defective Internalization of AMPA Receptors in NPC1 Mutant Mouse
Authors: Feng Xiao , Yang Fan , Rabenstein Michael , Wang Zhen , Frech Moritz J , Wree Andreas , Bräuer Anja U , Witt Martin , Gläser Anne , Hermann Andreas , Rolfs Arndt , Luo Jiankai
Published: July 2019

Niemann–Pick type C1 (NPC1) disease is characterized by neurodegeneration caused by cholesterol accumulation in the late endosome/lysosome. In this study, a defective basal and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-stimulated internalization of GluR2-containing AMPA receptors in NPC1−/− cortical neurons was detected. Our results show that the amount of cholesterol and group I metabotropic glutamate receptors (mGluR1/5) in lipid rafts of NPC1−/− cortical tissue and neurons are decreased and their downstream signals of p-ERK are defective, which are restored by a rebalance of cholesterol homeostasis through β-cyclodextrin (β-CD) treatment. Application of 3,5-dihydroxyphenylglycine (DHPG)—a mGluR1/5 agonist—and β-CD markedly increases the internalization of AMPA receptors and decreases over-influx of calcium in NPC1−/− neurons, respectively. Furthermore, the defective phosphorylated GluR2 and protein kinase C signals are ameliorated by the treatment with DHPG and β-CD, respectively, suggesting an involvement of them in internalization dysfunction. Taken together, our data imply that abnormal internalization of AMPA receptors is a critical mechanism for neuronal dysfunction and the correction of dysfunctional mGluR1/5 is a potential therapeutic strategy for NPC1 disease.
The Cortical Organization of Syntax
Authors: Matchin William , Hickok Gregory
Published: July 2019

Syntax, the structure of sentences, enables humans to express an infinite range of meanings through finite means. The neurobiology of syntax has been intensely studied but with little consensus. Two main candidate regions have been identified: the posterior inferior frontal gyrus (pIFG) and the posterior middle temporal gyrus (pMTG). Integrating research in linguistics, psycholinguistics, and neuroscience, we propose a neuroanatomical framework for syntax that attributes distinct syntactic computations to these regions in a unified model. The key theoretical advances are adopting a modern lexicalized view of syntax in which the lexicon and syntactic rules are intertwined, and recognizing a computational asymmetry in the role of syntax during comprehension and production. Our model postulates a hierarchical lexical-syntactic function to the pMTG, which interconnects previously identified speech perception and conceptual-semantic systems in the temporal and inferior parietal lobes, crucial for both sentence production and comprehension. These relational hierarchies are transformed via the pIFG into morpho-syntactic sequences, primarily tied to production. We show how this architecture provides a better account of the full range of data and is consistent with recent proposals regarding the organization of phonological processes in the brain.
Development and Comparison of Complementary Methods to Study Potential Skin and Inhalational Exposure to Pathogens During Personal Protective Equipment Doffing
Authors: Therkorn Jennifer , Drewry David , Andonian Jennifer , Benishek Lauren , Billman Carrie , Forsyth Ellen R , Garibaldi Brian T , Nowakowski Elaine , Rainwater-Lovett Kaitlin , Sauer Lauren , Schiffhauer Maggie , Maragakis Lisa L
Published: July 2019

Background

Fluorescent tracers are often used with ultraviolet lights to visibly identify healthcare worker self-contamination after doffing of personal protective equipment (PPE). This method has drawbacks, as it cannot detect pathogen-sized contaminants nor airborne contamination in subjects’ breathing zones.

Methods

A contamination detection/quantification method was developed using 2-µm polystyrene latex spheres (PSLs) to investigate skin contamination (via swabbing) and potential inhalational exposure (via breathing zone air sampler). Porcine skin coupons were used to estimate the PSL swabbing recovery efficiency and limit of detection (LOD). A pilot study with 5 participants compared skin contamination levels detected via the PSL vs fluorescent tracer methods, while the air sampler quantified potential inhalational exposure to PSLs during doffing.

Results

Average PSL skin swab recovery efficiency was 40% ± 29% (LOD = 1 PSL/4 cm2 of skin). In the pilot study, all subjects had PSL and fluorescent tracer skin contamination. Two subjects had simultaneously located contamination of both types on a wrist and hand. However, for all other subjects, the PSL method enabled detection of skin contamination that was not detectable by the fluorescent tracer method. Hands/wrists were more commonly contaminated than areas of the head/face (57% vs 23% of swabs with PSL detection, respectively). One subject had PSLs detected by the breathing zone air sampler.

Conclusions

This study provides a well-characterized method that can be used to quantitate levels of skin and inhalational contact with simulant pathogen particles. The PSL method serves as a complement to the fluorescent tracer method to study PPE doffing self-contamination.
Causes and Clinical Features of Childhood Encephalitis: A Multicenter, Prospective Cohort Study
Authors: Britton Philip N , Dale Russell C , Blyth Christopher C , Clark Julia E , Crawford Nigel , Marshall Helen , Elliott Elizabeth J , Macartney Kristine , Booy Robert , Jones Cheryl A
Published: July 2019

Background

We aimed to determine the contemporary causes, clinical features, and short-term outcome of encephalitis in Australian children.

Methods

We prospectively identified children (≤14 years of age) admitted with suspected encephalitis at 5 major pediatric hospitals nationally between May 2013 and December 2016 using the Paediatric Active Enhanced Disease Surveillance (PAEDS) Network. A multidisciplinary expert panel reviewed cases and categorized them using published definitions. Confirmed encephalitis cases were categorized into etiologic subgroups.

Results

From 526 cases of suspected encephalitis, 287 children met criteria for confirmed encephalitis: 57% (95% confidence interval [CI], 52%–63%) had infectious causes, 10% enterovirus, 10% parechovirus, 8% bacterial meningoencephalitis, 6% influenza, 6% herpes simplex virus (HSV), and 6% Mycoplasma pneumoniae; 25% (95% CI, 20%–30%) had immune-mediated encephalitis, 18% acute disseminated encephalomyelitis, and 6% anti-N-methyl-d-aspartate receptor encephalitis; and 17% (95% CI, 13%–21%) had an unknown cause. Infectious encephalitis occurred in younger children (median age, 1.7 years [interquartile range {IQR}, 0.1–6.9]) compared with immune-mediated encephalitis (median age, 7.6 years [IQR, 4.6–12.4]). Varicella zoster virus encephalitis was infrequent following high vaccination coverage since 2007. Thirteen children (5%) died: 11 with infectious causes (2 influenza; 2 human herpesvirus 6; 2 group B Streptococcus; 2 Streptococcus pneumoniae; 1 HSV; 1 parechovirus; 1 enterovirus) and 2 with no cause identified. Twenty-seven percent (95% CI, 21%–31%) of children showed moderate to severe neurological sequelae at discharge.

Conclusions

Epidemic viral infections predominated as causes of childhood encephalitis in Australia. The leading causes include vaccine-preventable diseases. There were significant differences in age, clinical features, and outcome among leading causes. Mortality or short-term neurological morbidity occurred in one-third of cases.
Interleukin (IL)-1β and IL-10 Host Responses in Patients With Staphylococcus aureus Bacteremia Determined by Antimicrobial Therapy
Authors: Volk Cecilia F , Burgdorf Sarah , Edwardson Graham , Nizet Victor , Sakoulas George , Rose Warren E
Published: July 2019

Background

Patient interleukin (IL)-1β and IL-10 responses early in Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on antimicrobial therapy, with particular interest in whether the superiority of β-lactams links to key cytokine pathways.

Methods

Three medical centers included 59 patients with SaB (47 methicillin-resistant S. aureus [MRSA], 12 methicillin-sensitive S. aureus [MSSA]) from 2015–2017. In the first 48 hours, patients were treated with either a β-lactam (n = 24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n = 35), that is, vancomycin or daptomycin. Patient sera from days 1, 3, and 7 were assayed for IL-1β and IL-10 by enzyme-linked immunosorbent assay and compared using the Mann-Whitney U test.

Results

On presentation, IL-10 was elevated in mortality (P = .008) and persistent bacteremia (P = .034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 were similar prior to receiving antibiotic. Patients treated with β-lactam had higher IL-1β on days 3 (median +5.6 pg/mL; P = .007) and 7 (+10.9 pg/mL; P = .016). Ex vivo, addition of the IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting an IL-1β functional significance in SaB clearance. β-lactam–treated patients had sharper declines in IL-10 than vancomycin or daptomycin –treated patients over 7 days.

Conclusions

These data underscore the importance of β-lactams for SaB, including consideration that the adjunctive role of β-lactams for MRSA in select patients helps elicit favorable host cytokine responses.
Targeting HSP90 attenuates angiotensin II-induced adventitial remodelling via suppression of mitochondrial fission
Authors: Huang Gaojian , Cong Zhilei , Wang Xiaoyan , Yuan Yanggang , Xu Renjie , Lu Zhaoyang , Wang Xuelian , Qi Jia
Published: July 2019

Aims

Adventitial remodelling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signalling and transcriptional pathways in vascular smooth muscle cells; however, little is known about its role on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin (CN), a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodelling in AngII-induced hypertensive mice.

Methods and results

In primary mouse AFs, we found that CN-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial reactive oxygen species production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and CN in AFs, while HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the CN-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodelling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by CN/Drp1 signalling pathways.

Conclusions

Our study suggests that CN/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodelling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodelling-related diseases.
Statistics on mortality following acute myocardial infarction in 842 897 Europeans
Authors: Alabas Oras A , Jernberg Tomas , Pujades-Rodriguez Mar , Rutherford Mark J , West Robert M , Hall Marlous , Timmis Adam , Lindahl Bertil , Fox Keith A A , Hemingway Harry , Gale Chris P
Published: July 2019

Aims

To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments.

Methods and results

National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), β-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4–8.5) vs. 6.7 (6.5–6.9)] and NSTEMI [6.8 (6.4–7.2) vs. 4.9 (4.7–5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5–3.3) vs. 2.3 (2.2–2.5)] and [21.4 (20.0–22.8) vs. 18.3 (17.6–19.0)], but was similar for STEMI [0.7 (0.4–1.0) vs. 0.9 (0.7–1.0)] and [8.4 (6.7–10.1) vs. 8.3 (7.5–9.1)].

Conclusion

Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.
Antegrade transapical branch deployment for endovascular aortic-arch repair by in situ fenestration
Authors: Murakami Takashi , Kishimoto Noriaki , Sohgawa Etsuji , Shibata Toshihiko
Published: July 2019

A 76-year-old man presented with an aortic arch aneurysm and was considered a candidate for endovascular aortic arch repair by in situ fenestration. Alternative access routes were explored because of atherosclerotic disease of the descending aorta and bilateral carotid arteries. Transapical deployment of both an aortic and a branched stent grafts was successfully conducted without cerebral complications. The transapical access might have the potential to reduce the risks of complications related to large bore-sheath insertion to the carotid arteries.
What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?
Authors: Packer Milton
Published: July 2019

Sudden death characterizes the mode of demise in 30–50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10–15 years, independent of the use of ICDs.
‘Real-world’ observational studies in arrhythmia research: data sources, methodology, and interpretation. A position document from European Heart Rhythm Association (EHRA), endorsed by Heart Rhythm Society (HRS), Asia-Pacific HRS (APHRS), and Latin America HRS (LAHRS)
Authors: Torp-Pedersen Christian , Goette Andreas , Nielsen Peter Bronnum , Potpara Tatjana , Fauchier Laurent , John Camm Alan , Arbelo Elena , Boriani Giuseppe , Skjoeth Flemming , Rumsfeld John , Masoudi Frederick , Guo Yutao , Joung Boyoung , Refaat Marwan M , Kim Young-Hoon , Albert Christine M , Piccini Jonathan , Avezum Alvaro , Lip Gregory Y H ,   External Reviewers, Gorenek Bulent , Dagres Nikolaos , Violi Francesco , Du Xin , Akao Masaharu , Choi Eue-Keun , Lopes Renato D , Ozcan Evren Emin , Lane Deirdre , Marin Francisco , Gale Christopher Peter , Vernooy Kevin , Kudaiberdieva Gulmira , Kutyifa Valentina , Traykov Vassil B , Guevara Carolina , Chao Tze-Fan , Al-Khatib Sana M
Published: July 2019

The field of observational studies or “real world studies” is in rapid development with many new techniques introduced and increased understanding of traditional methods. For this reason the current paper provides an overview of current methods with focus on new techniques. Some highlights can be emphasized: We provide an overview of sources of data for observational studies. There is an overview of sources of bias and confounding. Next There is an overview of causal inference techniques that are increasingly used. The most commonly used techniques for statistical modelling are reviewed with focus on the important distinction of risk versus prediction. The final section provides examples of common problems with reporting observational data.
How to perform electroanatomic mapping-guided cardiac resynchronization therapy using Carto 3 and ESI NavX three-dimensional mapping systems
Authors: Huang Henry D , Sharma Parikshit S , Nayak Hemal M , Serafini Nicholas , Trohman Richard G
Published: July 2019

Aims 

To examine the feasibility and safety of a novel protocol for low fluoroscopy, electroanatomic mapping (EAM)-guided Cardiac resynchronization therapy with a defibrillator (CRT-D) implantation and using both EnSite NavX (St. Jude Medical, St. Paul, MN, USA) and Carto 3 (Biosense Webster, Irvine, CA, USA) mapping systems.

Methods and results

Twenty consecutive patients underwent CRT implantation using either a conventional fluoroscopic approach (CFA) or EAM-guided lead placement with Carto 3 and EnSite NavX mapping systems. We compared fluoroscopy and procedural times, radiopaque contrast dose, change in QRS duration pre- and post-procedure, and complications in all patients. Fluoroscopy time was 86% lower in the EAM group compared to the conventional group [mean 37.2 min (CFA) vs. 5.5 min (EAM), P = 0.00003]. There was no significant difference in total procedural time [mean 183 min (CFA) vs. 161 min (EAM), P = 0.33] but radiopaque contrast usage was lower in the EAM group [mean 16 mL (CFA) vs. 4 mL (EAM), P = 0.006]. Likewise, there was no significant change in QRS duration with BiV pacing between the groups [mean −13 (CFA) vs. −25 ms (EAM), P = 0.09].

Conclusion 

Electroanatomic mapping-guided lead placement using either Carto or ESI NavX mapping systems is a feasible alternative to conventional fluoroscopic methods for CRT-D implantation utilizing the protocol described in this study.
‘La maleureuse bataille’: fifteenth-century French reactions to Agincourt
Authors: Taylor Craig
Published: July 2019

This article examines the military and political impact of the battle of Agincourt in France and the way in which this defeat was remembered up until the end of the Hundred Years’ War. The English presented their victory as a sign of God’s support for Henry V and his claims in France, but the French preferred to understand their defeat as a divine punishment for their sins. This led to debate about who had incurred God’s wrath, as civilians blamed soldiers, soldiers blamed their aristocratic leaders, and partisans for the Armagnac and Burgundian factions blamed one another. But most French commentators attempted to bridge these divisions, or at least to minimize the damage by attributing the disaster to the actions of foolish young hot-heads and to cowards. This avoided the need to name and shame specific noblemen, but also meant that only the most traditional lessons were highlighted from this defeat.
Frankia-Enriched Metagenomes from the Earliest Diverging Symbiotic Frankia Cluster: They Come in Teams
Authors: Nguyen Thanh Van , Wibberg Daniel , Vigil-Stenman Theoden , Berckx Fede , Battenberg Kai , Demchenko Kirill N , Blom Jochen , Fernandez Maria P , Yamanaka Takashi , Berry Alison M , Kalinowski Jörn , Brachmann Andreas , Pawlowski Katharina
Published: July 2019

Frankia strains induce the formation of nitrogen-fixing nodules on roots of actinorhizal plants. Phylogenetically, Frankia strains can be grouped in four clusters. The earliest divergent cluster, cluster-2, has a particularly wide host range. The analysis of cluster-2 strains has been hampered by the fact that with two exceptions, they could never be cultured. In this study, 12 Frankia-enriched metagenomes of Frankia cluster-2 strains or strain assemblages were sequenced based on seven inoculum sources. Sequences obtained via DNA isolated from whole nodules were compared with those of DNA isolated from fractionated preparations enhanced in the Frankia symbiotic structures. The results show that cluster-2 inocula represent groups of strains, and that strains not represented in symbiotic structures, that is, unable to perform symbiotic nitrogen fixation, may still be able to colonize nodules. Transposase gene abundance was compared in the different Frankia-enriched metagenomes with the result that North American strains contain more transposase genes than Eurasian strains. An analysis of the evolution and distribution of the host plants indicated that bursts of transposition may have coincided with niche competition with other cluster-2 Frankia strains. The first genome of an inoculum from the Southern Hemisphere, obtained from nodules of Coriaria papuana in Papua New Guinea, represents a novel species, postulated as Candidatus Frankia meridionalis. All Frankia-enriched metagenomes obtained in this study contained homologs of the canonical nod genes nodABC; the North American genomes also contained the sulfotransferase gene nodH, while the genome from the Southern Hemisphere only contained nodC and a truncated copy of nodB.
Draft Genome of Busseola fusca, the Maize Stalk Borer, a Major Crop Pest in Sub-Saharan Africa
Authors: Hardwick Kayla M , Ojwang' Awino Maureiq Edith , Stomeo Francesca , Maina Solomon , Bichang’a Gladys , Calatayud Paul-André , Filée Jonathan , Djikeng Appolinaire , Miller Caitlin , Cepko Leah , Darby Alistair C , Le Ru Bruno , Schaack Sarah
Published: July 2019

The maize stalk borer, Busseola fusca, is an important Lepidopteran pest of cereal crops in Central, East, and Southern Africa. Crop losses due to B. fusca feeding activity vary by region, but can result in total crop loss in areas with high levels of infestation. Genomic resources provide critical insight into the biology of pest species and can allow for the development of effective management tools and strategies to mitigate their impact on agriculture. To this end, we sequenced, assembled, and annotated the genome of B. fusca. The total assembled genome size was 492.9 Mb with 19,417 annotated protein-coding genes. Using a comparative approach, we identified a putative expansion in the Chorion gene family, which is involved in the formation of the egg shell structure. Our analysis revealed high repeat content within the B. fusca genome, with LTR sequences comprising the majority of the repetitive sequence. We hope genomic resources will provide a foundation for future work aimed at developing an integrated pest management strategy to reduce B. fusca’s impact on food security.
Change in Mobility: Consistency of Estimates and Predictors Across Studies of Older Adults
Authors: Cornman Jennifer C , Glei Dana A , Weinstein Maxine
Published: July 2019

Objectives

This study compares estimates and determinants of within-individual changes in mobility across surveys of older U.S. adults.

Methods

Data come from the Health and Retirement Study (HRS) and the Midlife in the United States (MIDUS) study. Measures of mobility comprise self-reported level of difficulty with walking several blocks, going up several flights of stairs, lifting and carrying 10 pounds, and stooping. Predictors include sociodemographic characteristics and indicators of health and health behaviors. We pool the datasets and estimate weighted lagged dependent variable logistic regression models for each activity, assessing cross-study differences using interaction terms between a survey indicator and relevant variables.

Results

Estimates of declines in mobility differ substantially across surveys for walking, lifting and carrying, and stooping, but there are no between-survey differences in the probability of (not) recovering from a limitation. With the exception of age, determinants of change are similar between studies. For lifting/carrying and stooping, the age-related increase in developing limitations is less steep at younger ages for HRS respondents than MIDUS respondents, but steeper at older ages.

Discussion

To compare estimates of mobility change across surveys, mobility measures would need to be harmonized. Determinants of mobility change, however, are more comparable.