bluuebunny/crossref_metadata_2025 huggingface dataset:
HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins
Authors: Steinauer Angela , LaRochelle Jonathan R. , Knox Susan L. , Wissner Rebecca F. , Berry Samuel , Schepartz Alanna
Published: January 2019

Significance

The potential of protein therapeutics is limited because most proteins cannot reach the cytosol. Like many cell-penetrating peptides (CPPs), cell-permeant miniature proteins (CPMPs) that embody a penta-Arg motif are endocytosed; the difference is that CPMPs are released efficiently from endosomes while other CPPs are not. Here, we report that the trafficking of CPMPs into the cytosol requires the homotypic fusion and protein-sorting (HOPS) complex, a membrane-tethering complex that fuses Rab7
+
endosomes. CPMPs neither inhibit nor activate HOPS function; instead, HOPS allows CPMPs to traffic into Lamp1
+
endosomes as a prerequisite for endosomal escape. The identification of Lamp1
+
late endosomes and lysosomes as portals for passing proteins into the cytosol will aid the development of next-generation biologics that overcome the limitations imposed by cellular membranes.
Single-molecule imaging of the transcription factor SRF reveals prolonged chromatin-binding kinetics upon cell stimulation
Authors: Hipp Lisa , Beer Judith , Kuchler Oliver , Reisser Matthias , Sinske Daniela , Michaelis Jens , Gebhardt J. Christof M. , Knöll Bernd
Published: January 2019

Significance

How transcription factors (TFs) activate transcription is a long-standing but still unsolved question. We analyzed serum response factor (SRF), a stimulus-responsive TF mediating immediate early gene (IEG) and cytoskeletal gene expression at single-molecule resolution. Cell stimulation enhanced SRF activity by increasing the number of long chromatin-associated SRF molecules in an oscillating pattern. Further, stimulation enhanced the SRF chromatin residence time, and SRF binding events segregated into three distinct residence time regimes (short, intermediate, and long bound). In summary, our single-molecule imaging study reveals highly dynamic and diverse SRF interactions with DNA. Thus, cell stimulation regulates TF activity by several interconnected mechanisms including nucleus−cytoplasm shuttling, TF phosphorylation, cofactor recruitment, and extension of chromatin residence time and enhancing chromatin-bound TF numbers.
The harmonic mean
p
-value for combining dependent tests
Authors: Wilson Daniel J.
Published: January 2019

Significance

The widespread use of Bonferroni correction encumbers the scientific process and wastes opportunities for discovery presented by big data, because it discourages exploratory analyses by overpenalizing the total number of statistical tests performed. In this paper, I introduce the harmonic mean
p
-value (HMP), a simple to use and widely applicable alternative to Bonferroni correction motivated by Bayesian model averaging that greatly improves statistical power while maintaining control of the gold standard false positive rate. The HMP has a range of desirable properties and offers a different way to think about large-scale exploratory data analysis in classical statistics.
Transcriptogramer: an R/Bioconductor package for transcriptional analysis based on protein–protein interaction
Authors: Morais Diego A A , Almeida Rita M C , Dalmolin Rodrigo J S
Published: January 2019

Motivation

Several freely available tools perform analysis using algorithms developed to identify significant variation of gene expression individually. The transcriptogramer R package uses protein–protein interaction to perform differential expression of functionally associated genes. The software assesses expression profile of entire genetic systems and reveals which biological systems are significantly altered in case-control designed transcriptome experiments.

Results

R/Bioconductor transcriptogramer package projects expression values on an ordered gene list to perform topological analysis, differential expression and gene ontology enrichment analysis, independently of data platform or operating system.

Availability and implementation

http://bioconductor.org/packages/transcriptogramer.

Supplementary information

Supplementary data are available at Bioinformatics online.
MULTiPly: a novel multi-layer predictor for discovering general and specific types of promoters
Authors: Zhang Meng , Li Fuyi , Marquez-Lago Tatiana T , Leier André , Fan Cunshuo , Kwoh Chee Keong , Chou Kuo-Chen , Song Jiangning , Jia Cangzhi
Published: January 2019

Motivation

Promoters are short DNA consensus sequences that are localized proximal to the transcription start sites of genes, allowing transcription initiation of particular genes. However, the precise prediction of promoters remains a challenging task because individual promoters often differ from the consensus at one or more positions.

Results

In this study, we present a new multi-layer computational approach, called MULTiPly, for recognizing promoters and their specific types. MULTiPly took into account the sequences themselves, including both local information such as k-tuple nucleotide composition, dinucleotide-based auto covariance and global information of the entire samples based on bi-profile Bayes and k-nearest neighbour feature encodings. Specifically, the F-score feature selection method was applied to identify the best unique type of feature prediction results, in combination with other types of features that were subsequently added to further improve the prediction performance of MULTiPly. Benchmarking experiments on the benchmark dataset and comparisons with five state-of-the-art tools show that MULTiPly can achieve a better prediction performance on 5-fold cross-validation and jackknife tests. Moreover, the superiority of MULTiPly was also validated on a newly constructed independent test dataset. MULTiPly is expected to be used as a useful tool that will facilitate the discovery of both general and specific types of promoters in the post-genomic era.

Availability and implementation

The MULTiPly webserver and curated datasets are freely available at http://flagshipnt.erc.monash.edu/MULTiPly/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies
Authors: Seidah Nabil G , Prat Annik , Pirillo Angela , Catapano Alberico Luigi , Norata Giuseppe Danilo
Published: January 2019

Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2–4 weeks, they trigger a ∼60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in ∼50–60% LDL-C lowering that lasts up to 6 months (Phases II–III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels.
Asbestosis and silicosis hospitalizations in Italy (2001–2015): results from the National Hospital Discharge Registry
Authors: Ferrante Pierpaolo
Published: January 2019

Background

This work is aimed at evaluating the quality of Italian hospitalizations data about asbestosis and silicosis, assessing the impact of these diseases on the national health system and providing advice related to public health.

Methods

Italian hospital discharge data (2001–15) with diagnosis of asbestosis or silicosis were analysed by the multiple correspondence analysis and diseases epidemics were evaluated through hospitalization rates.

Results

Hospitalizations were concentrated in the northwestern area, referred mainly to males and oldest people, the most treated tumors were lung cancer and mesothelioma (for asbestosis) and cares were aimed at reducing symptoms and increasing blood oxygenation. Overall adjusted Italian hospitalization rates of asbestosis and silicosis were, respectively, 25.2 and 74.9 per 1 000 000 residents. With respect to asbestosis, hospitalizations treating silicosis reported doubled mortality (10.5 vs. 5.7%), longer stays (10.4 vs. 8.6 mean days) and older patients (77 vs. 72 years on average). Diseases rates reduced over time (with a steeper slope for silicosis) and in both fibroses increased hospital mortality (92.1% in asbestoses, 59.5% in silicoses) and percentage of urgent hospitalizations (116.0% in asbestoses, 56.6% in silicoses).

Conclusion

Hospitalizations data regarding asbestosis and silicosis are consistent. Silicosis had a higher impact than asbestosis on the Italian health system. Although data show decreasing incidence of both fibroses, multiple correspondence analysis highlights that levels of illness severity were higher in silicosis and increased over time in both diseases. Further studies investigating the effectiveness of the current health surveillance programs concerning these diseases are suggested.
Plastid Genomes and Proteins Illuminate the Evolution of Eustigmatophyte Algae and Their Bacterial Endosymbionts
Authors: Ševčíková Tereza , Yurchenko Tatiana , Fawley Karen P , Amaral Raquel , Strnad Hynek , Santos Lilia M A , Fawley Marvin W , Eliáš Marek
Published: January 2019

Eustigmatophytes, a class of stramenopile algae (ochrophytes), include not only the extensively studied biotechnologically important genus Nannochloropsis but also a rapidly expanding diversity of lineages with much less well characterized biology. Recent discoveries have led to exciting additions to our knowledge about eustigmatophytes. Some proved to harbor bacterial endosymbionts representing a novel genus, Candidatus Phycorickettsia, and an operon of unclear function (ebo) obtained by horizontal gene transfer from the endosymbiont lineage was found in the plastid genomes of still other eustigmatophytes. To shed more light on the latter event, as well as to generally improve our understanding of the eustigmatophyte evolutionary history, we sequenced plastid genomes of seven phylogenetically diverse representatives (including new isolates representing undescribed taxa). A phylogenomic analysis of plastid genome-encoded proteins resolved the phylogenetic relationships among the main eustigmatophyte lineages and provided a framework for the interpretation of plastid gene gains and losses in the group. The ebo operon gain was inferred to have probably occurred within the order Eustigmatales, after the divergence of the two basalmost lineages (a newly discovered hitherto undescribed strain and the Pseudellipsoidion group). When looking for nuclear genes potentially compensating for plastid gene losses, we noticed a gene for a plastid-targeted acyl carrier protein that was apparently acquired by horizontal gene transfer from Phycorickettsia. The presence of this gene in all eustigmatophytes studied, including representatives of both principal clades (Eustigmatales and Goniochloridales), is a genetic footprint indicating that the eustigmatophyte–Phycorickettsia partnership started no later than in the last eustigmatophyte common ancestor.
Canonical Gelfand–Zeitlin Modules over Orthogonal Gelfand–Zeitlin Algebras
Authors: Early Nick , Mazorchuk Volodymyr , Vishnyakova Elizaveta
Published: January 2019

We prove that every orthogonal Gelfand–Zeitlin algebra $U$ acts (faithfully) on its Gelfand–Zeitlin subalgebra $\Gamma $. Considering the dual module, we show that every Gelfand–Zeitlin character of $\Gamma $ is realizable in a $U$-module. We observe that the Gelfand–Zeitlin formulae can be rewritten using divided difference operators. It turns out that the action of the latter operators on $\Gamma $ gives rise to an explicit basis in a certain Gelfand–Zeitlin submodule of the dual module mentioned above. This gives, generically, both in the case of regular and singular Gelfand–Zeitlin characters, an explicit construction of simple modules, which realize the given Gelfand–Zeitlin characters.
Competition law enforcement on digital markets—lessons from recent EU case law
Authors: Kuenzler Adrian
Published: January 2019

This article is set against the Court of Justice of the European Union’s (CJEU) decisions in Pierre Fabre and Coty Germany GmbH, observing that in the digital economy, price is no longer the sole important parameter of competition and that competition law therefore has to reconstruct the theoretical background required to explain the tensions contained in the design of concentrated marketplaces. As the CJEU’s approach taken in Pierre Fabre and Coty shows, competition authorities and courts also need to consider the market’s distinct psychological properties when they contemplate the legal framework that governs it. The article thus explains the CJEU’s decisions not against the well-known debate about inter- and intrabrand competition but with reference to the notion of creating distinct types of ‘variety’ in the marketplace so as to enable consumers to choose not just between the alternative options that they face but also to enable them to make decisions that will shape the manner in which they think about whether they should consider alternative options at all. The article’s findings aim to advance debates about the overarching policy goals of the way in which digital markets ought to be regulated.
Evaluation of the Preliminary Validity of Misuse of Prescription Pain Medication Items from the Patient-Reported Outcomes Measurement Information System (PROMIS)®
Authors: You Dokyoung Sophia , Hah Jennifer M , Collins Sophie , Ziadni Maisa S , Domingue Ben W , Cook Karon F , Mackey Sean C
Published: January 2019

Objective

The National Institutes of Health’s Patient-Reported Outcomes Measurement Information System (PROMIS)® includes an item bank for measuring misuse of prescription pain medication (PROMIS-Rx Misuse). The bank was developed and its validity evaluated in samples of community-dwelling adults and patients in addiction treatment programs. The goal of the current study was to investigate the validity of the item bank among patients with mixed-etiology chronic pain conditions.

Method

A consecutive sample of 288 patients who presented for initial medical evaluations at a tertiary pain clinic completed questionnaires using the open-source Collaborative Health Outcomes Information Registry. Participants were predominantly middle-aged (M [SD] = 51.6 [15.5] years), female (62.2%), and white/non-Hispanic (51.7%). Validity was evaluated by estimating the association between PROMIS-Rx Misuse scores and scores on other measures and testing the ability of scores to distinguish among risk factor subgroups expected to have different levels of prescription pain medicine misuse (known groups analyses).

Results

Overall, score associations with other measures were as expected and scores effectively distinguished among patients with and without relevant risk factors.

Conclusion

The study results supported the preliminary validity of PROMIS-Rx Misuse item bank scores for the assessment of prescription opioid misuse in patients visiting an outpatient pain clinic.
Country of birth and county of residence and association with overweight and obesity—a population-based study of 219 555 pregnancies in Norway
Authors: Torkildsen S E , Svendsen H , Räisänen S , Sole K B , Laine K
Published: January 2019

Background

The aim was to study the effect of country of birth, educational level and county of residence on overweight and obesity among pregnant women in Norway.

Methods

Observational study based on Medical Birth Registry Norway and Statistics Norway. The study population consisted of 219 555 deliveries in 2006–2014. Body mass index (BMI) was registered at the first antenatal care visit. Multivariate regression analysis was used to explore the study aims.

Results

Overweight (BMI 25–29.9) was recorded in 22.3% of the women, obesity (BMI ≥30) in 12.2%. Highest rates of overweight (30.8%) and obesity (13.5%) was recorded among women from the Middle East and North Africa or with no education (30.7% and 17.2%). The prevalence of overweight and obesity was 39.5% in sparsely populated counties and 26.4% for women living in Oslo. Adjusted for country of birth, education level, age, parity, smoking and marital status, the relative odds of overweight and obesity were 65% (95% CI 59–72%) higher in sparsely populated counties compared to Oslo.

Conclusions

The prevalence of overweight (BMI ≥25) was 34.5%. The factors associated with overweight were living in rural districts in Norway, lower education and being born in countries in the Middle East or Africa.
“Bargaining with Patriarchy” and “Bad Girl Femininity”: Relationship and Behaviors among Chicago Girl Gangs, 1959–62
Authors: Hughes Lorine A , Botchkovar Ekaterina V , Short James F
Published: January 2019

This study uses observational, social network, and self-report survey data from a large study of male gangs in Chicago, 1959–62, to examine intragroup relationships and behaviors among their female auxiliaries, particularly the Vice Ladies and Cobraettes. Unlike descriptions of the female gang as forming a cohesive “sisterhood,” our findings revealed frequent intragroup conflict and loosely connected friendship networks. Consistent with the bulk of contemporary literature, the Chicago gang girls appeared to maintain ties with one another less for affective reasons than for the benefits they provided in the streets (e.g., peer backup). Regarding their behaviors, the Chicago gang girls engaged in both socio-sexual and stereotypically male activities, including strong-arm robbery and purse-snatching. Although sex sometimes was used to gain favor with boys, we found no evidence of it being valued and rewarded with prestige among homegirls. Instead, the most sexually active girls tended to be the least popular in the gang. The implications of these findings are discussed in the context of “bad girl femininity” performed by gang girls and gang involvement as a resource for “bargaining with patriarchy.”
Community-level impacts of spatial repellents for control of diseases vectored by Aedes aegypti mosquitoes
Authors: Bosch Quirine A. ten , Wagman Joseph M. , Castro-Llanos Fanny , Achee Nicole L. , Grieco John P. , Perkins T. Alex
Published: January 2019

Spatial repellents (SRs) reduce human-mosquito contact by preventing mosquito entrance into human-occupied spaces and interfering with host-seeking and blood-feeding. A new model to synthesize experimental data on the effects of transfluthrin on Aedes aegypti explores how SR effects interact to impact the epidemiology of diseases vectored by these mosquitoes. Our results indicate that the greatest impact on force of infection is expected to derive from the chemical’s lethal effect but delayed biting and associated negative feedbacks on the vector population could elicit substantial impact in the absence of lethality. The relative contributions of these effects depend on coverage, chemical dose, mechanism of action, and housing density. We also demonstrate potential adverse impacts of increased partial blood-feeding and reduced exiting, which could offset gains achieved by other effects. Our analysis demonstrates how small-scale experimental data can be leveraged to derive expectations of epidemiological impact of SRs deployed at larger scales.
Harmonisation of Physical Activity Variables by Indirect Validation: A Doubly Labelled Water Study
Authors: Pearce Matthew , Bishop Tom R.P. , Sharp Stephen , Westgate Kate , Venables Michelle , Wareham Nicholas J. , Brage Søren
Published: January 2019

Harmonisation of data for pooled analysis relies on the principle of inferential equivalence between variables from different sources. Ideally, this is achieved using models of the direct relationship with gold standard criterion measures, but the necessary validation data are often unavailable. This study examines an alternative method of harmonisation by indirect validation. Starting methods were self-report or accelerometry, from which we derived indirect models of relationships with doubly labelled water (DLW)-measured physical activity energy expenditure (PAEE) using sets of two bridge equations via one of three intermediate measures. Coefficients and performance of indirect models were compared to corresponding direct validation models (linear regression of DLW-measured PAEE on starting methods). Indirect model beta coefficients were attenuated compared to direct model betas (10-63%), narrowing the range of PAEE values; attenuation was greater when bridge equations were weak. Directly and indirectly harmonised models had similar error variance but most indirectly derived values were biased at group-level. Correlations with DLW-measured PAEE were identical after harmonisation using continuous linear but not categorical models. Wrist acceleration harmonised to DLW-measured PAEE via combined accelerometry and heart rate sensing had lowest error variance (24.5%) and non-significant mean bias 0.9 (95%CI: −1.6; 3.4) kJ•day−1•kg−1. Associations between PAEE and BMI were similar for directly and indirectly harmonised values, but most fell outside the confidence interval of the criterion PAEE-to-BMI association. Indirect models can be used for harmonisation. Performance depends on the measurement properties of original data, variance explained by available bridge equations, and similarity of population characteristics.
Mixture of Experts for Predicting Antibody-Antigen Binding Affinity from Antigen Sequence
Authors: Pittala Srivamshi , Bailey-Kellogg Chris
Published: January 2019

Antibodies provide a key mode of defense employed by the immune system to fight disease, so eliciting potent antibodies is one of the main goals in vaccine development. Antibodies are also being conceived as powerful therapeutic agents, so engineering potent antibodies is one of the main goals in biologic drug development. The power of antibodies lies in their affinity and specificity in recognizing their cognate antigens. Unfortunately, experimental techniques to determine antibody-antigen binding affinities are difficult to scale up to large sets of new antibodies and antigens. Though computational methods are suitable for large-scale prediction, current methods lack sufficient accuracy. Here, we address the problem of predicting the binding affinity of an antibody against an antigen variant based on the amino acid sequence of that antigen variant. We develop a mixture of experts approach that learns models for individual antibodies against some antigen variants, and then combines information across the antibodies in order to make accurate predictions for a wide range of new variants. In evaluation on a dataset consisting of 52 antibodies and 608 strains of HIV, the predictive accuracy of our approach is demonstrated to be significantly better than that of an existing approach. Our method provides a fast and accurate way to predict antibody-antigen binding affinity, which has the potential to expedite the study of antibody-antigen interactions for vaccine design and therapy.
Crossing fitness valleys via double substitutions within codons
Authors: Belinky Frida , Sela Itamar , Rogozin Igor B. , Koonin Eugene V.
Published: January 2019

Single nucleotide substitutions in protein-coding genes can be divided into synonymous (S), with little fitness effect, and non-synonymous (N) ones that alter amino acids and thus generally have a greater effect. Most of the N substitutions are affected by purifying selection that eliminates them from evolving populations. However, additional mutations of nearby bases can modulate the deleterious effect of single substitutions and thus might be subject to positive selection. To elucidate the effects of selection on double substitutions in all codons, it is critical to differentiate selection from mutational biases. We approached this problem by comparing the fractions of double substitutions within codons to those of the equivalent double S substitutions in adjacent codons. Under the assumption that substitutions occur one at a time, all within-codon double substitutions can be represented as “ancestral-intermediate-final” sequences and can be partitioned into 4 classes: 1) SS: S intermediate – S final, 2) SN: S intermediate – N final, 3) NS: N intermediate – S final, 4) NN: N intermediate – N final. We found that the selective pressure on the second substitution markedly differs among these classes of double substitutions. Analogous to single S substitutions, SS evolve neutrally whereas, analogous to single N substitutions, SN are subject to purifying selection. In contrast, NS show positive selection on the second step because the original amino acid is recovered. The NN double substitutions are heterogeneous and can be subject to either purifying or positive selection, or evolve neutrally, depending on the amino acid similarity between the final or intermediate and the ancestral states. The general trend is that the second mutation compensates for the deleterious effect of the first one, resulting in frequent crossing of valleys on the fitness landscape.
Individual listening success explained by synergistic interaction of two distinct neural filters
Authors: Tune Sarah , Fiedler Lorenz , Alavash Mohsen , Obleser Jonas
Published: January 2019

Successful speech comprehension requires the listener to differentiate relevant from irrelevant sounds. Recent neurophysiological studies have typically addressed one of two candidate neural filter solutions for this problem: the selective neural tracking of speech in auditory cortex via the modulation of phase-locked cortical responses, or the suppression of irrelevant inputs via alpha power modulations in parieto-occipital cortex. However, empirical evidence on their relationship and direct relevance to behavior is scarce. Here, a large, age-varying sample (N=76, 39–70 years) underwent a challenging dichotic listening task. Irrespective of listeners’ age, measures of behavioral performance, neural speech tracking, and alpha power lateralization all increased in response to spatial-attention cues. Under most challenging conditions, individual listening success was predicted best by the synergistic interaction of these two distinct neural filter strategies. Trial-by-trial fluctuations of lateralized alpha power and ignored-speech tracking did not co-vary, which demonstrates two neurobiologically distinct filter mechanisms.
Social touch observation in adults with autism: intact neural representations of affective meaning but lack of embodied resonance
Authors: Masson Haemy Lee , Pillet Ineke , Amelynck Steffie , Plas Stien Van De , Hendriks Michelle , Beeck Hans Op de , Boets Bart
Published: January 2019

Humans can easily grasp the affective meaning of touch when observing social interactions. Several neural systems support this ability, including theory of mind (ToM) and somatosensory resonance systems, but it is unclear how these systems are affected in autism spectrum disorder (ASD). Individuals with ASD are characterized by impairments in social interaction and the use of (non)verbal communication such as social and reciprocal touch. The present study applies an ecologically valid stimulus set and multivoxel pattern fMRI neuroimaging to pinpoint atypicalities in the neural circuitry underlying socio-affective touch observation in adults with ASD as compared to matched neurotypical controls. The MVPA results reveal that the affective meaning of touch is well represented in the temporoparietal junction, a core ToM mentalizing area, in both groups. Conversely, only the neurotypical group hosts affective touch representations in the somatosensory cortex, not the ASD group, yielding a significant group difference. Lastly, individuals with a more positive attitude towards receiving, witnessing, and providing social touch and with a higher score on social responsivity, show more differentiated representations of the affective meaning of touch in these somatosensory areas. Together, our findings imply that individuals with ASD are able to cognitively represent the affective meaning of touch, but they lack the spontaneous embodied somatosensory resonance when observing social touch communications. Individual differences in this diminished resonance appear to be related to social touch avoidance and quantitative autism traits.

Significance Statement

Autism is characterized by socio-communicative impairments, including abnormal processing of interpersonal touch. Little is known about the neural basis of atypicalities in social touch processing in autism. Here, adults with and without autism watched video clips displaying social touch interactions and judged the affective valence of the touch. Subsequently, they underwent functional magnetic resonance imaging while watching the same videos. Brain activity patterns demonstrate that adults with autism show intact cognitive understanding (i.e. “knowing”) of observed socio-affective touch experiences but lack of embodied emotional resonance (i.e. “feeling”). This lack of emotional resonance is linked to social touch avoidance and quantitative autism traits. These findings highlight that the depth of experiencing the state of others is shallower in people with autism.
Comprehensive mapping of avian influenza polymerase adaptation to the human host
Authors: Soh Y.Q. Shirleen , Moncla Louise H. , Eguia Rachel , Bedford Trevor , Bloom Jesse D.
Published: January 2019

Viruses like influenza are infamous for their ability to adapt to new hosts. Retrospective studies of natural zoonoses and passaging in the lab have identified a modest number of host-adaptive mutations. However, it is unclear if these mutations represent all ways that influenza can adapt to a new host. Here we take a prospective approach to this question by completely mapping amino-acid mutations to the avian influenza virus polymerase protein PB2 that enhance growth in human cells. We identify numerous previously uncharacterized human-adaptive mutations. These mutations cluster on PB2’s surface, highlighting potential interfaces with host factors. Some previously uncharacterized adaptive mutations occur in avian-to-human transmission of H7N9 influenza, showing their importance for natural virus evolution. But other adaptive mutations do not occur in nature because they are inaccessible via single-nucleotide mutations. Overall, our work shows how selection at key molecular surfaces combines with evolutionary accessibility to shape viral host adaptation.
Development and evaluation of a new real‐time RT‐PCR assay for detecting the latest H9N2 influenza viruses capable of causing human infection
Authors: Saito Shinji , Takayama Ikuyo , Nakauchi Mina , Nagata Shiho , Oba Kunihiro , Odagiri Takato , Kageyama Tsutomu
Published: January 2019

The H9N2 subtype of avian influenza A viruses (AIV) has spread among domestic poultry and wild birds worldwide. H9N2 AIV is sporadically transmitted to humans from avian species. A total of 42 laboratory‐confirmed cases of non‐fatal human infection with the Eurasian Y280 and G1 lineages have been reported in China, Hong Kong, Bangladesh and Egypt since 1997. H9N2 AIV infections in poultry have become endemic in Asia and the Middle East and are a major source of viral internal genes for other AIV subtypes, such that continuous monitoring of H9N2 AIV is recommended. In this study, a new, one‐step, real‐time RT‐PCR assay was developed to detect two major Eurasian H9 lineages of AIV capable of causing human infection. The sensitivity of this assay was determined using in vitro‐transcribed RNA, and the detection limit was approximately 3 copies/reaction. In this assay, no cross‐reactivity was observed against RNA from H1–15 subtypes of influenza A viruses, influenza B viruses and other viral respiratory pathogens. In addition, this assay could detect the H9 hemagglutinin (HA) gene from artificially reconstituted clinical samples spiked with H9N2 virus without any non‐specific reactions. Therefore, this assay is highly sensitive and specific for H9 HA detection. The assay is useful both for diagnostic purposes in cases of suspected human infection with influenza H9N2 viruses and for the surveillance of both avian and human influenza viruses.
The Publius Paradox
Authors: Vermeule Adrian
Published: January 2019

At the Philadelphia convention assembled to draft a new Constitution, Alexander Hamilton argued ‘[e]stablish a weak government and you must at times overleap the bounds. Rome was obliged to create dictators’. Publius then expands upon this argument in several ways in the Federalist. I suggest that Publius identifies a dynamic or mechanism, the ‘Publius Paradox’, that warrants great attention: under particular conditions, excessive weakness of government may become excessive strength. If the bonds of constitutionalism are drawn too tightly, they will be thrown off altogether when circumstances warrant. After illustrating and then analysing this ‘Publius Paradox’, I turn briefly to its implications, the main one being that constitutional law should be cast as a loosely‐fitting garment – particularly the executive component of the constitution and the scope of executive powers.
901. HELIANTHUS SALICIFOLIUS
Authors: Hind Nicholas , Smith Alison
Published: January 2019

Helianthus salicifolius A. Dietr. (Compositae: Heliantheae: Helianthinae) is described and illustrated. Cultivation, propagation, pests and diseases and availability notes, of both the species and cultivars, are provided. The genus Helianthus, and the position of H. salicifolius is commented on, as well as its similarity to H. angustifolius. Distinguishing characters between these two species are given. Comments are provided on types and typification of some of the synonyms of H. salicifolius, as well as the complications of illustrating this species and compendia of references to these illustrations that have confused H. angustifolius. The presence of the natural hybrid, H. kellermannii, is also noted and discussed.
Teacher for Children with Autism
Authors: Abrams Michael , Saunders Zina
Published: January 2019

It is hard to learn about social interaction when human interaction itself is problematic. It’s no surprise, then, that multiple studies have shown the great potential that robots hold for teaching children with autism. Richard Margolin knew the progress children with autism make when working with them so he launched RoboKind to develop an affordable robot for the children that needed one. This article looks at the journey of Milo, a robot with all the patience in the world.
Micropolar Modeling of Auxetic Chiral Lattices With Tunable Internal Rotation
Authors: Bahaloo Hassan , Li Yaning
Published: January 2019

Based on micropolar continuum theory, the closed-form stiffness tensor of auxetic chiral lattices with V-shaped wings and rotational joints were derived. Representative volume element (RVE) of the chiral lattice was decomposed into V-shape wings with fourfold symmetry. A unified V-beam finite element was developed to reduce the nodal degrees of freedoms of the RVE to enable closed-form analytical solutions. The elasticity constants were derived as functions of the angle of the V-shaped wings, nondimensional in-plane thickness of the ribs, and the stiffness of the rotational joints. The influences of these parameters on the coupled chiral and auxetic effects were systematically explored. The results show that the elastic moduli were significantly influenced by all three parameters, while Poisson's ratio was barely influenced by the in-plane thickness of the ribs but is sensitive to the angle of the V-shaped wings and the stiffness of the rotational springs. There is a transition region out of which the spring stiffness does not considerably affect the auxeticity and the overall lattice stiffness.
Queensland Microbial Keratitis Database: 2005–2015
Authors: Green Matthew , Carnt Nicole , Apel Andrew , Stapleton Fiona
Published: January 2019

Aims

To estimate the incidence of culture-positive microbial keratitis in Queensland and analyse trends in the organisms and their sensitivities cultured from corneal scrapes, especially low-incidence organisms.

Methods

Retrospective multicentre case series of all positive corneal scrapes in Queensland, Australia between 2005 and 2015. Pathology organisations in Queensland were identified by online and local directory search and agreed to participate. Digital records of scrapes provided patient demographics and culture and susceptibility results. Trends in the incidence, organisms and sensitivities were monitored with linear regression. The yearly incidence of microbial keratitis was estimated from the Queensland population.

Results

The included corneal scrapes totalled 3182, while 1006 were excluded. The included scrapes yielded 4111 organisms. Pseudomonas aeruginosa was the most common single isolate (729, 17.7%), although Gram-positive organisms were more common overall (2737, 66.6%). Fungal organisms were cultured in 6% of cases, while Acanthamoeba comprised only 1% of records. Bacterial organisms were sensitive to all recorded antibiotics in 89% of all isolates and none of the reported antibiotics showed a decreasing trend in susceptibility. The incidence of protozoal isolation decreased over time (p=0.055). Cultures positive for yeasts showed a linear increase in incidence (p=0.045) while moulds showed a spike in incidence in 2010–2012 (p=0.0008).

Conclusion

The estimated incidence of microbial keratitis was 0.66 cases per 10 000 people, the rate of antibiotic susceptibility is high and stable, the incidence of keratitis secondary to protozoa is likely to be decreasing while the incidence of keratitis culturing yeast is increasing.
Can child-focused sanitation and nutrition programming improve health practices and outcomes? Evidence from a randomised controlled trial in Kitui County, Kenya
Authors: Gimaiyo Gerishom , McManus Jeffery , Yarri Matt , Singh Shiva , Trevett Andrew , Moloney Grainne , Robins Ann , Lehmann Lilian
Published: January 2019

Introduction

In Kenya’s Kitui County, 46% of children under 5 years are stunted. Sanitation and nutrition programmes have sought to reduce child undernutrition, though they are typically implemented separately. We evaluate the effectiveness of an integrated sanitation and nutrition (SanNut) intervention in improving caregiver sanitation and nutrition knowledge and behaviours.

Methods

We conducted a cluster-randomised controlled trial to evaluate the impact of the SanNut intervention on caregiver knowledge, sanitary and hygiene practices, sanitation outcomes and nutrition outcomes. The evaluation included caregivers of children under 5 years across 604 villages in Kitui County. 309 treatment villages were randomly assigned to receive both the SanNut intervention and the standard Community-Led Total Sanitation (CLTS) intervention, while 295 control villages only received the CLTS intervention. 8 households with children under 5 years were randomly selected from each evaluation village to participate in the endline survey, for a total of 4322 households.

Results

SanNut led to modest improvements in sanitary knowledge and practices emphasised by the programme. Caregivers in treatment villages were 3.3 pp (+32%) more likely to mention lack of handwashing after handling child faeces as a potential cause of diarrhoea, and 4.9 pp (+7.8%) more likely to report safe disposal of child faeces than caregivers in control villages. Treatment households were 1.9 pp (+79%) more likely to have a stocked handwashing station and 2.9 pp (−16%) less likely to report incidences of child diarrhoea. However, SanNut appears to have had no impact on nutritional practices, such as breastfeeding, vitamin A supplementation or deworming. Non-child outcomes traditionally associated with CLTS, including latrine use and homestead sanitary conditions, were similar in treatment and control groups.

Conclusion

Child-focused messaging can potentially be integrated into CLTS programming, though this integration was more successful for topics closer to CLTS objectives (sanitation practices, including limiting faecal contamination and handwashing) than for more disparate topics (nutritional practices).

Trial registration

Pan-African Clinical Trials Registry (PACTR201803003159346) and American Economic Association registry for randomised controlled trials (AEARCTR-0002019).
Implications of the introduction of new criteria for the diagnosis of gestational diabetes: a health outcome and cost of care analysis
Authors: Cade Thomas J , Polyakov Alexander , Brennecke Shaun P
Published: January 2019

Objective

To identify effects on health outcomes from implementing new criteria diagnosing gestational diabetes mellitus(GDM) and to analyse costs-of-care associated with this change.

Design

Quasi-experimental study comparing data from the calendar year before (2014) and after (2016) the change.

Setting

Single, tertiary-level, university-affiliated, maternity hospital.

Participants

All women giving birth in the hospital, excluding those with pre-existing diabetes or multiple pregnancy.

Main outcome measures

Primary outcomes were caesarean section, birth weight >90th percentile for gestation, hypertensive disorder of pregnancy and preterm birth less than 37 weeks. A number of secondary outcomes reported to be associated with GDM were also analysed.

Care packages were derived for those without GDM, diet-controlled GDM and GDM requiring insulin. The institutional Business Reporting Unit data for average occasions of service, pharmacy schedule for the costs of consumables and medications, and Medicare Benefits Schedule ultrasound services were used for costing each package. All costs were estimated in figures from the end of 2016 negating the need to adjust for Consumer Price Index increases.

Results

There was an increase in annual incidence of GDM of 74% without overall improvements in primary health outcomes. This incurred a net cost increase of AUD$560 093. Babies of women with GDM had lower rates of neonatal hypoglycaemia and special care nursery admissions after the change, suggesting a milder spectrum of disease.

Conclusion

New criteria for the diagnosis of GDM have increased the incidence of GDM and the overall cost of GDM care. Without obvious changes in short-term outcomes, validation over other systems of diagnosis may require longer term studies in cohorts using universal screening and treatment under these criteria.
Martial arts technique for control of severe external bleeding
Authors: Slevin John P , Harrison Cierra , Da Silva Eric , White Nathan J
Published: January 2019

Objectives

Haemorrhage control is a critical component of preventing traumatic death. Other than the battlefield, haemostatic devices, such as tourniquets or bandages, may not be available, allowing for significant avoidable blood loss. We hypothesised that compression of vascular pressure points using a position adapted from the martial art of Brazilian Jiu-Jitsu could be adapted to decrease blood flow velocity in major extremity arteries.

Methods

Knee mount compression was applied to the shoulder, groin and abdomen of healthy adult volunteer research subjects from Seattle, Washington, USA, from March through May 2018. Mean arterial blood flow velocity (MAV) was measured using ultrasound in the brachial and femoral arteries before and after compression. A MAV decrease greater than 20% with compression was deemed clinically relevant.

Results

For 11 subjects, median (IQR) MAV combining all anatomical locations tested was 29.2 (34.1, 24.1) cm/s at baseline and decreased to 3.3 (0, 19.1) cm/s during compression (Wilcoxon p<0.001). MAV was significantly decreased during compression for each individual anatomical position tested (Wilcoxon p≤0.004). Per cent (95% CI) MAV reduction was significantly greater than 20% for shoulder compression at 97.5%(94% to 100%) and groin compression at 78%(56% to 100%), but was not statistically greater for abdominal compression at 35%(12% to 57%). Complete vessel occlusion was most common with compression at the shoulder (73%), followed by groin (55%) and abdomen (9%) (χ² LR, p=0.018).

Conclusion

The Brazilian Jiu-Jitsu knee mount position can significantly decrease blood flow in major arteries of the extremities. This technique may be useful for bleeding control after injury.
Literature review and economic evaluation of oral and intramuscular ziprasidone treatment among patients with schizophrenia in China
Authors: Yeh Yu-Chen , Yu Xin , Zhang Congpei , Hao Wei , Du Fen , Liu Dongdong , Yang Lili , Gao Xin
Published: January 2019

Background

Over 10 million Chinese are affected by schizophrenia. The annual cost of schizophrenia in China was estimated at US$2586 per patient.

Aims

The study has two aims: (1) to conduct a targeted literature review of the economic literature on oral ziprasidone in China, and (2) to develop an inpatient economic model that compared the cost of intramuscular ziprasidone with other regimens including electroconvulsive therapy (ECT) for the management of acute agitation in patients with schizophrenia from a hospital’s perspective in China.

Methods

A targeted literature review was conducted using PubMed and the Chinese literature databases for studies published between January 2007 and December 2017. Studies that assessed costs associated with oral ziprasidone treatment for schizophrenia in China were summarised. In the inpatient economic model, cost measures included hospital room and board, antipsychotics, ECT and medications for the management of extrapyramidal symptoms (EPS). Input for standard antipsychotic regimens and unit cost were obtained from the literature. Hospital length of stay (LOS), utilisation of ECT and incidence of EPS were derived from the literature and supplemented/validated with a survey of psychiatrists in China. Cost was presented in 2017 Chinese yuan.

Results

The average estimated LOS was 29 days with ziprasidone, 33 days with risperidone+benzodiazepine, 32 days with olanzapine, 35 days with haloperidol and 29 days with ECT. The cost of antipsychotics was ¥1260 with ziprasidone, ¥137 with risperidone+benzodiazepine, ¥913 with olanzapine and ¥210 with haloperidol; ECT treatment cost ¥785. The base-case analysis suggested that higher antipsychotic cost with ziprasidone was offset by savings with shorter LOS. Using intramuscular ziprasidone for acute management was associated with a total cost of ¥11 157, the lowest among all antipsychotic regimens (¥11 424 with risperidone+benzodiazepine, ¥11 711 with olanzapine and ¥11 912 with haloperidol) and slightly higher than ECT (¥10 606). The cost of antipsychotics and ECT accounted for 1 %–11 % of the total cost. Varying LOS between the lower and upper bounds of the 95% CI, the total cost was comparable between these regimens.

Conclusions

Overall, the cost for the management of acute agitation was similar between intramuscular ziprasidone and other antipsychotics. Compared with other antipsychotics, the higher medication cost of intramuscular ziprasidone can be offset by savings with shorter hospital stay. The results from this economic analysis were complementary to the findings in the published literature assessing the economic outcomes of oral ziprasidone.