bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell transcriptome analysis reveals TOX as a promoting factor for T-cell exhaustion and a predictor for anti-PD1 responses in human cancer
Authors: Kim Kyungsoo , Park Seyeon , Park Seong Yong , Kim Gamin , Park Su Myeong , Cho Jae-Won , Kim Da Hee , Park Young Min , Koh Yoon Woo , Kim Hye Ryun , Ha Sang-Jun , Lee Insuk
Published: May 2019

Background

T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T-cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy.

Methods

We analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8+ T-cell population based on PDCD1 (PD-1) levels, i.e. PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T-cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8+ T cells was confirmed by single-cell trajectory and flow-cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses.

Results

We retrieved many known factors for regulating T-cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8+ T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8+ T cells become more exhausted. Flow-cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T-cell exhaustion. TOX knockdown in the human TI CD8+ T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T-cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC.

Conclusions

We predicted the regulatory factors involved in T-cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8+ T-cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T-cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.
Metacognitive awareness of difficulty in action selection: the role of the cingulo-opercular network
Authors: Desender Kobe , Teuchies Martyn , Garcia Carlos Gonzalez , de Baene Wouter , Demanet Jelle , Brass Marcel
Published: May 2019

The question whether and how we are able to monitor our own cognitive states (metacognition) has been a matter of debate for decades. Do we have direct access to our cognitive processes or can we only infer them indirectly based on their consequences? In the current study, we wanted to investigate the brain circuits that underlie the metacognitive experience of fluency in action selection. To manipulate action-selection fluency we used a subliminal response priming paradigm. On each trial, both male and female human participants additionally engaged in the metacognitive process of rating how hard they felt it was to respond to the target stimulus. Despite having no conscious awareness of the prime, results showed that participants rated incompatible trials (during which subliminal primes interfered with the required response) to be more difficult than compatible trials (where primes facilitated the required response) reflecting metacognitive awareness of difficulty. This increased sense of subjective difficulty was mirrored by increased activity in the rostral cingulate zone (RCZ) and the anterior insula, two regions that are functionally closely connected. Importantly, this reflected activations that were unique to subjective difficulty ratings and were not explained by reaction times or prime-response compatibility. We interpret these findings in light of a possible grounding of the metacognitive judgement of fluency in action selection in interoceptive signals resulting from increased effort.
Acute Thiamethoxam exposure in Apis mellifera : Absence of both stress-induced changes in mRNA splicing and synergistic effects of common fungicide and herbicide
Authors: Decio Pâmela , Ustaoglu Pinar , Roat Thaisa C. , Malaspina Osmar , Devaud Jean-Marc , Stöger Reinhard , Soller Matthias
Published: May 2019

Securing food supply for a growing population is one of the current major challenges and heavily relies on the use of agrochemicals to maximize crop yield. Neonicotinoids are globally one of the most widely used insecticides. It is increasingly recognized, that neonicotinoids have a negative impact on non-target organisms, including important pollinators such as the European honey bee Apis mellifera. Toxicity of neonicotinoids may be enhanced through simultaneous exposure with additional pesticides, which could help explain, in part, the global decline of honey bee colonies. Here we examined whether exposure effects of the neonicotinoid Thiamethoxam are enhanced by the commonly used fungicide Carbendazim and the herbicide Glyphosate. For the first time, we also analysed alternative splicing changes upon pesticide exposure in the honey bee. In particular, we examined transcripts of three genes: i) the stress sensor gene X box binding protein-1 (Xbp1), ii) the Down Syndrome Cell Adhesion Molecule (Dscam) gene and iii) the embryonic lethal/abnormal visual system (elav) gene, both important genes for neuronal function. Our results indicate that neonicotinoid toxicity applied at sub-lethal doses is not enhanced by Carbendazim nor Glyphosate. Likewise, toxicity of these compounds did not impact on the complex process of spliceosomal-directed joining of exons and non-spliceosomal intron excision in the analysed mRNAs.
mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations
Authors: Yim Annie , Koti Prasanna , Bonnard Adrien , Duerrbaum Milena , Mueller Cecilia , Villaveces Jose , Gamal Salma , Cardone Giovanni , Perocchi Fabiana , Storchova Zuzana , Habermann Bianca H.
Published: May 2019

Background

Mitochondria produce cellular energy in the form of ATP and are involved in various metabolic and signaling processes. However, the cellular requirements for mitochondria are different depending on cell type, cell state or organism. Information on the expression dynamics of genes with mitochondrial functions (mito-genes) is embedded in publicly available transcriptomic or proteomic studies and the variety of available datasets enables us to study the expression dynamics of mito-genes in many different cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for gene groups such as mito-genes.

Results

Here, we introduce the web-based visual data mining platform mitoXplorer, which systematically integrates expression and mutation data of mito-genes. The central part of mitoXplorer is a manually curated mitochondrial interactome containing ∼1200 genes, which we have annotated in 35 different mitochondrial processes. This mitochondrial interactome can be integrated with publicly available transcriptomic, proteomic or mutation data in a user-centric manner. A set of analysis and visualization tools allows the mining and exploration of mitochondrial expression dynamics and mutations across various datasets from different organisms and to quantify the adaptation of mitochondrial dynamics to different conditions. We apply mitoXplorer to quantify expression changes of mito-genes of a set of aneuploid cell lines that carry an extra copy of chromosome 21. mitoXplorer uncovers remarkable differences in the regulation of the mitochondrial transcriptome and proteome due to the dysregulation of the mitochondrial ribosome in retinal pigment epithelial trisomy 21 cells which results in severe defects in oxidative phosphorylation.

Conclusions

We demonstrate the power of the visual data mining platform mitoXplorer to explore expression data in a focused and detailed way to uncover underlying potential mechanisms for further experimental studies. We validate the hypothesis-creating power of mitoXplorer by testing predicted phenotypes in trisomy 21 model systems. MitoXplorer is freely available athttp://mitoxplorer.ibdm.univ-mrs.fr. MitoXplorer does not require installation nor programming knowledge and is web-based. Therefore, mitoXplorer is accessible to a wide audience of experimental experts studying mitochondrial dynamics.
Modelling the population dynamics of Plasmodium falciparum gametocytes in humans during malaria infection
Authors: Cao Pengxing , Collins Katharine A. , Zaloumis Sophie , Wattanakul Thanaporn , Tarning Joel , Simpson Julie A. , McCarthy James S. , McCaw James M.
Published: May 2019

Every year over two hundred million people are infected with the malaria parasite. Renewed efforts to eliminate malaria has highlighted the potential to interrupt transmission from humans to mosquitoes which is mediated through the gametocytes. Reliable prediction of transmission requires an improved understanding of in vivo kinetics of gametocytes. Here we study the population dynamics of Plasmodium falciparum gametocytes in human hosts by establishing a framework which incorporates improved measurements of parasitaemia in humans, a novel mathematical model of gametocyte dynamics, and model validation using a Bayesian hierarchical inference method. We found that the novel mathematical model provides an excellent fit to the available clinical data from 17 volunteers infected with P. falciparum, and reliably predicts observed gametocyte levels. We estimated the P. falciparum’s sexual commitment rate and gametocyte sequestration time in humans to be 0.54% (95% credible interval: 0.30-1.00) per life cycle and 8.39 (6.54-10.59) days respectively. Furthermore, we used the data-calibrated model to predict the effects of those gametocyte dynamics parameters on human-to-mosquito transmissibility, providing a method to link within-human host kinetics of malaria infection to epidemiological-scale infection and transmission patterns.
Benchmarking software tools for detecting and quantifying selection in Evolve and Resequencing studies
Authors: Vlachos Christos , Burny Claire , Pelizzola Marta , Borges Rui , Futschik Andreas , Kofler Robert , Schlötterer Christian
Published: May 2019

The combination of experimental evolution with whole genome re-sequencing of pooled individuals, also called Evolve and Resequence (E&R) is a powerful approach to study selection processes and to infer the architecture of adaptive variation. Given the large potential of this method, a range of software tools were developed to identify selected SNPs and to measure their selection coefficients. In this benchmarking study, we are comparing 15 test statistics implemented in 10 software tools using three different scenarios. We demonstrate that the power of the methods differs among the scenarios, but some consistently outperform others. LRT-1, which takes advantage of time series data consistently performed best for all three scenarios. Nevertheless, the CMH test, which requires only two time points had almost the same performance. This benchmark study will not only facilitate the analysis of already existing data, but also affect the design of future data collections.
MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing
Authors: Park Joun , Zhu Yi , Tao Xianzun , Brazill Jennifer M. , Li Chong , Wuchty Stefan , Zhai R. Grace
Published: May 2019

Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. While NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.
Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis
Authors: Su Dongxue , Wang Wenjuan , Hou Yongqiang , Wang Liyong , Wang Yue , Yang Chao , Liu Beibei , Chen Xing , Wu Xiaodi , Wu Jiajing , Yan Dong , Wei Shuqi , Han Lu , Liu Shumeng , Shi Lei , Shan Lin
Published: May 2019

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.
Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s
Authors: Park Eugene , Patel Swapneel J. , Wang Qiuling , Andhey Prabhakar S. , Zaitsev Konstantin , Porter Sofia I. , Hershey Maxwell L. , Bern Michael D. , Plougastel-Douglas Beatrice , Collins Patrick L. , Colonna Marco , Murphy Kenneth M. , Oltz Eugene M. , Artyomov Maxim N. , Sibley L. David , Yokoyama Wayne M.
Published: May 2019

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describeToxoplasma gondiiinfection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes−Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.
Deep evolutionary origin of nematode SL2
trans-splicing revealed by genome-wide
analysis of the Trichinella spiralis
transcriptome
Authors: Wenzel Marius , Johnston Christopher , Müller Berndt , Pettitt Jonathan , Connolly Bernadette
Published: May 2019

Spliced leader
trans-splicing is
intimately associated with the presence of
eukaryotic operons, allowing the processing of
polycistronic RNAs into individual mRNAs. Most of
our understanding of spliced leader
trans-splicing as it
relates to operon gene expression comes from
studies in C. elegans.
In this organism, two distinct spliced leader
trans-splicing events
are recognised: SL1, which is used to replace the
5’ ends of pre-mRNAs that have a nascent
monomethyl guanosine cap; and SL2, which provides
the 5’ end to uncapped pre-mRNAs derived from
polycistronic RNAs. Limited data on operons and
spliced leader
trans-splicing in other
nematodes suggested that SL2-type
trans-splicing is a
relatively recent innovation, associated with
increased efficiency of polycistronic processing,
and confined to only one of the five major
nematode clades, Clade V. We have conducted the
first transcriptome-wide analysis of spliced
leader trans-splicing
in a nematode species, Trichinella
spiralis, which belongs to a clade
distantly related to Clade V. Our work identifies
a set of T. spiralis
SL2-type spliced leaders that are specifically
used to process polycistronic RNAs, the first
examples of specialised spliced leaders that have
been found outside of Clade V. These
T. spiralis spliced
leader RNAs possess a perfectly conserved
stem-loop motif previously shown to be essential
for polycistronic RNA processing in
C. elegans. We show
that this motif is found in specific sets of
spliced leader RNAs broadly distributed across the
nematode phylum. This work substantially revises
our understanding of the evolution of nematode
spliced leader
trans-splicing, showing
that the machinery for SL2
trans-splicing evolved
much earlier during nematode evolution than was
previously appreciated, and has been conserved
throughout the radiation of the nematode
phylum.
Synthesizing the effects of large, wild herbivore exclusion on ecosystem function
Authors: Forbes Elizabeth S. , Cushman J. Hall , Burkepile Deron E. , Young Truman P. , Klope Maggie , Young Hillary S.
Published: May 2019

Wild large herbivores are declining worldwide. Despite extensive use of exclosure experiments to investigate herbivore impacts, there is little consensus on the effects of wild large herbivores on ecosystem function.

Of the ecosystem functions likely impacted, we reviewed the five most‐studied in exclosure experiments: ecosystem resilience/resistance to disturbance, nutrient cycling, carbon cycling, plant regeneration, and primary productivity.

Experimental data on large wild herbivores' effects on ecosystem functions were predominately derived from temperate grasslands (50% grasslands, 75% temperate zones). Additionally, data were from experiments that may not be of adequate size (median size 400 m2despite excluding all experiments below 25 m2) or duration (median duration 6 years) to capture ecosystem‐scale responses to these low‐density and wide‐ranging taxa.

Wild herbivore removal frequently impacted ecosystem functions; for example, net carbon uptake increased by three times in some instances. However, the magnitude and direction of effects, even within a single function, were highly variable.

A focus on carbon cycling highlighted challenges in interpreting effects on a single function. While the effect of large herbivore exclusion on carbon cycling was slightly positive when its components (e.g. pools vs. fluxes of carbon) were aggregated, effects on individual components were variable and sometimes opposed.

Given modern declines in large wild herbivores, it is critical to understand their effects on ecosystem function. However, this synthesis highlights strong variability in direction, magnitude, and modifiers of these effects. Some variation is likely due to disparity in what components are used to describe a given function. For example, for the carbon cycle we identified eight distinctly meaningful components, which are not easily combined yet are potentially misrepresentative of the larger cycle when considered alone. However, much of the observed difference in responses likely reflects real ecological variability across complex systems.

To move towards a general predictive framework we must identify where variation in effect is due to methodological differences and where due to ecosystem context. Two critical steps forward are (a) additional quantitative synthetic analyses of large herbivores' effects on individual functions, and (b) improved, increased systematic exclosure research focusing on effects of large herbivores' exclusion on functions.

A freePlain Language Summarycan be found within the Supporting Information of this article.
Tropodithietic acid induces oxidative stress response, cell envelope biogenesis and iron uptake in Vibrio vulnificus
Authors: Dittmann Karen K. , Porsby Cisse H. , Goncalves Priscila , Mateiu Ramona Valentina , Sonnenschein Eva C. , Bentzon‐Tilia Mikkel , Egan Suhelen , Gram Lone
Published: May 2019

The Roseobacter group is a widespread marine bacterial group, of which some species produce the broad‐spectrum antibiotic tropodithietic acid (TDA). A mode of action for TDA has previously been proposed in Escherichia coli, but little is known about its effect on non‐producing marine bacteria at in situ concentrations. The purpose of this study was to investigate how a sub‐lethal level of TDA affects Vibrio vulnificus at different time points (30 and 60 min) using a transcriptomic approach. Exposure to TDA for as little as 30 min resulted in the differential expression of genes associated with cell regeneration, including the up‐regulation of those involved in biogenesis of the cell envelope. Defence mechanisms including oxidative stress defence proteins and iron uptake systems were also up‐regulated in response to TDA, while motility‐related genes were down‐regulated. Gene expression data and scanning electron microscopy imaging revealed a switch to a biofilm phenotype in the presence of TDA. Our study shows that a low concentration of this antibiotic triggers a defence response to reactive oxygen species and iron depletion in V. vulnificus, which indicates that the mode of action of TDA is likely more complex in this bacterium than what is known for E. coli.
Only α‐Gal bound to lipids, but not to proteins, is transported across enterocytes as an IgE‐reactive molecule that can induce effector cell activation
Authors: Román‐Carrasco Patricia , Lieder Barbara , Somoza Veronika , Ponce Marta , Szépfalusi Zsolt , Martin Diana , Hemmer Wolfgang , Swoboda Ines
Published: May 2019

Background

The oligosaccharide galactose‐α‐1,3‐galactose (α‐Gal), present in mammalian proteins and lipids, causes an unusual delayed allergic reaction 3 to 6 hours after ingestion of mammalian meat in individuals with IgE antibodies against α‐Gal. To better understand the delayed onset of allergic symptoms and investigate whether protein‐bound or lipid‐bound α‐Gal causes these symptoms, we analyzed the capacity of α‐Gal conjugated proteins and lipids to cross a monolayer of intestinal cells.

Methods

Extracts of proteins and lipids from beef were prepared, subjected to in vitro digestions, and added to Caco‐2 cells grown on permeable supports. The presence of α‐Gal in the basolateral medium was investigated by immunoblotting, thin‐layer chromatography with immunostaining and ELISA, and its allergenic activity was analyzed in a basophil activation test.

Results

After addition of beef proteins to the apical side of Caco‐2 cells, α‐Gal containing peptides were not detected in the basolateral medium. Those peptides that crossed the Caco‐2 monolayer did not activate basophils from an α‐Gal allergic patient. Instead, when Caco‐2 cells were incubated with lipids extracted from beef, α‐Gal was detected in the basolateral medium. Furthermore, these α‐Gal lipids were able to activate the basophils of an α‐Gal allergic patient in a dose‐dependent manner.

Conclusion

Only α‐Gal bound to lipids, but not to proteins, is able to cross the intestinal monolayer and trigger an allergic reaction. This suggests that the slower digestion and absorption of lipids might be responsible for the unusual delayed allergic reactions in α‐Gal allergic patients and identifies glycolipids as potential allergenic molecules.
Meiotic gene activation in somatic and germ cell tumours
Authors: Feichtinger J. , McFarlane R. J.
Published: May 2019

Background

Germ cell tumours are uniquely associated with the gametogenic tissues of males and females. A feature of these cancers is that they can express genes that are normally tightly restricted to meiotic cells. This aberrant gene expression has been used as an indicator that these cancer cells are attempting a programmed germ line event, meiotic entry. However, work in non‐germ cell cancers has also indicated that meiotic genes can become aberrantly activated in a wide range of cancer types and indeed provide functions that serve as oncogenic drivers. Here, we review the activation of meiotic factors in cancers and explore commonalities between meiotic gene activation in germ cell and non‐germ cell cancers.

Objectives

The objectives of this review are to highlight key questions relating to meiotic gene activation in germ cell tumours and to offer possible interpretations as to the biological relevance in this unique cancer type.

Materials and Methods

PubMed and the GEPIA database were searched for papers in English and for cancer gene expression data, respectively.

Results

We provide a brief overview of meiotic progression, with a focus on the unique mechanisms of reductional chromosome segregation in meiosis I. We then offer detailed insight into the role of meiotic chromosome regulators in non‐germ cell cancers and extend this to provide an overview of how this might relate to germ cell tumours.

Conclusions

We propose that meiotic gene activation in germ cell tumours might not indicate an unscheduled attempt to enter a full meiotic programme. Rather, it might simply reflect either aberrant activation of a subset of meiotic genes, with little or no biological relevance, or aberrant activation of a subset of meiotic genes as positive tumour evolutionary/oncogenic drivers. These postulates provide the provocation for further studies in this emerging field.
A two‐tiered high‐flow nasal cannula approach to bronchiolitis was associated with low admission rate to intensive care and no adverse outcomes
Authors: Daverio Marco , Da Dalt Liviana , Panozzo Matteo , Frigo Anna Chiara , Bressan Silvia
Published: May 2019

Aim

We aimed to describe the characteristics and outcomes of infants with bronchiolitis who received high‐flow nasal cannula oxygen (HFNC) following a two‐tiered approach.

Methods

This retrospective study included 211 infants below 12 months of age needing oxygen therapy for bronchiolitis, between 2012 and 2017, on the general paediatric ward of the tertiary Paediatric Hospital of Padova, Italy. HFNC was used as first‐line therapy for moderate to severe disease and as rescue therapy for deterioration on low‐flow oxygen.

Results

Median age was 61 days (IQR 31–126), and 57.3% were males. HFNC was used as first‐line therapy in 35/211 (16.6%) infants and as rescue in 73/176 (41.5%) patients on low‐flow oxygen. Overall 9/211 patients (4.3%) were admitted to intensive care, representing a HFNC failure of 9/108 (8.3%). Intensive care admissions did not significantly differ between initial low‐flow oxygen therapy and HFNC (8/176, 4.5% versus 1/35, 2.8%, proportion difference 1.7%, 95%CI −10.2 to 6.7), or between initial and rescue HFNC (1/35, 2.8% versus 8/73, 10.9%; proportion difference 8.1%, 95%CI −4.5 to 18). Only two patients developed air leak and were treated conservatively.

Conclusion

A two‐tiered approach to HFNC use in bronchiolitis was associated with low intensive care admissions and no adverse outcomes.
Strong Start in birth centers: Socio‐demographic characteristics, care processes, and outcomes for mothers and newborns
Authors: Alliman Jill , Stapleton Susan R. , Wright Jennifer , Bauer Kate , Slider Kate , Jolles Diana
Published: May 2019

Background

A recent Center for Medicare and Medicaid Innovation report evaluated the four‐year Strong Start for Mothers and Newborns Initiative, which sought to improve maternal and newborn outcomes through exploration of three enhanced, evidence‐based care models. This paper reports the socio‐demographic characteristics, care processes, and outcomes for mothers and newborns engaged in care with American Association of Birth Centers (AABC) sites.

Methods

The authors examined data for 6424 Medicaid or Children's Health Insurance Program (CHIP) beneficiaries in birth center care who gave birth between 2013 and 2017. Using data from the AABC Perinatal Data Registry™, descriptive statistics were used to evaluate socio‐behavioral and medical risks, and core perinatal quality outcomes. Comparisons are made between outcomes in the AABC sample and national data during the study period.

Results

Childbearing mothers enrolled at AABC sites had diverse socio‐behavioral risk factors similar to the national profile. The AABC sites exceeded national quality benchmarks for low birthweight (3.28%), preterm birth (4.42%), and primary cesarean birth (8.56%). Racial disparities in perinatal indicators were present within the Strong Start sample; however, they were at narrower margins than in national data. The enhanced model of care was notable for use of midwifery‐led prenatal, labor, and birth care and decreased hospital admission.

Conclusions

Birth center care improves population health, patient experience, and value. The model demonstrates the potential to decrease racial disparity and improve population health. Reduction of regulatory barriers and implementation of sustainable reimbursement are warranted to move the model to scale for Medicaid beneficiaries nationwide.
Reconsidering self‐deprecation as a communication practice
Authors: Speer Susan A.
Published: May 2019

‘Self‐deprecation’ (SD) is widely understood within social psychology and popular culture as a form of self‐talk that reflects a cognitive state, such as low self‐esteem or negative self‐regard. However, most research on SD suffers theoretical and methodological problems that fail to account for how its cognitive and linguistic aspects can be reconciled. We know little about SD as it occurs in interactional settings. Utilizing a conversation analytic (CA) perspective that brackets cognitive explanations for linguistic phenomena, this paper draws on more than 100 hours of transcribed recordings of interactions from diverse settings to systematically examine the form and function of a common class of SD: critical comments by a speaker on their current talk or actions (self‐deprecatory meta‐comments; SDMCs). Analyses demonstrate that SDMCs are used in environments of possible or actual interactional trouble, and manage this trouble in different sequential positions. The paper shows that SDs can be treated as a communication practice. Rigorous analysis of SDMCs can enrich understanding of the construction of ‘identities’ in talk. It advances a CA understanding of the ascription of social actions, and the preference for self‐criticism over criticism by others. Findings suggest that widespread advice to self‐deprecate less may be invalid.
Multiparametric MRI prior to radical prostatectomy identifies intraductal and cribriform growth patterns in prostate cancer
Authors: Tonttila Panu P. , Ahtikoski Anne , Kuisma Mari , Pääkkö Eija , Hirvikoski Pasi , Vaarala Markku H.
Published: May 2019

Objectives

To evaluate the diagnostic value of multiparametric prostate magnetic resonance imaging (mpMRI) prior to radical prostatectomy with curative intent for the detection of cribriform architecture (CA) and intraductal prostate cancer (IDC), which have recently been demonstrated to be adverse pathological features.

Patients and Methods

The study included 124 men who underwent mpMRI prior to radical prostatectomy at our centre. Preoperative mpMRI, prostatectomy histology and clinical follow‐up details were reviewed retrospectively. The diagnostic value of mpMRI was evaluated on the basis of the detection rate. Secondly, the prognostic significance of CA/IDC among grade group (GG)2 cancers with regard to biochemical recurrence (BCR)‐free survival was assessed using Kaplan–Meier analysis, with the log rank test and Fisher's exact test.

Results

Pathological examination of radical prostatectomy specimens identified CA/IDC in 89 of 124 cases (71%) and mpMRI identified 86/95 of tumours including any CA/IDC with a sensitivity of 90.5% (95% confidence interval 82.8–95.6%). When localization of the lesions was compared, there was an association between the highest Prostate Imaging‐Reporting and Data System classification and the highest pathological grade in 106 of the 124 cases (85.5%). In patients with GG2 lesions, BCR occurred in 11 of 31 (35.5%) with CA/IDC and two of 21 (9.5%) without CA/IDC (P = 0.034).

Conclusion

Multiparametric MRI has good sensitivity for detection of pathological primary prostate cancer, including most cases with CA/IDC; however, reliable prediction of GG2 tumours with CA/IDC for individual risk stratification remains challenging.
Sex‐moderated interactions between IL4/IL13 pathway genes and prenatal environment on cord blood IgE levels
Authors: Chen Chien‐Han , Lee Yungling Leo , Wu Ming‐Hsun , Chen Pao‐Jen , Wei Tien‐Shan , Chen Pau‐Chung , Tseng Ching‐Ing , Chen Wei J.
Published: May 2019

Background

Elevated cord blood IgE (cIgE), a predictor of atopic diseases, is influenced by genetic and environmental factors. However, gene‐environment interactions on cIgE elevation and their difference by sex remain largely unexplored.

Objective

This study aimed to determine whether there are sex‐moderated interactions between genetic variants in the IL4/IL13 pathway and prenatal environments on cIgE elevation.

Methods

Comprehensive information on environmental tobacco smoke (ETS), home dampness (indexed by combining mildewy odour, visible mould and water stamp on the wall) and other household environments was obtained using a structured questionnaire during the third trimester of pregnancy in 1107 full‐term newborns. The cord blood was collected for measuring cIgE levels, with elevation defined as ≥0.5 IU/mL, and for genotyping of five single nucleotide polymorphisms of three candidate genes (IL‐13 rs1800925, rs20541, rs848, IL‐4 rs2243250 and STAT6 rs324011).

Results

Gene‐environment interactions on cIgE elevation were observed in male but not female newborns, including those between ETS and IL13 rs20541, between home dampness and STAT6 rs324011, and between composite environmental exposure (combined ETS and the three home dampness indices) and STAT6 rs324011 (P for interaction = 0.03, 0.006, and 0.001, respectively). Male newborns carrying STAT6 rs324011 CT or TT genotype manifested with a significant dose‐response association of the composite environmental exposure with cIgE elevation.

Conclusion and Clinical Relevance

Sex moderates the gene‐environment interactions involving IL4/IL13 pathway genes and prenatal household environments on cIgE elevation. The absence of prenatal exposure to ETS and home dampness in male neonates carrying the STAT6 rs324011 CT or TT genotype is least likely associated with cIgE elevation.
Impact of delayed radioiodine therapy in intermediate‐/high‐risk papillary thyroid carcinoma
Authors: Kim Mijin , Han Minkyu , Jeon Min Ji , Kim Won Gu , Kim In Joo , Ryu Jin‐Sook , Kim Won Bae , Shong Young Kee , Kim Tae Yong , Kim Bo Hyun
Published: May 2019

Objective

It remains unclear whether the time interval between total thyroidectomy and radioactive iodine therapy (RAIT) affects clinical outcomes in papillary thyroid carcinoma (PTC). Therefore, we evaluated the impact of timing of the first post‐thyroidectomy RAIT in intermediate‐to‐high‐risk PTC.

Design and Patients

This retrospective propensity score‐matched cohort study included 720 PTC patients who received RAIT for <90 or 90‐180 days (early and delayed groups, n = 360 each) after thyroidectomy. Responses to therapy, disease‐free survival (DFS) and overall survival (OS) were compared between the two groups.

Results

After matching, the baseline characteristics of the 360 patients in each group were similarly adjusted. Within the first 2 years after initial therapy, the number of patients classified into excellent, indeterminate, biochemical incomplete and structural incomplete response categories were 221 (61%), 74 (21%), 39 (11%) and 26 (7%) in the early group, and 204 (57%), 73 (20%), 59 (16%) and 24 (7%) in the delayed group, respectively. There was no significant difference in response to therapy between the two groups (P = 0.183). During the median follow‐up of 8.6 years, there was no significant difference in DFS (P = 0.060) and OS (P = 0.400) curves between the two groups. Delayed RAIT was not significantly associated with worse DFS (HR = 1.3, 95% CI 0.9‐1.8, P = 0.061) or OS (HR = 1.5, 95% CI 0.6‐3.4, P = 0.388).

Conclusions

Delaying the first RAIT until 180 days after total thyroidectomy had no impact on restaging, recurrence and mortality in intermediate‐to‐high‐risk PTC.
Veneered zirconia abutments cemented on non‐original titanium bases: 1‐year results of a prospective case series
Authors: Asgeirsson Asgeir G. , Sailer Irena , Gamper Felix , Jung Ronald E. , Hämmerle Christoph H. F. , Thoma Daniel S.
Published: May 2019

Objectives

To assess clinical, technical, and esthetic outcomes of veneered zirconia reconstructions cemented on non‐original titanium bases over 1 year.

Materials and methods

Twenty‐four healthy patients presented with one missing tooth in the anterior maxilla or mandible and received a two‐piece dental implant. The implants were restored with a screw‐retained crown using a directly veneered zirconia reconstruction, which was extraorally cemented on a titanium base. After crown insertion, patients were scheduled for a baseline examination and re‐examined at 6 months and at 1 year of loading. Measurements included biological, technical, and esthetic parameters. Data were analyzed with nonparametric tests.

Results

Mean marginal bone levels measured 0.54 ± 0.39 mm (median: 0.47, range: 0.07–1.75 mm) at baseline and 0.54 ± 0.45 mm (median: 0.44, range: 0.06–1.52 mm) at 1 year. Mean probing depth (PD) (3.0 ± 0.6 mm at baseline to 3.5 ± 0.7 mm at 1 year [p = 0.002]), bleeding on probing (BOP) (27.1% ± 20.7% at baseline to 43.9% ± 28.0% at 1 year [p = 0.041]), plaque index (PI) (11.1% ± 21.2% at baseline to 18.2% ± 21.8% at 1 year [p = 0.381]) increased, whereas the width of the keratinized mucosa decreased from baseline to 1 year (3.1 ± 1.3 mm at baseline to 3.0 ± 1.2 mm at 1 year [p = 0.398]). Four implants (16.7%) were diagnosed with peri‐implantitis (BOP positive, bone loss >1 mm) during the 1‐year observation period. One implant was lost at 3 ½ months, resulting in a 95.8% survival rate. Four technical complications occurred and led to 83.3% complication‐free reconstructions.

Conclusion

A significant increase in PD and BOP values was observed using directly veneered zirconia reconstructions cemented on non‐original titanium bases.
A new vessel segmentation algorithm for robust blood flow quantification from two‐dimensional phase‐contrast magnetic resonance images
Authors: Bidhult Sebastian , Hedström Erik , Carlsson Marcus , Töger Johannes , Steding‐Ehrenborg Katarina , Arheden Håkan , Aletras Anthony H. , Heiberg Einar
Published: May 2019

Blood flow measurements in the ascending aorta and pulmonary artery from phase‐contrast magnetic resonance images require accurate time‐resolved vessel segmentation over the cardiac cycle. Current semi‐automatic segmentation methods often involve time‐consuming manual correction, relying on user experience for accurate results. The purpose of this study was to develop a semi‐automatic vessel segmentation algorithm with shape constraints based on manual vessel delineations for robust segmentation of the ascending aorta and pulmonary artery, to evaluate the proposed method in healthy volunteers and patients with heart failure and congenital heart disease, to validate the method in a pulsatile flow phantom experiment, and to make the method freely available for research purposes. Algorithm shape constraints were extracted from manual reference delineations of the ascending aorta (n = 20) and pulmonary artery (n = 20) and were included in a semi‐automatic segmentation method only requiring manual delineation in one image. Bias and variability (bias ± SD) for flow volume of the proposed algorithm versus manual reference delineations were 0·0 ± 1·9 ml in the ascending aorta (n = 151; seven healthy volunteers; 144 heart failure patients) and −1·7 ± 2·9 ml in the pulmonary artery (n = 40; 25 healthy volunteers; 15 patients with atrial septal defect). Interobserver bias and variability were lower (P = 0·008) for the proposed semi‐automatic method (−0·1 ± 0·9 ml) compared to manual reference delineations (1·5 ± 5·1 ml). Phantom validation showed good agreement between the proposed method and timer‐and‐beaker flow volumes (0·4 ± 2·7 ml). In conclusion, the proposed semi‐automatic vessel segmentation algorithm can be used for efficient analysis of flow and shunt volumes in the aorta and pulmonary artery.
Multidrug‐resistant Gram‐negative bacterial infections in solid organ transplant recipients—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Pouch Stephanie M. , Patel Gopi ,   the AST Infectious Diseases Community of Practice
Published: May 2019

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of infections due to multidrug‐resistant (MDR) Gram‐negative bacilli in the pre‐ and post‐transplant period. MDR Gram‐negative bacilli, including carbapenem‐resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and carbapenem‐resistant Acinetobacter baumannii, remain a threat to successful organ transplantation. Clinicians now have access to at least five novel agents with activity against some of these organisms, with others in the advanced stages of clinical development. No agent, however, provides universal and predictable activity against any of these pathogens, and very little is available to treat infections with MDR nonfermenting Gram‐negative bacilli including A baumannii. Despite advances, empiric antibiotics should be tailored to local microbiology and targeted regimens should be tailored to susceptibilities. Source control remains an important part of the therapeutic armamentarium. Morbidity and mortality associated with infections due to MDR Gram‐negative organisms remain unacceptably high. Heightened infection control and antimicrobial stewardship initiatives are needed to prevent these infections, curtail their transmission, and limit the evolution of MDR Gram‐negative pathogens, especially in the setting of organ transplantation.
Intergenerational transmission of literacy skills among Filipino families
Authors: Dulay Katrina M. , Cheung Sum K. , McBride Catherine
Published: May 2019

We examined the joint role of parental word reading skills and conventional home literacy environment measures among 320 Filipino low‐ to middle‐income families in Cebu City, Philippines with children aged 5–8 years old. A ranking of parent‐reported ratings of their frequency of engaging in home literacy activities and adult literacy practices revealed that book‐related behaviors were less frequently practiced relative to other behaviors, and mean ratings on the home literacy resources scale suggested a relatively print‐poor environment. Nevertheless, scale items about book reading and direct literacy instruction at home correlated with child's language and literacy skills. Structural equation modeling showed that parent's education and frequency of engaging in home literacy activities uniquely accounted for variance in child's oral language and print knowledge skills. In a second model, parent's word reading skills were significantly related to child's skills, but did not eliminate or attenuate influences from parent's education and home literacy activities. Results are important in relation to theories on the intergenerational transmission of literacy skills and the generalizability of findings from developed countries to developing country contexts.
A comparative analysis of egg provisioning using mass spectrometry during rapid life history evolution in sea urchins
Authors: Davidson Phillip L. , Thompson J. Will , Foster Matthew W. , Moseley M. Arthur , Byrne Maria , Wray Gregory A.
Published: May 2019

A dramatic life history switch that has evolved numerous times in marine invertebrates is the transition from planktotrophic (feeding) to lecithotrophic (nonfeeding) larval development—an evolutionary tradeoff with many important developmental and ecological consequences. To attain a more comprehensive understanding of the molecular basis for this switch, we performed untargeted lipidomic and proteomic liquid chromatography‐tandem mass spectrometry on eggs and larvae from three sea urchin species: the lecithotroph Heliocidaris erythrogramma, the closely related planktotroph Heliocidaris tuberculata, and the distantly related planktotroph Lytechinus variegatus. We identify numerous molecular‐level changes possibly associated with the evolution of lecithotrophy in H. erythrogramma. We find the massive lipid stores of H. erythrogramma eggs are largely composed of low‐density, diacylglycerol ether lipids that, contrary to expectations, appear to support postmetamorphic development and survivorship. Rapid premetamorphic development in this species may instead be powered by upregulated carbohydrate metabolism or triacylglycerol metabolism. We also find proteins involved in oxidative stress regulation are upregulated in H. erythrogramma eggs, and apoB‐like lipid transfer proteins may be important for echinoid oogenic nutrient provisioning. These results demonstrate how mass spectrometry can enrich our understanding of life history evolution and organismal diversity by identifying specific molecules associated with distinct life history strategies and prompt new hypotheses about how and why these adaptations evolve.
Sex differences in the association of APOE ε4 genotype with longitudinal hippocampal atrophy in cognitively normal older people
Authors: Shen S. , Zhou W. , Chen X. , Zhang J. ,   for Alzheimer's Disease Neuroimaging Initiative
Published: May 2019

Background and purpose

The aim of this study was to determine the effects of apolipoprotein E ε4 (APOE ε4) genotype and sex together on longitudinal change in adjusted hippocampal volume [hippocampal volume:intracranial volume ratio (HpVR)] across the Alzheimer's disease (AD) continuum.

Methods

At baseline, we included 372 individuals with normal cognition (NC), 738 individuals with mild cognitive impairment (MCI) and 271 patients with mild AD from the Alzheimer's Disease Neuroimaging Initiative database. We examined the effects of the APOE ε4 by sex interaction on longitudinal change in HpVR within the overall sample and within each diagnostic group.

Results

Female gender was found to be associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Similarly, APOE ε4 was associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Further, female APOE ε4 carriers showed a greater longitudinal reduction of HpVR than their male counterparts in the NC group, but not in the MCI or AD group. However, due to the relatively short duration of follow‐up visits in patients with AD, further studies are needed to replicate these findings.

Conclusion

Female APOE ε4 carriers show a greater longitudinal reduction of HpVR than their male counterparts in cognitively normal older adults.