bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of CP77 as the third orthopoxvirus SAMD9L inhibitor with a unique specificity for a rodent SAMD9L
Authors: Zhang Fushun , Meng Xiangzhi , Townsend Michael B , Satheshkumar Panayampalli Subbian , Xiang Yan
Published: February 2019

Orthopoxviruses (OPXVs) have a broad host range in mammalian cells, but Chinese hamster ovary (CHO) cells are non-permissive for vaccinia virus (VACV). Here, we revealed a species-specific difference in host restriction factor SAMD9L as the cause for the restriction and identified orthopoxvirus CP77 as a unique inhibitor capable of antagonizing Chinese hamster SAMD9L (chSAMD9L). Two known VACV inhibitors of SAMD9 and SAMD9L (SAMD9&L), K1 and C7, can bind human and mouse SAMD9&L, but neither can bind chSAMD9L. CRISPR-Cas9 knockout of chSAMD9L from CHO cells removed the restriction for VACV, while ectopic expression of chSAMD9L imposed the restriction for VACV in a human cell line, demonstrating that chSAMD9L is a potent restriction factor for VACV. Contrary to K1 and C7, cowpox virus CP77 can bind chSAMD9L and rescue VACV replication in cells expressing chSAMD9L, indicating that CP77 is yet another SAMD9L inhibitor but has a unique specificity for chSAMD9L. Binding studies showed that the N-terminal 382 amino acids of CP77 were sufficient for binding chSAMD9L and that both K1 and CP77 target a common internal region of SAMD9L. Growth studies with nearly all OPXV species showed that the ability of OPXVs in antagonizing chSAMD9L correlates with CP77 gene status and that a functional CP77 ortholog was maintained in many OPXVs, including monkeypox virus. Our data suggest that species-specific difference in rodent SAMD9L poses a barrier for cross-species OPXV infection and that OPXVs have evolved three SAMD9L inhibitors with different specificities to overcome this barrier.

IMPORTANCE

Several OPXV species, including monkeypox virus and cowpox virus, cause zoonotic infection in humans. They are believed to use wild rodents as the reservoir or intermediate hosts, but the host or viral factors that are important for OPXV host range in rodents are unknown. Here, we showed that the abortive replication of several OPXV species in a Chinese hamster cell line was caused by a species-specific difference in the host antiviral factor SAMD9L, indicating that SAMD9L divergence in different rodent species poses a barrier for cross-species OPXV infection. While the Chinese hamster SAMD9L could not be inhibited by two previously identified OPXV inhibitors of human and mouse SAMD9L, it can be inhibited by cowpox virus CP77, indicating that OPXVs encode three SAMD9L inhibitors with different specificity. Our data suggest that OPXV host range in broad rodent species depends on three SAMD9L inhibitors with different specificities.
Diversity of photosynthetic picoeukaryotes in eutrophic shallow lakes as assessed by combining flow cytometry cell-sorting and high throughput sequencing
Authors: Metz Sebastián , dos Santos Adriana Lopes , Berman Manuel Castro , Bigeard Estelle , Licursi Magdalena , Not Fabrice , Lara Enrique , Unrein Fernando
Published: February 2019

Photosynthetic picoeukaryotes (PPE) are key components of primary production in marine and freshwater ecosystems. In contrast with those of marine environments, freshwater PPE groups have received little attention. In this work, we used flow cytometry cell sorting, microscopy and metabarcoding to investigate the composition of small photosynthetic eukaryote communities from six eutrophic shallow lakes in South America, Argentina. We compared the total molecular diversity obtained from PPE sorted populations as well as from filtered total plankton samples (FTP). Most reads obtained from sorted populations belonged to the classes: Trebouxiophyceae, Chlorophyceae and Bacillariophyceae. We retrieved sequences from non-photosynthetic groups, such as Chytridiomycetes and Ichthyosporea which contain a number of described parasites, indicating that these organisms were probably in association with the autotrophic cells sorted. Dominant groups among sorted PPEs were poorly represented in FTP and their richness was on average lower than in the sorted samples. A significant number of operational taxonomic units (OTUs) were exclusively found in sorting samples, emphasizing that sequences from FTP underestimate the diversity of PPE. Moreover, 22% of the OTUs found among the dominant groups had a low similarity (<95%) with reported sequences in public databases, demonstrating a high potential for novel diversity in these lakes.
An assay to measure the activity of RNA elements and proteins that promote the expression of mRNA with retained introns
Authors: Jackson Patrick E. H. , Huang Jing , Sharma Monika , Rasmussen Sara K. , Hammarskjold Marie-Louise , Rekosh David
Published: February 2019

The ability to overcome cellular restrictions that exist for the export and translation of mRNAs with retained introns is a requirement for the replication of retroviruses and also for the expression of many mRNA isoforms transcribed from cellular genes. In some cases, RNA structures have been identified in the mRNA that directly interact with cellular factors to promote the export and expression of isoforms with retained introns. In other cases, a viral protein is also required to act as an adapter. In this report we describe a novel vector system that allows measurement of the ability ofcis-andtrans-acting factors to promote the export and translation of mRNA with retained introns.

One reporter vector used in this system is derived from an HIV proviral clone engineered to express two different fluorescent proteins from spliced and unspliced transcripts. The ratio of fluorescent signals is a measurement of the efficiency of export and translation. A second vector utilizes a third fluorescent protein to measure the expression of viral export proteins that interact with some of the export elements. Both vectors can be packaged into viral particles and be used to transduce cells, allowing expression at physiological levels from the integrated vector.
Noradrenergic responsiveness preserves selective attention across the adult life span
Authors: Dahl Martin J. , Mather Mara , Sander Myriam C. , Werkle-Bergner Markus
Published: February 2019

Selectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in non-invasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a non-invasive marker of phasic norepinephrine (NE) release, while concurrently recording the electroencephalogram (EEG), of younger (N=39♂; 25.2±3.2 years) and older adults (N=38♂; 70.6±2.7 years). NE release was triggered on a trial-by-trial basis using fear-conditioned (CS+) stimuli. During conditioning, pupil and EEG markers related to heightened NE activity were identified. Afterwards, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears.

During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired fear response, as reflected in pupil and EEG alpha–beta-band responses. Critically, pupil dilation to CS+ was correlated with stronger EEG alpha–beta desynchronization, suggesting a common dependence on NE release. On a behavioral level, NE release facilitated attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the life span.

Significance statement

In old age the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants’ noradrenergic system while recording pupillometry and electroencephalography (EEG) to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups a more responsive noradrenergic system was strongly associated to attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late life cognition.
A novel cellular structure in the photoreceptors of insectivorous birds
Authors: Tyrrell Luke P. , Teixeira Leandro B.C. , Dubielzig Richard R. , Pita Diana , Baumhardt Patrice , Moore Bret A. , Fernández-Juricic Esteban
Published: February 2019

The keen visual systems of birds have been relatively well-studied. The foundations of avian vision rest on their cone and rod photoreceptors. Most birds use four cone photoreceptor types for color vision, a fifth cone for achromatic tasks, and a rod for low-light levels. The cones, along with their oil droplets, and rods are conserved across birds – with the exception of a few shifts in spectral sensitivity – despite taxonomic, behavioral and ecological differences. Here, however, we describe a novel photoreceptor in a group of New World flycatchers (Empidonax spp.) in which the traditional oil droplet is replaced with a complex of electron-dense megamitochondria surrounded by hundreds of small, orange oil droplets. These photoreceptors were unevenly distributed across the retina, being present in the central region (including in the fovea), but absent from the retinal periphery and the area temporalis. Many bird species have had their oil droplets and photoreceptors characterized, but only the two flycatchers described here (E. virescens and E. minimus) possess this unusual structure. We discuss the potential functional significance of the unique sub-cellular structure in these photoreceptors providing an additional visual channel for these small predatory songbirds.
High-throughput single-particle tracking reveals nested membrane nanodomain organization that dictates Ras diffusion and trafficking
Authors: Lee Yerim , Phelps Carey , Huang Tao , Mostofian Barmak , Wu Lei , Zhang Ying , Chang Young Hwan , Stork Philip J. S. , Gray Joe W. , Zuckerman Daniel M. , Nan Xiaolin
Published: February 2019

Membrane nanodomains have been implicated in Ras signaling, but what these domains are and how they interact with Ras remain obscure. Using high throughput single particle tracking with photoactivated localization microscopy and detailed trajectory analysis, here we show that distinct membrane domains dictate KRas diffusion and trafficking in U2OS cells. KRas exhibits an immobile state in domains ∼70 nm in size, each embedded in a larger domain (∼200 nm) that confers intermediate mobility, while the rest of the membrane supports fast diffusion. Moreover, KRas is continuously removed from the membrane via the immobile state and replenished to the fast state, likely coupled to internalization and recycling. Importantly, both the diffusion and trafficking properties of KRas remain invariant over a broad range of protein expression levels. Our results reveal how membrane organization dictates KRas diffusion and trafficking and offer insight into how Ras signaling may be regulated through spatial mechanisms.
STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition
Authors: Ergun Sabrina L. , Ferdandez Daniel , Weiss Thomas M. , Li Lingyin
Published: February 2019

How the central innate immune protein, STING, is activated by its ligands remains unknown. Here, using structural biology and biochemistry, we report that the metazoan second messenger 2’3’-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2’3’-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a novel therapeutic hypothesis for autoimmune syndrome treatment.
A transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans
Authors: Saraiva Luis R. , Riveros-McKay Fernando , Mezzavilla Massimo , Abou-Moussa Eman H. , Arayata Charles J. , Trimmer Casey , Ibarra-Soria Ximena , Khan Mona , Gerven Laura Van , Jorissen Mark , Gibbs Matthew , O’Flynn Ciaran , McGrane Scott , Mombaerts Peter , Marioni John C. , Mainland Joel D. , Logan Darren W.
Published: February 2019

The mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) sub-types across 95 million years of mammalian evolution, we applied RNA-sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque and human. We find that OSN subtypes representative of all known mouse chemosensory receptor gene families are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors (ORs) are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order-specific. Interestingly, highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles, and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Taken together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes in mouse and human.
Sequencing red fox Y chromosome fragments to develop phylogenetically informative SNP markers and glimpse male-specific trans-Pacific phylogeography
Authors: Sacks BN , Lounsberry ZL , Rando HM , Kluepfel K , Fain S , Brown SK , Kukekova AV
Published: February 2019

The red fox (Vulpes vulpes) has a wide global distribution with many ecotypes, and has been bred in captivity for various traits, making it a useful evolutionary model system. The Y chromosome represents one of the most informative markers of phylogeography, yet it has not been well-studied in the red fox due to a lack of the necessary genomic resources. We used a target capture approach to sequence a portion of the red fox Y chromosome in a geographically diverse red fox sample, along with other canid species, to develop single nucleotide polymorphism (SNP) markers, 13 of which we validated for use in subsequent studies. Phylogenetic analyses of the Y chromosome sequences, including calibration to outgroups, confirmed previous estimates of the timing of two intercontinental exchanges of red foxes, the initial colonization of North America from Eurasia approximately half a million years ago and a subsequent continental exchange before the last Pleistocene glaciation (∼100,000 years ago). However, in contrast to mtDNA, which showed unidirectional transfer from Eurasia to North America prior to the last glaciation, the Y chromosome appears to have been transferred from North America to Eurasia during this period. Additional sampling is needed to confirm this pattern and to further clarify red fox Y chromosome phylogeography.
Highly Efficient Hypothesis Testing Methods for Regression-type Tests with Correlated Observations and Heterogeneous Variance Structure
Authors: Zhang Yun , Bandyopadhyay Gautam , Topham David J. , Falsey Ann R. , Qiu Xing
Published: February 2019

Background

For many practical hypothesis testing (H-T) applications, the data are correlated and/or with heterogeneous variance structure. The regressiont-test for weighted linear mixed-effects regression (LMER) is a legitimate choice because it accounts for complex covariance structure; however, high computational costs and occasional convergence issues make it impractical for analyzing high-throughput data. In this paper, we propose computationally efficient parametric and semiparametric tests based on a set of specialized matrix techniques dubbed as the PB-transformation. The PB-transformation has two advantages: 1. The PB-transformed data will have a scalar variance-covariance matrix. 2. The original H-T problem will be reduced to an equivalent one-sample H-T problem. The transformed problem can then be approached by either the one-sample Studentst-test or Wilcoxon signed rank test.

Results

In simulation studies, the proposed methods outperform commonly used alternative methods under both normal and double exponential distributions. In particular, the PB-transformedt-test produces notably better results than the weighted LMER test, especially in the high correlation case, using only a small fraction of computational cost (3 versus 933 seconds). We apply these two methods to a set of RNA-seq gene expression data collected in a breast cancer study. Pathway analyses show that the PB-transformedt-test reveals more biologically relevant findings in relation to breast cancer than the weighted LMER test․.

Conclusions

As fast and numerically stable replacements for the weighted LMER test, the PB-transformed tests are especially suitable for “messy” high-throughput data that include both independent and matched/repeated samples. By using our method, the practitioners no longer have to choose between using partial data (applying paired tests to only the matched samples) or ignoring the correlation in the data (applying two sample tests to data with some correlated samples).
Molecular chaperones accelerate the evolution of their protein clients in yeast
Authors: Alvarez-Ponce David , Aguilar-Rodríguez José , Fares Mario A.
Published: February 2019

Protein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone-protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence ofSaccharomyces cerevisiaeandS. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains ofS. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding nonclient proteins when controlling for their number of protein-protein interactions. We also find that genes encoding client proteins have accumulated more intra-specific genetic diversity than those encoding nonclient proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype-phenotype maps, have a considerable accelerating effect on protein evolution.
Anthropogenic Soils Promote Biodiversity in Amazonian Rainforests
Authors: Demetrio Wilian C. , Conrado Ana C. , Acioli Agno , Ferreira Alexandre Casadei , Bartz Marie L.C. , James Samuel W. , Silva Elodie da , Maia Lilianne S. , Martins Gilvan C. , Macedo Rodrigo S. , Stanton David W.G. , Lavelle Patrick , Velasquez Elena , Zangerlé Anne , Barbosa Rafaella , Tapia-Coral Sandra , Muniz Aleksander W. , Santos Alessandra , Ferreira Talita , Segalla Rodrigo F. , Decaëns Thibaud , Nadolny Herlon S. , Peña-Venegas Clara P. , Maia Cláudia S. , Pasini Amarildo , Motta André F. , Taube Júnior Paulo S. , Silva Telma A. , Rebellato Lilian , Júnior Raimundo C. Oliveira , Neves Eduardo , Lima Helena Pinto , Feitosa Rodrigo , Torrado Pablo Vidal , McKey Doyle , Clement Charles R. , Shock Myrtle P. , Teixeira Wenceslau G. , Motta Antônio Carlos V. , de Freitas Melo Vander , Dieckow Jefferson , Garrastazu Marilice , Chubatsu Leda ,   TPI Network, Kille Peter , Brown George G. , Cunha Luís
Published: February 2019

Amazonian Dark Earths (ADEs) are fertile anthropic soils found throughout Amazonia, resulting from long-term occupation by pre-Columbian societies. Although the chemistry of these soils is well known, their biodiversity, particularly soil invertebrate communities have been neglected. To address this, we characterised soil macroinvertebrate communities and their activities in ADEs, comparing them with adjacent reference soils under forests and agriculture, at nine archaeological sites. We found 667 morphospecies and a tenacious pre-Columbian biodiversity footprint, with 40% of species found exclusively in ADEs. Soil biological activity was higher in ADEs than in adjacent soils, and associated with higher biomass and richness of organisms known to engineer the ecosystem. We show that these habitats have unique species pools, but that contemporary land-use causes nutrient loss and threatens their diversity. Both past and present human activities alter biodiversity and its distribution in Amazonia, and further efforts are needed to recognize and preserve these ADEs and their biodiversity.
The importance of non‐technical performance for teams managing postpartum haemorrhage: video review of 99 obstetric teams
Authors: Brogaard L , Kierkegaard O , Hvidman L , Jensen KR , Musaeus P , Uldbjerg N , Manser T
Published: February 2019

Objective

Little is known about how teams’ non‐technical performance influences clinical performance in obstetric emergencies such as postpartum haemorrhage.

Design

Video review – observational study.

Setting

A university hospital (5000 deliveries) and a regional hospital (2000 deliveries) in Denmark.

Population

Obstetric teams managing real‐life postpartum haemorrhage.

Methods

We systematically assessed 99 video recordings of obstetric teams managing real‐life major postpartum haemorrhage. Exposure was the non‐technical score (AOTP); outcomes were the clinical performance score (TeamOBS) and the delayed transfer to the operating theatre (defined as blood loss >1500 ml in the delivery room).

Results

Teams with an excellent non‐technical score performed significantly better than teams with a poor non‐technical score: 83.7 versus 0.3% chance of a high clinical performance score (P < 0.001), 0.2 versus 80% risk of a low clinical performance score (P < 0.001), and 3.5 versus 31.7% risk of delayed transfer to the operating theatre (P = 0.008). The results remained robust when adjusting for potential confounders such as bleeding velocity, aetiology, time of day, team size, and hospital. The specific non‐technical skills associated with high clinical performance were vigilance, role assignment, problem‐solving, management of disruptive behavior, and leadership. Communication with the patient and closing the loop were of minor importance. All performance assessments showed good reliability: the intraclass correlation was 0.97 (95% CI 0.96–0.98) for the non‐technical score and 0.84 (95% CI 0.76–0.89) for the clinical performance score.

Conclusion

Video review offers a new method and new perspectives for research in obstetric teams to identify how teams become effective and safe; the skills identified in this study can be included in future obstetric training programmes.

Tweetable abstract

Non‐technical performance is important for teams managing postpartum haemorrhage; video review of 99 obstetric teams.
Diagnostic reference levels for 18F‐FDG whole body PET/CT procedures: Results from a survey of 12 centres in Australia and New Zealand
Authors: Alkhybari Essam M , McEntee Mark F , Brennan Patrick C , Willowson Kathy P , Kench Peter L
Published: February 2019

Introduction

The aim of this work is to report diagnostic reference levels (DRLs) for hybrid positron emission tomography and x‐ray computed tomography (PET/CT) exams in Australia (AU) for Queensland (QLD) and Western Australia (WA) (AU QLD/WA) and New Zealand (NZ).

Methods

Two‐structured booklets were designed to collect dose information, patient demographics, equipment details and acquisition protocols for fluoride‐18 fluorodeoxyglucose (18F‐FDG) PET/CT procedures, and any additional diagnostic CT routinely performed as part of 18F‐FDG whole‐body examination. The DRL was reported based on the 75th percentile and achievable dose for 18F‐FDG, CT dose index volume (CTDIvol) and dose length product (DLP). The effective dose and total effective dose was reported for 18F‐FDG whole‐body PET/CT examination. Also, the effective dose was reported separately for identified additional diagnostic CT.

Results

The findings of this study show that the current DRL for 18F‐FDG in AU QLD/WA and NZ was 333.75 MBq and 332.87 MBq, respectively. The reported AU QLD/WA CTDIvol and DLP associated with 18F‐FDG whole‐body PET/CT examinations from vertex to thigh (VT) was 4.41 mGy and 474 mGy.cm. In NZ, the reported VT CTDIvol and DLP was 13.07 mGy and 1319.05 mGy.cm. The effective dose for 18F‐FDG and CT component was 5.6 mSv and 4.7 mSv for AU QLD/WA. For NZ, the effective dose was 5.7 mSv and 10.9 mSv for 18F‐FDG and CT component. The total effective dose delivered from the 18F‐FDG whole‐body scan from the AU QLD/WA PET/CT centres (10.44 mSv) were lower than the radiation doses delivered from the NZ (16.65 mSv).

Conclusions

The current DRLs were proposed for AU QLD/WA and NZ for 18F‐FDG whole‐body PET/CT examinations. Variations existed in the current practice of AU QLD/WA and NZ PET/CT examinations. There is a need to optimize the radiation doses delivered from PET/CT examinations.
Rates and outcomes of total knee replacement for rheumatoid arthritis compared to osteoarthritis
Authors: Mooney Luke , Lewis Peter L. , Campbell David G. , Peng Yi , Hatton Alesha
Published: February 2019

Background

Total knee replacement (TKR) has been shown to perform differently in patients with rheumatoid arthritis (RA) when compared to osteoarthritis (OA). In this study, we compare the survivorship between these two groups and examine patient and prosthesis factors that impact the revision rate.

Methods

All RA and OA patients undergoing TKR in Australia from 1 September 1999 to 31 December 2016 were included. Revision rates were assessed using Kaplan–Meier estimates of survivorship. The cumulative percent revision analysed age, gender, prosthesis constraint and revision for infection.

Results

There were 541 744 TKR procedures performed including 7542 patients with RA. RA declined as the primary diagnosis from 2.4% of all TKR in 2003 to 0.9% in 2016. Male sex was an independent revision risk in RA patients (hazard ratio (HR) = 1.66, P < 0.001) and OA patients (3.5 years+: HR = 1.09 (1.04–1.15), P < 0.001). Male RA patients had a higher revision rate for infection than females (HR = 3.14, P < 0.001). Females with RA had a lower cumulative percent revision compared to OA females, but males showed no difference between diagnoses. Revision in RA patients was not influenced by age. Compared to OA, RA patients had a decreased revision rate for those aged <65 years, but not for patients aged ≥65 years.

Conclusion

The rate of revision after TKR in RA patients is lower than those with OA, but patients with RA are at increased risk of infection, particularly the male group. Prosthesis constraint had no influence on revision rate. Mortality in those undergoing TKR with RA was higher than in those with OA.
Prevalence of deaths in a cohort of girls and women with cryopreserved ovarian tissue
Authors: Macklon Kirsten Tryde
Published: February 2019

Introduction

Ovarian tissue cryopreservation (OTC) is increasingly offered to women in need of fertility preservation. However, little is known about the risk of these women dying before they use the preserved material.

Material and methods

From 1999 to 2016, 927 girls and women underwent OTC in our center, before receiving gonadotoxic treatment. All patients were without disseminated disease and with an estimated chance of survival after 5 years of >50%. For each patient the specific indication for OTC was noted, and through a national registry linked to a personal identification number, we were able to identify those who had died and the date and cause of death.

Results

By December 2017, 124/927 patients had died from their disease (13%). The highest relative prevalence of death was seen in patients with liver cancer (2/2; 100%), gall bladder cancer (2/2; 100%), stomach cancer (1/1; 100%), hemophagocytic lymphohistiocytosis (2/3; 66%), scleroderma (1/2; 50%), and sarcoma (24/78; 31%). The lowest risk of dying was seen in the group of individuals with non‐Hodgkin lymphoma (3/30; 10%) and breast cancer (31/313; 10%). The shortest time from OTC to death was seen in those with hemophagocytic lymphohistiocytosis (mean interval 0.25 years), gall bladder cancer, non‐Hodgkin disease and acute myeloid leukemia (mean interval 0.7 years) and the longest time from OTC to death was in women with breast cancer (mean interval 3.4 years). Of those who died, 34 had received chemotherapy at some point before OTC, indicating a relapse or non‐responsiveness to the initial treatment.

Conclusions

Patients with upper gastrointestinal cancers and sarcoma had the highest risk of dying from their disease. Breast cancer patients had the lowest risk. This knowledge may guide clinicians in their decisions on whether to offer OTC to girls and younger women with a life‐threatening disease.
The efficacy of misoprostol vaginal insert compared with oral misoprostol in the induction of labor of nulliparous women: A randomized national multicenter trial
Authors: Hokkila Emma , Kruit Heidi , Rahkonen Leena , Timonen Susanna , Mattila Mirjami , Laatio Liisa , Ordén Maija‐Riitta , Uotila Jukka , Luukkaala Tiina , Tihtonen Kati
Published: February 2019

Introduction

Our objective was to compare the efficacy of a 200‐μg misoprostol vaginal insert vs oral misoprostol regarding the cesarean section rate and the time interval to vaginal delivery in nulliparous women with unfavorable cervix.

Material and methods

In this prospective multicenter trial, 283 nulliparous women at term with Bishop score <6 were randomized to induction of labor with either a misoprostol vaginal insert (n = 140) or oral misoprostol (n = 143). In the oral misoprostol group, a 50‐μg dose of oral misoprostol was administered every 4 hours up to three times during the first day; during the second day, the dose was increased to 100‐μg every 4 hours up to three times during the first day, if necessary. Primary outcome was the cesarean section rate. Secondary outcomes were the time from induction of labor to vaginal delivery, the rate of other induction methods needed, labor augmentation with oxytocin and/or amniotomy, use of tocolytics and adverse neonatal and maternal events.

Results

In the misoprostol vaginal insert group, median time to vaginal delivery was shorter (24.5 hours vs 44.2 hours, P < 0.001), whereas no difference was found in the cesarean section rate (33.8% vs 29.6%, odds ratio [OR] 1.21, 95% confidence interval [CI] 0.66‐1.91, P = 0.67). Other induction methods and labor augmentation with oxytocin and/or amniotomy were less frequent in the misoprostol vaginal insert group (OR 0.32, 95% CI 0.18‐0.59 and OR 0.56, 95% CI 0.32‐0.99, respectively). Need for tocolysis and meconium‐stained amniotic fluid were more common in the misoprostol vaginal insert group (OR 3.63, 95% CI 1.12‐11.79 and OR 2.38, 95% CI 1.32‐4.29, respectively). Maternal and neonatal adverse events did not differ between groups.

Conclusions

Misoprostol vaginal insert proved to shorten the time to vaginal delivery and to reduce the use of other methods of labor induction and augmentation, but it did not reduce the cesarean section rate compared with oral misoprostol. The benefit of more rapid delivery associated with misoprostol vaginal insert should be weighed against the greater risks for uterine hyperstimulation and meconium‐stained amniotic fluid.
The exaggerated natriuresis of essential hypertension occurs independently of changes in renal medullary blood flow
Authors: Assersen Kasper B. , Høilund‐Carlsen Poul F. , Olsen Michael H. , Greve Sara V. , Gam‐Hadberg Jens C. , Braad Poul‐Erik , Damkjaer Mads , Bie Peter
Published: February 2019

Aims

In patients with essential hypertension, abnormal renal sodium handling includes exaggerated natriuresis in response to extracellular volume expansion. We tested the hypothesis that exaggerated natriuresis is associated with increases in medullary and/or cortical renal blood flow.

Methods

Patients with mild essential hypertension, but no signs of end organ damage, and control subjects were studied after 4 days of dietary standardization (<60 mmol Na+ day−1) preceded in patients by a 14‐day drug washout period. On the study day, subjects received a 4‐hour intravenous volume expansion with saline (2.1% of body mass). Renal medullary and cortical blood flows were measured by PET scanning using H215O as tracer; anatomical regions of interest were defined by contrast‐enhanced CT scanning.

Results

In patients, arterial blood pressure increased during volume expansion (107 ± 2‐114 ± 3 mm Hg, P < 0.05) in contrast to the control group (92 ± 2‐92 ± 2 mm Hg). Renal sodium excretion increased more in patients than in controls (+133 ± 31 µmol min−1 vs +61 ± 14 µmol min−1, respectively, P < 0.05) confirming exaggerated natriuresis. During volume expansion, renal medullary blood flow did not change significantly in patients (2.8 ± 0.4‐2.5 ± 0.5 mL (g tissue)−1 min−1) or in controls (3.2 ± 0.3‐3.1 ± 0.2 mL (g tissue)−1 min−1). In control subjects, renal cortical blood flow fell during volume expansion (4.1 ± 0.3‐3.7 ± 0.2 mL (g tissue)−1 min−1, P < 0.05) in contrast to patients in which deviations remained insignificant.

Conclusion

Exaggerated natriuresis, a hallmark of essential hypertension, is not mediated by increases in regional, renal blood flow.
Enrichment of CLDN18‐ARHGAP fusion gene in gastric cancers in young adults
Authors: Nakayama Izuma , Shinozaki Eiji , Sakata Seiji , Yamamoto Noriko , Fujisaki Junko , Muramatsu Yusuke , Hirota Toru , Takeuchi Kengo , Takahashi Shunji , Yamaguchi Kensei , Noda Tetsuo
Published: February 2019

Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease, and diffuse‐type histology. Comprehensive molecular analyses of gastric cancers have led to molecular‐based classifications and to specific and effective treatment options. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here, we studied 146 gastric cancer patients diagnosed at the age of 40 years or younger at the Cancer Institute Hospital (Tokyo, Japan). Tumor specimens were examined for Helicobacter pylori infection, Epstein‐Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications, and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and FISH. Although only a small number of cases were positive for Epstein‐Barr virus and microsatellite instability (n = 2 each), we repeatedly found tumors with gene fusion between a tight‐junction protein claudin, CLDN18, and a regulator of small G proteins, ARHGAP, in as many as 22 cases (15.1%), and RNA sequencing identified 2 novel types of the fusion. Notably, patients with the CLDN18‐ARHGAP fusion revealed associations between aggressive disease and poor prognosis, even when grouped by their clinical stage. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age‐onset gastric cancers, and its presence could contribute to their aggressive characteristics.
Academic achievement of adolescents with asthma or atopic disease
Authors: Brew Bronwyn K. , Söderberg Joakim , Lundholm Cecilia , Afshar Soren , Holmberg Kirsten , Almqvist Catarina
Published: February 2019

Background

Over a fifth of children and adolescents suffer with asthma or atopic disease. It is unclear whether asthma impacts academic performance in children and adolescents, and little is known about the association of eczema, food allergy or hayfever and academic performance.

Objective

To examine whether asthma, eczema, food allergy or hayfever impacts on adolescent academic performance and to assess the role of unmeasured confounding.

Methods

This study used the Childhood and Adolescent Twin Study of Sweden cohort born 1992‐1998. At age 9‐12 years, parents reported on their child's ever or current asthma, eczema, food allergy and hayfever status (n = 10 963). At age 15, linked national patient and medication register information was used to create current and ever asthma definitions including severe and uncontrolled asthma for the same children. Academic outcomes in Grade 9 (age 15‐16 years) included: eligibility for high school (Grades 10‐12), and total mark of the best 16 subject units, retrieved from the Grade 9 academic register. Whole cohort analyses adjusted for known covariates were performed, and co‐twin control analyses to assess unmeasured confounders.

Results

There were no associations found for asthma or food allergy at 9‐12 years and academic outcomes in adolescence. In addition, at age 15, there were no statistically significant associations with current, ever, severe or uncontrolled asthma and academic outcomes. Eczema and hayfever at age 9‐12 years were found to be positively associated with academic outcomes; however, co‐twin control analyses did not support these findings, suggesting the main analyses may be subject to unmeasured confounding.

Conclusion and clinical relevance

Having asthma or an atopic disease during childhood or adolescence does not negatively impact on academic performance. This information can be used by clinicians when talking with children and parents about the implications of living with asthma or atopic disease.
Immune cell metabolism in autoimmunity
Authors: Teng X , Li W , Cornaby C , Morel L
Published: February 2019

Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases.
The Renew® anal insert for passive faecal incontinence: a retrospective audit of our use of a novel device
Authors: Leo C. A. , Thomas G. P. , Hodgkinson J. D. , Segal J. P. , Maeda Y. , Murphy J. , Vaizey C. J.
Published: February 2019

Aim

The Renew® anal insert is a recent treatment for patients who suffer from passive faecal incontinence (FI). Our aim was to assess the effectiveness of the insert and patients’ satisfaction with it.

Method

A retrospective audit of patients who were treated with the Renew® anal insert was undertaken. The St Mark's Incontinence Score was used to evaluate clinical outcome. Renew® size, the number of inserts used per day and per week had also been recorded. Subjective assessment of symptoms, how beneficial Renew® was and how satisfied patients were with the device were all recorded. Major events and side effects were also noted.

Results

Thirty patients received Renew® as a treatment for passive incontinence in 2016. The median St Mark's Incontinence Score was 15 (range 7–18) at baseline and 10 (range 2–18) at first follow‐up (P < 0.0001) at a median of 11 (range 8–14) weeks. Eleven (37%) patients used the regular size and 19 (63%) the large size. Patients used an average of 1.67 inserts per day (range 1–3) on an average of 3.58 days per week (1–7). Three patients reported a deterioration in symptoms, seven (23%) had no change and 20 (67%) showed a significant improvement. Six patients (20%) did not like the device while 24 (80%) liked it. Seventeen patients (57%) wanted to continue this treatment in the long term.

Conclusion

The Renew® device seems to be an acceptable and effective therapeutic option for passive FI. Further work is needed to compare it with other treatments and establish its position in the treatment pathway.
Characterization of blood flow patterns and endothelial shear stress during flow‐mediated dilation
Authors: Morales‐Acuna Francisco , Ochoa Luis , Valencia Carolina , Gurovich Alvaro N.
Published: February 2019

Introduction

Endothelial dysfunction is considered the first step in the development of atherosclerosis. Flow‐mediated dilation (FMD) has been the most common assessment of endothelial function in research but it has failed in obtaining a widespread use in clinical settings due to a lack of standardization and a large inter‐subject variability. Normalization of FMD to endothelial shear stress (ESS) has been proposed to solve its technical limitations. However, studies have not considered the characteristic of the blood flow during FMD under pulsatile conditions in their ESS estimations.

Methods

A total of 26 young healthy subjects (15 females and 11 males) underwent FMD testing. Microhematocrit measurement was used to determine blood viscosity (μ). ESS was calculated by Womersley's approximation, ESS = μ*2K*Velocity/Diameter, where K is a function of Womersley's parameter (α). Blood flow patterns were determined by critical Reynolds number. Statistical analysis included repeated measures ANOVA to detect ESS differences during FMD until peak dilation. Significance was established at P≤0.05.

Results

The mean (SD) FMD% and time to peak dilation were 7·4 (3·1) % and 35 (9·3) seconds, respectively. ESS was significantly reduced during FMD until peak dilation (P<0·001). Turbulent blood flow was the only pattern observed until peak dilation in 96·15% of the sample.

Conclusion

Peak FMD dilation in a young healthy population is triggered mostly by high‐ESS under turbulent flow conditions. Due to the pulsatile nature of blood flow and the appearance of a turbulent pattern during FMD, ESS should be estimated by Womersley's approximation rather than Poiseuille's law.
Impact of gender on echocardiographic characteristics in heart transplant recipients
Authors: Ingvarsson Annika , Werther‐Evaldsson Anna , Smith Gustav J. , Waktare Johan , Nilsson Johan , Stagmo Martin , Roijer Anders , Rådegran Göran , Meurling Carl
Published: February 2019

Aims

Assessment following heart transplantation (HTx) is routinely performed using transthoracic echocardiography. Differences in long‐term mortality following HTx related to donor‐recipient matching have been reported, but effects of gender on cardiac size and function are not well studied. The aims of this study were to evaluate differences in echocardiographic characteristics of HTx recipients defined by gender.

Methods and results

The study prospectively enrolled 123 (n = 34 female) HTx recipients of which 23 recipients was donor‐recipient gender mismatched. Patients were examined with 2‐dimensional echocardiography using Philips iE33 ultrasound system. Data were analysed across strata based on recipient gender and gender mismatch. Male recipients had larger left ventricular (LV) mass, thicker septal wall (P<0·001) and larger absolute LV volumes (P<0·001). Mean LV ejection fraction (EF) was higher in females (P<0·05), but no differences in conventional parameters of right ventricular (RV) function were found. Ventricular strain was higher in females than in males: LV global longitudinal strain (P<0·01), RV global longitudinal strain (P<0·05) and RV lateral free wall (P<0·05). The male group receiving a female donor heart had comparable EF and strain parameters to the female group receiving a gender‐matched heart.

Conclusion

We found that female recipient gender was associated with smaller chamber size, higher LV EF and better LV and RV longitudinal strain. Gender‐mismatched male recipients appeared to exhibit function parameters similar to gender‐matched female recipients. Our results indicate that the gender aspect, analogous to current reference guidelines in general population, should be taken into consideration when examining patients post‐HTx.
Pulmonary arterial hypertension in adults with systemic right ventricles referred for cardiac transplantation
Authors: Kim Yuli Y. , Awh Katherine , Acker Michael , Atluri Pavan , Bermudez Christian , Crespo Maria , Diamond Joshua M. , Drajpuch David , Forde‐Mclean Rhondalyn , Fuller Stephanie , Goldberg Lee , Mazurek Jeremy , Mascio Christopher , Menachem Jonathan N. , Rame Eduardo , Ruckdeschel Emily , Tobin Lynda , Wald Joyce
Published: February 2019

Background

Systemic right ventricular (RV) failure may progress necessitating referral for orthotropic heart transplantation (OHT). Pulmonary hypertension (PH) frequently coexists in adult congenital heart disease and can complicate the assessment for OHT.

Methods

Single‐center case series of six patients (median age 34.9 years [IQR, 31.9‐42.4]) with systemic RV physiology with PH referred for OHT evaluation from 2008 to 2017.

Results

One‐third (n = 6) of 18 patients with systemic RV physiology referred for OHT evaluation had pulmonary arterial hypertension (PAH) defined as mean pulmonary artery pressure (mPAP) > 25 mm Hg and pulmonary vascular resistance (PVR) > 3 Wood Units. Two of the six patients were considered OHT‐ineligible due to PH and comorbidities. Of the remaining four, two had pre‐capillary PH and underwent heart‐lung transplant (HLTx). The other two demonstrated reversibility of PVR with vasodilator testing and underwent OHT alone, one of whom died post‐transplant from PH crisis.

Conclusions

Pulmonary arterial hypertension is common in systemic RV patients referred for OHT. Systemic RV dysfunction places these patients at risk for post‐capillary PH but pre‐capillary PH can exist. Despite management with selective pulmonary vasodilators and afterload reduction, criteria for listing patients for HLTx vs OHT are not known and need further elucidation.