bluuebunny/crossref_metadata_2025 huggingface dataset:
JNK MAPK Regulates IFN-Stimulated Genes and Cell Adhesion in Chemoresistant, Quiescent Leukemic Cells
Authors: Lee Sooncheol , Vasudevan Shobha
Published: July 2019

Cancer cells survive environmental stresses including DNA damage-inducing chemotherapy by entering cellular quiescence (G0). In our previous study, to elucidate how G0 leukemic cells become resistant to chemotherapy, we profiled them at the transcriptome, translatome and proteome levels. We interrogated these datasets and find that IFN-stimulated genes are enhanced in our G0 models of leukemic cells induced by chemotherapy or serum-starvation. Mechanistically, upon induction of G0, STAT1 is phosphorylated on tyrosine 701, leading to transcription of IFN-stimulated genes. Importantly, our data reveal that activation of JNK and p38 MAPK is integral to STAT1 phosphorylation and expression of IFN-stimulated genes. Pharmacological inhibition of JNK or p38 MAPK greatly reduced expression of IFN-stimulated genes as well as STAT1 phosphorylation, revealing a JNK-STAT1 pathway that regulates IFN-stimulated genes. We find that the JNK-STAT1 pathway enhances adherence of G0 leukemic cells. Consistently, inhibition of the JNK-STAT1 pathway dramatically reduced the number of adherent G0 cells. STAT1 is transiently phosphorylated within 24 hours of chemotherapy, leading to transcriptional expression of IFN-stimulated genes. Subsequently, translational regulation attenuates their expression in G0 leukemic cells. These studies uncover translational and transcriptional regulation of IFN-stimulated genes by a JNK-STAT1 pathway that enhances cell adhesion in G0 leukemic cells.
Lymph Nodes Inhibit T-cell Effector Functions Locally by Establishing Acidic Niches
Authors: Wu Hao , Estrella Veronica , Enriquez-Navas Pedro , El-Kenawi Asmaa , Russell Shonagh , Abrahams Dominique , Ibrahim-Hashim Arig , Longo Dario , Reshetnyak Yana , Luddy Kimberly , Damaghi Mehdi , Pillai Smitha Ravindranadhan , Beatty Matthew , Pilon-Thomas Shari , Swietach Pawel , Gillies Robert J.
Published: July 2019

Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying mechanisms of this inhibition are unknown, but may relate to glycolysis, which is obligatory for expression of effector functions. Here, we demonstrate that acidification rapidly and potently inhibits monocarboxylate transporter-dependent lactic acid efflux, which dually inhibits glycolysis by end-product accumulation and by reducing cytoplasmic pH. Based on the robustness of these responses, we propose that acid-evoked T-cell inhibition is physiologically important, and that lymph nodes are a natural site for such modulation. Using multiple imaging techniques, we show that paracortical T-zones of lymph nodes are highly acidic. We further show that T-cells can be activated by dendritic cells at low pH, and their effector functions are restored rapidly upon increasing pH. Thus, we describe a novel physiological mechanism whereby activated T-cells are kept in stasis by acidosis whilst resident in lymph nodes.
A database for ITS2 sequences from nematodes
Authors: Workentine Matthew L. , Chen Rebecca , Zhu Shawna , Gavriliuc Stefan , Shaw Nicolette , de Rijke Jill , Redman Elizabeth M. , Avarmenko Russell W. , Wit Janneke , Poissant Jocelyn , Gilleard John S.
Published: July 2019

Marker gene surveys have a wide variety of applications in species identification, population genetics, and molecular epidemiology. As these methods expand to new types of organisms and additional markers beyond 16S and 18S rRNA genes, comprehensive databases are a critical requirement for proper analysis of these data. Here we present an ITS2 rDNA database for maker gene surveys of both free-living and parasitic nematode populations and the software used to build the database. This is an important resource for researchers working on nematodes and also provides a tool to create ITS2 databases for any given taxonomy.

Availability and Implementation

The database is available as an interactive web app at https://cooperia.chgi.ucalgary.ca/Nematode_ITS2/. The full database can also be downloaded from zenodo https://doi.org/10.5281/zenodo.3235802, and the open source software used to create the database, markerDB is available at https://github.com/ucvm/markerDB/releases/latest.
Predicting Primary Site of Secondary Liver Cancer with a Neural Estimator of Metastatic Origin (NEMO)
Authors: Schau Geoffrey F. , Burlingame Erik A. , Thibault Guillaume , Anekpuritanang Tauangtham , Wang Ying , Gray Joe W. , Corless Christopher , Chang Young Hwan
Published: July 2019

Pathologists rely on clinical information, tissue morphology, and sophisticated molecular diagnostics to accurately infer the metastatic origin of secondary liver cancer. In this paper, we introduce a deep learning approach to identify spatially localized regions of cancerous tumor within hematoxylin and eosin stained tissue sections of liver cancer and to generate predictions of the cancer’s metastatic origin. Our approach achieves an accuracy of 90.2% when classifying metastatic origin of whole slide images into three distinct classes, which compares favorably to an established clinical benchmark by three board-certified pathologists whose accuracies ranged from 90.2% to 94.1% on the same prediction task. This approach illustrates the potential impact of deep learning systems to leverage morphological and structural features of H&E stained tissue sections to guide pathological and clinical determination of the metastatic origin of secondary liver cancers.
Critical slowing as a biomarker for seizure susceptibility
Authors: Maturana Matias I. , Meisel Christian , Dell Katrina , Karoly Philippa J. , D’Souza Wendyl , Grayden David B. , Burkitt Anthony N. , Jiruska Premysl , Kudlacek Jan , Hlinka Jaroslav , Cook Mark J. , Kuhlmann Levin , Freestone Dean R.
Published: July 2019

The human brain has the capacity to rapidly change state, and in epilepsy these state changes can be catastrophic, resulting in loss of consciousness, injury and even death. Theoretical interpretations considering the brain as a dynamical system would suggest that prior to a seizure recorded brain signals may exhibit critical slowing, a warning signal preceding many critical transitions in dynamical systems. Using long-term intracranial electroencephalography (iEEG) recordings from fourteen patients with focal epilepsy, we found key signatures of critical slowing prior to seizures. Signals related to a critically slowing process fluctuated over temporally long scales (hours to days), longer than would be detectable in standard clinical evaluation settings. Seizure risk was associated with a combination of these signals together with epileptiform discharges. These results provide strong validation of theoretical models and demonstrate that critical slowing is a reliable indicator that could be used in seizure forecasting algorithms.
Transient uterine hypercontractility causes fetal cerebral oxidative stress and enduring mitochondrial and behavioral abnormalities in adolescent male rat offspring
Authors: Palanisamy Arvind , Giri Tusar , Jiang Jia , Bice Annie , Quirk James D. , Conyers Sara B. , Maloney Susan E. , Raghuraman Nandini , Bauer Adam Q. , Garbow Joel R. , Wozniak David F.
Published: July 2019

The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI imaging, we confirmed that oxytocin-induced aberrant uterine hypercontractility significantly compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 h after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.
Depression, GABA and age correlate with the plasma levels of inflammatory markers
Authors: Bhandage Amol K. , Cunningham Janet L. , Jin Zhe , Shen Qiujin , Bongiovanni Santiago , Korol Sergiy V. , Syk Mikaela , Kamali-Moghaddam Masood , Ekselius Lisa , Birnir Bryndis
Published: July 2019

Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined if levels of immunological protein markers altered with depression, age or by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Analysis of plasma samples from patients with major depressive episode and control blood donors (CBD) revealed expression of 67 inflammatory markers. Thirteen of these markers had augmented levels in patients as compared to CBD. and 21 markers correlated with age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and in the CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients and so was the average plasma GABA concentration. GABA modulated release of seven cytokines in CD3+ stimulated peripheral blood mononuclear cells (PBMC) from the patients. The study reveals significant changes in plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.
Detection and identification of bacterialspp.from culture negative surgical site infection patients using molecular tool
Authors: Behera Himanshu Sekhar , Chayani Nirupama , Bal Madhusmita , Pati Sanghamitra , Das Sashibhusan , Khuntia Hemant Kumar , Ranjit Manoranjan
Published: July 2019

Surgical site infection (SSI) is the most common post operative infections, that sometimes cause postoperative morbidity, mortality and increase in hospital costs. Managing surgical site infections, with negative culture report in routine diagnosis is a common dilemma in microbiology. The present study was carried out to know the presence and frequencies of various bacteria in wound aspirates/ swabs of some culture negative surgical site infection patients attending a tertiary care hospital of eastern India with molecular methods. Ninety seven (97) patients with post-operative SSI whose wound swabs/ aspirate were negative in the conventional aerobic culture after 48 hrs of incubation were taken for finding the presence and identification of any bacteria in sample with 16S rRNA gene specific broad PCR and submitted to NCBI. Of the 97 patients, 16S rRNA based broad range PCR assay could able to identify the presence of bacterial pathogen in 53(54.63%) cases, out of which 29 isolates were of viable but non-culturable bacteria(VBNC), 07 were of obligatory anaerobes and 13 were of unculturable bacteria, 04 were with polybacterial infections. Some measures should be taken in the microbiology laboratory along with conventional culture, for better patient care such as, culture plates should be allowed to incubate for an additional 3 – 4 days that will allow the growth any fastidious bacteria, anaerobic culture system should be developed along with aerobic system, and molecular diagnosis by 16S broad range PCR should be performed routinely.
Hierarchical non-negative matrix factorization using clinical information for microbial communities
Authors: Abe Ko , Hirayama Masaaki , Ohno Kinji , Shimamura Teppei
Published: July 2019

Background

The human microbiome forms very complex communities that consist of hundreds to thousands of different microorganisms that not only affect the host, but also participate in disease processes. Several state-of-the-art methods have been proposed for learning the structure of microbial communities and to investigate the relationship between microorganisms and host environmental factors. However, these methods were mainly designed to model and analyze single microbial communities that do not interact with or depend on other communities. Such methods therefore cannot comprehend the properties between interdependent systems in communities that affect host behavior and disease processes.

Results

We introduce a novel hierarchical Bayesian framework, called BALSAMICO (BAyesian Latent Semantic Analysis of MIcrobial COmmunities), which uses microbial metagenome data to discover the underlying microbial community structures and the associations between microbiota and their environmental factors. BALSAMICO models mixtures of communities in the framework of nonnegative matrix factorization, taking into account environmental factors. This method first proposes an efficient procedure for estimating parameters. A simulation then evaluates the accuracy of the estimated parameters. Finally, the method is used to analyze clinical data. In this analysis, we successfully detected bacteria related to colorectal cancer. These results show that the method not only accurately estimates the parameters needed to analyze the connections between communities of microbiota and their environments, but also allows for the effective detection of these communities in real-world circumstances.
Neural network and random forest models in protein function prediction
Authors: Hakala Kai , Kaewphan Suwisa , Björne Jari , Mehryary Farrokh , Moen Hans , Tolvanen Martti , Salakoski Tapio , Ginter Filip
Published: July 2019

Over the past decade, the demand for automated protein function prediction has increased due to the volume of newly sequenced proteins. In this paper, we address the function prediction task by developing an ensemble system automatically assigning Gene Ontology (GO) terms to the given input protein sequence.

We develop an ensemble system which combines the GO predictions made by random forest (RF) and neural network (NN) classifiers. Both RF and NN models rely on features derived from BLAST sequence alignments, taxonomy and protein signature analysis tools. In addition, we report on experiments with a NN model that directly analyzes the amino acid sequence as its sole input, using a convolutional layer. The Swiss-Prot database is used as the training and evaluation data.

In the CAFA3 evaluation, which relies on experimental verification of the functional predictions, our submitted ensemble model demonstrates competitive performance ranking among top-10 best-performing systems out of over 100 submitted systems. In this paper, we evaluate and further improve the CAFA3-submitted system. Our machine learning models together with the data pre-processing and feature generation tools are publicly available as an open source software athttps://github.com/TurkuNLP/CAFA3

Author summary

Understanding the role and function of proteins in biological processes is fundamental for new biological discoveries. Whereas modern sequencing methods have led to a rapid growth of protein databases, the function of these sequences is often unknown and expensive to determine experimentally. This has spurred a lot of interest in predictive modelling of protein functions.

We develop a machine learning system for annotating protein sequences with functional definitions selected from a vast set of predefined functions. The approach is based on a combination of neural network and random forest classifiers with features covering structural and taxonomic properties and sequence similarity. The system is thoroughly evaluated on a large set of manually curated functional annotations and shows competitive performance in comparison to other suggested approaches. We also analyze the predictions for different functional annotation and taxonomy categories and measure the importance of different features for the task. This analysis reveals that the system is particularly efficient for bacterial protein sequences.
Sex-dependent and -independent transcriptional changes during haploid phase gametogenesis in the sugar kelpSaccharina latissima
Authors: Pearson Gareth A , Martins Neusa , Madeira Pedro , Serrão Ester A , Bartsch Inka
Published: July 2019

In haplodiplontic lineages, sexual reproduction occurs in haploid parents without meiosis. Although widespread in multicellular lineages such as brown algae (Phaeophyceae), haplodiplontic gametogenesis has been little studied at the molecular level. We addressed this by generating an annotated reference transcriptome for the gametophytic phase of the sugar kelp,Saccharina latissima. Transcriptional profiles of microscopic male and female gametophytes were analysed at four time points during the transition from vegetative growth to gametogenesis. Gametogenic signals resulting from a switch in culture irradiance from red to white light activated a core set of genes in a sex-independent manner, involving rapid activation of ribosome biogenesis, transcription and translation related pathways, with several acting at the post-transcriptional or post-translational level. Additional genes regulating nutrient acquisition and key carbohydrate-energy pathways were also identified. Candidate sex-biased genes under gametogenic conditions had potentially key roles in controlling female- and male-specific gametogenesis. Among these were several sex-biased or - specific E3 ubiquitin-protein ligases that may have important regulatory roles. Females specifically expressed several genes that coordinate gene expression and/or protein degradation, and the synthesis of inositol-containing compounds. Other female-biased genes supported parallels with oogenesis in divergent multicellular lineages, in particular reactive oxygen signalling via an NADPH-oxidase. Males specifically expressed the hypothesised brown algal sex-determining factor. Male-biased expression mainly involved upregulation of genes that control mitotic cell proliferation and spermatogenesis in other systems, as well as multiple flagella-related genes. Our data and results enhance genome-level understanding of gametogenesis in this ecologically and economically important multicellular lineage.
Prevalence of pelagic dependence among coral reef predators across an atoll seascape
Authors: Skinner Christina , Newman Steven P. , Mill Aileen C. , Newton Jason , Polunin Nicholas V. C.
Published: July 2019

Coral reef food webs are complex, vary spatially and remain poorly understood. Certain large predators, notably sharks, are subsidized by pelagic production on outer reef slopes, but how widespread this dependence is across all teleost fishery target species and within atolls is unclear.

North Malé Atoll (Maldives) includes oceanic barrier as well as lagoonal reefs. Nine fishery target predators constituting ca. 55% of the local fishery target species biomass at assumed trophic levels 3–5 were selected for analysis. Data were derived from carbon (δ13C), nitrogen (δ15N) and sulphur (δ34S) stable isotopes from predator white dorsal muscle samples, and primary consumer species representing production source end‐members.

Three‐source Bayesian stable isotope mixing models showed that uptake of pelagic production extends throughout the atoll, with predatory fishes showing equal planktonic reliance between inner and outer edge reefs. Median plankton contribution was 65%–80% for all groupers and 68%–88% for an emperor, a jack and snappers.

Lagoonal and atoll edge predators are equally at risk from anthropogenic and climate‐induced changes, which may impact the linkages they construct, highlighting the need for management plans that transcend the boundaries of this threatened ecosystem.
Associations between gamebird releases and generalist predators
Authors: Pringle Henrietta , Wilson Mark , Calladine John , Siriwardena Gavin
Published: July 2019

The release of more than 40 million captive‐bred pheasants and red‐legged partridges in Britain annually represents a significant addition to the potential food resource base for predators and scavengers. If this extra food availability subsidizes predator populations, gamebird releases could increase predation pressure on other wild birds, affecting their populations.

Using three extensive datasets, we examined the spatial relationships between reared and free‐roaming gamebirds (pheasant Phasianus colchicus and red‐legged partridge Alectoris rufa), and explored spatial and temporal associations between these gamebirds and five species of avian predator (buzzard Buteo buteo, jay Garrulus glandarius, raven Corvus corax, magpie Pica pica and hooded Corvus cornix and carrion Corvus corone crows combined) in lowland rural Britain.

Patterns of spatial variation in the abundance of free‐roaming gamebirds across Britain appear to be largely determined by gamebird releases, over and above any effects of land use or habitat. Predominantly positive associations between gamebird abundance (both reared and free‐roaming) and the abundance and inter‐annual population growth rates of predators tested suggest that large‐scale variation in avian predator populations may be positively affected by gamebird releases.

Synthesis and applications. The positive associations between large‐scale gamebird release and predator populations shown here may have implications for prey populations if the releases cause increased predation pressure. If this occurs, game management could have an indirect negative impact on some prey species partially counteracting previously reported positive or benign effects of game management on wider biodiversity. Overall impacts of gamebird releases are likely to be determined by complex interactions between multiple factors, including induced predation pressure, better understanding of which would be possible with compulsory recording of releases and numbers of predators killed. Restriction of releases warrants further investigation and consideration as a potential conservation tool for wild bird populations.
Sustaining the HIV care provider workforce: Medical Monitoring Project HIV Provider Survey, 2013‐2014
Authors: Weiser John , Chen Guangnan , Beer Linda , Boccher‐Lattimore Daria , Armstrong Wendy , Kurth Ann , Shouse R. Luke
Published: July 2019

Objective

To describe delivery of recommended HIV care and work satisfaction among infectious disease (ID) physicians, non‐ID physicians, nurse practitioners (NPs), and physician assistants (PAs).

Data Sources

Medical Monitoring Project 2013‐2014 HIV Provider Survey.

Study Design

Population‐based complex sample survey.

Data Collection/Analysis Methods

We surveyed 2208 HIV care providers at 505 US HIV care facilities and computed weighted percentages of provider characteristics, stratified by provider type. Rao‐Scott chi‐square tests and logistic regression used to compare characteristics of ID physicians with each other provider type.

Principal Findings

The adjusted provider response rate was 64 percent. Among US HIV care providers, 45 percent were ID physicians, 35 percent non‐ID physicians, 15 percent NPs, and 5 percent PAs. Satisfaction with administrative burden was lowest among non‐ID physicians (27 percent). Compared with ID physicians, satisfaction with remuneration was lower among non‐ID physicians and higher among NPs (37, 28, and 51 percent, respectively). NPs were more likely than ID physicians to report performing four of six services that are key to providing comprehensive HIV care, but more NPs planned to leave clinical practice within 5 years (19 vs 7 percent).

Conclusion

Addressing physician dissatisfaction with remuneration and administrative burden could help prevent a provider shortage. Strengthening the role of NPs may help sustain a high‐quality workforce.
Best Management Practices Influence Modeled Erosion Rates at Forest Haul Road Stream Crossings in Virginia
Authors: Dangle C.L. , Bolding M.C. , Aust W.M. , Barrett S.M. , Schilling E.B.
Published: July 2019

Forestry best management practices (BMPs) reduce sedimentation by minimizing soil erosion and trapping sediment. These practices are particularly important in relation to road construction and use due to the heightened potential for sediment delivery at stream crossings. This study quantifies the implementation and effectiveness of BMPs at 75 randomly selected forest road stream crossings on recent timber harvests in the Mountains, Piedmont, and Coastal Plain regions of Virginia. Road characteristics at stream crossings were used to estimate erosion using the Universal Soil Loss Equation for Forests and the Water Erosion Prediction Project for Roads. Stream crossings were evaluated based on the Virginia Department of Forestry (VDOF) BMP manual guidelines and categorized as BMP−, BMP‐standard, or BMP+ based on the quality of road template, drainage, ground cover, and stream crossing structure. BMP implementation scores were calculated for each stream crossing using VDOF audit questions. Potential erosion effects due to upgrading crossings were estimated by adjusting ground cover percentage and approach length parameters in the erosion models. Results indicate that erosion rates decrease as BMP implementation scores increase (p < 0.05). BMP‐standard and BMP+ ratings made up 83% of crossings sampled, with an average erosion rate of 6.8 Mg/ha/yr. Hypothetical improvements beyond standard BMP recommendations provided minimal additional erosion prevention.
Prevalence of viral photosynthesis genes along a freshwater to saltwater transect in Southeast USA
Authors: Ruiz‐Perez Carlos A. , Tsementzi Despina , Hatt Janet K. , Sullivan Matthew B. , Konstantinidis Konstantinos T.
Published: July 2019

Bacteriophages encode host‐acquired functional genes known as auxiliary metabolic genes (AMGs). Photosynthesis AMGs are commonly found in marine cyanobacteria‐infecting Myoviridae and Podoviridae cyanophages, but their ecology remains understudied in freshwater environments. To advance knowledge of this issue, we analysed viral metagenomes collected in the summertime for four years from five lakes and two estuarine locations interconnected by the Chattahoochee River, Southeast USA. Sequences representing ten different AMGs were recovered and found to be prevalent in all sites. Most freshwater AMGs were 10‐fold less abundant than estuarine and marine AMGs and were encoded by novel Myoviridae and Podoviridae cyanophage genera. Notably, several of the corresponding viral genomes showed endemism to a specific province along the river. This translated into psbA gene phylogenetic clustering patterns that matched a marine vs. freshwater origin indicating that psbA may serve as a robust classification and source‐tracking biomarker. Genomes classified in a novel viral lineage represented by isolate S‐EIVl contained psbA, which is unprecedented for this lineage. Collectively, our findings indicated that the acquisition of photosynthesis AMGs is a widespread strategy used by cyanophages in aquatic ecosystems, and further indicated the existence of viral provinces in which certain viral species and/or genotypes are locally abundant.
The ratio of PACU length‐of‐stay to surgical duration: Practical observations
Authors: Weissman Charles , Scemama Jeremy , Weiss Yoram G.
Published: July 2019

Background

Operating room (OR) and post‐anesthesia care unit (PACU) activity are closely linked since the number, type, and sequence of surgeries influence subsequent PACU activity. We aimed to explore the relationship between duration‐of‐surgery (DOS) and PACU length‐of‐stay (LOS), the PACU‐LOS:DOS ratio, since it is among the determinants of the number of PACU beds and nurse staffing required to insure efficient egress of patients from the OR.

Methods

PACU‐LOS:DOS ratio was examined using retrospective data from a tertiary medical center's surgical information system (Phase 1) and prospectively collected data from a convenience sample of post‐operative patients (Phase 2).

Results

Phase 1 included 17 047 patients, the majority (73%) with PACU‐LOS:DOS ratios >1.0, indicating PACU‐LOS longer than DOS. Median PACU‐LOS was 117 minutes, median DOS was 80 minutes, and median PACU‐LOS/DOS ratio was 1.5. PACU‐LOS showed greater variability than DOS because of extended PACU stays. Phase 2 (n = 2054) confirmed Phase 1 results (median PACU‐LOS/DOS ratio ‐ 1.8). In both phases at a DOS of >130 minutes PACU‐LOS/DOS ratio became <1.0. In 24% of Phase 2 patients PACU‐LOS was prolonged because of administrative issues. Post‐operative, more than pre‐ and intra‐operative, measurements influenced PACU‐LOS.

Conclusions

The PACU‐LOS/DOS ratio proved useful for demonstrating interactions between 2 central components of the surgical system. The many patients with PACU‐LOS:DOS ratios >1.0 provides objective evidence for the number of PACU beds exceeding the number of ORs.
Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation
Authors: Hu Bin , Li Guangjin , Ye Zhongde , Gustafson Claire E. , Tian Lu , Weyand Cornelia M. , Goronzy Jörg J.
Published: July 2019

With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment.
Cortical thickness following electroconvulsive therapy in patients with depression: a longitudinal MRI study
Authors: Gbyl K. , Rostrup E. , Raghava J. M. , Carlsen J. F. , Schmidt L. S. , Lindberg U. , Ashraf A. , Jørgensen M. B. , Larsson H. B. W. , Rosenberg R. , Videbech P.
Published: July 2019

Objective

Several studies have found an increase in hippocampal volume following electroconvulsive therapy (ECT), but the effect on cortical thickness has been less investigated. We aimed to examine the effects of ECT on cortical thickness and their associations with clinical outcome.

Method

Using 3 Tesla MRI scanner, we obtained T1‐weighted brain images of 18 severely depressed patients at three time points: before, right after and 6 months after a series of ECT. The thickness of 68 cortical regions was extracted using Free Surfer, and Linear Mixed Model was used to analyze the longitudinal changes.

Results

We found significant increases in cortical thickness of 26 regions right after a series of ECT, mainly within the frontal, temporal and insular cortex. The thickness returned to the baseline values at 6‐month follow‐up. We detected no significant decreases in cortical thickness. The increase in the thickness of the right lateral orbitofrontal cortex was associated with a greater antidepressant effect, r = 0.75, P = 0.0005. None of the cortical regions showed any associations with cognitive side effects.

Conclusion

The increases in cortical thickness induced by ECT are transient. Further multimodal MRI studies should examine the neural correlates of these increases and their relationship with the antidepressant effect.
Social functioning and subclinical psychosis in adolescence: a longitudinal general adolescent population study
Authors: Heins M. , Achterhof R. , Collip D. , Viechtbauer W. , Kirtley O. J. , Gunther N. , van Os J. , Feron F. , Myin‐Germeys I.
Published: July 2019

Objectives

To investigate the longitudinal relationship between subclinical psychotic symptoms and social functioning in a representative general population sample of adolescents.

Method

Data were derived from a routine general health screening of 1909 adolescents in a circumscribed region. Baseline measurement was in the second grade of secondary school (T0), and follow‐up occurred approximately 2 years later (T1). Social functioning and subclinical psychotic symptoms of hallucinations and delusions were assessed at both time points.

Results

Baseline (T0) social problems preceded follow‐up (T1) subclinical delusions, but not T1 subclinical hallucinations. Similarly, T0 delusions preceded social problems at T1, but T0 hallucinations did not.

Conclusion

This longitudinal general population study demonstrated a bidirectional association between social problems and delusions, but found no link between social problems and hallucinations. This may reflect a downward negative spiral where delusional thoughts and social problems reinforce each other.
A prognostic nomogram constructed for relapsed or refractory diffuse large B‐cell lymphoma patients
Authors: Jiang Shiyu , Qin Yan , Liu Peng , Yang Jianliang , Yang Sheng , He Xiaohui , Zhou Shengyu , Gui Lin , Zhang Changgong , Zhou Liqiang , Sun Yan , Shi Yuankai
Published: July 2019

Aim

The clinical course of diffuse large B‐cell lymphoma (DLBCL) is variable and there is a lack of prognostic markers and models for relapsed or refractory (r/r) DLBCL. Hence, we conducted this study to identify independent factors that can predict the survival rate of r/r DLBCL patients.

Methods

A total of 416 r/r DLBCL patients who were pretreated with first‐line anthracycline‐based chemotherapy at the National Cancer Center in China between 2006 and 2016 were divided into the primary (n = 291) and validation (n = 125) cohorts. The effect of preclinical and clinical indicators on DLBCL survival rates of the two cohorts were evaluated by univariate and multivariate analyses. Factors showing good correlation with patient survival rates were used to construct a prognostic nomogram.

Results

Multivariate analysis of the primary cohort revealed five independent prognostic factors: lactate dehydrogenase level at diagnosis, response to front line treatment, progression/recurrence pattern, location, and invasion on progression/recurrence, which were then used to construct a nomogram. The nomogram was shown to have a C‐index of 0.76 and AUC values of 0.81 and 0.80 for the primary and validation cohorts, respectively, suggesting good prognostic power. We further stratified the r/r DLBCL patients into four risk groups according to the newly developed nomogram.

Conclusion

The prognostic nomogram constructed using the five identified clinical indicators can potentially be applied in the clinical setting to guide treatment decision.
A gene dysfunction module reveals the underlying pathogenesis of hidradenitis suppurativa: An update
Authors: Li Xueli , Jiang Lei , Huang Yong , Ren Zhilong , Liang Xiaoqin , Wang Peng
Published: July 2019

Hidradenitis suppurativa is a chronic skin disease characterised by repeated skin abscesses with sinus tracts and scar formation. Currently, the aetiology and pathogenesis of hidradenitis suppurativa remain unclear. Genetic factors, immune disorders, hormonal abnormalities, skin‐microbial dysbiosis, smoking, obesity and mechanical friction all influence hidradenitis suppurativa pathogenesis. Moreover, hidradenitis suppurativa has a familial subset with autosomal dominant transmission proposed and is related to a mutation of γ‐secretase component genes. In this review, we analyse and summarise research progress regarding the relationship between the γ‐secretase gene dysfunction and the pathogenesis of hidradenitis suppurativa.
Prenatal testing: Does reproductive autonomy succeed in dispelling eugenic concerns?
Authors: Begović Dunja
Published: July 2019

Traditionally, two main rationales for the provision of prenatal testing and screening are identified: the expansion of women’s reproductive choices and the reduction of the burden of disease on society. With the number of prenatal tests available and the increasing potential for their widespread use, it is necessary to examine whether the reproductive autonomy model remains useful in upholding the autonomy of pregnant women or whether it allows public health considerations and even eugenic aims to be smuggled in under the smokescreen of autonomy. In this article I argue that if we are serious about upholding women’s autonomy in the context of prenatal testing, what is needed is a model based on a more robust conception of reproductive autonomy, such as the one defended by Josephine Johnston and Rachel Zacharias as ‘reproductive autonomy worth having’. While Johnston and Zacharias put forward a basic outline of this conception, I apply it to the specific case of prenatal testing and show how it responds to objections levelled against the reproductive autonomy model. I argue that adopting this kind of conception is necessary to avoid fundamental challenges to women’s autonomy when it comes to prenatal screening and testing.
Moral enhancement, at the peak of pharmacology and at the limit of ethics
Authors: Macpherson Ignacio , Roqué María Victoria , Segarra Ignacio
Published: July 2019

The debate over the improvement of moral capacity or moral enhancement through pharmacology has gained momentum in the last decade as a result of advances in neuroscience. These advances have led to the discovery and allowed the alteration of patterns of human behavior, and have permitted direct interventions on the neuronal structure of behavior. In recent years, this analysis has deepened regarding the anthropological foundations of morality and the reasons that would justify the acceptance or rejection of such technology. We present a review of proposals for pharmacological interventions directed directly towards moral enhancement. In addition, we identify the ethical dilemmas that such interventions may generate, as well as the moral assessment of the authors of these studies. There is a moderate consensus on the risks of any intervention on the intimate structure of the human condition, its autonomy and identity, but there are large differences in explaining the reasons for this concern and especially in justifying such interventions. These findings show that it is necessary to investigate the moral assessment of authors and the ethical dimension within the field of pharmacology in order to identify future trends.
Leveraging Nonlinear Dynamic Models to Predict Progression of Neuroimaging Biomarkers
Authors: Sun Ming , Zeng Donglin , Wang Yuanjia
Published: July 2019

Using biomarkers to model disease course effectively and make early prediction is a challenging but critical path to improving diagnostic accuracy and designing preventive trials for neurological disorders. Leveraging the domain knowledge that certain neuroimaging biomarkers may reflect the disease pathology, we propose a model inspired by the neural mass model from cognitive neuroscience to jointly model nonlinear dynamic trajectories of the biomarkers. Under a nonlinear mixed-effects model framework, we introduce subject- and biomarker-specific random inflection points to characterize the critical time of underlying disease progression as reflected in the biomarkers. A latent liability score is shared across biomarkers to pool information. Our model allows assessing how the underlying disease progression will affect the trajectories of the biomarkers, and, thus, is potentially useful for individual disease management or preventive therapeutics. We propose an EM algorithm for maximum likelihood estimation, where in the E step, a normal approximation is used to facilitate numerical integration. We perform extensive simulation studies and apply the method to analyze data from a large multisite natural history study of Huntington's Disease (HD). The results show that some neuroimaging biomarker inflection points are early signs of the HD onset. Finally, we develop an online tool to provide the individual prediction of the biomarker trajectories given the medical history and baseline measurements.
Differential regulation of Kidins220 isoforms in Huntington's disease
Authors: Sebastián‐Serrano Álvaro , Simón‐García Ana , Belmonte‐Alfaro Alicia , Pose‐Utrilla Julia , Santos‐Galindo María , del Puerto Ana , García‐Guerra Lucía , Hernández Ivó H. , Schiavo Giampietro , Campanero Miguel R. , Lucas José J. , Iglesias Teresa
Published: July 2019

Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain‐overactivation, among others. Kinase D‐interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat‐rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy‐terminal length and critical protein‐protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220‐C32) and the recently identified exon 33 (Kidins220‐C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220‐C33 as a form detrimental for neurons. However, the functional role of Kidins220‐C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220‐C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33‐specific as Kidins220‐C32 variant remains unchanged. We also find the early decrease in Kidins220‐C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220‐C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain‐mediated Kidins220‐C33 proteolysis modulates onset and/or progression of HD.
Dysregulation of sputum columnar epithelial cells and products in distinct asthma phenotypes
Authors: Qin Ling , Gibson Peter G. , Simpson Jodie L. , Baines Katherine J. , McDonald Vanessa M. , Wood Lisa G. , Powell Heather , Fricker Michael
Published: July 2019

Background

Dysfunction of the bronchial epithelium plays an important role in asthma; however, its measurement is challenging. Columnar epithelial cells are often quantified, yet rarely analysed, in induced sputum studies.

Objective

We aimed to test whether sputum columnar epithelial cell proportion and count are altered in asthma, and whether they are associated with clinical and inflammatory variables. We aimed to test whether sputum‐based measures could provide a relatively non‐invasive means through which to monitor airway epithelial activation status.

Methods

We examined the relationship of sputum columnar epithelial cells with clinical and inflammatory variables of asthma in a large retrospective cross‐sectional cohort (901 participants with asthma and 138 healthy controls). In further studies, we used flow cytometry, microarray, qPCR and ELISA to characterize sputum columnar epithelial cells and their products.

Results

Multivariate analysis and generation of 90th centile cut‐offs (≥11% or ≥18.1 × 104/mL) to identify columnar epithelial cell “high” asthma revealed a significant relationship between elevated sputum columnar cells and male gender, severe asthma and non‐neutrophilic airway inflammation. Flow cytometry showed viable columnar epithelial cells were present in all sputum samples tested. An epithelial gene signature (SCGB3A1, LDLRAD1, FOXJ1, DNALI1, CFAP157, CFAP53) was detected in columnar epithelial cell‐high sputum. CLCA1 mRNA and periostin protein, previously identified biomarkers of IL‐13‐mediated epithelial activation, were elevated in columnar epithelial cell‐high sputum samples, but only when accompanied by eosinophilia.

Conclusions & clinical relevance

Sputum columnar epithelial cells are related to important clinical and inflammatory variables in asthma. Measurement of epithelial biomarkers in sputum samples could allow non‐invasive assessment of altered bronchial epithelium status in asthma.
Pragmatic evaluation of inhaled corticosteroid particle size formulations on asthma control
Authors: Kuo Chris RuiWen , Jabbal Sunny , Anderson William , Lipworth Brian J.
Published: July 2019

Background

Extra‐fine particle formulations of inhaled corticosteroid (ICS) are associated with improved lung delivery.

Objectives

A pragmatic study to assess patient‐reported outcomes after switching from fine to extra‐fine particle ICS in persistent asthma.

Methods

Twenty‐four patients (mean age 48 year, FEV1 84%, ACQ 1.67) received 4 weeks run‐in with a constant dose of fine particle ICS (mean dose 710 µg), followed by switching to an equivalent dose of extra‐fine particle hydrofluoroalkane beclomethasone dipropionate (mean dose 355µg). Asthma control questionnaire (ACQ), the primary outcome and mini asthma quality of life questionnaire (mAQLQ) were measured pre‐ and post‐run‐in (baseline) and after 4 weeks and 8 weeks of switching.

Results

Comparing pre‐ vs post‐run‐in, there were no differences for ACQ: 1.67 vs 1.65 or AQLQ: 5.08 vs 5.34. There were mean (95%CI) improvements (P < 0.001) from baseline after 8 weeks for ACQ: −0.53 (−0.83, −0.23) and AQLQ: 0.69 (0.35, 1.04), which exceeded the minimal clinically important difference (MCID) of 0.5 for both. There were also differences (P < 0.05) in domiciliary symptoms and reliever use. There were no significant changes at 8 weeks in lung function, FeNO or blood eosinophils.

Conclusions

Pragmatic switching from fine to extra‐fine particle ICS at half the dose was associated with clinically relevant improvements in asthma control and quality of life, but not lung function or type 2 biomarkers.