bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomics of Extracellular Vesicles Produced byGranulicatellaSpecies that cause Infective Endocarditis
Authors: Alkandari Sarah A , Bhardwaj Radhika G , Ellepola Arjuna , Karched Maribasappa
Published: December 2019

When oral bacteria accidentally enter the bloodstream due to transient tissue damage during dental procedures, they have the potential to attach to the endocardium or an equivalent surface of an indwelling prosthesis and cause infection. Many bacterial species produce extracellular vesicles (EVs) as part of normal physiology, but also use it as a virulence strategy. In this study, it was hypothesized thatGranulicatellaspecies produce EVs that possibly help them in virulence. Therefore, the objectives were to isolate and characterize EVs produced by these species and to investigate their immune-stimulatory effects. The reference strainsG. adiacensCCUG 27809 andG. elegansCCUG 38949 were cultured on chocolate blood agar for 2 days. From subsequent broth cultures, the EVs were isolated using differential centrifugation and filtration protocol and then observed using scanning electron microscopy. Proteins in the vesicle preparations were identified by nano LC-ESI-MS/MS. The EVs proteomes were analyzed and characterized using different bioinformatics tools. The immune-stimulatory effect of the EVs was studied via ELISA quantification of IL-8, IL-1β and CCL5, major proinflammatory cytokines, produced from stimulated human PBMCs. It was revealed that bothG. adiacensandG. elegansproduced EVs, ranging in diameter from 30 to 250 nm. Overall,G. adiacensEVs contained 160 proteins, andG. elegansEVs contained 107 proteins. Both proteomes consist of several ribosomal proteins, DNA associated proteins, binding proteins, and metabolic enzymes. It was also shown that these EVs carry putative virulence factors including moonlighting proteins. These EVs were able to induce the production of IL-8, IL-1β and CCL5 from human PBMCs. The diversity in EVs content indicates that these vesicles could have possible roles in bacterial survival, invasion, host immune modulation as well as infection. Further functional characterization of theGranulicatellaEVs may provide new insights into virulence mechanisms of these important but less studied oral bacterial species.
A non-invasive digital biomarker for the detection of rest disturbances in the SOD1G93A mouse model of ALS
Authors: Golini E. , Rigamonti M. , Iannello F. , De Rosa C. , Scavizzi F. , Raspa M. , Mandillo S.
Published: December 2019

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that affects both central and peripheral nervous system, leading to the degeneration of motor neurons, which eventually results in muscle atrophy, paralysis and death. Sleep disturbances are common in patients with ALS, leading to even further deteriorated quality of life. Investigating methods to potentially assess sleep and rest disturbances in animal models of ALS is thus of crucial interest.

We used an automated home cage monitoring system (DVC®) to capture activity patterns that can potentially be associated with sleep and rest disturbances and thus to the progression of ALS in the SOD1G93A mouse model. DVC®enables non-intrusive 24/7 long term animal activity monitoring, which we assessed together with body weight decline and neuromuscular function deterioration measured by grid hanging and grip strength tests in male and female mice from 7 until 24 weeks of age.

We show that as the ALS progresses over time in SOD1G93A mice, activity patterns during day time start becoming irregular, with frequent activity bouts that are neither observed in control mice nor in SOD1G93A at a younger age. The increasing irregularities of activity patterns during day time are quantitatively captured by designing a novel digital biomarker, referred to as Rest Disturbance Index (RDI). We show that RDI is a robust measure capable of detecting rest/sleep-related disturbances during the disease progression earlier than conventional methods, such as the grid hanging test. Moreover RDI highly correlates with grid hanging and body weight decline, especially in males.

The non-intrusive long-term continuous monitoring of animal activity enabled by DVC®has been instrumental in discovering activity patterns potentially correlated with sleep and rest disturbances in the SOD1G93A mouse model of the ALS disease.
XFlow: An algorithm for extracting ion chromatograms
Authors: Gutierrez Mathew , Smith Rob
Published: December 2019

Mass spectrometry is a fundamental tool for modern proteomics. The increasing availability of mass spectrometry data paired with the increasing sensitivity and fidelity of the instruments necessitates new and more potent analytical methods. To that end, we have created and present XFlow, a feature detection algorithm for extracting ion chromatograms from MS1 LC-MS data. XFlow is a parameter-free procedurally agnostic feature detection algorithm that utilizes the latent properties of ion chromatograms to resolve them from the surrounding noise present in MS1 data. XFlow is designed to function on either profile or centroided data across different resolutions and instruments. This broad applicability lends XFlow strong utility as a one-size-fits-all method for MS1 analysis or target acquisition for MS2. XFlow is written in Java and packaged with JS-MS, an open-source mass spectrometry analysis toolkit.
Abrogation of RAB27A expression transiently affects melanoma cell proliferation
Authors: Guo Dajiang , Beaumont Kimberley A. , Sharp Danae M. , Lui Goldie Y. L. , Weninger Wolfgang , Haass Nikolas K. , Tikoo Shweta
Published: December 2019

The role of the small GTPase RAB27A as an essential melanosome trafficking regulator in melanocytes is well-accepted. A decade ago, RAB27A was identified as a tumor dependency gene that promotes melanoma cell proliferation. RAB27A has since been linked to another propeller of cancer progression: exosome secretion. We have recently demonstrated that RAB27A is overexpressed in a subset of melanomas. High RAB27A gene and protein expression correlates with poor prognosis in melanoma patients. Mechanistic investigations revealed that the generation of pro-invasive exosomes was RAB27A-dependent and, therefore, silencing RAB27A reduced melanoma cell invasionin vitroandin vivo. However, previous studies have implicated RAB27A to be involved in both proliferation and invasion of melanoma cells. In this study, we demonstrate that the effects of abrogating RAB27A expression on proliferation are temporary, in contrast to the previously reported persistent effects on tumor invasion and metastasis. Therefore, we assist in the dissection of the short-term versus long-term effects of RAB27A knockdown on melanoma cell proliferation, invasion, and metastasis. We believe that our findings provide novel insights into the effects of RAB27A blockade.

Significance

RAB27A is known to serve as an essential regulator for melanosome trafficking. However, to date its role in melanoma biology has not been completely deciphered. While there are consistent independent reports on the pro-invasive effects of RAB27A, there are conflicting data on its impact on cell proliferation. Here we show that indeed abrogation of RAB27A does reduce cellular proliferation; however, this effect is only transient, while the impact on invasion as reported previously is persistent. This finding offers an explanation for the apparent contradiction in the literature and provides a deeper understanding of RAB27A function in melanoma cell biology.
Oxygen-generated spatial distribution of cell population links to p53 status
Authors: Taxak Shashank , Pati Uttam
Published: December 2019

Low oxygen induces wild type p53 inactivation and selects for mutant-like p53 phenotypes for aggressive tumor growth. Recently, we have shown wild type p53 as a cellular oxygen-sensor that operates in switch-like fashion to transform its characters of a tumor suppressor or promoter in a gradient of hypoxia. However, it is unclear how hypoxic tumors select for wild type p53 phenotypes for oxygen-sensitive responses. Here, we show that oxygen-generated spatial distribution of the cell population induces p53 phenotype-specific survival or death. We have found that a dynamic state of spatial scatters or clustering patterns of cell populations favor the survival of wild type more than the mutant phenotypes in a wide range of oxygen fluctuation by affecting p53 subcellular localization. Our results demonstrate how spatial distribution could function to establish wild type p53-mediated oxygen sensing and cell fate decisions in a cell population with heterogeneous p53 allele status. We anticipate that such behavior of cells in a gradient of oxygen can be utilized by the hypoxic tumors to maintain distinct p53 alleles and determine the release and metastasis of single or clustered circulating tumor cells (CTCs).

Summary sentence

Oxygen variation results in p53 phenotype-specific cell fate via the spatial distribution pattern of the cell population
Laminin alpha 5 is Necessary for Mammary Epithelial Growth and Function by Maintaining Luminal Epithelial Cell Identity
Authors: Englund Johanna I , Cojoc Hanne , Blaas Leander , Ritchie Alexandra , Pentinmikko Nalle , Döhla Julia , Munne Pauliina , Patarroyo Manuel , Klefström Juha , Ivaska Johanna , Katajisto Pekka
Published: December 2019

Epithelial attachment to the basement membrane (BM) is essential for mammary gland development, yet the exact roles of specific BM components remain unclear. Here, we demonstrate that expression of distinct laminin α-isoforms by luminal and basal mammary epithelial cells enforces lineage identity that is necessary for normal mammary gland growth and function. Laminin α5 (LMα5) is mainly expressed by the luminal epithelial cells, and it is necessary for pubertal mammary gland growth, pregnancy induced gland remodeling, and for alveolar function. Adhesion to LMα5 containing laminin promotes luminal traits in both luminal and basal epithelial cells, and reduces progenitor activity of basal epithelial cells. Mechanistically, we show thatLama5loss interferes with differentiation of hormone receptor positive luminal cells, which results in reduced Wnt4 expression and defective crosstalk between luminal and basal epithelial cells during gland remodeling. Our results reveal a novel BM-mediated mechanism, which regulates mammary gland remodeling and function via specification of luminal epithelial cells.
Perturbation analysis of a multi-morphogen Turing Reaction-Diffusion stripe patterning system reveals key regulatory interactions
Authors: Economou Andrew D. , Monk Nicholas A.M. , Green Jeremy B.A.
Published: December 2019

Periodic patterning is extremely widespread in developmental biology and is broadly modelled by Reaction-Diffusion (RD) processes. However, the minimal two-component RD system is vastly simpler than the multimolecular events that current biology is now able to describe. Moreover, RD models are typically underconstrained such that it is often hard to meaningfully relate the model architecture to real interactions measured experimentally. To address both these issues, we investigated the periodic striped patterning of the rugae (transverse ridges) in the roof of the mammalian palate. We experimentally implicated a small number of major signalling pathways and established theoretical limits on the number of pathway network topologies that can account for the stable spatial phase relationships of their observed signalling outputs. We further conducted perturbation analysis both experimentally and in silico, critically to assess the effects of perturbations on established patterns. We arrived at a relatively highly-constrained number of possible networks and found that these share some common motifs. Finally, we examined the dynamics of pattern appearance and discovered a core network consisting of epithelium-specific FGF and Wnt as mutually antagonistic “activators” and Shh as the “inhibitor”, which initiates the periodicity and whose existence constrains the network topology still further. Together these studies articulate the principles of multi-morphogen RD patterning and demonstrate the utility of perturbation analysis as a tool for constraining networks in this and, in principle, any RD system.
The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction
Authors: Pan Bo , Parajuli Nirmal , Tian Zongwen , Li Jie , Wu Penglong , Lewno Megan T. , Bedford Lynn , Mayer R. John , Fang Jing , Liu Jinbao , Cui Taixing , Su Huabo , Wang Xuejun
Published: December 2019

Rationale

The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime for example, show cardiotoxicity. Moreover, UPS and ALP defects are implicated in the pathogenesis of a large subset of heart disease. Hence, a better understanding of the cross-talk between the two catabolic pathways should help advance cardiac pathophysiology and medicine.

Objective

Systemic pharmacological proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. The present study investigates whether cardiomyocyte-restricted PSMI activates myocardial ALP and, more importantly, how proteasome malfunction activates the ALP in the heart.

Methods and Results

Myocardial macroautophagy, transcription factor EB (TFEB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation ofPsmc1(a 19S proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted markedly by calcineurin inhibition (cyclosporine A) and by siRNA-mediatedMolcn1silence. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null mice. In cultured wild type, but not p62-null, mouse cardiomyocytes, PSMI induced increases in LC3-II flux and in the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62 null mice compared with wild type mice.

Conclusions

(1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) both Mocln1 and p62 form a feed-forward loop with TFEB during TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac ALP activation in a proteasome malfunction setting.
Role of omega‐6 and omega‐3 fatty acids in fetal programming
Authors: Shrestha Nirajan , Sleep Simone L. , Cuffe James S.M. , Holland Olivia J. , Perkins Anthony V. , Yau Suk Yu , McAinch Andrew J. , Hryciw Deanne H.
Published: December 2019

Maternal nutrition plays a critical role in fetal development and can influence adult onset of disease. Linoleic acid (LA) and alpha‐linolenic acid (ALA) are major omega‐6 (n‐6) and n‐3 polyunsaturated fatty acids (PUFA), respectively, that are essential in our diet. LA and ALA are critical for the development of the fetal neurological and immune systems. However, in recent years, the consumption of n‐6 PUFA has increased gradually worldwide, and elevated n‐6 PUFA consumption may be harmful to human health. Consumption of diets with high levels of n‐6 PUFA before or during pregnancy may have detrimental effects on fetal development and may influence overall health of offspring in adulthood. This review discusses the role of n‐6 PUFA in fetal programming, the importance of a balance between n‐6 and n‐3 PUFAs in the maternal diet, and the need of further animal models and human studies that critically evaluate both n‐6 and n‐3 PUFA contents in diets.
Alpha‐pinene promotes osteoblast differentiation and attenuates TNFα‐induced inhibition of differentiation in MC3T3‐E1 pre‐osteoblasts
Authors: Min Hyeon‐Young , Son Hyo‐Eun , Jang Won‐Gu
Published: December 2019

Alpha‐pinene (α‐pinene) is an organic compound, found in the oils of many species of coniferous trees, especially pine. α‐Pinene reportedly has antioxidant and anti‐inflammatory activities; however, its effects on osteoblasts are unknown. This study investigated the effects of α‐pinene on osteoblast differentiation and tumour necrosis factor‐alpha (TNFα)‐induced inhibition of osteogenesis. Culture in control or osteogenic medium containing α‐pinene increased osteogenic marker expression. Alkaline phosphatase staining and alizarin red S staining confirmed that α‐pinene enhanced osteoblast differentiation. Also, α‐pinene attenuated TNFα‐induced inhibition of Smad1/5/9 phosphorylation and extracellular matrix mineralization. Taken together, our findings suggest that α‐pinene enhances osteoblast differentiation and mineralization in MC3T3‐E1 pre‐osteoblasts.
Cancer stemness contributes to cluster formation of colon cancer cells and high metastatic potentials
Authors: Kapeleris Joanna , Zou Hong , Qi Yan , Gu Yushu , Li Jingyun , Schoning Jennifer , Monteiro Michael J. , Gu Wenyi
Published: December 2019

The ability of cancer cells to form clusters is a characteristic feature in the development of metastatic tumours with drug resistance. Several studies demonstrated that clusters of circulating tumour cells (CTCs) have a greater metastatic potential to establish new tumours at secondary sites than single CTCs. However, the mechanism of cluster formation is not well understood. In this study, we investigated whether cancer stemness would contribute to cluster formation. We used a tumour sphere culture method to enrich cancer stem cells (CSCs) from colon cancer cells and found that during the second generation of sphere culture, clusters (between 3 and 5 cells) formed within the first 24 hours, whereas the rest remained as single cells. The clusters were analysed for stemness and metastatic potential, including gene expressions for cancer stemness (CD133 and Lgr5), epithelial‐mesenchymal transition (E‐cadherin and TGF‐β 1‐3) and hypoxia‐induced factors (HIF‐1α and HIF‐2α). The results showed that the clusters expressed higher levels of these genes and colon CSC surface markers (including CD24, CD44 and CD133) than the single cells. Among these markers, CD24 seemed the major contributor linking the cells into the clusters. These clusters also showed a stronger ability to both form colonies and migrate. Our data collectively suggest that colon cancer stemness contributes to cluster formation and that clustered cells exhibit a great metastatic potential. Our study thus provides a method to study the CTC clusters and derive insight into oncogenesis and metastasis.
No evidence of physiological stress in an urban animal: Comparison of fecal cortisol metabolites between urban and rural Eurasian red squirrels
Authors: Shimamoto Tatsuki , Uchida Kenta , Koizumi Itsuro , Matsui Motozumi , Yanagawa Hisashi
Published: December 2019

Over the last few decades, urban environments have been regarded as alternative habitats for wildlife. Given the continuous anthropogenic disturbance, however, it remains largely unknown whether urban environments are truly beneficial to some animals or whether the animals are merely just surviving. Glucocorticoids, which play an important role in coping with environmental challenges, are often measured as primary biomarkers of physiological stress. Chronic secretions of these hormones can have deleterious effects on animal health. Some urban stressors are constantly present and may increase the risk of chronic stress. In this study, we compared fecal cortisol metabolite (FCM) levels to evaluate stress levels between an urban and rural population of Eurasian red squirrels Sciurus vulgaris. We hypothesized that if squirrels suffer from greater stress in urban environments, their FCM levels would be significantly higher than that of rural squirrels. Our results showed that FCM levels were not significantly different between the urban and rural squirrel populations, and urban squirrels did not weigh less than rural squirrels. We conclude that the urban squirrels were not subjected to greater stress than their rural counterparts. Urban environments may be preferable for red squirrels, possibly because of release from predators and increased food availability through artificial feeding.
Amino acids levels in early pregnancy predict subsequent gestational diabetes
Authors: Jiang Rong , Wu Shuhua , Fang Chen , Wang Chang , Yang Ya , Liu Chao , Hu Ji , Huang Yun
Published: December 2019

Background

We aimed to estimate the performance of amino acids levels in predicting the risk of subsequent gestational diabetes mellitus (GDM).

Methods

A total of 431 women at 12 to 16 weeks of gestation in the Department of Obstetrics and Gynecology of the Second Affiliated Hospital of Soochow University were recruited. High‐performance liquid chromatography electrospray tandem mass spectrometry was used to measure amino acids levels in maternal blood at 12 to 16 weeks of gestation. At 24 to 28 weeks of gestation, all participants were administered 75‐g oral glucose tolerance tests for the diagnosis of GDM.

Results

Alanine, isoleucine, and tyrosine levels in early pregnancy were significantly different between women who developed GDM and those who remained normal glucose tolerant. Logistic regressions showed that after adjustments for age, parity, body mass index, family history of diabetes, γ‐glutamyltranspeptidase, triglycerides, fasting glucose and fasting insulin levels, alanine (odds ratio [OR], 1.46; 95% CI, 1.05‐2.04; P = .027), isoleucine (OR, 1.48; 95% CI, 1.12‐1.96; P = .0062), and tyrosine (OR, 1.46; 95% CI, 1.07‐2.03; P = .020) levels in early pregnancy were independently associated with subsequent GDM. The addition of isoleucine and tyrosine into the conventional model improved the area under curve from 0.692 to 0.737 (P = .036) and significantly increased the net reclassification improvement (+13.7%, P = .0025).

Conclusions

The present study suggests that elevated isoleucine, tyrosine, and alanine levels are independently and significantly associated with subsequent incidence of GDM. New models including conventional risk factors, isoleucine and tyrosine levels in early pregnancy might help physicians identify high‐risk population of GDM.
Close relatives in population samples: Evaluation of the consequences for genetic stock identification
Authors: Östergren Johan , Palm Stefan , Gilbey John , Dannewitz Johan
Published: December 2019

Determining the origin of individuals in mixed population samples is key in many ecological, conservation and management contexts. Genetic data can be analyzed using genetic stock identification (GSI), where the origin of single individuals is determined using Individual Assignment (IA) and population proportions are estimated with Mixed Stock Analysis (MSA). In such analyses, allele frequencies in a reference baseline are required. Unknown individuals or mixture proportions are assigned to source populations based on the likelihood that their multilocus genotypes occur in a particular baseline sample. Representative sampling of populations included in a baseline is important when designing and performing GSI. Here, we investigate the effects of family sampling on GSI, using both simulated and empirical genotypes for Atlantic salmon (Salmo salar). We show that nonrepresentative sampling leading to inclusion of close relatives in a reference baseline may introduce bias in estimated proportions of contributing populations in a mixed sample, and increases the amount of incorrectly assigned individual fish. Simulated data further show that the induced bias increases with increasing family structure, but that it can be partly mitigated by increased baseline population sample sizes. Results from standard accuracy tests of GSI (using only a reference baseline and/or self‐assignment) gave a false and elevated indication of the baseline power and accuracy to identify stock proportions and individuals. These findings suggest that family structure in baseline population samples should be quantified and its consequences evaluated, before carrying out GSI.
Aberrant expansion of circulating CD4+CXCR5+CCR7loPD1hi Tfh precursor cells in idiopathic inflammatory myopathy
Authors: Zhang Lu , Li Wenli , Cai Ying , Liu Xia , Peng Qinglin , Liang Lin
Published: December 2019

Objective

To determine circulating follicular T helper (Tfh) cell precursor and its relationship with clinical characteristics in idiopathic inflammatory myopathy (IIM).

Methods

The study population included 47 patients with IIM and 30 healthy controls. Circulating CD4+CXCR5+CCR7loPD‐1hi T cells and intracellular interleukin (IL)‐21 were assessed by flow cytometry. Serum IL‐21 levels were measured by enzyme‐linked immunosorbent assay. The disease activity was evaluated using myositis disease activity assessment visual analog scales (VAS) as well as muscle and physician global assessment (PGA).

Results

The percentage of the CCR7loPD‐1hi subset cells within CD4+CXCR5+ T cells was significantly increased in patients with IIM compared to that in healthy controls (14.3 ± 6.5 vs 11.4 ± 2.6, P = .009). Patients with higher percentages of CCR7loPD‐1hi subsets presented with higher PGA VAS (P = .000), muscle VAS (P = .000), as well as serum creatinine kinase (CK) levels (P = .000) than those with lower percentages of CCR7loPD‐1hi subsets. IL‐21 expression significantly increased in CD4+CXCR5+CCR7loPD‐1hi T cells in patients with IIM compared to that in healthy controls (26.07 ± 7.38 vs 19.25 ± 5.67, P = .001). Meanwhile, both the CCR7loPD‐1hi subset and intracellular IL‐21 expression in IIM patients showed significantly positive correlation with PGA VAS, muscle VAS and serum CK levels. Circulating CD4+CXCR5+CCR7loPD‐1hi T cells and intracellular IL‐21 decreased significantly when disease was improved (P = .018; P = .028).

Conclusion

The percentage of circulating CCR7loPD‐1hi subset among total CD4+CXCR5+ T cells and intracellular IL‐21 expression expanded and showed significant correlation with disease activity in IIM. The circulating follicular helper T cell precursor may be involved in the pathogenesis, especially muscle injury in IIM.
Routine management of postoperative delirium outside the ICU: Results of an international survey among anaesthesiologists
Authors: Bilotta Federico , Weiss Bjoern , Neuner Bruno , Kramer Sylvia , Aldecoa César , Bettelli Gabriella , Sanders Robert D. , Delp Simon M. , Spies Claudia D.
Published: December 2019

Background

Postoperative delirium (POD) is a severe brain dysfunction. Although data indicate a high relevance, no survey has investigated the routine practice to monitor delirium outside the ICU setting after surgery. Prior to publishing of the new European Society of Anaesthesiology (ESA) guidelines on POD, an international survey was conducted to assess current practice.

Methods

European Society of Anaesthesiology‐endorsed online survey; Trial Registration: NCT‐identifier: 02513537.

Results

In total, 566 respondents from 62 countries accessed, and 564 (99.6%) completed the survey (completion rate). Overall, 385 (68%) of the respondents reported that delirium is either “very relevant” or “relevant” for their daily clinical practice. In all, 38 (7%) of the respondents routinely monitor for delirium in >50% of all patients. Asked on the monitoring time point, more than half (n = 308, 55%) indicated to screen before or at recovery room discharge, 235 (42%) up to the first postoperative day, 143 (25%) up to 3 days, and 77 (14%) up to 5 postoperative days. Although there is a lack of long‐term monitoring, nearly all respondents (n = 530, 94%) reported to treat delirium. Availability of EEG/EMG‐based monitoring to assess the depth of anaesthesia was high in the study group (n = 547, 97%) and was used by more than one‐third of the respondents to reduce risk of burst suppression (n = 189, 34%).

Conclusion

Although delirium is perceived as a relevant condition among anaesthesiologists, there is a high demand for implementing monitoring strategies after publishing of the POD Guideline. The survey shows that tools necessary for POD Guideline implementation are available in the centres represented by the respondents.
Social capital and access to informal finance – evidence from Chinese private firms
Authors: Deng Lu , Jiang Ping , Li Sifei , Liao Mingqing
Published: December 2019

This study investigates how firms’ social capital affects their access to informal finance. We argue that social capital helps reduce information asymmetry, increase trust between related parties and enforce lending contracts, so it has positive effects on firms’ access to informal finance. Using novel survey data of Chinese private firms, we find that firms with more social capital have more access to informal finance with lower costs. Further tests show that the effect of social capital is more significant when firms are located in regions with less developed market and lower community’s social capital and during the 2008 financial crisis.
Concordance between health administrative data and survey‐derived diagnoses for mood and anxiety disorders
Authors: Edwards J. , Thind A. , Stranges S. , Chiu M. , Anderson K. K.
Published: December 2019

Objective

To assess whether estimates of survey structured interview diagnoses of mood and anxiety disorders were concordant with diagnoses of these disorders obtained from health administrative data.

Methods

All Ontario respondents to the 2012 Canadian Community Health Survey‐Mental Health (CCHS‐MH) were linked to health administrative databases at ICES (formerly known as the Institute for Clinical Evaluative Sciences). Survey structured interview diagnoses were compared with health administrative data diagnoses obtained using a standardized algorithm. We used modified Poisson regression analyses to assess whether socio‐demographic factors were associated with concordance between the two measures.

Results

Of the 4157 Ontarians included in our sample, 20.4% had either a structured interview diagnosis (13.9%) or health administrative diagnosis (10.4%) of a mood or anxiety disorder. There was high discordance between measures, with only 19.4% agreement. Migrant status, age, employment, and income were associated with discordance between measures.

Conclusions

Our findings indicate that previous estimates of the 12‐month prevalence of mood and anxiety disorders in Ontario may be underestimating the true prevalence, and that population‐based surveys and health administrative data may be capturing different groups of people. Understanding the limitations of data commonly used in epidemiologic studies is a key foundation for improving population‐based estimates of mental disorders.
The effect of maternal body mass index on duration of induced labor
Authors: Carlhäll Sara , Källén Karin , Blomberg Marie
Published: December 2019

Introduction

Obese primiparous women with induction of labor are at high risk for a cesarean section. There are contradictory results regarding time in induced labor in relation to maternal body mass index (BMI). It is important to characterize the course of induced labor to prevent unnecessary cesarean section. We aimed to evaluate whether the duration of labor was associated with maternal BMI in primiparous women with induction of labor.

Material and methods

A national retrospective cohort study, including 15 259 primiparae with a single term pregnancy, admitted for induction of labor from January 2014 to August 2017. Data were obtained from the Swedish Pregnancy Registry. Cox regression analyses were used to illustrate the association between BMI and active labor and between BMI and time from admission until start of active labor.

Results

Duration of active labor was shorter in underweight women and prolonged in women with BMI ≥40 kg/m2 compared with women in other BMI classes, illustrated by Cox regression graphs (P < .001). The median durations of active labor in underweight women were 6.1 and 7.4 hours in women with BMI ≥40 kg/m2. The time from admission until start of active labor increased with maternal BMI, illustrated by Cox regression graphs (P < .001) and the median duration increased from 12.9 hours in underweight women to 22.6 hours in women with BMI ≥40 kg/m2. The cesarean section rate in active labor increased significantly with BMI (P < .001) from 7.4% in underweight women to 22.0% in women with BMI ≥40 kg/m2. Obese and normal weight women had similar rates of spontaneous vaginal delivery (69.9% in the total study population).

Conclusions

The duration of active labor was associated with maternal BMI for underweight women and women with BMI ≥40 kg/m2. Although women with BMI ≥40 kg/m2 who reached the active phase of labor had the same chance for a spontaneous vaginal delivery as normal weight women, the duration of active labor and the cesarean section rate were increased. The time from admission until start of active labor increased successively with maternal BMI.
Initiation of abortion before there is definitive ultrasound evidence of intrauterine pregnancy: A systematic review with meta‐analyses
Authors: Schmidt‐Hansen Mia , Cameron Sharon , Lord Jonathan , Hasler Elise
Published: December 2019

Introduction

Women are increasingly presenting for abortion at very early gestation. However, providers may be reluctant to conduct abortion at this stage as they may be concerned that they cannot exclude an ectopic pregnancy or that they may terminate a non‐viable pregnancy, or may be concerned that both medical and surgical methods may be less effective at this stage of gestation. This provider concern may result in delays in the abortion as additional investigations may be required until an intrauterine pregnancy can be confirmed. Additional unnecessary visits may be distressing for women and waste health service resources. The objective of this systematic review was to determine whether it is safe and effective to initiate abortion before there is ultrasound evidence of an intrauterine pregnancy.

Material and methods

We searched Embase Classic, Embase; Ovid MEDLINE® Epub Ahead‐of‐Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily, Ovid MEDLINE®; and Cochrane Library on 25 October 2019. Eligible studies were randomized and non‐randomized comparative studies, published in English from 1985, comparing initiation of abortion before there is definitive evidence of an intrauterine pregnancy with initiation afterwards. We assessed risk‐of‐bias using the Newcastle‐Ottowa scale. All outcomes were analyzed as risk ratios (RR) and meta‐analyzed using the Mantel‐Haenszel method. The quality of the evidence was assessed using GRADE.

Results

Two non‐randomized studies (n = 3785) showed no differences in “missed ectopic pregnancy” (RR = 0.26, 95% CI 0.03‐2.12), “ongoing pregnancy” (RR = 1.06, 95% CI 0.34‐3.34), or “complete abortion without surgical intervention” (RR = 1, 95% CI 0.98‐1.02) between initiation of medical abortion before or after ultrasound evidence of an intrauterine pregnancy. A third non‐randomized study (n = 1530) showed no differences between initiation of surgical abortion before or after ultrasound evidence of an intrauterine pregnancy in “missed ectopic pregnancy” (no events), “ongoing pregnancy” (RR = 0.56, 95% CI 0.03‐11.59) or “complete abortion without repeat surgical intervention” (RR = 1, 95% CI 0.99‐1.01). The quality of evidence was very low.

Conclusions

Initiation of abortion before there is definitive ultrasound evidence of an intrauterine pregnancy in women without signs or symptoms of an ectopic pregnancy should be considered.
Short stay unit for patients in acute mental health crisis: A case‐control study of readmission rates
Authors: Sveticic Jerneja , Turner Kathryn , Bethi Shailendhra , Krishnaiah Ravikumar , Williams Lee , Almeida‐Crasto Alice , Stapelberg Nicolas J. C. , Roy Samit
Published: December 2019

Introduction

Past evaluations of psychiatric short stay units have shown positive outcomes for patients, yet very little is known about the factors related to readmissions.

Methods

A Short Stay Pathway (SSP) has been introduced on the Gold Coast, Australia, for patients in acute mental health crisis with admissions of up to 3 days. Rates of readmissions within 28 days were compared for SSP patients (N = 678), and a diagnosis‐matched control group of patients from acute mental health beds (N = 1356). Demographic and clinical factors were considered as predictors of subsequent readmissions.

Results

Average length of stay for SSP patients was 3.4 days, compared to 7.6 days in the control group. 10.6% of SSP patients and 18.4% of the control group were readmitted within 28 days (P < .001). For both groups, a 7‐day follow up significantly reduced readmissions (P < .05). Indigenous patients on SSP had higher odds of readmissions than non‐Indigenous patients (P < .05), and a diagnosis of a personality disorder increased readmission in the control group but not the SSP group (P < .001).

Discussion

SSP reduced repeated hospitalizations for patients in acute crisis by 42%. An identification of factors related to future admissions can inform future tailoring of this model of care to subgroups of patients.
White matter microstructure in youth with and at risk for bipolar disorder
Authors: Linke Julia O. , Stavish Caitlin , Adleman Nancy E. , Sarlls Joelle , Towbin Kenneth E. , Leibenluft Ellen , Brotman Melissa A.
Published: December 2019

Objectives

Bipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto‐limbic pathways. These abnormalities might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation.

Methods

To determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first‐degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging.

Results

Individuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age‐related in‐creases in BD compared to REL and HV. Further, individuals with BD and REL showed in‐creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation.

Discussion

Alterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation—a core characteristic of BD.
Operating characteristics of the rank‐based inverse normal transformation for quantitative trait analysis in genome‐wide association studies
Authors: McCaw Zachary R. , Lane Jacqueline M. , Saxena Richa , Redline Susan , Lin Xihong
Published: December 2019

Quantitative traits analyzed in Genome‐Wide Association Studies (GWAS) are often nonnormally distributed. For such traits, association tests based on standard linear regression are subject to reduced power and inflated type I error in finite samples. Applying the rank‐based inverse normal transformation (INT) to nonnormally distributed traits has become common practice in GWAS. However, the different variations on INT‐based association testing have not been formally defined, and guidance is lacking on when to use which approach. In this paper, we formally define and systematically compare the direct (D‐INT) and indirect (I‐INT) INT‐based association tests. We discuss their assumptions, underlying generative models, and connections. We demonstrate that the relative powers of D‐INT and I‐INT depend on the underlying data generating process. Since neither approach is uniformly most powerful, we combine them into an adaptive omnibus test (O‐INT). O‐INT is robust to model misspecification, protects the type I error, and is well powered against a wide range of nonnormally distributed traits. Extensive simulations were conducted to examine the finite sample operating characteristics of these tests. Our results demonstrate that, for nonnormally distributed traits, INT‐based tests outperform the standard untransformed association test, both in terms of power and type I error rate control. We apply the proposed methods to GWAS of spirometry traits in the UK Biobank. O‐INT has been implemented in the R package RNOmni, which is available on CRAN.
Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker
Authors: Kloos Robin , van der Sluis Inge M. , Mastrobattista Enrico , Hennink Wim , Pieters Rob , Verhoef Jan‐Jaap
Published: December 2019

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG‐moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL‐11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti‐PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti‐PEG antibodies exclusively. Pre‐existing anti‐PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS‐linker were predominantly detected during induction (50% IgG; 42% IgM). Anti‐asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti‐PEG and anti‐SS‐linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.
The molecular biology of medulloblastoma metastasis
Authors: Van Ommeren Randy , Garzia Livia , Holgado Borja L. , Ramaswamy Vijay , Taylor Michael D.
Published: December 2019

Medulloblastoma (MB) is the most common primary malignant brain tumor of childhood and a significant contributor to pediatric morbidity and death. While metastatic dissemination is the predominant cause of morbidity and mortality for patients with this disease, most research efforts and clinical trials to date have focused on the primary tumor; this is due mostly to the paucity of metastatic tumor samples and lack of robust mouse models of MB dissemination. Most current insights into the molecular drivers of metastasis have been derived from comparative molecular studies of metastatic and non‐metastatic primary tumors. However, small studies on matched primary and metastatic tissues and recently developed mouse models of dissemination have begun to uncover the molecular biology of MB metastasis more directly. With respect to anatomical routes of dissemination, a hematogenous route for MB metastasis has recently been demonstrated, opening new avenues of investigation. The tumor micro‐environment of the primary and metastatic niches has also been increasingly scrutinized in recent years, and further investigation of these tumor compartments is likely to result in a better understanding of the molecular mediators of MB colonization and growth in metastatic compartments.
Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects
Authors: Robles‐Vera Iñaki , Toral Marta , de la Visitación Néstor , Sánchez Manuel , Gómez‐Guzmán Manuel , Muñoz Raquel , Algieri Francesca , Vezza Teresa , Jiménez Rosario , Gálvez Julio , Romero Miguel , Redondo Juan Miguel , Duarte Juan
Published: December 2019

Background and Purpose

Hypertension is associated with gut dysbiosis. Here we have evaluated the effects of the angiotensin receptor antagonist losartan on gut microbiota in spontaneously hypertensive rats (SHR) to assess their contribution to its antihypertensive effects.

Experimental Approach

Twenty‐week‐old Wistar Kyoto rats (WKY) and SHR were treated with losartan for 5 weeks (SHR‐losartan). Faecal microbiota transplantation (FMT) was performed from donor SHR‐losartan group to recipient untreated‐SHR. Blood pressure (BP) was measured using tail‐cuff plethysmography. Composition of the gut microbiota was assessed by amplification of the V3‐V4 region of 16S rRNA gene. T cells were analysed in gut/aorta by flow cytometry.

Key Results

Faeces from SHR showed gut dysbiosis, characterised by higher Firmicutes/Bacteroidetes ratios, lower acetate‐ and higher lactate‐producing bacteria, and lower levels of strict anaerobic bacteria, effects which were restored to normal by losartan. Improvement of gut dysbiosis was linked to higher colonic integrity and lower sympathetic drive in the gut. In contrast, hydralazine reduced BP, but it neither restored gut dysbiosis nor colonic integrity. FMT from SHR‐losartan to SHR reduced BP, improved the aortic endothelium‐dependent relaxation to ACh, and reduced NADPH oxidase activity. These vascular changes were accompanied by both increased Treg and decreased Th17 cell populations in the vascular wall.

Conclusion and Implications

In SHR, losartan treatment reduced gut dysbiosis and sympathetic drive in the gut, thus improving gut integrity. The changes induced by losartan in gut microbiota contributed, in part, to protecting the vasculature and reducing BP, possibly by modulating the immune system in the gut.
β‐Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents
Authors: He Yi , Galaj Ewa , Bi Guo‐Hua , Wang Xiao‐Fei , Gardner Eliot , Xi Zheng‐Xiong
Published: December 2019

Background and Purpose

β‐Caryophyllene (BCP) is a plant‐derived terpenoid used as a food additive for many decades. Recent studies indicate that BCP is a cannabinoid CB2 receptor agonist with medical benefits for a number of human diseases. However, little is known about its therapeutic potential for drug abuse and addiction.

Experiment Approach

We used pharmacological, transgenic, and optogenetic approaches to systematically evaluate the effects of BCP on nicotine‐taking and nicotine‐seeking behaviour in animal models of drug self‐administration, electrical, and optical brain‐stimulation reward.

Key Results

Systemic administration of BCP dose‐dependently inhibited nicotine self‐administration and motivation for nicotine seeking in rats and mice. The reduction in nicotine self‐administration was blocked by AM630, a selective CB2 receptor antagonist, but not by AM251, a selective CB1 receptor antagonist, suggesting involvement of a CB2 receptor mechanism. Genetic deletion of CB2 receptors in mice blocked the reduction in nicotine self‐administration produced only by low doses, but not by high doses, of BCP, suggesting involvement of both CB2 and non‐CB2 receptor mechanisms. Furthermore, in the intracranial self‐stimulation paradigm, BCP attenuated electrical brain‐stimulation reward and nicotine‐enhanced brain‐stimulation reward in rats. Lastly, BCP also attenuated brain‐stimulation reward maintained by optogenetic stimulation of dopaminergic neurons in the ventral tegmental area in DAT‐cre mice, suggesting the involvement of a dopamine‐dependent mechanism in BCP's action.

Conclusions and Implications

The present findings suggest that BCP has significant anti‐nicotine effects via both CB2 and non‐CB2 receptor mechanisms and, therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.