bluuebunny/crossref_metadata_2025 huggingface dataset:
functionInk: An efficient method to detect functional groups in multidimensional networks reveals the hidden structure of ecological communities
Authors: Pascual‐García Alberto , Bell Thomas
Published: February 2020

Complex networks have been useful to link experimental data with mechanistic models, and have become widely used across many scientific disciplines. Recently, the increasing amount and complexity of data, particularly in biology, has prompted the development of multidimensional networks, where dimensions reflect the multiple qualitative properties of nodes, links or both. As a consequence, traditional quantities computed in single dimensional networks should be adapted to incorporate this new information. A particularly important problem is the detection of communities, namely sets of nodes sharing certain properties, which reduces the complexity of the networks, hence facilitating its interpretation.

In this work, we propose an operative definition of ‘function’ for the nodes in multidimensional networks. We exploit this definition to show that it is possible to detect two types of communities: (a) modules, which are communities more densely connected within their members than with nodes belonging to other communities, and (b) guilds, which are sets of nodes connected with the same neighbours, even if they are not connected themselves. We provide two quantities to optimally detect both types of communities, whose relative values reflect their importance in the network.

The flexibility of the method allowed us to analyse different ecological examples encompassing mutualistic, trophic and microbial networks. We showed that by considering both metrics we were able to obtain deeper ecological insights about how these different ecological communities were structured. The method mapped pools of species with properties that were known in advance, such as plants and pollinators. Other types of communities found, when contrasted with external data, turned out to be ecologically meaningful, allowing us to identify species with important functional roles or the influence of environmental variables. Furthermore, we found that the method was sensitive to community‐level topological properties like nestedness.

In ecology there is often a need to identify groupings including trophic levels, guilds, functional groups or ecotypes. The method is therefore important in providing an objective means of distinguishing modules and guilds. The method we developed, functionInk (functional linkage), is computationally efficient at handling large multidimensional networks since it does not require optimization procedures or tests of robustness. The method is available at: https://github.com/apascualgarcia/functionInk.
Outcomes after percutaneous dilatation tracheostomy: Patients view 6 years after the procedure
Authors: Modalsli Lena , Liknes Kristin , Flaatten Hans
Published: February 2020

Background

Percutaneous dilatational tracheostomy have been performed increasingly since its introduction in 1985, and is today one of the most commonly performed operative procedures in intensive care units. The aim of this study was to document patient‐reported outcomes from percutaneous dilatational tracheostomy after hospital discharge.

Methods

This study is based on retrospective extraction of data from the databases in the ICU at Haukeland University Hospital from 2004 to 2016. Patients alive by April 2018 and with a code for dilatation tracheostomy were sent a questionnaire about their experiences with having a tracheostomy performed. The occurrence of problems and their relations were registered.

Results

Of 5769 admitted patients, 900 patients ≥ 15 years (15.7%) had a percutaneous dilatation tracheostomy performed. The median time from admission to follow‐up was 6.1 years, and the 30 days mortality in those who received a tracheostomy was 315/900 (35%). Of the 441 survivors contacted, 181 answered the questionnaire and a total of 293 problems were reported. The majority of these problems were reported as no or moderate in 115 patients (78.3%). The presence of any problem was significantly associated with occurrence for other problems; however, there were no significant differences related to the elapsed time since the ICU stay. Pain and difficulties with breathing were the two single factors most often related to occurrence of other problems.

Conclusion

Although self‐reported problems after percutaneous tracheostomy occurring after hospital discharge were often reported, most (78.3%) were considered by the patients to be moderate.
Prophylactic use of acid suppressants in adult acutely ill hospitalised patients: A systematic review with meta‐analysis and trial sequential analysis
Authors: Marker Søren , Barbateskovic Marija , Perner Anders , Wetterslev Jørn , Jakobsen Janus C. , Krag Mette , Granholm Anders , Anthon Carl T. , Møller Morten H.
Published: February 2020

Background

Acutely ill patients are at risk of stress‐related gastrointestinal (GI) bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors (PPIs) or histamine‐2 receptor antagonists (H2RAs) versus placebo or no prophylaxis in acutely ill hospitalised patients.

Methods

We conducted the review according to the PRISMA statement, the Cochrane Handbook and GRADE, using conventional meta‐analysis and trial sequential analysis (TSA). The primary outcomes were all‐cause mortality, clinically important GI bleeding and serious adverse events (SAEs). The primary analyses included overall low risk of bias trials.

Results

We included 65 comparisons from 62 trials (n = 9713); 43 comparisons were from intensive care units. Only three trials (n = 3596) had overall low risk of bias. We did not find an effect on all‐cause mortality (RR 1.03, 95% CI 0.94 to 1.14; TSA‐adjusted CI 0.90 to 1.18; high certainty). The rate of clinically important GI bleeding was lower with SUP (RR 0.62, 95% CI 0.43 to 0.89; TSA‐adjusted CI 0.14 to 2.81; moderate certainty). We did not find a difference in pneumonia rates (moderate certainty). Effects on SAEs, Clostridium difficile enteritis, myocardial ischaemia and health‐related quality of life (HRQoL) were inconclusive due to sparse data. Analyses of all trials regardless of risk of bias were consistent with the primary analyses.

Conclusions

We did not observe a difference in all‐cause mortality or pneumonia with SUP. The incidence of clinically important GI bleeding was reduced with SUP, whereas any effects on SAEs, myocardial ischaemia, Clostridium difficile enteritis and HRQoL were inconclusive.

Study registration

PROSPERO registration number CRD42017055676; published study protocol: Marker, et al 2017 in Systematic Reviews.
Monitoring or colluding: the role of venture capital investors in the IPO process
Authors: Liu Qigui , Tang Jinghua , Tian Gary
Published: February 2020

We argue and provide evidence that instead of playing a monitoring role, venture capital (VC) investors collude with controlling shareholders in the IPO process of Chinese non‐state‐owned enterprises (non‐SOEs). We show that VC‐backed IPOs’ applications are more likely to be approved by regulators, especially in firms with excess control rights, but have worse post‐IPO performance. Through investing in firms with excess control rights, VC investors are able to make higher exit returns. We further document that VC investors’ role in the IPO process is stronger when they have political connections, hold higher ownership, and when they make pre‐IPO investment.
Share‐pledging and the cost of debt
Authors: Puleo Michael , McDonald Michael , Kozlowski Steven
Published: February 2020

We examine how corporate insiders pledging their equity stakes to collateralise personal loans influences firm cost of debt. Pledging enables managers to diversify personal holdings, potentially increasing risk‐taking incentives. However, exposure to contingent risks creates potentially stronger risk‐reducing incentives. Using hand‐collected data with OLS, difference‐in‐differences, and instrumental variables models, we find significant decreases in yield spreads associated with executive share‐pledging. Reductions in spreads surrounding share‐pledge disclosures suggest investors update their risk assessment to reflect pledging managers’ risk‐taking incentives. Consistent with risk‐reducing incentives, firms with share‐pledging executives subsequently reduce leverage.
Research productivity of Australian accounting academics
Authors: Bond David , Clout Victoria J. , Czernkowski Robert M. J. , Wright Anna
Published: February 2020

In recent decades, substantial changes have impacted the global academy, such as the increasing use of key performance metrics for academics. This study provides recent evidence of Australian accounting academics’ performance in publishing in A/A* journals during the period 2010–2018. We find that the top 25 percent of Australian academics produce approximately 60 percent of published journal articles through an analysis of the A/A* Australian Business Deans′ Council (ABDC) accounting journal listing. The majority of published Australian co‐authored research output in the sample is in A ranked journals (80 percent), with only 20 percent observed in A* ranked journals.
Trade credit and cost stickiness
Authors: Costa Mabel D. , Habib Ahsan
Published: February 2020

Using a large sample of US data, we examine the relation between trade credit and cost behaviour and further investigate the moderating effects on this relation of agency problem, product market competition, and customer concentration. We find that firms using high levels of trade credit exhibit lower cost stickiness and this is prevalent in the high agency problem sub‐sample. In addition, in a non‐competitive market, where the agency problem arises owing to lack of competition, trade credit plays an external monitoring role by attenuating cost stickiness. However, high customer concentration curtails this monitoring ability.
Qualitative and quantitative comparison of Thiel and phenol‐based soft‐embalmed cadavers for surgery training
Authors: Venne Gabriel , Zec Michelle L. , Welte Lauren , Noel Geoffroy P. J. C.
Published: February 2020

Introduction

Surgical skills training has traditionally been limited to formalin embalming that does not provide a realistic model. The aim of this study was to qualitatively and quantitatively compare Thiel and phenol‐based soft‐embalming techniques: qualitatively in a surgical training setup, and quantitatively by comparing the mechanical and histomorphometric properties of skin specimens embalmed using each method.

Materials and Methods

Thirty‐four participants were involved in surgical workshops comparing Thiel and phenol‐based embalmed bodies. Participants were asked to evaluate the utility of the different models for surgical skills training. In parallel, tensile elasticity evaluation was performed on skin flaps from six fresh‐frozen cadavers. Flaps were divided into three groups for each specimen: fresh‐frozen, Thiel, and phenol‐based embalmed and compared together at 1 month or 1 year after embalming. A histological investigation of the skin structural properties was performed for each embalming type using haematoxylin and eosin and Masson's trichrome.

Results

All participants rated the phenol‐based specimens consistently better or equivalent to Thiel for the evaluated parameters. Quantitatively, there were statistically significant differences for the tensile elasticity between the embalming techniques (p < .05). There were no significant differences for the tensile elasticity between phenol‐based embalmed skin and fresh state (p = .30), and no significant difference between embalming time was reported (p = .47). Histologically, the integrity of the skin was better preserved with the phenol‐based technique.

Conclusion

Phenol‐based embalming provides as realistic or better of a model as Thiel embalming for surgical training skills and was generally preferred over Thiel model. The phenol‐based embalming better preserved the integrity of the skin.
Site Fight! Toward the Abolition of Immigrant Detention on Tacoma’s Tar Pits (and Everywhere Else)
Authors: Ybarra Megan
Published: February 2020

This paper theorises the spatialisation of White supremacy through the siting and expansion of a US immigrant detention centre, the Northwest Detention Center (NWDC). This case reveals the spatial relationship between the detention centre’s displacement with the Seattle‐Tacoma region’s increasing wealth, highlighting the role of detention and incarceration in the spatialisation of White supremacy. If White advantage maps onto whiteness as property, then White supremacy maps onto interlocking systems of settler colonialism and racial capitalism that dispossess people of colour of land and turns their bodies into devalued pollution sinks, where the less‐than‐citizen is forced to live on Tar Pits that they cannot even call “home”. Since 2014, detained immigrants’ activism has fuelled conversations about the punitive nature of administrative immigrant detention, racial profiling, and the city’s responsibility to enforce health, safety and environmental regulations for all residents. Through the stories of detainees, deportees and their co‐conspirators, this site fight illustrates how abolition ecologies call for tearing down toxic detention centres. Beyond rejecting White supremacist logics in immigration enforcement, abolitionists make freedom as a place together.
A positive nitrite test was an independent risk factor for invasive bacterial infections in infants under 90 days of age with fever without source
Authors: Velasco Roberto , Gomez Borja , de la Torre Mercedes , Benito Javier , Mintegi Santiago
Published: February 2020

Aim

This study analysed the association between a positive nitrite dipstick test and an invasive bacterial infection (IBI) in infants younger than 90 days of age with fever without source (FWS).

Methods

We performed a secondary analysis of data from a prospective multicentre study of infants up to 90 days of age with FWS undergoing care in 19 paediatric EDs between October 2011 and September 2013. Invasive bacterial infection was defined as a positive blood or cerebrospinal fluid culture.

Results

The dipstick urinalysis was positive for nitrite or leucocyte esterase in 766 (22.5%) of the 3401 infants we studied, and 270 (35.2%) had a dipstick test that was just positive for nitrite. Overall, 107 were diagnosed with an IBI (3.1%). The IBI prevalence was 2.2% among patients with a normal urine dipstick, 4.4% if they had positive leucocyte esterase test results, 8.3% where the nitrite test was positive and 10.6% when both tests were positive. After multivariate analysis, a positive nitrite test remained an independent risk factor for IBI (odds ratio 2.7, 95% confidence interval 1.4‐4.9).

Conclusion

In infants under 90 days of age with FWS, a positive nitrite urine dipstick test was an independent risk factor for IBI.
The pharmacokinetics of metformin in patients receiving intermittent haemodialysis
Authors: Sinnappah Klarissa A. , Kuan Isabelle H.S. , Thynne Tilenka R.J. , Doogue Matthew P. , Wright Daniel F.B.
Published: February 2020

The aims of this study were to characterise the population pharmacokinetics of metformin in patients receiving haemodialysis, and to determine the doses that will maintain median metformin plasma concentrations below 5 mg L−1 for a typical individual. Metformin plasma concentrations from 5 patients receiving thrice weekly intermittent haemodialysis followed by metformin 500 mg postdialysis were fitted to a published pharmacokinetic model. Additional models to describe the dialytic pharmacokinetics of metformin were explored. Doses of 250 and 500 postdialysis were simulated from the model for a typical haemodialysis patient. The published 2‐compartment pharmacokinetic model with an additional parameter to describe haemodialysis clearance provided a reasonable fit to the data. Deterministic simulations from the model for a typical individual suggest that metformin doses of 250–500 mg postdialysis and 250 mg given once daily should maintain median metformin plasma concentrations below 5 mg L−1.
Phosphorylation of GATA4 at serine 105 is required for left ventricular remodelling process in angiotensin II‐induced hypertension in rats
Authors: Jurado Acosta Alicia , Rysä Jaana , Szabo Zoltan , Moilanen Anne‐Mari , Serpi Raisa , Ruskoaho Heikki
Published: February 2020

In this study, we investigated whether local intramyocardial GATA4 overexpression affects the left ventricular (LV) remodelling process and the importance of phosphorylation at serine 105 (S105) for the actions of GATA4 in an angiotensin II (AngII)‐induced hypertension rat model. Adenoviral constructs overexpressing wild‐type GATA4 or GATA4 mutated at S105 were delivered into the anterior LV free wall. AngII (33.3 µg/kg/h) was administered via subcutaneously implanted minipumps. Cardiac function and structure were examined by echocardiography, followed by histological immunostainings of LV sections and gene expression measurements by RT‐qPCR. The effects of GATA4 on cultured neonatal rat ventricular fibroblasts were evaluated. In AngII‐induced hypertension, GATA4 overexpression repressed fibrotic gene expression, reversed the hypertrophic adult‐to‐foetal isoform switch of myofibrillar genes and prevented apoptosis, whereas histological fibrosis was not affected. Overexpression of GATA4 mutated at S105 resulted in LV chamber dilatation, cardiac dysfunction and had minor effects on expression of myocardial remodelling genes. Fibrotic gene expression in cardiac fibroblasts was differently affected by overexpression of wild‐type or mutated GATA4. Our results indicate that GATA4 reduces AngII‐induced responses by interfering with pro‐fibrotic and hypertrophic gene expressions. GATA4 actions on LV remodelling and fibroblasts are dependent on phosphorylation site S105.
Not the doctor’s business: Privacy, personal responsibility and data rights in medical settings
Authors: Véliz Carissa
Published: February 2020

This paper argues that assessing personal responsibility in healthcare settings for the allocation of medical resources would be too privacy‐invasive to be morally justifiable. In addition to being an inappropriate and moralizing intrusion into the private lives of patients, it would put patients’ sensitive data at risk, making data subjects vulnerable to a variety of privacy‐related harms. Even though we allow privacy‐invasive investigations to take place in legal trials, the justice and healthcare systems are not analogous. The duty of doctors and healthcare professionals is to help patients as best they can—not to judge them. Patients should not be forced into giving up any more personal information than what is strictly necessary to receive an adequate treatment, and their medical data should only be used for appropriate purposes. Medical ethics codes should reflect these data rights. When a doctor asks personal questions that are irrelevant to diagnose or treat a patient, the appropriate response from the patient is: ‘none of your business’.
Metaphysics to the rescue?: Four‐dimensionalism and the twinning argument against conceptionism
Authors: Lee Chunghyoung
Published: February 2020

The view that human beings begin to exist at fertilization (namely conceptionism) faces a serious challenge from the twinning argument, that identical twins coming from the same zygote must be numerically distinct from the zygote and so did not exist at fertilization. Recently, some philosophers have claimed that the twinning argument rests on a particular metaphysical theory of persistence, namely endurantism, on which a human being, for example, is wholly present at every moment of her existence. And we can easily refute the argument, they claim, by employing perdurantism or exdurantism, according to which a human being is a temporally extended entity with temporal parts or a momentarily existing stage who has other momentarily existing stages as counterparts. I argue that such claims are mistaken. The twinning argument does not rest on endurantism and can be formulated in terms of perdurantism to provide a good reason for perdurantists to reject conceptionism. And exdurantism does not have any advantage in defending conceptionism either, for it already concedes more than what the twinning argument aims to show.
On the empirical choice of the time window for restricted mean survival time
Authors: Tian Lu , Jin Hua , Uno Hajime , Lu Ying , Huang Bo , Anderson Keaven M. , Wei LJ
Published: February 2020

The t‐year mean survival or restricted mean survival time (RMST) has been used as an appealing summary of the survival distribution within a time window [0, t]. RMST is the patient's life expectancy until time t and can be estimated nonparametrically by the area under the Kaplan‐Meier curve up to t. In a comparative study, the difference or ratio of two RMSTs has been utilized to quantify the between‐group‐difference as a clinically interpretable alternative summary to the hazard ratio. The choice of the time window [0, t] may be prespecified at the design stage of the study based on clinical considerations. On the other hand, after the survival data have been collected, the choice of time point t could be data‐dependent. The standard inferential procedures for the corresponding RMST, which is also data‐dependent, ignore this subtle yet important issue. In this paper, we clarify how to make inference about a random “parameter.” Moreover, we demonstrate that under a rather mild condition on the censoring distribution, one can make inference about the RMST up to t, where t is less than or even equal to the largest follow‐up time (either observed or censored) in the study. This finding reduces the subjectivity of the choice of t empirically. The proposal is illustrated with the survival data from a primary biliary cirrhosis study, and its finite sample properties are investigated via an extensive simulation study.
Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options
Authors: Bencsik Péter , Gömöri Kamilla , Szabados Tamara , Sántha Péter , Helyes Zsuzsanna , Jancsó Gábor , Ferdinandy Péter , Görbe Anikó
Published: February 2020

During the last decades, mortality from acute myocardial infarction has been dramatically reduced. However, the incidence of post‐infarction heart failure is still increasing. Cardioprotection by ischaemic conditioning had been discovered more than three decades ago. Its clinical translation, however, is still an unmet need. This is mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors, co‐morbidities and the medication being taken. Sensory neuropathy is one of the co‐morbidities that has been shown to interfere with cardioprotection. In the present review, we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which these neuropathies may interfere with ischaemic heart disease and cardioprotective signalling. Finally, we suggest future therapeutic options targeting both ischaemic heart and sensory neuropathy simultaneously.

LINKED ARTICLES

This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc
JQ1, a bromodomain inhibitor, suppresses Th17 effectors by blocking p300‐mediated acetylation of RORγt
Authors: Wang Xiunan , Yang Yan , Ren Dandan , Xia Yuanyuan , He Wenguang , Wu Qingsi , Zhang Junling , Liu Miao , Du Yinan , Ren Cuiping , Li Bin , Shen Jijia , Zhang Yuxia
Published: February 2020

Background and Purpose

Th17 cells play critical roles in chronic inflammation, including fibrosis. Histone acetyltransferase p300, a bromodomain‐containing protein, acetylates RORγt and promotes Th17 cell development. The bromodomain inhibitor JQ1 was shown to alleviate Th17‐mediated pathologies, but the underlying mechanism remains unclear. We hypothesized that JQ1 suppresses the response of Th17 cells by impairing p300‐mediated acetylation of RORγt.

Experimental Approach

The effect of JQ1 on p300‐mediated acetylation of RORγt was investigated in HEK293T (overexpressing Flag‐p300 and Myc‐RORγt) and human Th17 cells through immunoprecipitation and western blotting. To determine the regions of p300 responsible for JQ1‐mediated suppression of HAT activity, we performed HAT assays on recombinant p300 fragments with/without the bromodomain, after exposure to JQ1. Additionally, the effect of JQ1 on p300‐mediated acetylation of RORγt and Th17 cell function was verified in vivo, using murine Schistosoma‐induced fibrosis models. Liver injury was assessed by histopathological examination and measurement of serum enzyme levels. Expression of Th17 effectors was detected by qRT‐PCR, whereas IL‐17‐ and RORγt‐positive granuloma cells were detected by FACS.

Key Results

JQ1 impaired p300‐mediated RORγt acetylation in human Th17 and HEK293T cells. JQ1 failed to suppress the acetyltransferase activity of p300 fragments lacking the bromodomain. JQ1 treatment attenuated Schistosoma‐induced fibrosis in mice, by inhibiting RORγt acetylation and IL‐17 expression.

Conclusions and Implications

JQ1 impairs p300‐mediated RORγt acetylation, thus reducing the expression of RORγt target genes, including Th17‐specific cytokines. JQ1‐mediated inhibition of p300 acetylase activity requires the p300 bromodomain. Strategies targeting p300 may provide new therapeutic approaches for controlling Th17‐related diseases.
Implication of in vivo circulating fibrocytes ablation in experimental pulmonary hypertension murine model
Authors: Nikam Vandana S. , Nikam Sandeep , Sydykov Akyl , Ahlbrecht Katrin , Morty Rory E. , Seeger Werner , Voswinckel Robert
Published: February 2020

Background and Purpose

Recruitment and involvement of bone‐/blood‐derived circulating fibrocytes (CF) in the promotion of fibrotic tissue remodelling processes have been shown. However, their direct contribution to pathological changes is not clear. The present study investigates the causal role of CF in the pathogenesis of pulmonary hypertension (PH).

Experimental Approach

For selective ablation of CF, we applied the suicidal gene strategy with herpes simplex virus thymidine kinase (HSV‐TK) and ganciclovir. The transgenic mice were generated, having HSV‐TK‐GFP transgene under the collagen 1 promoter. To selectively target CF, HSV‐TK‐GFP+ bone marrow transplanted into irradiated wild type mice. These chimera mice were subjected to hypoxia for PH induction and ganciclovir for CF ablation.

Key Results

In vivo CF ablation reduced right ventricular hypertrophy and vascular remodelling with reduced total collagen content. We quantified the CF recruited in the perivascular area and arterial wall of small pulmonary arteries. There was significant recruitment of CF in the lung in response to hypoxia. The characterization of CF showed the expression of CD45 and collagen1 (GFP) along with α‐smooth muscle actin (αSMA).

Conclusion and Implications

Our data demonstrated that CF ablation has a potential impact on right ventricular hypertrophy and vascular remodelling in the setting of experimental pulmonary hypertension induced by hypoxia. The beneficial effects may be related to the direct contribution of fibrocytes or its paracrine effect on other resident cell types. Thus, clinical manipulation of CF may represent a novel therapeutic approach to ameliorate the disease state in pulmonary hypertension.
Myeloid‐specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage
Authors: Han Xiao , Ni Jianbo , Wu Zengkai , Wu Jianghong , Li Bin , Ye Xin , Dai Juanjuan , Chen Congying , Xue Jing , Wan Rong , Wen Li , Wang Xingpeng , Hu Guoyong
Published: February 2020

Background and Purpose

Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). We have shown that pancreas‐specific D2 receptor signalling protects against AP severity. As it is unclear to what extent myeloid‐specific D2 receptor mediates AP, we investigated the role of myeloid‐specific D2 receptor signalling in AP.

Experimental Approach

Using wild‐type and LysM+/creD2fl/fl mice, AP was induced by l‐arginine, caerulein and LPS. Murine bone marrow‐derived macrophages and human peripheral blood mononuclear cells (PBMCs) were isolated, cultured and then induced to M1 phenotype. AP severity was assessed by measurements of serum amylase and lipase and histological grading. Macrophage phenotype was assessed by flow cytometry and qRT‐PCR. NADPH oxidase‐induced oxidative stress and NF‐κB and NLRP3 inflammasome signalling pathways were also evaluated.

Key Results

We found that dopaminergic system was activated and dopamine reduced inflammatory cytokine expression in M1‐polarized macrophages from human PBMCs. Dopaminergic synthesis was also activated, but D2 receptor expression was down‐regulated in M1‐polarized macrophages from murine bone marrows. During AP, myeloid‐specific D2 receptor deletion worsened pancreatic injury, systematic inflammation and promoted macrophages to M1 phenotype. Furthermore, M1 macrophages from LysM+/creD2fl/fl mice exhibited increased NADPH oxidase‐induced oxidative stress and enhanced NF‐κB and NLRP3 inflammasome activation. D2 receptor activation inhibited M1 macrophage polarization, oxidative stress‐induced NF‐κB and NLRP3 inflammasome activation.

Conclusion and Implications

Our data for the first time showed that myeloid‐specific D2 receptor signalling controls pancreatic injury and systemic inflammation via inhibiting M1 macrophage, suggesting D2 receptor activation might serve as therapeutic target for AP.
Functional marriage in plasma membrane: Critical cholesterol level–optimal protein activity
Authors: Meza Ulises , Delgado‐Ramírez Mayra , Romero‐Méndez Catalina , Sánchez‐Armass Sergio , Rodríguez‐Menchaca Aldo A.
Published: February 2020

In physiology, homeostasis refers to the condition where a system exhibits an optimum functional level. In contrast, any variation from this optimum is considered as a dysfunctional or pathological state. In this review, we address the proposal that a critical cholesterol level in the plasma membrane is required for the proper functioning of transmembrane proteins. Thus, membrane cholesterol depletion or enrichment produces a loss or gain of direct cholesterol–protein interaction and/or changes in the physical properties of the plasma membrane, which affect the basal or optimum activity of transmembrane proteins. Whether or not this functional switching is a generalized mechanism exhibited for all transmembrane proteins, or if it works just for an exclusive group of them, is an open question and an attractive subject to explore at a basic, pharmacological and clinical level.
GPCRs in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets
Authors: Sriram Krishna , Salmerón Cristina , Wiley Shu Z. , Insel Paul A.
Published: February 2020

Pancreatic cancer has one of the highest mortality rates (5‐year survival ~9%) among cancers. Pancreatic adenocarcinoma (PAAD) is the most common (>80%) and the most lethal type of pancreatic cancer. A need exists for new approaches to treat pancreatic adenocarcinoma. GPCRs, the largest family of cell‐surface receptors and drug targets, account for ~35% of approved drugs. Recent studies have revealed roles for GPCRs in PAAD cells and cells in the tumour micro‐environment. This review assesses current information regarding GPCRs in PAAD by summarizing omics data for GPCRs expression in PAAD. The PAAD “GPCRome” includes GPCRs with approved agents, thereby offering potential for their repurposing/repositioning. We then reviewed the evidence for functional roles of specific GPCRs in PAAD. We also highlight gaps in understanding the contribution of GPCRs to PAAD biology and identify several GPCRs that may be novel therapeutic targets for future work in search of GPCR‐targeted drugs to treat PAAD tumours.
Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives
Authors: Miyai Yuki , Esaki Nobutoshi , Takahashi Masahide , Enomoto Atsushi
Published: February 2020

The roles of cancer‐associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer‐restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single‐cell transcriptome analyses. While cancer‐promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer‐restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor‐permissive and tumor‐promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future.
Design, microwave‐assisted synthesis, biological evaluation and molecular modeling studies of 4‐phenylthiazoles as potent fatty acid amide hydrolase inhibitors
Authors: Wilt Stephanie R. , Rodriguez Mark , Le Thanh N. H. , Baltodano Emily V. , Salas Adrian , Pecic Stevan
Published: February 2020

Endocannabinoids, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti‐inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids; thus, inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2‐naphthyl‐ and 4‐phenylthiazole scaffolds were identified, but up to the present time, very little structure–activity relationship studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.
Primary anastomosis and nonrestorative resection for perforated diverticulitis with peritonitis: meta‐analysis of randomized trials
Authors: Gachabayov M. , Tuech J. J. , Tulina I. , Coget J. , Bridoux V. , Bergamaschi R.
Published: February 2020

Aim

The aim of this meta‐analysis was to comparatively evaluate the outcomes of primary anastomosis (PRA) and nonrestorative resection (NRR) as emergency surgery and ostomy reversal in patients with perforated diverticulitis and peritonitis.

Methods

PubMed, MEDLINE via Ovid, Embase, CINAHL, Cochrane Library and Web of Science databases were systematically searched. Postoperative morbidity following emergency resection was the primary end‐point. Quality assessment of the included studies was performed using the Cochrane Quality Assessment Tool including recruitment bias and crossover with intention‐to‐treat analysis. The Haenszel–Mantel method with odds ratios (OR, 95% CI) and the inverse variance method with mean difference (MD, 95% CI) as effect measures were utilized for dichotomous and continuous outcomes, respectively.

Results

Four randomized controlled trials totaling 382 patients (180 PRA vs 204 NRR) were included. Morbidity rates following emergency resection did not differ (OR = 0.99, 95% CI 0.65, 1.51; P = 0.95; number needed to treat/harm (NNT) 96). Organ/space surgical site infection rates were 3.3% in PRA vs 11.3% in NRR (OR = 0.29, 95% CI 0.12, 0.74; P = 0.009; NNT = 13). Postoperative morbidity rates following ostomy reversal were significantly lower in PRA (OR = 0.31, 95% CI 0.15, 0.64; P = 0.001; NNT = 7). Pooled ostomy non‐reversal rates were 16% in PRA vs 35.5% in NRR (OR = 0.37, 95% CI 0.22, 0.62; P = 0.0001; NNT = 6) with high heterogeneity (I2 = 63%; τ2 = 8.17). Meta‐regression analysis revealed significant negative correlation between the PRA‐to‐NRR crossover rate and the ostomy non‐reversal rate (P = 0.029).

Conclusion

This meta‐analysis found that PRA was associated with better short‐ and long‐term outcomes at the cost of significantly longer operating time at emergency surgery.
Conservation decision‐making under uncertainty: Identifying when to reintroduce tiger Panthera tigris to Cambodia
Authors: Gray Thomas N. E. , Grainger Matthew J. , Grosu Romica
Published: February 2020

Conservationists need to present biological monitoring data to decision makers in a way which clearly represents uncertainty. Providing results in terms of the probability of a hypothesis being true may have greater utility for decision‐making than traditionally used frequentist statistical approaches. Here, we demonstrate such an approach with regard to assessing the suitability of the Cardamom Rainforest Landscape, Cambodia for Panthera tigris (tiger) reintroduction. We estimated the density of tiger prey in the core of the landscape using the Random Encounter Model from camera‐trap data and used Monte Carlo simulation to prorogate uncertainty around our model parameter estimates. This suggests there is currently a low probability that the core area of the landscape supports sufficient prey for a population of 25 adult tigers and that significant prey recovery is thus required prior to any reintroduction into the landscape. The Random Encounter Model contains a number of assumptions and we stress our main purpose is to illustrate an approach to incorporating uncertainty into conservation decision‐making rather than providing robust estimation of current tiger prey densities in the Cardamom Rainforest Landscape. Our approach has wide utility for conveying species monitoring information to conservation planners in a simple to understand fashion.
A retrospective comparison of salivary gland fine needle aspiration reporting with the Milan system for reporting salivary gland cytology
Authors: Mullen Dorinda , Gibbons David
Published: February 2020

Background

Fine needle aspiration (FNA) is a routine sampling method in the diagnostic work up of salivary gland lesions. Despite universal use, no standardised classification existed for the cytopathological reporting of such entities until recently. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) aims to standardise the reporting of these lesions, offering risk of malignancy rates and clinical management recommendations.

Methods

We retrospectively applied MSRSGC to cases reported over a 5‐year period. Salivary FNA specimens were reclassified according to the MSRSGC as (I) non‐diagnostic, (II) non‐neoplastic, (III) atypia of undetermined significance (AUS), (IV) benign neoplasm and salivary gland neoplasm of uncertain malignant potential, (V) suspicious for malignancy, and (VI) malignant. Cases with surgical resections were documented and risk of malignancy calculated for each group, where possible. We compared our outcomes with similar studies performed since publication of the Milan criteria.

Results

In total, 192 specimens were reassigned as non‐diagnostic (n = 30), non‐neoplastic (n = 31), AUS (n = 1), benign neoplasm (n = 97) and salivary gland neoplasm of uncertain malignant potential (n = 4), suspicious for malignancy (n = 3), and malignant (n = 26). There were 73 surgical resections. Our calculated risk of malignancy was within the proposed MSRSGC rates for the non‐diagnostic, benign neoplasm and malignant groups. One AUS case did not undergo surgery. Benign and malignant sensitivities and specificities for the original reporting categories were 88.24% and 95.72%, and 100% and 95.45% for the MSRSGC, respectively.

Conclusion

Salivary gland FNA has high diagnostic accuracy and the MSRSGC offers standardised reporting and assistance in the stratification of cases. This may improve communication between pathologists and clinicians with improved outcomes for patients.
Endoscopic closure of a large‐size perforation using a novel through‐the‐scope twin endoclip in an ex vivo porcine stomach model
Authors: Zhang Qiang , Wang Zhen
Published: February 2020

Watch a video of this article
Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations
Authors: Spencer‐Smith Megan , Knight Jacquelyn L , Lacaze Emmanuelle ,   Irc5 Consortium, Depienne Christel , Lockhart Paul J , Richards Linda J , Heron Delphine , Leventer Richard J , Robinson Gail A
Published: February 2020

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8–50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability.

What this paper adds

Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum.

A DCC pathogenic variant in isolation is associated with the best prognosis.
Intracranial hypertension and cortical thickness in syndromic craniosynostosis
Authors: Wilson Alexander T , Den Ottelander Bianca K , De Goederen Robbin , Van Veelen Marie‐Lise C , Dremmen Marjolein H G , Persing John A , Vrooman Henri A , Mathijssen Irene M J
Published: February 2020

Aim

To evaluate the impact of risk factors for intracranial hypertension (ICH) on cerebral cortex thickness in syndromic craniosynostosis.

Method

ICH risk factors including papilloedema, hydrocephalus, obstructive sleep apnea (OSA), cerebellar tonsillar position, occipitofrontal circumference (OFC) curve deflection, age, and sex were collected from the records of patients with syndromic craniosynostosis (Apert, Crouzon, Pfeiffer, Muenke, Saethre‐Chotzen syndromes) and imaging. Magnetic resonance images were analysed and exported for statistical analysis. A linear mixed model was developed to determine correlations with cerebral cortex thickness changes.

Results

In total, 171 scans from 107 patients (83 males, 88 females [including repeated scans], mean age 8y 10mo, range 1y 1mo–34y, SD 5y 9mo) were evaluated. Mean cortical thickness in this cohort was 2.78mm (SD 0.17). Previous findings of papilloedema (p=0.036) and of hydrocephalus (p=0.007) were independently associated with cortical thinning. Cortical thickness did not vary significantly by sex (p=0.534), syndrome (p=0.896), OSA (p=0.464), OFC (p=0.375), or tonsillar position (p=0.682).

Interpretation

Detection of papilloedema or hydrocephalus in syndromic craniosynostosis is associated with significant changes in cortical thickness, supporting the need for preventative rather than reactive treatment strategies.

What this paper adds

Papilloedema is associated with thinning of the cerebral cortex in syndromic craniosynostosis, independently of hydrocephalus.
Clinical observation of noncoronary cardiac abnormalities in Chinese children with Kawasaki disease
Authors: Liu Fei Fei , Liu Hui Hui , Qiu Zhen , Wang Jing Jing , Samadli Sama , Wu Yue , Wu Yang Fang , Xu Yao , Luo Huang Huang , Chen Wei Xia , Zhang Dong Dong , Hu Peng
Published: February 2020

Background

Kawasaki disease (KD) is an acute, self‐limited vasculitis. Coronary artery aneurysm (CAA) serves as a major contributor to the long‐term prognosis of KD. In addition, acute KD usually also leads to several kinds of noncoronary cardiac abnormalities (NCA) involving the pericardium, myocardium and endocardium.

Materials and methods

A total of 142 Chinese children with KD were recruited from July 2015 to April 2018. Blood samples were collected at 24 hours pre‐intravenous immunoglobulin (IVIG) therapy. Several inflammatory mediators and biomarkers for acute myocardial infarction were detected. Echocardiography and electrocardiography (ECG) were performed.

Results

Plasma white blood cell counts (WBC) were significantly increased in patients with IVIG‐nonresponsive KD when compared with their IVIG‐responsive counterparts. A total of 106 children (74.65%) suffered from NCA, including 8 patients (5.63%) with pericardial effusion, 23 patients (16.20%) with acute myocarditis, 101 patients (71.13%) with valvular regurgitation and 8 patients (5.63%) with abnormal ECG. No significant differences were observed in the distribution of clinical classification and the response to IVIG therapy regardless of NCA exhibited or not.

Conclusions

Noncoronary cardiac abnormalities is almost universal in acute KD and mainly manifests as valvular regurgitation. However, it has no influence on clinical classification and the response to IVIG therapy.