bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting Accounting Fraud in Publicly Traded U.S. Firms Using a Machine Learning Approach
Authors: BAO YANG , KE BIN , LI BIN , YU Y. JULIA , ZHANG JIE
Published: November 2019

We develop a state‐of‐the‐art fraud prediction model using a machine learning approach. We demonstrate the value of combining domain knowledge and machine learning methods in model building. We select our model input based on existing accounting theories, but we differ from prior accounting research by using raw accounting numbers rather than financial ratios. We employ one of the most powerful machine learning methods, ensemble learning, rather than the commonly used method of logistic regression. To assess the performance of fraud prediction models, we introduce a new performance evaluation metric commonly used in ranking problems that is more appropriate for the fraud prediction task. Starting with an identical set of theory‐motivated raw accounting numbers, we show that our new fraud prediction model outperforms two benchmark models by a large margin: the Dechow et al. logistic regression model based on financial ratios, and the Cecchini et al. support‐vector‐machine model with a financial kernel that maps raw accounting numbers into a broader set of ratios.
Ethyl‐N‐dodecanoyl‐l‐arginate hydrochloride combats pathogens with low‐resistance generation by membrane attack and modifies gut microbiota structure
Authors: Shao Ting , Fan Tingting , Tang Wenshu , Sun Yanting , Gao Song , Chen Huang , Sun Zhenliang , Liu Mingyao , Yi Zhengfang
Published: November 2019

Ethyl‐N‐dodecanoyl‐l‐arginate hydrochloride (LAE, ethyl lauroyl arginate HCl) is a cationic surfactant used as a food preservative with broad‐spectrum antibacterial activities. However, its resistance development, influences on gut microbiome and molecular target are unclear. In this study, bacteria were stimulated by LAE for 30 days to test the bacterial resistance. Several infected animal models were used to evaluate the antibacterial effect of LAE in vivo. Mice were orally treated with LAE to test its effect on animal growth. The influence of LAE on mice gut microbiome was analysed by 16S rDNA sequencing. The results indicated that Escherichia coli did not develop resistance to LAE. LAE significantly combats bacterial infection in mice, ducklings and piglets. Moreover, LAE promotes mouse weight gain without changing body composition or reducing animal vitality, and induces lower hepatotoxicity than ampicillin. In the mouse gut microbiome assessment and characterization, LAE modifies host gut microbiota structure. Mechanistically, LAE specifically binds to acidic phospholipids including phosphatidylserine, depolarizes the membrane and disrupts the bacterial membrane followed by bacterial growth inhibition. This study investigates the molecular mechanism of LAE as well as its antibacterial functions in poultry and livestock. Our data suggest LAE is a potential antibacterial agent in animal health.
Debt Covenant Restriction, Financial Misreporting, and Auditor Monitoring*
Authors: Pittman Jeffrey , Zhao Yuping
Published: November 2019

Theory suggests that financial report‐based debt covenants engender incentives for the manager to relax covenant constraints through accounting choices in order to avoid costly covenant violations. Prior studies directly testing this hypothesis in the context of financial misreporting fail to find consistent evidence. Using a more refined measure of debt covenant restriction, we find that debt covenant restriction is positively associated with the probability of financial statement misstatements. This positive association is driven by performance covenants rather than capital covenants and is more consistent with the manager striving to avoid a “false‐positive” violation than to delay the violation. Our results also imply that managers resort to both income‐increasing and non–income‐increasing misreporting to relieve covenant constraints and rely more on the latter when faced with greater earnings management constraints. Additionally, the auditor charges higher audit fees to firms with more binding covenants even outside the violation state, and audit fees increase with constraints relative to both performance and capital covenants, reflecting greater financial reporting risk and bankruptcy risk, respectively. Within capital covenants, we find some evidence of even higher audit fees for tighter intangible‐inclusive versus intangible‐exclusive capital covenants. Lastly, our evidence suggests that the positive association between covenant constraints and misreporting is attenuated when the auditor has more experience with debt covenants, has greater bargaining power over the client, or faces greater litigation risk.
Adaptive evolution and response to phytoplasma: A genome‐wide study of TCP transcription factors in Sesamum indicum L.
Authors: Parakkunnel Ramya , Bindhani Nirupama , Purru Supriya , Lakhanpaul Suman , Venkataramanna Bhat Kangila
Published: November 2019

Intraspecific divergence study of TCP (teosinte branched [TB1], cycloidea [CYC] and proliferating cell factors [PCF]) transcription factors was conducted in Indian and Chinese varieties including landraces of sesame to understand the effects of breeding and adaptive selection on genomic architecture. The varieties included “Swetha,” a pedigree selection and “Zhongzhi‐13,” a space mutant; whereas the landraces studied were “Baizhima” and “Mishouzhima” adapted to widely different ecological niches. “Swetha” the Indian variety contained 33 TCP genes, including 14 Class‐I and 19 Class‐II genes, whereas “Zhongzhi‐13” the RefSeq variety contained 13 Class‐I and 15 Class‐II genes. Sixteen Class‐I genes and six CYC genes were common in both the landraces whereas an additional gene variant was found in “Baizhima.” Class‐II TCP genes were found more conserved within species while Class‐I genes differed widely within and across species. A cluster of 12 Class‐I genes was found unique to the Chinese genotypes, whereas two of the Class‐I genes in landrace “Baizhima” were found more similar to the Indian variety “Swetha” genes. A varied number of retrocopies and retropseudogenes were also found among Class‐I TCPs, due to insertion of TY1/Copia transposons. A number of active TY1/Copia retrotransposons containing “chimeric retrogenes” with multiple introns were discovered in sesame. One set involved “SiwTCP3” from “Swetha” and its homologues from the landraces with a mutation in the conserved Cys‐20 residue which abolished the redox sensitivity whereas the second set was present only in the landraces without the above mutation. None of the “Zhongzhi‐13” genes contained TY1/Copia insertions. Transposon insertions resulted in heavy methylation of unique genes in “Swetha” while methylation spread was noticed in the upstream and downstream regulatory regions. Although CIN‐TCPs were established as preferred binding partners of phytoplasma effectors, we found many mutations in the functional domains which altered the protein folding mechanisms among the protein homologues, with one set reported unique in the Chinese varieties. More duplication was noted in the CIN‐TCP's of “Swetha” whereas multiple exons and exon fusions resulted in the acquisition of novel functions for sesame TCP genes. The insertions, deletions and the duplications acquired through genome evolution under marginal environment conditions altered the binding abilities of CIN‐TCP transcription factors which ultimately resulted in variable response to sesame phyllody caused by phytoplasma.
Descriptive Norms but not Harm Reduction Strategies as a Mediator of Personalized Boosters After a Computerized College Drinking Intervention
Authors: Braitman Abby L. , Lau‐Barraco Cathy
Published: November 2019

Background

Computer‐delivered programs to reduce college drinking have strong appeal but are sometimes less efficacious than their in‐person counterparts. Boosters may be an ideal way to strengthen and extend the effects of computerized interventions while maintaining low cost and easy dissemination. However, little is known about how they work. Consequently, the current study aimed to explore descriptive perceived drinking norms and use of protective behavioral strategies (PBS) as potential mediators of booster effects. We also examined norms and PBS as mediators of the main intervention. The present study was a follow‐up analysis of data from a randomized controlled trial (Alcohol Clin Exp Res 42, 2018, 1735) testing the efficacy of emailed boosters containing personalized feedback after a computerized alcohol intervention.

Methods

Participants were 537 (67.4% women) emerging adult college drinkers (M age = 19.65, SD = 1.67). They were randomly assigned to one of 3 conditions: general health education, alcohol intervention only, or alcohol intervention plus booster email. Participants completed assessments at baseline and follow‐ups through 9 months.

Results

Descriptive norms were a mediator of booster efficacy where receiving the booster yielded stronger reductions in alcohol use through reduced concurrent norms; however, fully longitudinal models did not reach significance. There was also an indirect effect for the intervention where those who received the intervention experienced an increase in drinking through increased concurrent norms. However, a stronger direct effect was found where those who received the intervention experienced a stronger decrease in drinking after controlling for norms. There was no support for PBS as a mediator of booster or intervention efficacy.

Conclusions

The present study was the first, to our knowledge, to demonstrate a potential mechanism of change in booster interventions. A simple, succinct reminder via email led to reductions in perceptions of how much peers drink, and this led to reductions in alcohol consumption. Our findings support the promise of utilizing brief and easily implemented targeted messaging to enhance the potency of computerized interventions for college drinkers.
Distribution of Phosphatidylethanol in Maternal and Fetal Compartments After Chronic Gestational Binge Alcohol Exposure
Authors: Naik Vishal , Lunde‐Young Raine , Ramirez Josue , Lee Jehoon , Ramadoss Jayanth
Published: November 2019

Background

Phosphatidylethanol (PEth) is a promising biomarker for gestational alcohol exposure. Studies show PEth accumulation in maternal and fetal blood following alcohol exposure; however, distribution of specific PEth homologues (16:0/18:1, 16:0/18:2, 16:0/20:4) in maternal and fetal blood is unknown. Additionally, PEth levels in highly vulnerable FASD targets in maternal and fetal compartments remain unexplored. We hypothesized that all 3 major PEth homologues will be detectable in the maternal and fetal blood, the maternal uterine artery (a reproductive tissue that delivers oxygen and nutrients to fetoplacental unit), and fetal brain regions following gestational binge alcohol exposure and that homologue distribution profiles will be tissue‐specific.

Methods

Pregnant rats received once‐daily orogastric gavage of alcohol (Alcohol; BAC 216 mg/dl@4.5g/kg/d; BAC 289 mg/dl@6g/kg/d) or iso‐caloric maltose dextrin (Pair‐fed control) from gestation days (GD) 5 to 20 or 21. Following chronic exposure, maternal and fetal tissues were analyzed for PEth homologue concentrations utilizing LC‐MS/MS technology.

Results

All 3 PEth homologues were detected in alcohol‐exposed maternal blood, fetal blood, maternal uterine artery, and fetal brain regions (hippocampus, cerebral cortex, and cerebellum). In both maternal and fetal blood, respectively, PEth 16:0/18:2 was more abundant compared to 16:0/18:1 (p < 0.0001,~66%,↑; p = 0.0159, 20.4%↑) and 16:0/20:4 (p = 0.0072,~25%↑; p = 0.0187, 19.4%↑). Maternal PEth 16:0/20:4 was ~ 42% higher than 16:0/18:1 (p = 0.0015). Maternal PEth 16:0/18:2 and 16:0/20:4 were ~ 25%↑ and ~ 20%↑ higher than in fetal blood (p < 0.05). No homologue differences were detected in the maternal uterine artery. In all fetal brain regions, PEth 16:0/18:1 was significantly higher (p < 0.0001) than 16:0/18:2 (~48 to 78%↑) and 16:0/20:4 (~31 to 62%↑) concentrations. PEth 16:0/20:4 was ~ 18% higher than 16:0/18:1 (p < 0.05) in the fetal hippocampus and cortex.

Conclusion

All major PEth homologues were detected in maternal and fetal blood following chronic gestational binge alcohol exposure; homologue distribution profiles were tissue‐specific. This study also provides insights into PEth accumulation in critical FASD targets, specifically the maternal uterine artery and fetal brain.
Differentiating borderline personality disorder (BPD) from bipolar disorder: diagnostic efficiency of DSM BPD criteria
Authors: Bayes A.J. , Parker G. B.
Published: November 2019

Objective

We sought to determine the differential diagnostic efficiency of all DSM‐IV borderline personality disorder (BPD) criteria by studying a sample of those with BPD and a contrast group with a bipolar disorder (BP).

Method

Participants were clinically assessed and assigned diagnoses based on DSM criteria – with prevalence rates and diagnostic efficiency values calculated.

Results

Fifty‐three participants were assigned a BPD diagnosis, 83 a BP diagnosis, with comorbid participants excluded. The mean number of DSM BPD criteria assigned was 6.6 (SD = 1.0) in the BPD group and 1.9 (SD = 1.3) in the BP group. The most prevalent criterion in the BPD group was ‘affective instability’ (AI) (92.5%), with ‘inappropriate anger’ least endorsed (49%). The highest specificity criterion was ‘abandonment fears’, which displayed the greatest positive predictive value (PPV) = 0.9, and with AI offering the lowest specificity. ‘Unstable relationships’ had the highest overall negative predictive value (NPV) = 0.91. The highest percentage accuracy of classification was provided by ‘identity disturbance’ and ‘abandonment fears’ criteria, both 85%.

Conclusion

The transdiagnostic nature of ‘affective instability’ means it is less useful for diagnostic decisions, whereas ‘abandonment fears’ and ‘identity disturbance’ offer superior diagnostic efficiency in distinguishing BPD from BP.
Macrophage‐derived progranulin promotes allergen‐induced airway inflammation
Authors: Choi Jun‐Pyo , Park So Young , Moon Keun‐Ai , Ha Eun Hee , Woo Yeon Duk , Chung Doo Hyun , Kwon Hyouk‐Soo , Kim Tae‐Bum , Park Hae‐Sim , Moon Hee‐Bom , Song Woo‐Jung , Cho You Sook
Published: November 2019

Background

Progranulin (PGRN), mainly produced by immune and epithelial cells, has been known to be involved in the development of various inflammatory diseases. However, the function of PGRN in allergic airway inflammation has not been clearly elucidated, and we investigated the role of PGRN in allergic airway inflammation.

Methods

Production of PGRN and various type 2 cytokines was evaluated in mouse airways exposed to house dust mite allergen, and main cellular sources of these molecules were investigated using macrophage, airway epithelial cell, and NKT cell lines. We elucidated the role of PGRN in allergic airway inflammation in mouse models of asthma using macrophage‐derived PGRN‐deficient mice and NKT cell knockout mice by evaluating cytokine levels in bronchoalveolar lavage fluids and histopathology. We also supplemented recombinant PGRN in the mouse models to confirm the role of PGRN in allergic airway inflammation.

Results

PGRN production preceded other cytokines, mainly from macrophages, in the airway exposed to allergen. PGRN induced IL‐4 and IL‐13 production in NKT cells and IL‐33 and TSLP in airway epithelial cells. PGRN‐induced Th2 cytokine production was abolished in NKT‐deficient mice. Finally, allergic inflammation was significantly attenuated in allergen‐exposed PGRN‐deficient mice, but inflammation was restored when recombinant PGRN was supplemented during the allergen sensitization period.

Conclusion

The presence of macrophage‐derived PGRN in airways in the early sensitization period may be critical for mounting a Th2 immune response and for following an allergic airway inflammation pathway via induction of type 2 cytokine production in NKT and airway epithelial cells.
Is allergy immunotherapy with birch sufficient to treat patients allergic to pollen of tree species of the birch homologous group?
Authors: Kleine‐Tebbe Jörg , Zuberbier Torsten , Werfel Thomas , Krüll Matthias , Wagenmann Martin , Johansen Niels , Adler Würtzen Peter , Wolf Hendrik , Mücke Victoria , Wüstenberg Eike , Biedermann Tilo
Published: November 2019

Pollen from various Fagales tree species prolongs the season and makes tree pollen allergy a major health problem. Despite involving the same causative allergens, allergy immunotherapy (AIT) treatment habits differ significantly across different geographical regions. Diagnosis and treatment with AIT in patients allergic to tree pollen were discussed by a group of German medical experts who give practical recommendations based on the available data. Regulatory perspective: According to current guidelines on allergen products, birch pollen are the representative allergen source of the birch homologous group including several Fagales trees based on sequence and structural similarity of their allergen proteins. Immunological perspective: A high level of IgE cross‐reactivity towards allergens from the birch homologous group has been observed in basic research and clinical trials. Clinical perspective: Clinical trial data show that the efficacy of birch pollen AIT is not only related to birch pollen allergy but extends to pollen from other trees, especially alder, hazel and oak. In order to optimize diagnosis and treatment of tree pollen allergy, the experts recommend to focus diagnosis and respective treatment with AIT primarily to birch as the representative allergen of the Fagales tree homologous group, but further diagnostics may be needed for some patients to determine adequate treatment.
The maternal and perinatal implications of hypertensive disorders of pregnancy in a multiple pregnancy cohort
Authors: Hayes‐Ryan Deirdre , Meaney Sarah , Hodnett Aoibhin , Geisler Minna , O'Donoghue Keelin
Published: November 2019

Introduction

Hypertensive disorders of pregnancy are common and may result in increased maternal and neonatal morbidity and mortality. Multiple pregnancies confer an increased risk of development of a hypertensive disorder of pregnancy. The purpose of this study was to examine a large cohort of women delivering a multiple pregnancy in a single large tertiary unit, and to evaluate the implications of hypertensive disorders of pregnancy on both maternal and perinatal outcomes.

Material and methods

Retrospective study of all twin pregnancies delivered at Cork University Maternity Hospital, Ireland over a 9‐year period (2009‐2017). The twin pregnancies were divided according to the presence or absence of hypertensive disorder of pregnancy and the two groups were compared.

Results

Maternal age >40 years, nulliparity, conception through use of a donor oocyte, and presence of obstetric cholestasis are all risk factors for the development of hypertensive disorders of pregnancy in women with a multiple pregnancy. When a hypertensive disorder complicates a twin pregnancy, it increases the incidence of iatrogenic late prematurity and neonatal hypoglycemia.

Conclusions

This study is informative for clinicians caring for women with a multiple pregnancy with its relevant data on perinatal outcomes following a diagnosis of hypertensive disorder in pregnancy.
Improving prescribing through big data approaches—Ten years of the Scottish Prescribing Information System
Authors: Bennie Marion , Malcolm William , McTaggart Stuart , Mueller Tanja
Published: November 2019

Medicines are a major component of modern healthcare delivery, both in resource consumption and as drivers of innovation. The ever‐increasing application of digitalisation within day‐to‐day living and as part of our healthcare systems—with the resultant data generation—presents the opportunity to better define the populations exposed to medicines, and their benefits and harm in real world settings. This article outlines the development of the Scottish National Prescribing Information System (PIS) and describes how this capability is being used to support the safe and effective use of medicines, both nationally and internationally. Since 2009, PIS has included e‐prescribed/e‐dispensed and reimbursed medicines data, now totalling 976 million prescriptions, with codified structured data on dose instructions. A literature review, covering the period from January 2009 to March 2019, identified 40 full publications using PIS, the first occurring in 2014. The majority involved pharmacoepidemiology/drug‐use studies (50%) in cancer and cardiovascular disease. Measuring the value and impact of PIS was extended beyond publication quantification by illustrating the translation of PIS outputs into the learning health system at scale. The developing Scottish capabilities add breadth and depth to the wider evolving international environment, and offer the potential to contribute collegiately to the global effort on medicine safety and effectiveness, including support for the World Health Organisation Global Patient Safety Challenge: Medication Without Harm.
First‐in‐human, randomized dose‐escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF‐06480605 in healthy subjects
Authors: Banfield Christopher , Rudin Dan , Bhattacharya Indranil , Goteti Kosalaram , Li Gang , Hassan‐Zahraee Mina , Brown Lisa S. , Hung Kenneth E. , Pawlak Sylvester , Lepsy Christopher
Published: November 2019

Aims

Human genetic, tissue expression, proteomics, transcriptomics and nonclinical studies implicate tumour necrosis factor α‐like ligand 1A (TL1A) as a novel target in inflammatory bowel disease (IBD). PF‐06480605, a fully human immunoglobulin G1 monoclonal antibody, targets TL1A. This first‐in‐human, Phase 1, dose‐escalation study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of intravenous (IV) and subcutaneous (SC) PF‐06480605 in healthy subjects (NCT01989143).

Methods

Ninety‐two subjects were randomized to single ascending doses (SAD), PF‐06480605 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg or 800 mg IV, or multiple ascending doses (MAD), PF‐06480605 3 × 500 mg IV, or 3 × 30 mg, 3 × 100 mg, or 3 × 300 mg SC every 2 weeks for three doses, or placebo. Safety, tolerability, pharmacokinetics, immunogenicity profiles and total TL1A, anti‐drug antibody (ADA) and neutralizing antibody (NAb) levels were assessed at pre‐determined times.

Results

PF‐06480605 SAD up to 800 mg IV and MAD up to 300 mg ×3 SC and 500 mg ×3 IV were well tolerated. Overall, there were 45 and 44 treatment‐emergent adverse events in SAD and MAD cohorts, respectively, and no deaths or serious adverse events. PF‐06480605 exposure generally increased dose‐dependently. ADA and NAb levels did not impact safety, pharmacokinetics, or pharmacodynamics at higher doses. Target engagement was demonstrated through dose‐dependent differences in serum total soluble TL1A concentrations for PF‐06480605 vs placebo cohorts.

Conclusions

PF‐06480605 was generally well tolerated, and binding of soluble TL1A was maintained throughout the dose interval, supporting further study of PF‐06480605 in patients with IBD and other inflammatory conditions.
Post‐marketing assessment of generic tamoxifen in Brazilian breast cancer patients
Authors: Ximenez João P. , Lanchote Vera L. , Bello Marcelo A. , Iocken Fernanda H. S. , Obadia Renata C. M. , de Sousa Valéria P. , Suarez‐Kurtz Guilherme
Published: November 2019

Generic formulations of tamoxifen are commonly prescribed to oestrogen receptor‐positive breast cancer patients at the Brazilian National Cancer Institute (INCA). We carried out a post‐marketing surveillance of the generic tamoxifen formulation in current use at INCA, by comparing plasma concentrations of the parent drug and metabolites obtained with the generic vs the reference formulation. Thirty patients participated in an open‐label, bracketed protocol, comprising 3 successive phases of 30‐32 days each: the generic formulation was used in phases 1 and 3 and the reference formulation in phase 2. Two blood samples were collected in the last 4 days of each phase, for LC‐MS/MS quantification of tamoxifen and metabolites in plasma. The median plasma concentrations (ng/mL) for the reference formulation were as follows: tamoxifen, 135.0 (CI 95% 114.2‐155.8); endoxifen, 35.3 (30.0‐40.8); and 4‐hydroxytamoxifen, 4.8 (4.2‐5.4). The endoxifen/tamoxifen plasma concentration ratio was 0.27 (0.21‐0.25). ANOVA detected no statistically significant difference in plasma concentrations of tamoxifen, metabolites or the endoxifen/tamoxifen ratio among the three phases. The genetic component (rGC) of the CYP2D6‐mediated conversion of tamoxifen into endoxifen, estimated using the repeated drug administration procedure across the three phases, was 0.87, pointing to an important component of genetic variability. In conclusion, this first post‐marketing surveillance trial of oncologic generic drugs carried out in Brazilian patients verified the switchability between the reference and the generic tamoxifen formulation currently used at our institution. The adopted bracketed protocol adds confidence to this conclusion and may serve as a frame for future trials of post‐marketing assessment of other generic drug products.
Pollen‐recorded bioclimatic variations of the last ~2000 years retrieved from Bayan Nuur in the western Mongolian Plateau
Authors: Yang Yunpeng , Ran Min , Sun Aizhi
Published: November 2019

The palaeoclimatic variations during the past ~2000 years in western Mongolia were reconstructed using a high‐resolution pollen sequence obtained from Bayan Nuur. The pollen‐based mean annual precipitation (MAP) from Bayan Nuur and the tree ring‐based temperature anomalies from the nearby Altai Mountains exhibit a ‘warm‐dry’ Roman Warm Period (RWP; ~1900 to ~1500 cal. aBP), a ‘cool‐wet’ Dark Age Cold Period (DACP; ~1500 to ~1150 cal. aBP), a ‘warm‐dry’ Medieval Warm Period (MWP; ~1150 to ~800 cal. aBP) and a ‘cool‐wet’ Little Ice Age (LIA; ~800 to ~100 cal. aBP). Nevertheless, the Current Warm Period (CWP; since ~100 cal. aBP) is an exception that fits a ‘warm‐wet’ mode. A more detailed comparison between the pollen‐basedMAPcurve and the North Atlantic Oscillation (NAO) index curve suggests that the higher‐precipitation episodes generally corresponded with more negativeNAOepisodes. The chronological correspondence between the higher‐precipitation episodes and the more negativeNAOepisodes means that more Atlantic storm tracks originated from the southern part of the North Atlantic Ocean and also from the Mediterranean Sea during negativeNAOepisodes. It implies that the precipitation variations during the past two millennia have been modulated primarily byNAOvariations and negatively phasedNAOsettings contributed to more winter precipitation in Bayan Nuur basin.
Naringenin attenuates non‐alcoholic fatty liver disease by down‐regulating the NLRP3/NF‐κB pathway in mice
Authors: Wang Qinyu , Ou Yangjie , Hu Guomin , Wen Cong , Yue Shanshan , Chen Cong , Xu Lu , Xie Jiawei , Dai Hui , Xiao Han , Zhang Youyi , Qi Rong
Published: November 2019

Background and Purpose

Naringenin, a flavonoid compound with strong anti‐inflammatory activity, attenuated non‐alcoholic fatty liver disease (NAFLD) induced by a methionine‐choline deficient (MCD) diet in mice. However, the mechanisms underlying this suppression of inflammation and NAFLD remain unknown.

Experimental Approach

WT and NLRP3−/− mice were fed with MCD diet for 7 days to induce NAFLD and were given naringenin by gavage at the same time. in vitro experiments used HepG2 cells, primary hepatocytes, and Kupffer cells (KCs) stimulated by LPS or LPS plus oleic acid (OA).

Key Results

Treating WT mice with naringenin (100 mg·kg−1·day−1) attenuated hepatic lipid accumulation and inflammation in the livers of mice given the MCD diet. NLRP3−/− mice showed less hepatic lipid accumulation than WT mice, but naringenin did not ameliorate hepatic lipid accumulation further in NLRP3−/− mice. Treating the HepG2 cells with naringenin or NLRP3 inhibitor MCC950 reduced lipid accumulation. Naringenin inhibited activation of the NLRP3/NF‐κB pathway stimulated by OA together with LPS. In KCs isolated from WT mice, naringenin inhibited NLRP3 expression. Naringenin also inhibited lipid deposition, NLRP3 and IL‐1β expression in WT hepatocytes but was not effective in NLRP3−/− hepatocytes. After re‐expressing NLRP3 in NLRP3−/− hepatocytes by adenovirus, the anti‐lipid deposition effect of naringenin was restored.

Conclusion and Implications

Naringenin prevented NAFLD via down‐regulating the NLRP3/NF‐κB signalling pathway both in KCs and in hepatocytes, thus attenuating inflammation in the mice livers.
Ca2+ signalling in fibroblasts and the therapeutic potential of KCa3.1 channel blockers in fibrotic diseases
Authors: Roach Katy M. , Bradding Peter
Published: November 2019

The role of Ca2+ signalling in fibroblasts is of great interest in fibrosis‐related diseases. Intracellular free Ca2+ ([Ca2+]i) is a ubiquitous secondary messenger, regulating a number of cellular functions such as secretion, metabolism, differentiation, proliferation and contraction. The intermediate conductance Ca2+‐activated K+ channel KCa3.1 is pivotal in Ca2+ signalling and plays a central role in fibroblast processes including cell activation, migration and proliferation through the regulation of cell membrane potential. Evidence from a number of approaches demonstrates that KCa3.1 plays an important role in the development of many fibrotic diseases, including idiopathic pulmonary, renal tubulointerstitial fibrosis and cardiovascular disease. The KCa3.1 selective blocker senicapoc was well tolerated in clinical trials for sickle cell disease, raising the possibility of rapid translation to the clinic for people suffering from pathological fibrosis. This review after analysing all the data, concludes that targeting KCa3.1 should be a high priority for human fibrotic disease.
Adding the missing third and fourth dimensions to trajectory analysis in carbonate systems
Authors: Tesch Philipp , Reece Robert S. , Markello James R. , Laya Juan Carlos , Pope Michael C.
Published: November 2019

We developed a seismic geomorphology‐based procedure to enhance traditional trajectory analysis with the ability to visualize and quantify lateral variability along carbonate prograding‐margin types (ramps and rimmed shelves) in 3D and 4D. This quantitative approach analysed the shelf break geometric evolution of the Oligo‐Miocene carbonate clinoform system in the Browse Basin and delineated the feedback between antecedent topography and carbonate system response as controlling factor on shelf break rugosity. Our geometrical analysis identified a systematic shift in the large‐scale average shelf break strike direction over a transect of 10 km from 62° to 55° in the Oligo‐Miocene interval of the Browse Basin, which is likely controlled by far‐field allogenic forcing from the Timor Trough collision zone. Plotting of 3D shelf break trajectories represents a convenient way to visualize the lateral variability in shelf break evolution. Shelf break trajectories that indicate contemporaneous along‐strike progradation and retrogradation correlate with phases of autogenic slope system re‐organization and may be a proxy for morphological stability of the shelf break. Shelf break rugosity and shelf break trajectory rugosity are not inherited parameters and antecedent topography does not dictate long‐term differential movement of the shelf margin through successive depositional sequences. The autogenic carbonate system response to antecedent topography smooths high‐rugosity areas by filling accommodation and maintains a relatively constant shelf break rugosity of ~150 m. Color‐coding of the vertical component in the shelf break trajectory captures the creation and filling of accommodation, and highlights areas of the transect that are likely to yield inconsistent 2D sequence stratigraphic interpretations.
Cannabis policy diffusion in Ontario and New Brunswick: Coercion, learning, and replication
Authors: Train Andrew , Snow Dave
Published: November 2019

This article integrates Hall’s (1993) social learning framework, as well as more recent contributions, into the literature on policy diffusion to better identify the goals, instruments, and precise settings for recreational cannabis policy in New Brunswick and Ontario. We analyze committee hearings, Hansard debates, and government reports and find that policy diffused via three mechanisms: coercion due to the federal criminal law power, learning from Washington and Colorado, and replication of analogous provincial policies concerning tobacco and alcohol. We also find the non‐binding federal Task Force on Cannabis Legalization and Regulation had a considerable effect on the diffusion of goals, instruments, and settings.
Cannabis legalization and the machinery of government
Authors: Wesley Jared J. , Salomons Geoff
Published: November 2019

This study compares provincial and territorial approaches re‐organizing the machinery of government to promote efficiency, innovation, and continuous improvement in legalizing recreational cannabis. Based on interviews with government officials from across Canada, our research assesses the effectiveness of various models, which ranged from officials‐level working groups and task teams to cabinet committees and formal secretariats. Findings reveal that, while governments took more integrated, network‐style approaches to policy development, modes of policy implementation and evaluation involved more conventional modes of hierarchy and market‐based organization. This shift will impact governments’ ability to execute and evaluate the legalization process.
Cross‐Domain Trajectories of Students’ Ability Self‐Concepts and Intrinsic Values in Math and Language Arts
Authors: Gaspard Hanna , Lauermann Fani , Rose Norman , Wigfield Allan , Eccles Jacquelynne S.
Published: November 2019

Different cross‐domain trajectories in the development of students’ ability self‐concepts (ASCs) and their intrinsic valuing of math and language arts were examined in a cross‐sequential study spanning Grades 1 through 12 (n = 1,069). Growth mixture modeling analyses identified a Moderate Math Decline/Stable High Language Arts class and a Moderate Math Decline/Strong Language Arts Decline class for students’ ASC trajectories. Students’ intrinsic value trajectories included a Strong Math Decline/Language Arts Decline Leveling Off, a Moderate Math Decline/Strong Language Arts Decline, and a Stable Math and Language Arts Trajectories class. These classes differed with regard to student characteristics, including gender, family background, and math and reading aptitudes. They also resulted in different high school math course enrollments, career aspirations, and adult careers.
IL-1-dependent electrophysiological changes and cardiac neural remodeling in a mouse model of Kawasaki disease vasculitis
Authors: Abe M , Rastelli D D , Gomez A C , Cingolani E , Lee Y , Soni P R , Fishbein M C , Lehman T J A , Shimada K , Crother T R , Chen S , Noval Rivas M , Arditi M
Published: November 2019

Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40–80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. LCWE-injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE-injected mice developed cardiac ganglion inflammation, that may affect the impulse-conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE-injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)-1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1−/− mice and in wild-type mice treated with anakinra. Thus, similar to clinical KD, the LCWE-induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL-1 signaling. These data support the acceleration of anti-IL-1 therapy trials to benefit KD patients.
Integrated analysis of COL2A1 variant data and classification of type II collagenopathies
Authors: Zhang Boyan , Zhang Yue , Wu Naichao , Li Jianing , Liu He , Wang Jincheng
Published: November 2019

The COL2A1 gene encodes the alpha‐1 chain of type II procollagen. Type II collagen, comprised of three identical alpha‐1 chains, is the major component of cartilage. COL2A1 gene variants are the etiologies of genetic diseases, termed type II collagenopathies, with a wide spectrum of clinical presentations. To date, at least 460 distinct COL2A1 mutations, identified in 663 independent probands, and 21 definite disorders have been reported. Nevertheless, a well‐defined genotype‐phenotype correlation has not been established, and few hot spots of mutation have been reported. In this study, we analyzed data of COL2A1 variants and clinical information of patients obtained from the Leiden Open Variation Database 3.0, as well as the currently available relevant literature. We determined the characteristics of the COL2A1 variants and distributions of the clinical manifestations in patients, and identified four likely genotype‐phenotype correlations. Moreover, we classified 21 COL2A1‐related disorders into five categories, which may assist clinicians in understanding the essence of these complex phenotypes and prompt genetic screening in clinical practice.
Becoming Favela: Forced Resettlement and Reverse Transitions of Urban Space in Brazil
Authors: Kolling Marie
Published: November 2019

This article examines the forced resettlement offavelaresidents to a new neighborhood and the life they tried to make for themselves in the new state‐built social housing. They experienced a sense of betrayal by their new neighbors and by the state; much of what they had been promised was not delivered, and in the aftermath of resettlement they were left by the state project to their own devices. In the new neighborhood, the “territorial stigma” (Wacquant 2008) of the favela lingered on, placing the newcomers at the bottom of the local social hierarchy in the impoverished periphery of the city. While battling this stigma, they were also pursuing their dreams for a better future by investing their scarce resources into the improvement of their new but poorly built homes. Their house‐building practices resemble the urban development processes of “peripheral urbanization” (Caldeira 2016), as the slow and uneven self‐built constructions encroach on the ordered state‐built housing. The gradual transition of the new urban space followed a similar development pattern as the favela where they used to live, but in a reverse order, producing an inverse transition of urban space. I treat the negligence of the state, the housing practices of the residents, and the discursive practices of labeling the social housing a favela—by the long‐term neighbors and eventually the residents themselves—as co‐constituting an urban form, lived experience, and socio‐spatial process in which the housing project becomes favela. This analysis provides new insights into the anthropological literature on urban development and illicit house‐building in peripheral neighborhoods in the Global South and the socio‐spatial dynamics of forced resettlement.
DUETS (Dallas UtErus Transplant Study): Complete report of 6‐month and initial 2‐year outcomes following open donor hysterectomy
Authors: Ramani Azaan , Testa Giuliano , Ghouri Yumna , Koon Eric C. , Di Salvo Marco , McKenna Greg J. , Bayer Johanna , Marie Warren Ann , Wall Anji , Johannesson Liza
Published: November 2019

Introduction

Uterus transplantation has shown success in treating women with uterine factor infertility who want to carry their own pregnancy.

Methods

We report the medical, sexual, and psychological outcomes of our first cohort of 13 living donor hysterectomies. As we have transitioned from open to robotically assisted hysterectomy, this report represents the complete series of open donor hysterectomies at our center, all with ≥6‐month postoperative outcomes.

Results

The open donor hysterectomy had a median of a 6.5‐hour surgical time, 0.8 L estimated blood loss, 6‐day hospital stay, and 28‐day sick leave. Three donors had a grade III or IV complications, one reported new‐onset psychological symptoms, and 9 experienced transient sexual discomfort. All complications were addressed and resolved, and all donors returned to their presurgical social and physical activities.

Conclusion

Since uterus transplantation is not life‐saving or life‐extending, the risks in living uterus donation must be weighed against the benefit of giving another woman the opportunity to give birth to her own child. This report provides data to support more detailed informed consent regarding the medical, psychological, and sexual complications of open living donor hysterectomy and allows for further evaluation of the ethical acceptability of this procedure.
Hanging donor lungs give good short‐, mid‐ and long‐term results in lung transplantation
Authors: De Wolf Julien , Renard Regis , Lehouerou Thomas , Glorion Matthieu , Pricopi Ciprian , Bonnette Pierre , Parquin Francois , Roux Antoine , Leguen Morgan , Chapelier Alain , Sage Edouard
Published: November 2019

Background

Hanging donors are considered as marginal donors and frequently unsuitable for lung transplantation. However, there is no evidence of higher lung transplantation (LTx) morbidity‐mortality with lungs providing by hanging donor.

Methods

Between January 2010 and July 2015, we performed a retrospective study at Foch hospital. We aimed to assess whether hanging donor grafts are suitable for lung transplantation.

Results

A total of 299 LTx were performed. Subjects were allocated to a hanging group (HG) (n = 20) and a control group (CG) (n = 279). Donor and recipient characteristics did not differ. Primary graft dysfunction (PGD) at 72 hours was comparable in both groups (P = .75). The median duration of postoperative mechanical ventilation (1 [range, 0‐84] vs 1 [range, 0‐410] day, P = .35), the hospital length of stay (31 days [20‐84] vs 32 days [12‐435], P = .36) did not differ between the two groups. No statistically significant difference was found in 1‐year and 5‐year survival between the HG (83% and 78%) and the CG (86% and 75%), P = .85.

Conclusion

We believe that hanging donors should be considered as conventional donors with particular caution in the final evaluation of the graft and in perioperative management.
Clinical Utility of Pharmacogene Panel‐Based Testing in Patients Undergoing Percutaneous Coronary Intervention
Authors: El Rouby Nihal , Alrwisan Adel , Langaee Taimour , Lipori Gloria , Angiolillo Dominick J , Franchi Francesco , Riva Alberto , Elsey Amanda , Johnson Julie A. , Cavallari Larisa H. , Winterstein Almut G.
Published: November 2019

We aimed to estimate the utility of panel‐based pharmacogenetic testing of patients undergoing percutaneous coronary intervention (PCI). Utilization of Clinical Pharmacogenetic Implementation Consortium (CPIC) level A/B drugs after PCI was estimated in a national sample of IBM MarketScan beneficiaries. Genotype data from University of Florida (UF) patients (n = 211) who underwent PCI were used to project genotype‐guided opportunities among MarketScan beneficiaries with at least one (N = 105,547) and five (N = 12,462) years of follow‐up data. The actual incidence of genotype‐guided prescribing opportunities was determined among UF patients. In MarketScan, 50.0% (52,799/105,547) over 1 year and 68.0% (8,473/12,462) over 5 years had ≥ 1 CPIC A/B drug besides antiplatelet therapy prescribed, with a projected incidence of genotype‐guided prescribing opportunities of 39% at 1 year and 52% at 5 years. Genotype‐guided prescribing opportunities occurred in 32% of UF patients. Projected and actual incidence of genotype‐guided opportunities among two cohorts supports the utility of panel‐based testing among patients who underwent PCI.
Making Better Dose Decisions: Using Exposure‐Response Modeling to Integrate Efficacy Outcome of Two Phase IIb Clinical Trials of Ubrogepant for Migraine Treatment
Authors: Li Chi‐Chung , Voss Tiffini , Kowalski Ken , Yang Bei , Kleijn Huub Jan , Jones Christopher J. , Bosch Rolien , Michelson David , DeAngelis Matthew , Xu Yang , Xie Iris , Kothare Prajakti A.
Published: November 2019

Ubrogepant (MK‐1602) is a novel, oral, calcitonin gene‐related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure‐response (E‐R) modeling and simulations, which were used to inform the phase III dose‐selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose‐finding clinical trials. The E‐R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2‐hour pain relief and 2‐hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E‐R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model‐based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E‐R helped support the dose selection for the phase III clinical trials.
Cytomorphology of late‐onset Leishmania endophthalmitis: A case report
Authors: Sučić Mirna , Ljubić Nives , Čulig Zdravka
Published: November 2019

This article describes the cytomorphological features of a case of late‐onset endophthalmitis caused by Leishmania. The latter is a rare clinical presentation of leishmaniasia and the cytologigal features have not previously been described.
Childhood abuse as a risk factor for injection drug use: A systematic review of observational studies
Authors: Prangnell Amy , Imtiaz Sameer , Karamouzian Mohammad , Hayashi Kanna
Published: November 2019

Issues

Childhood abuse is a public health challenge with lifelong impacts, including future drug use. However, previous research has been mixed regarding impacts on injection drug use. This systematic review examines the impact of childhood abuse (sexual, physical and emotional) on adult injection drug use.

Approach

We searched MEDLINE, EMBASE, PsycINFO, CINAHL, Web of Science and grey literature to identify relevant studies from database inception to 26 September 2018. Studies were eligible if: (i) they were empirical original research published in English; (ii) considered childhood abuse as potential risk factors for lifetime history of injection drug use; and (iii) included adult participants. Risk of bias was assessed using the modified Newcastle‐Ottawa Scale.

Key Findings

Of the 1994 articles screened, 17 studies met the inclusion criteria. Most studies were conducted in the USA and utilised cross‐sectional research designs. All of the 17 studies measured sexual abuse, six studies measured physical abuse and three studies measured emotional abuse; most (N = 11) of which reported a statistically significant and positive association between at least one sub‐scale of childhood abuse and injection drug use.

Implications

Our findings highlight the need for devising interventions to reduce the harms associated with childhood abuse.

Conclusions

The evidence base suggests a significant positive association between experiences of childhood physical abuse and elevated risks of injection drug initiation with mixed results for sexual and emotional abuse.