bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virulence Genetics of anErwinia amylovoraPutative Polysaccharide Transporter Family Member
Authors: Klee Sara M. , Sinn Judith P. , Christian Elena , Holmes Aleah C. , Zhao Kaixi , Lehman Brian L. , Peter Kari A. , Rosa Cristina , McNellis Timothy W. 
Published: August 2020

ABSTRACTThe Gram-negative enterobacteriumErwinia amylovoracauses fire blight disease in apple and pear trees. Lipopolysaccharides and the exopolysaccharide amylovoran are essentialE. amylovoravirulence factors. We found that mutations inrfbXdisrupted amylovoran production and virulence in apple fruits and tree shoots and that the deletion ofyibDsuppressed therfbXmutant phenotype. The level of expression ofyibDwas about 10-fold higher in the ΔrfbXmutant than the wild type. A forward genetic suppressor screen in the ΔrfbXmutant uncovered multiple mutations inyibDand supported the conclusion that the virulence defect ofrfbXmutants is due to reduced amylovoran production. TheyibDandrfbXgenes are expressed as a two-gene operon,yibD rfbX. TherfbXgene encodes a previously uncharacterized putative polysaccharide subunit transporter, whileyibDencodes a predicted glycosyltransferase. Mutation ofrfbXdid not have a detectable effect on lipopolysaccharide patterns; however, the overexpression ofyibDin both the wild-type and ΔyibDΔrfbXgenetic backgrounds disrupted both amylovoran and lipopolysaccharide production. Additionally, the overexpression ofyibDin the ΔyibDΔrfbXmutant inhibited bacterial growth in amylovoran-inducing medium. This growth inhibition phenotype was used in a forward genetic suppressor screen and reverse-genetics tests to identify several genes involved in lipopolysaccharide production, which, when mutated, restored the ability of the ΔyibDΔrfbXmutant overexpressingyibDto grow in amylovoran-inducing medium. Remarkably, all the lipopolysaccharide gene mutants tested were defective in lipopolysaccharide and amylovoran production. These results reveal a genetic connection between amylovoran and lipopolysaccharide production inE. amylovora.IMPORTANCEThis study discovered previously unknown genetic connections between exopolysaccharide and lipopolysaccharide production in the fire blight pathogenErwinia amylovora. This represents a step forward in our understanding of the biology underlying the production of these two macromolecules. Fire blight is an economically important disease that impacts the production of apples and pears worldwide. Few fire blight control measures are available, and growers rely heavily on antibiotic applications at bloom time. Both exopolysaccharide and lipopolysaccharide areE. amylovoravirulence factors. Our results indicate that the overexpression of theyibDgene inE. amylovoradisrupts both lipopolysaccharide production and exopolysaccharide production. This effect could potentially be used as the basis for the development of an antivirulence treatment for the prevention of fire blight disease.
Stagnant slab front within the mantle transition zone controls the formation of Cenozoic intracontinental high-Mg andesites in northeast Asia
Authors: Xu Wen-Liang , Chen Jia-Hui , Weng Ai-Hua , Tang Jie , Wang Feng , Wang Chun-Guang , Guo Peng , Wang Yi-Ni , Yang Hao , Sorokin Andrey A. 
Published: August 2020

AbstractThe geochemistry of Cenozoic intracontinental high-Mg andesites (HMAs) in northeast Asia, together with regional geophysical data, offers an opportunity to explore the genetic relationship between the formation of intracontinental HMAs and subduction of the Pacific plate. Compared with primary HMAs in arcs, Cenozoic intracontinental HMAs in northeast Asia have lower Mg# [100 × Mg/(Mg + Fe2+)] values (53–56) and CaO contents (5.8–6.6 wt%), higher alkali (Na2O + K2O) contents (5.15–6.45 wt%), and enriched Sr-Nd-Hf isotopic compositions (87Sr/86Sr = 0.7056–0.7059; εNd = −4.9 to −3.4; εHf = −4.7 to −2.6) as well as lower Pb isotope ratios (206Pb/204Pb = 16.76–19.19; 207Pb/204Pb = 15.42–15.45; 208Pb/204Pb = 36.71–37.11). These Cenozoic intracontinental HMAs are similar to Cenozoic potassic basalts in northeast China with respect to their Sr-Nd-Pb-Hf isotopic compositions but have higher SiO2 and Al2O3 contents and lower K2O, MgO, and light rare earth element contents. These features indicate that these Cenozoic intracontinental HMAs originated from the mantle, where recycled ancient sediments and water contributed to partial melting of peridotite. Combined with the presence of a large low-resistivity anomaly derived from the mantle transition zone (MTZ) near these intracontinental HMAs, and their occurrence above the stagnant slab front within the MTZ (at 600 km depth) in northeast Asia, we conclude that the stagnant slab front, with high contents of recycled ancient sediments and water, has controlled the formation of Cenozoic intracontinental HMAs in northeast Asia.
Impact of fault damage on eastern Tibet topography
Authors: Kirkpatrick Heather M. , Moon Seulgi , Yin An , Harrison T. Mark 
Published: August 2020

AbstractTectonic deformation can influence spatiotemporal patterns of erosion by changing both base level and the mechanical state of bedrock. Although base-level change and the resulting erosion are well understood, the impact of tectonic damage on bedrock erodibility has rarely been quantified. Eastern Tibet, a tectonically active region with diverse lithologies and multiple active fault zones, provides a suitable field site to understand how tectonic deformation controls erosion and topography. In this study, we quantified erosion coefficients using the relationship between millennial erosion rates and the corresponding channel steepness. Our work shows a twofold increase in erosion coefficients between basins within 15 km of major faults compared to those beyond 15 km, suggesting that tectonic deformation through seismic shaking and rock damage significantly affects eastern Tibet erosion and topography. This work demonstrates a field-based, quantitative relationship between rock erodibility and fault damage, which has important implications for improving landscape evolution models.
Rebalancing glucolipid metabolism and gut microbiome dysbiosis by nitrate-dependent alleviation of high-fat diet-induced obesity
Authors: Ma Linsha , Hu Liang , Jin Luyuan , Wang Jiangyi , Li Xiangchun , Wang Weili , Chang Shimin , Zhang Chunmei , Wang Jingsong , Wang Songlin 
Published: August 2020

IntroductionHigh-fat diet (HFD)-induced obesity is accompanied by compromised nitric oxide (NO) signaling and gut microbiome dysregulation. Inorganic dietary nitrate, which acts as a NO donor, exerts beneficial effects on metabolic disorders. Here, we evaluated the effects of dietary nitrate on HFD-induced obesity and provided insights into the underlying mechanism.Research design and methodsTo investigate the preventive effect of dietary nitrate on HFD-induced obesity, C57BL/6 mice were randomly assigned into four groups (n=10/group), including normal control diet group (normal water and chow diet), HFD group (normal water and HFD), HFD+NaNO3group (water containing 2 mM NaNO3and HFD), and HFD+NaCl group (water containing 2 mM NaCl and HFD). During the experiment, body weight was monitored and glucolipid metabolism was evaluated. The mechanism underlying the effects of nitrate on HFD-induced obesity was investigated by the following: the NO3--NO2--NO pathway; endothelial NO synthase (eNOS) and cyclic guanosine monophosphate (cGMP) levels; gut microbiota via 16SRNA analysis.ResultsDietary nitrate reduced the body weight gain and lipid accumulation in adipose and liver tissues in HFD-fed mice. Hyperlipidemia and insulin resistance caused by HFD were improved in mice supplemented with nitrate. The level of eNOS was upregulated by nitrate in the serum, liver, and inguinal adipose tissue. Nitrate, nitrite, and cGMP levels were decreased in mice fed on HFD but reversed in the HFD+NaNO3group. Nitrate also rebalanced the colon microbiota and promoted a normal gut microbiome profile by partially attenuating the impacts of HFD.Bacteroidales S24-7,Alistipes,Lactobacillus, andRuminococcaceaeabundances were altered, andBacteroidales S24-7andAlistipesabundances were higher in the HFD+NaNO3group than that in the HFD group.ConclusionsInorganic dietary nitrate alleviated HFD-induced obesity and ameliorated disrupted glucolipid metabolism via NO3--NO2--NO pathway activation and gut microbiome modulation.
Association between race/ethnicity and the risk of amputation of lower extremities among medicare beneficiaries with diabetic foot ulcers and diabetic foot infections
Authors: Tan Tze-Woei , Armstrong David G , Concha-Moore Kirsten C , Marrero David G , Zhou Wei , Calhoun Elizabeth , Chang Ching-Yuan , Lo-Ciganic Wei-Hsuan 
Published: August 2020

IntroductionThis study aimed to examine the association of race and ethnicity on the risk of lower extremity amputations among Medicare beneficiaries with diabetic foot ulcers (DFUs) and diabetic foot infections (DFIs).Research design and methodsA retrospective study included 2011–2015 data of a 5% sample of fee-for-service Medicare beneficiaries with a newly diagnosed DFU and/or DFI. The primary outcome was the time to the first major amputation episode after a DFU and/or DFI were identified using the diagnosis and procedure codes. We used multivariable Cox proportional hazards models to estimate the risk of time to the first major amputation across races, adjusting for sociodemographic and health status factors. Adjusted hazard ratios (aHRs) with a 95% CI were reported.ResultsAmong 92 929 Medicare beneficiaries newly diagnosed with DFUs and/or DFIs, 77% were whites, 14.3% African Americans (AAs), 3.3% Hispanics, 0.7% Native Americans (NAs), and 4.0% were other races. The incidence rates of major amputation were 0.02 person-years for NAs, 0.02 person-years for AAs, 0.01 person-years for Hispanics, 0.01 person-years for other races, and 0.01 person-years for whites (p<0.05). Multivariable analysis showed that AAs (aHR=1.9, 95% CI 1.7 to 2.2, p<0.0001) and NAs (aHR=1.8, 95% CI 1.3 to 2.6, p=0.001) were associated with an increased risk of major amputation compared with whites. Beneficiaries with DFUs and/or DFIs diagnosed by a podiatrist or primary care physician (aHR=0.7, 95% CI 0.6 to 0.8, p<0.0001, specialists as reference) or at an outpatient visit (aHR=0.3, 95% CI 0.3 to 0.3, p<0.0001, inpatient stay as reference) were associated with a decreased risk of major amputation.ConclusionsRacial and ethnic disparities in the risk of lower extremity amputations appear to exist among fee-for-service Medicare beneficiaries with diabetic foot problems. AAs and NAs with DFUs and/or DFIs were associated with an increased risk of major amputations compared with white Medicare beneficiaries.
Ultrasound-guided bilateral pudendal nerve blocks of nulliparous women with epidural labour analgesia in the second stage of labour: a randomised, double-blind, controlled trial
Authors: Xu Jialing , Zhou Riyong , Su Weijue , Wang Shi , Xia Yun , Papadimos Thomas , Zhao Junzhao , Xu Xuzhong 
Published: August 2020

ObjectiveTo explore whether an ultrasound-guided pudendal nerve block (PNB) could decrease anaesthetic use, thereby shortening the length of the second stage of labour in women undergoing epidural analgesia.DesignProspective, single-centre, randomised, double-blind, controlled trial.SettingAn obstetric centre in a general hospital in China.Participants72 nulliparous women were randomised, and 71 women completed the study.InterventionAn ultrasound-guided bilateral PNB was administered to all study participants; the PNB group were given 0.25% ropivacaine 10 mL, while the control group were given 10 mL saline.Main outcome measureThe primary outcome measure was the duration of the second stage of labour. Secondary outcomes included additional bolus administration, total hourly bupivacaine consumption, difference in thickness between the contracted and relaxed rectus abdominis muscle before (DRAM1) and 30 min after (DRAM2) PNB, urge to defecate, maternal cooperation, preservation of the lower limb motor function, tightness of the perineum, and Numeric Rating Scale (NRS) score for pain.ResultsThe duration of the second stage of labour was shorter in the PNB group than in the control group (difference of 33.8 min (95% CI 15.6 to 52.0), p<0.001). Additional bolus administration and total hourly bupivacaine consumption were lower in the PNB group than in the control group (p<0.001). DRAM2 was greater (p<0.001), rate of parturient women with the urge to defecate was higher (p=0.014), maternal cooperation was superior (p=0.002), and lower limb motor function preservation was greater (p=0.004) in the PNB group relative to the control group. Tightness of the perineum was eliminated from the results due to the inconsistent application of the criteria by the nursing staff. There was no significant difference in NRS scores between the groups.ConclusionsNulliparous women with epidural analgesia who received an ultrasound-guided bilateral PNB may reduce their need for bupivacaine and consequently shorten the length of the second stage of labour, therein indicating that a bilateral PNB may serve as an additional effective adjunct method of labour analgesia.Trial registration numberChiCTR-IOR-16009121.
Prevalence of and rationale for antimicrobial prescription during ambulatory care visits in Japan: a prospective, multicentre, cross-sectional study
Authors: Komagamine Junpei , Kobayashi Masaki , Mori Takahiro 
Published: August 2020

ObjectiveTo determine the rate of outpatient antimicrobial use and the rationale for antimicrobial prescription.DesignA prospective, multicentre, cross-sectional study.SettingAmbulatory care settings at community general hospitals.ParticipantsA total of 1972 consecutive ambulatory visits by 1952 patients were included from 2 February 2020 to 13 February 2020. Visits resulting in hospital admission and regularly scheduled visits were excluded.Main outcome measuresThe primary outcome was the proportion of ambulatory visits resulting in antimicrobial drug prescriptions. The secondary outcomes were the reasons for antimicrobial drug prescription and the proportion of unnecessary antimicrobial prescriptions among all antimicrobial drugs used for treatment.ResultsThe mean patient age was 53.8 (SD 25.8) years old, and the proportion of women was 52.6%. A total of 162 antimicrobial drugs were prescribed in 153 (7.8%) visits. The most common antimicrobial drugs were penicillins (n=48, 29.6%), followed by third-generation cephalosporins (n=35, 21.6%) and quinolones (n=20, 12.4%). Among all the antimicrobial drugs prescribed, 125 (77.2%), 18 (11.1%) and 11 (6.8%) were used for infection treatment, wound prophylaxis and surgical prophylaxis, respectively. Of the 125 antimicrobial drugs used for infection treatment, 60 (48.0%) were judged to be unnecessary.ConclusionsOne in every 13 ambulatory visits resulted in antimicrobial use in Japan. Three-fourths of the prescribed antimicrobial drugs were used for infection treatment, but approximately half of those drugs may have been unnecessary. Further efforts to reduce unnecessary antimicrobial drug use are needed.Trial registration numberUMIN000039360.
Psychometric properties of the Urdu version of the Hospital Anxiety and Depression Scale (HADS) among pregnant women in Abbottabad, Pakistan
Authors: Lodhi Fahad Saqib , Elsous Aymen M , Irum Saadia , Khan Adeel Ahmed , Rabbani Unaib 
Published: August 2020

BackgroundThe Hospital Anxiety and Depression Scale (HADS) is a widely used instrument to measure anxiety and depression symptoms.AimsThis study aimed to translate, validate and test the applicability of the Urdu version of the Hospital Anxiety and Depression Scale (HADS/UV) among pregnant women.MethodsThe original English version of the HADS was translated into Urdu by three bilingual experts and retranslated to English using the forward–backward approach. The questionnaire was administered to a sample of 200 pregnant women availing obstetrics and gynaecology services for routine prenatal check-ups of Ayub Teaching Hospital, Abbottabad, Pakistan. Psychometric properties of the instrument, including reliability (internal consistency, test–retest analysis and interitems correlation), were tested. Face and content validity were also assessed. Content Validity Index (CVI) was determined using the average approach and Item-Level Content Validity Index (I-CVI) and Scale-Level Content Validity Index (S-CVI) were calculated accordingly. Construct validity was examined through exploratory factor analysis.ResultsCronbach’s alpha coefficient has been found to be 0.82 for the anxiety subscale and 0.64 for the depression subscale, while overall alpha of the HADS/UV is 0.84. The Urdu version is content valid, and the S-CVI of anxiety subscale, depression subscale and HADS/UV are 0.947, 948 and 0.947, respectively. Test–retest reliability is 0.884 and 0.934 as measured by Pearson correlation and intraclass correlation, respectively. HADS/UV items correlated positively with the whole scale (p<0.001). Factor analysis with varimax rotation revealed that two factors explained 42.75% of the variance. Items’ distribution was quite similar to the original HADS.ConclusionThe HADS/UV is a psychometrically sound instrument with satisfactory measurement, including good internal consistency. The instrument shows promise to be a sound tool to assess anxiety and depression in pregnancy.
Impact of significant paravalvular leaks after transcatheter aortic valve implantation on anaemia and mortality
Authors: Lopez-Pais Javier , Lopez-Otero Diego , Garcia-Touchard Arturo , Izquierdo Coronel Barbara , Antúnez Muiños Pablo José , Cia Mendioroz Xabier , Pérez-Poza Marta , Otero Garcia Óscar , Martinez Peredo Carlos Gustavo , Arellano Flores Carlos , Álvarez-Rodríguez Leyre , Gomez Peña Fernando , Juskova Mária , Sanmartín Pena Juan Carlos , Estevez-Loureiro Rodrigo , Cid Álvarez Ana Belén , Trillo Nouche Ramiro , Alonso-Martín Joaquín Jesús , González-Juanatey Jose Ramón , Oteo Juan Francisco 
Published: August 2020

ObjectiveThe aim of this work is to assess the relationship between significant paravalvular leak (SPL) after transcatheter aortic valve implantation (TAVI) on anaemia and their impact on prognosis.MethodsObservational analytic study developed at two university hospitals, including all consecutive patients who underwent TAVI during a 10-year period (2009 to 2018). A logistic regression model was created to determine independent predictors of anaemia at 3 months. Time to event outcomes were analysed with Cox regression. Median follow-up was 21.3±21.9 months.Results788 patients were included. 5.3% had SPL. SPL was an independent predictor of anaemia 3 months after TAVI (OR: 8.31, 95% CI: 2.06 to 33.50). SPL and anaemia at 3 months were independently associated with long-term mortality (HR: 1.82, 95% CI: 1.16 to 2.85; HR: 2.07, 95% CI: 1.39 to 3.08).ConclusionSPL is an independent predictor of anaemia at 3 months after TAVI, a condition that doubles long-term mortality. Our findings could explain in part the worse prognosis of SPL after TAVI. Further pathophysiological studies are necessary to explain this association.
Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors
Authors: Naing Aung , Eder Joseph P , Piha-Paul Sarina A , Gimmi Claude , Hussey Elizabeth , Zhang Sen , Hildebrand Vera , Hosagrahara Vinayak , Habermehl Christina , Moisan Jacques , Papadopoulos Kyriakos P 
Published: August 2020

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.MethodsIn preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsIn mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).ConclusionsThere were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration numberNCT03306420.
Assessing performance of pathogenicity predictors using clinically relevant variant datasets
Authors: Gunning Adam C , Fryer Verity , Fasham James , Crosby Andrew H , Ellard Sian , Baple Emma L , Wright Caroline F 
Published: August 2020

BackgroundPathogenicity predictors are integral to genomic variant interpretation but, despite their widespread usage, an independent validation of performance using a clinically relevant dataset has not been undertaken.MethodsWe derive two validation datasets: an ‘open’ dataset containing variants extracted from publicly available databases, similar to those commonly applied in previous benchmarking exercises, and a ‘clinically representative’ dataset containing variants identified through research/diagnostic exome and panel sequencing. Using these datasets, we evaluate the performance of three recent meta-predictors, REVEL, GAVIN and ClinPred, and compare their performance against two commonly used in silico tools, SIFT and PolyPhen-2.ResultsAlthough the newer meta-predictors outperform the older tools, the performance of all pathogenicity predictors is substantially lower in the clinically representative dataset. Using our clinically relevant dataset, REVEL performed best with an area under the receiver operating characteristic curve of 0.82. Using a concordance-based approach based on a consensus of multiple tools reduces the performance due to both discordance between tools and false concordance where tools make common misclassification. Analysis of tool feature usage may give an insight into the tool performance and misclassification.ConclusionOur results support the adoption of meta-predictors over traditional in silico tools, but do not support a consensus-based approach as in current practice.