bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Colibactin Genotoxin Generates DNA Interstrand Cross-Links in Infected Cells
Authors: Bossuet-Greif Nadège , Vignard Julien , Taieb Frédéric , Mirey Gladys , Dubois Damien , Petit Claude , Oswald Eric , Nougayrède Jean-Philippe 
Published: March 2018

ABSTRACT

Colibactins are hybrid polyketide-nonribosomal peptides produced by
Escherichia coli
,
Klebsiella pneumoniae
, and other
Enterobacteriaceae
harboring the
pks
genomic island. These genotoxic metabolites are produced by
pks
-encoded peptide-polyketide synthases as inactive prodrugs called precolibactins, which are then converted to colibactins by deacylation for DNA-damaging effects. Colibactins are bona fide virulence factors and are suspected of promoting colorectal carcinogenesis when produced by intestinal
E. coli
. Natural active colibactins have not been isolated, and how they induce DNA damage in the eukaryotic host cell is poorly characterized. Here, we show that DNA strands are cross-linked covalently when exposed to enterobacteria producing colibactins. DNA cross-linking is abrogated in a
clbP
mutant unable to deacetylate precolibactins or by adding the colibactin self-resistance protein ClbS, confirming the involvement of the mature forms of colibactins. A similar DNA-damaging mechanism is observed
in cellulo
, where interstrand cross-links are detected in the genomic DNA of cultured human cells exposed to colibactin-producing bacteria. The intoxicated cells exhibit replication stress, activation of ataxia-telangiectasia and Rad3-related kinase (ATR), and recruitment of the DNA cross-link repair Fanconi anemia protein D2 (FANCD2) protein. In contrast, inhibition of ATR or knockdown of FANCD2 reduces the survival of cells exposed to colibactin-producing bacteria. These findings demonstrate that DNA interstrand cross-linking is the critical mechanism of colibactin-induced DNA damage in infected cells.

IMPORTANCE
Colorectal cancer is the third-most-common cause of cancer death. In addition to known risk factors such as high-fat diets and alcohol consumption, genotoxic intestinal
Escherichia coli
bacteria producing colibactin are proposed to play a role in colon cancer development. Here, by using transient infections with genotoxic
E. coli
, we showed that colibactins directly generate DNA cross-links
in cellulo
. Such lesions are converted into double-strand breaks during the repair response. DNA cross-links, akin to those induced by metabolites of alcohol and high-fat diets and by widely used anticancer drugs, are both severely mutagenic and profoundly cytotoxic lesions. This finding of a direct induction of DNA cross-links by a bacterium should facilitate delineating the role of
E. coli
in colon cancer and engineering new anticancer agents.
Targeting skeletal muscle tissue oxygenation (StO2) in adults with severe sepsis and septic shock: a randomised controlled trial (OTO-StS Study)
Authors: Nardi Olivier , Zavala Elizabeth , Martin Claude , Nanas Serafim , Scheeren Thomas , Polito Andrea , Borrat Xavi , Annane Djillali 
Published: March 2018

ObjectiveEvaluation of the ratio of oxyhaemoglobin to total haemoglobin in skeletal muscle (StO2) using near-infrared spectroscopy may aid in the monitoring of patients with sepsis. This study assessed the benefits and risks of targeting StO2in adults with severe sepsis or septic shock.DesignA European randomised controlled trial was performed on two parallel groups.SettingFive intensive care units (ICU) in France, Greece, Spain and Germany were used for the study.ParticipantsA total of 103 adults with severe sepsis or septic shock on ICU admission were randomised (54 subjects in the experimental arm and 49 subjects in the control arm).InterventionsHaemodynamic management using an algorithm that was adapted from the 2004 Surviving Sepsis Campaign guidelines with (experimental arm) or without (control arm) targeting an StO2value greater than 80% at a minimum of two different sites.OutcomesThe primary outcome was a composite: 7-day all-cause mortality or worsening of organ function, defined as a positive difference in Sepsis-related Organ Failure Assessment (SOFA) score between day 7 and randomisation (ie, delta SOFA >0). Secondary endpoints: 30-day mortality, duration of mechanical ventilation and vasopressor therapy up to 30 days from randomisation.ResultsThe study ended prematurely due to lack of funding after enrolment of 103/190 patients. Eighteen patients (33.3%) in the experimental arm and 14 (28.6%, P=0.67) in the control arm died or exhibited delta SOFA >0 on day 7. The mean number of days on mechanical ventilation was 12.2±10.6 in the experimental group and 7.6±7.9 in the control group (P=0.03). Thirty-one (57%) patients in the experimental arm and 14 (29%) patients in the control arm received red cells by day 7 (P=0.01).ConclusionDespite the limitation related to premature termination, this study provides no data to support the routine implementation of resuscitation protocols incorporating StO2>80% at two or more muscle sites as a target. StO2-guided therapy may be associated with prolonged use of mechanical ventilation and an increased number of red blood cell transfusions.Trial registration numberNCT00167596; Results.
Association of prehypertension and hyperhomocysteinemia with subclinical atherosclerosis in asymptomatic Chinese: a cross-sectional study
Authors: Liu Bo , Chen Zhihao , Dong Xiaoqi , Qin Guangming 
Published: March 2018

ObjectivesComorbid hypertension and hyperhomocysteinemia is an important risk factor for carotid atherosclerotic plaque formation. We put forward the hypothesis that the subjects with comorbid prehypertension and hyperhomocysteinemia also had an increased risk of subclinical atherosclerosis, using carotid intima–media thickness (CIMT) as the marker of the atherosclerotic process.MethodsA total of 4102 asymptomatic Chinese subjects aged 18–60 years were divided into four groups according to blood pressure (BP) and homocysteine (HCY) level: the control group without prehypertension or hyperhomocysteinemia, isolated prehypertension group, simple hyperhomocysteinemia group and prehypertension with hyperhomocysteinemia group. Serum lipids, fasting blood glucose (FBG), HCY and CIMT were measured.ResultsThere was significant difference in the positive rates of increased CIMT among four groups. Compared with the controls, the subjects in the other three groups had a higher risk of increased CIMT (isolated prehypertension group, OR 2.049, 95% CI 1.525 to 2.754; simple hyperhomocysteinemia group, OR 2.145, 95% CI 1.472 to 3.125; prehypertension and hyperhomocysteinemia group, OR 3.199, 95% CI 2.362 to 4.332). However, by multiple logistic regression analysis, only comorbid prehypertension and hyperhomocysteinemia was independently associated with increased CIMT (OR 1.485, 95% CI 1.047 to 2.108, P<0.05).ConclusionsComorbid prehypertension and hyperhomocysteinemia was an independent risk factor of subclinical atherosclerosis in asymptomatic Chinese, but isolated prehypertension or hyperhomocysteinemia was not. Therefore, combined intervention for prehypertension and hyperhomocysteinemia may contribute to decrease the incident of cardiovascular disease.
Effect of age and cone dimensions on cervical regeneration: an Italian multicentric prospective observational study
Authors: Ciavattini Andrea , Delli Carpini Giovanni , Moriconi Lorenzo , Clemente Nicolò , Montik Nina , De Vincenzo Rosa , Del Fabro Anna , Buttignol Monica , Ricci Caterina , Moro Francesca , Sopracordevole Francesco 
Published: March 2018

ObjectivesTo evaluate cervical regeneration at 6 months following excisional treatment for high-grade cervical intraepithelial neoplasia (CIN), and to investigate the effect of cone dimensions, age of patients and technique of excision on the efficacy of the regeneration process.DesignProspective observational multicentric study.SettingThree tertiary care and research centres.ParticipantsAmong the 197 eligible women of childbearing age, older than 25 years of age, undergoing for the first time a loop electrosurgical excision procedure or carbon dioxide laser cervical excision for a high-grade CIN at the colposcopy-directed cervical punch biopsy, and with a final diagnosis of high-grade CIN, 165 completed the 6-month follow-up and were included in the analysis.Primary outcome measuresThe cervical length and volume regeneration (%) after 6 months from procedure were determined by three-dimensional ultrasound, and the correlation of regeneration with cone dimensions, age and excision technique was evaluated.ResultsThe mean±SD cervical length regeneration at 6 months was 89.5%±6.3% and the mean±SD cervical volume regeneration was 86.3%±13.2%. At the multivariate analysis, a significant and independent inverse correlation between excised cone length and cervical regeneration emerged (r=−0.39, P<0.001). A significantly negative trend in length regeneration at 6 months from procedure with an increasing class of cone length was found (P<0.001). No significant association was found in relation with patient age at the time of procedure or with the technique of excision.ConclusionsCervical length regeneration at 6 months from excisional treatments is negatively affected by an increasing cone length but not from the age of the patient or the technique of excision. While still achieving equal clinical efficacy, it is crucial to contain cone dimensions, in order to favour a greater length regeneration, reducing the cervical harm and the potential future obstetric complications.
Improving driving advice provided to cardiology patients on discharge
Authors: Vusirikala Amoolya , Backhouse Mark , Schimansky Sarah 
Published: March 2018

Certain cardiac conditions can limit patients’ ability to drive. It remains the doctors' responsibility to advise patients of any driving restrictions and is particularly important after certain diagnoses or procedures. We identified that the quality of documented advice was variable and frequently no written driving advice was recorded on discharge. It was apparent that there was a lack of awareness and knowledge of the current Driving and Vehicle Licensing Agency (DVLA) guidance among junior doctors.We therefore designed a quality improvement project using Plan–Do–Study–Act (PDSA) methodology to improve the provision of driving advice on discharge from a cardiology ward by focusing on staff education. After collecting baseline data, we created a template with cardiology-specific DVLA advice. During the second PDSA cycle, we improved the electronic template and also introduced a hard copy on the ward. During the third PDSA cycle, we incorporated information on DVLA guidance in the specialty induction session. We also evaluated junior doctors’ confidence of providing driving advice before and after this intervention.Baseline measurements showed that 10% (9/92) of all discharge summaries included driving advice. This improved to 49% (34/69) after the third PDSA cycle. Importantly, after receiving information on driving advice in the induction, junior doctors felt more confident in providing driving advice to cardiology patients on discharge. In conclusion, the provision of driving advice on discharge is an important element of patient safety. However, clinicians’ knowledge and awareness of current DVLA guidance is often limited. We demonstrated a significant increase in the provision of driving advice by introducing a standardised template.
Can first-year medical students acquire quality improvement knowledge prior to substantial clinical exposure? A mixed-methods evaluation of a pre-clerkship curriculum that uses education as the context for learning
Authors: Brown Allison , Nidumolu Aditya , Stanhope Alexandra , Koh Justin , Greenway Matthew , Grierson Lawrence 
Published: March 2018

BackgroundQuality Improvement (QI) training for health professionals is essential to strengthen health systems. However, QI training during medical school is constrained by students’ lack of contextual understanding of the health system and an already saturated medical curriculum. The Program for Improvement in Medical Education (PRIME), an extracurricular offered at the Michael G. DeGroote School of Medicineat McMaster University (Hamilton, Canada), addresses these obstacles by having first-year medical students engage in QI by identifying opportunities for improvement within their own education.MethodsA sequential explanatory mixed-methods approach, which combines insights derived from quantitative instruments and qualitative interview methods, was used to examine the impact of PRIME on first-year medical students and the use of QI in the context of education.ResultsThe study reveals that participation in PRIME increases both knowledge of, and comfort with, fundamental QI concepts, even when applied to clinical scenarios. Participants felt that education provided a meaningful context to learn QI at this stage of their training, and were motivated to participate in future QI projects to drive real-world improvements in the health system.ConclusionsEarly exposure to QI principles that uses medical education as the context may be an effective intervention to foster QI competencies at an early stage and ultimately promote engagement in clinical QI. Moreover, PRIME also provides a mechanism to drive improvements in medical education. Future research is warranted to better understand the impact of education as a context for later engagement in clinical QI applications as well as the potential for QI methods to be translated directly into education.
AAC Glenview sainfoin (Onobrychis viciifoila subsp. viciifolia)
Authors: Acharya S.N. 
Published: March 2018

AAC Glenview sainfoin, tested as LRC 4342, was developed by the Agriculture and Agri-Food Canada (AAFC) Lethbridge Research and Development Centre, Lethbridge, Alberta. This cultivar was derived from parental clones selected for improved forage yield in mixed stands with alfalfa under grazing and regrowth after grazing. When grown under irrigated and rainfed conditions in western Canada, Glenview out yielded Nova (check) by 21% in pure stands over 37 location–years and 19% in mixed stands with alfalfa over 17 location–years. This cultivar flowers and matures about 8 d earlier than Nova and has slightly larger seed than Nova (24.7 g 1000 seeds−1 vs 20 g 1000 seeds−1). It can be grown for hay and pasture in pure stands but Glenview is well suited for mixed sainfoin–alfalfa stands. Breeder seed for the cultivar will be produced by AAFC and the multiplication and distribution rights were awarded to Monarch Feeders Ltd., Monarch, AB, Canada.
Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
Authors: Welti Jonathan , Sharp Adam , Yuan Wei , Dolling David , Nava Rodrigues Daniel , Figueiredo Ines , Gil Veronica , Neeb Antje , Clarke Matthew , Seed George , Crespo Mateus , Sumanasuriya Semini , Ning Jian , Knight Eleanor , Francis Jeffrey C. , Hughes Ashley , Halsey Wendy S. , Paschalis Alec , Mani Ram S. , Raj Ganesh V. , Plymate Stephen R. , Carreira Suzanne , Boysen Gunther , Chinnaiyan Arul M. , Swain Amanda , de Bono Johann S. 
Published: March 2018

Abstract
Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.
Experimental Design: We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models.
Results: Nuclear BRD4 protein expression increases significantly (P ≤ 0.01) with castration resistance in same patient treatment-naïve (median H-score; interquartile range: 100; 100–170) and CRPC (150; 110–200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50–7.01; P ≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all P ≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (P ≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.
Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149–62. ©2018 AACR.
Longitudinal Assessment of the Doppler-Estimated Maximum Gradient in Patients With Congenital Valvar Aortic Stenosis Pre- and Post-Balloon Valvuloplasty
Authors: Kuebler Joseph D. , Shivapour Jill , Yaroglu Kazanci Selcen , Gauvreau Kimberlee , Colan Steven D. , McElhinney Doff B. , Brown David W. 
Published: March 2018

Background—
Aortic stenosis has been reported to manifest a slow rate of progression in mild disease, with a greater likelihood of progression in patients with moderate-severe disease. The natural history of the Doppler-estimated maximum gradient (DEMG) in patients after balloon aortic valvuloplasty (BAVP) has not previously been studied on a large scale.

Methods and Results—

A retrospective review was performed of 360 patients from 1984 to 2012 with aortic stenosis, providing a total of 2059 echocardiograms both before and after BAVP. Patients were excluded if they had an intervention within the first 30 days of life. The relationships between the aortic stenosis DEMG and several predictors (age at initial study, body surface area, valve morphology, and initial DEMG) were explored using linear mixed effect models. Patients with a unicommissural aortic valve had a significantly higher rate of progression compared with those with a bicommissural aortic valve (0.81 and 0.45 mm Hg/year;
P
<0.001). The median rate of progression in the post-BAVP group was significantly lower than the median pre-BAVP rate of progression (n=34; pre-BAVP 3.97 [1.69–8.7] mm Hg/year; post-BAVP 0.40 [−1.80 to 3.88] mm Hg/year;
P
<0.008). When adjusted for body surface area, there was no significant increase in the DEMG (−0.03 mm Hg/m
2
per year;
P
<0.001).

Conclusions—
There is a statistically significant increase in the DEMG over time in patients with aortic stenosis. After balloon dilation, the DEMG rate of change is reduced compared with that pre-dilation. Given the effect of body surface area on DEMG progression, more frequent observation should be made during periods of rapid somatic growth.
Comparison of Cardiac Computed Tomography With Transesophageal Echocardiography for Identifying Vegetation and Intracardiac Complications in Patients With Infective Endocarditis in the Era of 3-Dimensional Images
Authors: Kim In-Cheol , Chang Suyon , Hong Geu-Ru , Lee Seung Hyun , Lee Sak , Ha Jong-Won , Chang Byung-Chul , Kim Young Jin , Shim Chi Young 
Published: March 2018

Background—
Recent evolution of cardiac computed tomography (CT) provides useful information about valvular and perivalvular structures. We compared the diagnostic performance of CT and transesophageal echocardiography (TEE) with applications of 3-dimensional reconstruction in detecting vegetation and intracardiac complications in patients with infective endocarditis (IE).

Methods and Results—

Seventy-five patients (53 men; age, 58±15 years) with definite IE who underwent TEE and CT with 3-dimensional reconstruction within 3 days were analyzed. The diagnostic performances of the 2 modalities for vegetation and IE-related intracardiac complications (valve perforation, valve aneurysm, perivalvular abscess, pseudoaneurysm, fistula, and prosthetic valve dehiscence) were compared. The detection rate of vegetation in TEE and CT was 97.3% and 72.0%, respectively. The maximum sizes of vegetation identified by TEE and CT were well correlated (
r
=0.593;
P
<0.001), especially in patients with large vegetation (≥10 mm), suggestive of a high risk of systemic embolism (
r
=0.608;
P
<0.001). However, small vegetation (<10 mm) was underdiagnosed by CT (52.8%) compared with TEE (94.4%), and the sizes of the 2 modalities were poorly correlated (
r
=0.187;
P
=0.445). Both modalities showed fair diagnostic performance for detecting IE-related intracardiac complications with excellent agreement. TEE was more useful for diagnosing valve perforation and intracardiac fistula, whereas CT was better for diagnosing perivalvular abscess.

Conclusions—
Cardiac CT shows a comparable diagnostic performance with TEE for large vegetation and several IE-related complications. TEE is better for detecting small vegetation, valve perforation, and intracardiac fistula, whereas CT is more useful for detecting perivalvular abscess and coronary artery disease.
Evaluation of Coronary Artery Stenosis by Quantitative Flow Ratio During Invasive Coronary Angiography
Authors: Westra Jelmer , Tu Shengxian , Winther Simon , Nissen Louise , Vestergaard Mai-Britt , Andersen Birgitte Krogsgaard , Holck Emil Nielsen , Fox Maule Camilla , Johansen Jane Kirk , Andreasen Lene Nyhus , Simonsen Jo Krogsgaard , Zhang Yimin , Kristensen Steen Dalby , Maeng Michael , Kaltoft Anne , Terkelsen Christian Juhl , Krusell Lars Romer , Jakobsen Lars , Reiber Johan H.C. , Lassen Jens Flensted , Bøttcher Morten , Bøtker Hans Erik , Christiansen Evald Høj , Holm Niels Ramsing 
Published: March 2018

Background—
Quantitative flow ratio (QFR) is a novel diagnostic modality for functional testing of coronary artery stenosis without the use of pressure wires and induction of hyperemia. QFR is based on computation of standard invasive coronary angiographic imaging. The purpose of WIFI II (Wire-Free Functional Imaging II) was to evaluate the feasibility and diagnostic performance of QFR in unselected consecutive patients.

Methods and Results—
WIFI II was a predefined substudy to the Dan-NICAD study (Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease), referring 362 consecutive patients with suspected coronary artery disease on coronary computed tomographic angiography for diagnostic invasive coronary angiography. Fractional flow reserve (FFR) was measured in all segments with 30% to 90% diameter stenosis. Blinded observers calculated QFR (Medis Medical Imaging bv, The Netherlands) for comparison with FFR. FFR was measured in 292 lesions from 191 patients. Ten (5%) and 9 patients (5%) were excluded because of FFR and angiographic core laboratory criteria, respectively. QFR was successfully computed in 240 out of 255 lesions (94%) with a mean diameter stenosis of 50±12%. Mean difference between FFR and QFR was 0.01±0.08. QFR correctly classified 83% of the lesions using FFR with cutoff at 0.80 as reference standard. The area under the receiver operating characteristic curve was 0.86 (95% confidence interval, 0.81–0.91) with a sensitivity, specificity, negative predictive value, and positive predictive value of 77%, 86%, 75%, and 87%, respectively. A QFR–FFR hybrid approach based on the present results enables wire-free and adenosine-free procedures in 68% of cases.

Conclusions—
Functional lesion evaluation by QFR assessment showed good agreement and diagnostic accuracy compared with FFR. Studies comparing clinical outcome after QFR- and FFR-based diagnostic strategies are required.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02264717.