bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in
Pseudomonas aeruginosa
Authors: Jorth Peter , McLean Kathryn , Ratjen Anina , Secor Patrick R. , Bautista Gilbert E. , Ravishankar Sumedha , Rezayat Amir , Garudathri Jayanthi , Harrison Joe J. , Harwood Rachel A. , Penewit Kelsi , Waalkes Adam , Singh Pradeep K. , Salipante Stephen J. 
Published: November 2017

ABSTRACT

While much attention has been focused on acquired antibiotic resistance genes, chromosomal mutations may be most important in chronic infections where isolated, persistently infecting lineages experience repeated antibiotic exposure. Here, we used experimental evolution and whole-genome sequencing to investigate chromosomally encoded mutations causing aztreonam resistance in
Pseudomonas aeruginosa
and characterized the secondary consequences of resistance development. We identified 19 recurrently mutated genes associated with aztreonam resistance. The most frequently observed mutations affected negative transcriptional regulators of the
mexAB-oprM
efflux system and the target of aztreonam,
ftsI
. While individual mutations conferred modest resistance gains, high-level resistance (1,024 µg/ml) was achieved through the accumulation of multiple variants. Despite being largely stable when strains were passaged in the absence of antibiotics, aztreonam resistance was associated with decreased
in vitro
growth rates, indicating an associated fitness cost. In some instances, evolved aztreonam-resistant strains exhibited increased resistance to structurally unrelated antipseudomonal antibiotics. Surprisingly, strains carrying evolved mutations which affected negative regulators of
mexAB-oprM
(
mexR
and
nalD
) demonstrated enhanced virulence in a murine pneumonia infection model. Mutations in these genes, and other genes that we associated with aztreonam resistance, were common in
P. aeruginosa
isolates from chronically infected patients with cystic fibrosis. These findings illuminate mechanisms of
P. aeruginosa
aztreonam resistance and raise the possibility that antibiotic treatment could inadvertently select for hypervirulence phenotypes.

IMPORTANCE
Inhaled aztreonam is a relatively new antibiotic which is being increasingly used to treat cystic fibrosis patients with
Pseudomonas aeruginosa
airway infections. As for all antimicrobial agents, bacteria can evolve resistance that decreases the effectiveness of the drug; however, the mechanisms and consequences of aztreonam resistance are incompletely understood. Here, using experimental evolution, we have cataloged spontaneous mutations conferring aztreonam resistance and have explored their effects. We found that a diverse collection of genes contributes to aztreonam resistance, each with a small but cumulative effect. Surprisingly, we found that selection for aztreonam resistance mutations could confer increased resistance to other antibiotics and promote hypervirulence in a mouse infection model. Our study reveals inherent mechanisms of aztreonam resistance and indicates that aztreonam exposure can have unintended secondary effects.
Is governance, gross domestic product, inequality, population size or country surface area associated with coverage and equity of health interventions? Ecological analyses of cross-sectional surveys from 80 countries
Authors: Wehrmeister Fernando C , da Silva Inácio Crochemore M , Barros Aluisio J D , Victora Cesar G 
Published: November 2017

ObjectiveTo assess associations between national characteristics, including governance indicators, with a proxy for universal health coverage in reproductive, maternal, newborn and child health (RMNCH).DesignEcological analysis based on data from national standardised cross-sectional surveys.SettingLow-income and middle-income countries with a Demographic and Health Survey or a Multiple Indicator Cluster Survey since 2005.Participants1 246 710 mothers and 2 129 212 children from 80 national surveys.Exposures of interestGross domestic product (GDP), country surface area, population, Gini index and six governance indicators (control of corruption, political stability and absence of violence, government effectiveness, regulatory quality, rule of law, and voice and accountability).Main outcomesLevels and inequality in the composite coverage index (CCI), a weighted average of eight RMNCH interventions. Relative and absolute inequalities were measured through the concentration index (CIX) and slope index of inequality (SII) for CCI, respectively.ResultsThe average values of CCI (70.5% (SD=13.3)), CIX (5.3 (SD=5.1)) and mean slope index (19.8 (SD=14.7)) were calculated. In the unadjusted analysis, all governance variables and GDP were positively associated with the CCI and negatively with inequalities. Country surface showed inverse associations with both inequality indices. After adjustment, among the governance indicators, only political stability and absence of violence was directly related to CCI (β=6.3; 95% CI 3.6 to 9.1; p<0.001) and inversely associated with relative (CIX; β=−1.4; 95% CI −2.4 to −0.4; p=0.007) and absolute (SII; β=−5.3; 95% CI –8.9 to −1.7; p=0.005) inequalities. The strongest associations with governance indicators were found in the poorest wealth quintile. Similar patterns were observed for GDP. Country surface area was inversely related to inequalities on CCI.ConclusionsLevels and equity in RMNCH interventions are positively associated with political stability and absence of violence, and with GDP, and inversely associated with country surface area.
Cohort profile: the China Ageing REespiratory infections Study (CARES), a prospective cohort study in older adults in Eastern China
Authors: Cowling Benjamin J , Xu Cuiling , Tang Fenyang , Zhang Jun , Shen Jinjin , Havers Fiona , Wendladt Rachael , Leung Nancy HL , Greene Carolyn , Iuliano A Danielle , Shifflett Pat , Song Ying , Zhang Ran , Kim Lindsay , Chen Yuyun , Chu Daniel KW , Zhu Huachen , Shu Yuelong , Yu Hongjie , Thompson Mark G 
Published: November 2017

PurposeThis study was established to provide direct evidence on the incidence of laboratory-confirmed influenza virus and respiratory syncytial virus (RSV) infections in older adults in two cities in Jiangsu Province, China, and the potential impact of acute respiratory infections on frailty.ParticipantsThe cohort was enrolled in Suzhou and Yancheng, two cities in Jiangsu Province in Eastern China. Between November 2015 and March 2016, we enrolled 1532 adults who were 60–89 years of age, and collected blood samples along with baseline data on demographics, general health, chronic diseases, functional status and cognitive function through face-to-face interviews using a standardised questionnaire. Participants are being followed weekly throughout the year to identify acute respiratory illnesses. We schedule home visits to ill participants to collect mid-turbinate nasal and oropharyngeal swabs for laboratory testing and detailed symptom information for the acute illness. Regular follow-up including face-to-face interviews and further blood draws will take place every 6–12 months.Findings to dateAs of 3 September 2016, we had identified 339 qualifying acute respiratory illness events and 1463 (95%) participants remained in the study. Laboratory testing is ongoing.Future plansWe plan to conduct laboratory testing to estimate the incidence of influenza virus and RSV infections in older adults. We plan to investigate the impact of these infections on frailty and functional status to determine the association of pre-existing immune status with protection against influenza and RSV infection in unvaccinated older adults, and to assess the exposure to avian influenza viruses in this population.
Factors influencing the decisions of senior UK doctors to retire or remain in medicine: national surveys of the UK-trained medical graduates of 1974 and 1977
Authors: Smith Fay , Lachish Shelly , Goldacre Michael J , Lambert Trevor W 
Published: October 2017

ObjectiveTo report attitudes to retirement of late-career doctors.DesignQuestionnaires sent in 2014 to all UK medical graduates of 1974 and 1977.SettingUnited Kingdom.Participants3695 medical graduates.Main outcome measuresFactors which influenced doctors’ decisions to retire and factors which encouraged doctors to remain in work.ResultsThe response rate was 85% (3695/4369). 55% of respondents overall were still working in medicine (whether they had not retired or had retired and returned; 61% of men, 43% of women). Of the retirees, 67% retired when they had originally planned to, and 28% had changed their retirement plans. Fifty per cent of retired doctors cited ‘increased time for leisure/other interests’ as a reason; 43% cited ‘pressure of work’. Women (21%) were more likely than men (11%) to retire for family reasons. Women (27%) were more likely than men (9%) to retire because of the retirement of their spouse. General practitioners (GPs) were more likely than doctors in other specialties to cite ‘pressure of work’. Anaesthetists and GPs were more likely than doctors in other specialties to cite the ‘possibility of deteriorating skill/competence’. Radiologists, surgeons, obstetricians and gynaecologists, and anaesthetists were most likely to cite ‘not wanting to do out-of-hours work’.Doctors who were still working were asked what would encourage them to stay in medicine for longer. Factors cited most frequently were ‘reduced impact of work-related bureaucracy’ (cited by 45%) and ‘workload reduction/shorter hours’ (42%). Men (30%) were more motivated than women (20%) by ‘financial incentivisation’. Surgeons were most motivated by ‘reduction of on-call or emergency commitments’.ConclusionsRetention policy should address ways of optimising the clinical contribution of senior doctors while offering reduced workloads in the areas of bureaucracy and working hours, particularly in respect of emergency commitments.
Contrast-induced acute kidney injury and mortality in ST elevation myocardial infarction treated with primary percutaneous coronary intervention
Authors: Silvain Johanne , Nguyen Lee S , Spagnoli Vincent , Kerneis Mathieu , Guedeney Paul , Vignolles Nicolas , Cosker Kristel , Barthelemy Olivier , Le Feuvre Claude , Helft Gérard , Collet Jean-Philippe , Montalescot Gilles 
Published: November 2017

ObjectivesContrast-induced acute kidney injury (CI-AKI) is a common and potentially severe complication in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). There is no consensus on the best definition of CI-AKI to identify patients at risk of haemodialysis or death. The objective of this study was to assess the association of CI-AKI, using four definitions, on inhospital mortality, mortality or haemodialysis requirement over 1-year follow-up, in patients with STEMI treated with pPCI.MethodsIn this prospective, observational study, all patients with STEMI referred for pPCI were included. We identified independent variables associated with CI-AKI and mortality.ResultsWe included 1114 consecutive patients with STEMI treated by pPCI. CI-AKI occurred in 18.3%, 12.2%, 15.6% and 10.5% of patients according to the CIN, Acute Kidney Injury Network (AKIN), Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) Modification of Diet in Renal Disease (MDRD) and RIFLE Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) definitions, respectively. The RIFLE (CKD-EPI) definition was the most discriminant definition to identify patients at higher risk of inhospital mortality (27.1% vs 4.0%; adjusted OR 2.7 (95% CI 1.4 to 5.1), p=0.003), 1-year mortality (27.4% vs 6.6%; adjusted OR 2.8 (95% CI 1.5 to 5.3), p=0.002) and haemodialysis requirement at 1-year follow-up (15.6% vs 2.7%; adjusted OR 6.7 (95% CI 3.3 to 13.6), p=0.001). Haemodynamic instability, cardiac arrest, preexisting renal failure, elderly age and a high contrast media volume were independently associated with 1-year mortality. Of interest, contrast-media volume was not correlated to increase of creatininaemia (r=0.06) or decrease in estimated glomerular filtration rate (r=0.05) after percutaneous coronary intervention in our population.ConclusionsCI-AKI is a frequent and serious complication of STEMI treated by pPCI. The RIFLE definition is the most accurate definition to identify patients with CI-AKI at high risk of mortality or haemodialysis.
Voxel based analysis of recurrence dynamics in intracranial aneurysms after coiling
Authors: Ernst Marielle , Buchholz Anika , Bourcier Romain , Desal Hubert , Le Floch Pierre-Yves , Möhlenbruch Markus , Bendszus Martin , Fiehler Jens 
Published: November 2017

BackgroundUnderstanding aneurysm growth is critical for the appropriate follow-up of patients after coil embolization and the need for retreatment. The purpose of the study was to stratify the growth dynamics of aneurysm recurrences after coiling by volumetric analysis and to determine predictive factors for aneurysm recurrences.MethodsSource images of follow-up three-dimensional time of flight MR angiography (ToF-MRA) scans were compared with the first post-interventional ToF-MRA scan and analyzed for residual flow after co-registration using ANALYZE-software. In the event of incomplete occlusion, the residual volume was segmented and calculated. Growth dynamic was determined for each aneurysm after embolization.ResultsWe analyzed 326 patients with 345 aneurysms from two centers. Each case had at least two ToF-MRA examinations after endovascular therapy. The mean observation interval was 59 months. Volumetric analysis of 1139 follow-up MRAs revealed that 218/345 aneurysms (63.2%) showed complete occlusion on initial follow-up imaging, and of these 95.0% remained stable. A steady increase in intra-aneurysmal flow was observed in 83/345 (24.1%). Less frequent observations were a steep increase (21/345; 6.1%) and a decrease (27/345; 7.8%). Independent predictors of increasing residual flow were greatest aneurysm diameter, total coil length, and incomplete occlusion.ConclusionsVolumetric analysis of registered three-dimensional ToF-MRA follow-up datasets allows the detection of different growth patterns with high precision, avoids the low inter-rater reliability, and represents a promising approach for future studies that include analysis of more complex predictors of residual flow. In cases of aneurysm recurrence after coiling, the major pattern seems to be a steady increase in intra-aneurysmal flow over several months.
Algebraic graphs with class (functional pearl)
Authors: Mokhov Andrey 
Published: November 2017

The paper presents a minimalistic and elegant approach to working with graphs in Haskell. It is built on a rigorous mathematical foundation --- an algebra of graphs --- that allows us to apply equational reasoning for proving the correctness of graph transformation algorithms. Algebraic graphs let us avoid partial functions typically caused by `malformed graphs' that contain an edge referring to a non-existent vertex. This helps to liberate APIs of existing graph libraries from partial functions.
The algebra of graphs can represent directed, undirected, reflexive and transitive graphs, as well as hypergraphs, by appropriately choosing the set of underlying axioms. The flexibility of the approach is demonstrated by developing a library for constructing and transforming polymorphic graphs.
Back to the future: time travel in FRP
Authors: Perez Ivan 
Published: November 2017

Functional Reactive Programming (FRP) allows interactive applications to be modelled in a declarative manner using time-varying values. For practical reasons, however, operational constraints are often imposed, such as having a fixed time domain, time always flowing forward, and limiting the exploration of the past.
In this paper we show how these constraints can be overcome, giving local control over the time domain, the direction of time and the sampling step. We study the behaviour of FRP expressions when time flows backwards, and demonstrate how to synchronize subsystems running asynchronously and at different sampling rates. We have verified the practicality of our approach with two non-trivial games in which time control is central to the gameplay.
Ornaments: exploiting parametricity for safer, more automated code refactorization and code reuse (invited talk)
Authors: Rémy Didier 
Published: November 2017

Inductive datatypes and parametric polymorphism are two key features introduced in the ML family of languages, which have already been widely exploited for structuring programs: Haskell and ML programs are often more elegant and more correct by construction. Still, we sometimes need code to be refactored or adapted to be reused in a slightly different context. While the type system is considerably helpful in these situations, by automatically locating type-inconsistent program points or incomplete pattern matchings, this process could be made safer and more automated by further exploiting parametricity. We propose a posteriori program abstraction as a principle for such code transformations.
We apply this principle to ornamentation which is a way to describe changes in datatype definitions reorganizing, adding, or dropping some pieces of data so that functions operating on the bare definition can be partially and sometimes totally lifted into functions operating on the ornamented structure.
We view ornamentation as an a posteriori abstraction of the bare code, called a generic lifting, which can then be instantiated into a concrete lifting, meta-reduced, and simplified. Both the source and target code live in core ML while the lifted code lives in a meta-language above ML equipped with a limited form of dependent types needed to capture some invariants of the generic lifting so that the concrete lifting can be simplified back into an ML program. Importantly, the lifted code can be closely related to the bare code, using logical relations thanks to the generic lifting detour.
Different, typical use cases of ornaments will be shown and the approach will be mainly illustrated on examples.
SlicerDMRI: Open Source Diffusion MRI Software for Brain Cancer Research
Authors: Norton Isaiah , Essayed Walid Ibn , Zhang Fan , Pujol Sonia , Yarmarkovich Alex , Golby Alexandra J. , Kindlmann Gordon , Wassermann Demian , Estepar Raul San Jose , Rathi Yogesh , Pieper Steve , Kikinis Ron , Johnson Hans J. , Westin Carl-Fredrik , O'Donnell Lauren J. 
Published: November 2017

Abstract
Diffusion MRI (dMRI) is the only noninvasive method for mapping white matter connections in the brain. We describe SlicerDMRI, a software suite that enables visualization and analysis of dMRI for neuroscientific studies and patient-specific anatomic assessment. SlicerDMRI has been successfully applied in multiple studies of the human brain in health and disease, and here, we especially focus on its cancer research applications. As an extension module of the 3D Slicer medical image computing platform, the SlicerDMRI suite enables dMRI analysis in a clinically relevant multimodal imaging workflow. Core SlicerDMRI functionality includes diffusion tensor estimation, white matter tractography with single and multi-fiber models, and dMRI quantification. SlicerDMRI supports clinical DICOM and research file formats, is open-source and cross-platform, and can be installed as an extension to 3D Slicer (www.slicer.org). More information, videos, tutorials, and sample data are available at dmri.slicer.org. Cancer Res; 77(21); e101–3. ©2017 AACR.
CRAVAT 4: Cancer-Related Analysis of Variants Toolkit
Authors: Masica David L. , Douville Christopher , Tokheim Collin , Bhattacharya Rohit , Kim RyangGuk , Moad Kyle , Ryan Michael C. , Karchin Rachel 
Published: November 2017

Abstract
Cancer sequencing studies are increasingly comprehensive and well powered, returning long lists of somatic mutations that can be difficult to sort and interpret. Diligent analysis and quality control can require multiple computational tools of distinct utility and producing disparate output, creating additional challenges for the investigator. The Cancer-Related Analysis of Variants Toolkit (CRAVAT) is an evolving suite of informatics tools for mutation interpretation that includes mutation mapping and quality control, impact prediction and extensive annotation, gene- and mutation-level interpretation, including joint prioritization of all nonsilent mutation consequence types, and structural and mechanistic visualization. Results from CRAVAT submissions are explored in an interactive, user-friendly web environment with dynamic filtering and sorting designed to highlight the most informative mutations, even in the context of very large studies. CRAVAT can be run on a public web portal, in the cloud, or downloaded for local use, and is easily integrated with other methods for cancer omics analysis. Cancer Res; 77(21); e35–38. ©2017 AACR.
Chemopreventive and Antitumor Efficacy of Curcumin in a Spontaneously Developing Hen Ovarian Cancer Model
Authors: Sahin Kazim , Orhan Cemal , Tuzcu Mehmet , Sahin Nurhan , Tastan Hakkı , Özercan İbrahim Hanifi , Güler Osman , Kahraman Nermin , Kucuk Omer , Ozpolat Bulent 
Published: November 2017

AbstractWe investigated the effect of daily dietary curcumin intake on the development and progression of spontaneous ovarian cancer in a galline (hen) model, as the chicken is the only nonhuman animal in which ovarian cancer spontaneously develops with a high prevalence. At the end of 12 months, ovarian cancer had spontaneously developed in 39% (35/90) of control hens not fed curcumin (n = 90). In comparison, it spontaneously developed in 27% (24/90) and 17% (15/90) of hens given curcumin at 25.8 (n = 90) and 53.0 mg/day (n = 90), respectively (P = 0.004). This represented significant dose-dependent reductions in overall ovarian cancer incidence in the 25.8 and 53.0 mg/day curcumin-fed groups (31% and 57%, respectively). Daily curcumin intake also reduced ovarian tumor sizes (P = 0.04) and number of tumors (P = 0.006). Evaluation of the molecular mechanisms underlying the chemopreventive and antitumor effects of curcumin revealed that NF-κB and STAT3 signaling pathways were significantly inhibited but that the nuclear factor erythroid 2/heme oxygenase 1 antioxidant pathway was induced by curcumin intake in a dose-dependent manner in ovarian tissues (P &lt; 0.05). Sequencing of the Ras family genes (KRAS, NRAS, and HRAS) revealed less frequent KRAS and HRAS mutations in ovarian tumors in the curcumin-fed animals. In conclusion, our results demonstrated for the first time that daily curcumin intake leads to a significant and dose-dependent reduction in spontaneous ovarian cancer incidence and tumor growth, indicating a tremendous role for curcumin as a chemopreventive strategy for ovarian cancer. Cancer Prev Res; 11(1); 59–67. ©2017 AACR.