bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model
Authors: Monogue Marguerite L. , Tsuji Masakatsu , Yamano Yoshinori , Echols Roger , Nicolau David P. 
Published: August 2017

ABSTRACT

Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent
in vitro
activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored
in vivo
. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log
10
CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of
Enterobacteriaceae
,
Acinetobacter baumannii
, and
Pseudomonas aeruginosa
, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log
10
reduction was observed in only 2 of 28 (8
Enterobacteriaceae
, 19
A. baumannii
, and 1
P. aeruginosa
) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its
in vivo
efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.
Salmonella FraE, an Asparaginase Homolog, Contributes to Fructose-Asparagine but Not Asparagine Utilization
Authors: Sabag-Daigle Anice , Sengupta Anindita , Blunk Henry M. , Biswas Pradip K. , Cron Mary Claire , Bogard Alexander J. , Behrman Edward J. , Gopalan Venkat , Ahmer Brian M. M. 
Published: August 2017

ABSTRACT

Salmonella enterica
can utilize fructose-asparagine (F-Asn) as a source of carbon and nitrogen. This capability has been attributed to five genes in the
fra
locus. Previously, we determined that mutations in
fraB
(deglycase),
fraD
(kinase), or
fraA
(transporter) eliminated the ability of
Salmonella
to grow on F-Asn, while a mutation in
fraE
allowed partial growth. We hypothesized that FraE, a putative periplasmic fructose-asparaginase, converts F-Asn to NH
4
+
and fructose-aspartate (F-Asp). FraA could then transport F-Asp into the cytoplasm for subsequent catabolism. Here, we report that growth of the
fraE
mutant on F-Asn is caused by a partially redundant activity provided by AnsB, a periplasmic asparaginase. Indeed, a
fraE ansB
double mutant is unable to grow on F-Asn. Moreover, biochemical assays using periplasmic extracts of mutants that express only FraE or AnsB confirmed that each of these enzymes converts F-Asn to F-Asp and NH
4
+
. However, FraE does not contribute to growth on asparagine. We tested and confirmed the hypothesis that a
fraE ansB
mutant can grow on F-Asp, while mutants lacking
fraA
,
fraD
, or
fraB
cannot. This finding provides strong evidence that FraA transports F-Asp but not F-Asn from the periplasm to the cytoplasm. Previously, we determined that F-Asn is toxic to a
fraB
mutant due to the accumulation of the FraB substrate, 6-phosphofructose-aspartate (6-P-F-Asp). Here, we found that, as expected, a
fraB
mutant is also inhibited by F-Asp. Collectively, these findings contribute to a better understanding of F-Asn utilization by
Salmonella
.

IMPORTANCE
Salmonella
is able to utilize fructose-asparagine (F-Asn) as a nutrient. We recently reported that the disruption of a deglycase enzyme in the F-Asn utilization pathway inhibits the growth of
Salmonella
in mice and recognized this pathway as a novel and specific drug target. Here, we characterize the first step in the pathway wherein FraE hydrolyzes F-Asn to release NH
4
+
and F-Asp in the periplasm of the cell. A
fraE
mutant continues to grow slowly on F-Asn due to asparaginase activity encoded by
ansB
.
Ferric Uptake Regulator Fur Is Conditionally Essential in Pseudomonas aeruginosa
Authors: Pasqua Martina , Visaggio Daniela , Lo Sciuto Alessandra , Genah Shirley , Banin Ehud , Visca Paolo , Imperi Francesco 
Published: August 2017

ABSTRACT

In
Pseudomonas aeruginosa
, the ferric uptake regulator (Fur) protein controls both metabolism and virulence in response to iron availability. Differently from other bacteria, attempts to obtain
fur
deletion mutants of
P. aeruginosa
failed, leading to the assumption that Fur is an essential protein in this bacterium. By investigating a
P. aeruginosa
conditional
fur
mutant, we demonstrate that Fur is not essential for
P. aeruginosa
growth in liquid media, biofilm formation, and pathogenicity in an insect model of infection. Conversely, Fur is essential for growth on solid media since Fur-depleted cells are severely impaired in colony formation. Transposon-mediated random mutagenesis experiments identified pyochelin siderophore biosynthesis as a major cause of the colony growth defect of the conditional
fur
mutant, and deletion mutagenesis confirmed this evidence. Impaired colony growth of pyochelin-proficient Fur-depleted cells does not depend on oxidative stress, since Fur-depleted cells do not accumulate higher levels of reactive oxygen species (ROS) and are not rescued by antioxidant agents or overexpression of ROS-detoxifying enzymes. Ectopic expression of
pch
genes revealed that pyochelin production has no inhibitory effects on a
fur
deletion mutant of
Pseudomonas syringae
pv.
tabaci
, suggesting that the toxicity of the
pch
locus in Fur-depleted cells involves a
P. aeruginosa
-specific pathway(s).

IMPORTANCE
Members of the ferric uptake regulator (Fur) protein family are bacterial transcriptional repressors that control iron uptake and storage in response to iron availability, thereby playing a crucial role in the maintenance of iron homeostasis. While
fur
null mutants of many bacteria have been obtained, Fur appears to be essential in
Pseudomonas aeruginosa
for still unknown reasons. We obtained Fur-depleted
P. aeruginosa
cells by conditional mutagenesis and showed that Fur is dispensable for planktonic growth, while it is required for colony formation. This is because Fur protects
P. aeruginosa
colonies from toxicity exerted by the pyochelin siderophore. This work provides a functional basis to the essentiality of Fur in
P. aeruginosa
and highlights unique properties of the Fur regulon in this species.
Academic performance of children born preterm: a meta-analysis and meta-regression
Authors: Twilhaar E Sabrina , de Kieviet Jorrit F , Aarnoudse-Moens Cornelieke SH , van Elburg Ruurd M , Oosterlaan Jaap 
Published: August 2017

BackgroundAdvances in neonatal healthcare have resulted in decreased mortality after preterm birth but have not led to parallel decreases in morbidity. Academic performance provides insight in the outcomes and specific difficulties and needs of preterm children.ObjectiveTo study academic performance in preterm children born in the antenatal steroids and surfactant era and possible moderating effects of perinatal and demographic factors.DesignPubMed, Web of Science and PsycINFO were searched for peer-reviewed articles. Cohort studies with a full-term control group reporting standardised academic performance scores of preterm children (<37 weeks of gestation) at age 5 years or older and born in the antenatal steroids and surfactant era were included. Academic test scores and special educational needs of preterm and full-term children were analysed using random effects meta-analysis. Random effects meta-regressions were performed to explore the predictive role of perinatal and demographic factors for between-study variance in effect sizes.ResultsThe 17 eligible studies included 2390 preterm children and 1549 controls. Preterm children scored 0.71 SD below full-term peers on arithmetic (p<0.001), 0.44 and 0.52 SD lower on reading and spelling (p<0.001) and were 2.85 times more likely to receive special educational assistance (95% CI 2.12 to 3.84, p<0.001). Bronchopulmonarydysplasia explained 44% of the variance in academic performance (p=0.006).ConclusionPreterm children born in the antenatal steroids and surfactant era show considerable academic difficulties. Preterm children with bronchopulmonarydysplasia are at particular risk for poor academic outcome.
Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis
Authors: Fernández Javier , Acevedo Juan , Wiest Reiner , Gustot Thierry , Amoros Alex , Deulofeu Carme , Reverter Enric , Martínez Javier , Saliba Faouzi , Jalan Rajiv , Welzel Tania , Pavesi Marco , Hernández-Tejero María , Ginès Pere , Arroyo Vicente 
Published: August 2017

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival.

Patients
407 patients with ACLF and 235 patients with acute decompensation (AD).

Results
152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%).

Conclusion
Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.
Factors associated with coronary artery disease and stroke in adults with congenital heart disease
Authors: Bokma Jouke P , Zegstroo Ineke , Kuijpers Joey M , Konings Thelma C , van Kimmenade Roland R J , van Melle Joost P , Kiès Philippine , Mulder Barbara J M , Bouma Berto J 
Published: August 2017

ObjectiveTo determine factors associated with coronary artery disease (CAD) and ischaemic stroke in ageing adult congenital heart disease (ACHD) patients.MethodsWe performed a multicentre case–control study, using data from the national CONgenital CORvitia (CONCOR) registry to identify ACHD patients within five participating centres. Patients with CAD were matched (1:2 ratio) with ACHD patients without CAD on age, CHD defect group and gender. Patients with ischaemic stroke (or transient ischaemic attack) were matched similarly. Medical charts were reviewed and a standardised questionnaire was used to determine presence of risk factors.ResultsOf 6904 ACHD patients, a total of 55 cases with CAD (80% male, mean age 55.1±12.4 years) and 56 cases with stroke (46% male, mean age 46.9±15.2) were included and matched with control patients. In multivariable logistic regression analysis, traditional atherosclerotic risk factors (hypertension (OR 2.45; 95% CI 1.15 to 5.23), hypercholesterolaemia (OR 3.99; 95% CI 1.62 to 9.83) and smoking (OR 2.25; 95% CI 1.09 to 4.66)) were associated with CAD. In contrast, these risk factors were not associated with ischaemic stroke. In multivariable analysis, stroke was associated with previous shunt operations (OR 4.20; 95% CI 1.36 to 12.9), residual/unclosed septal defects (OR 2.38; 95% CI 1.03 to 5.51) and left-sided mechanical valves (OR 2.67; 95% CI 1.09 to 6.50).ConclusionsTraditional atherosclerotic risk factors were associated with CAD in ACHD patients. In contrast, ischaemic stroke was related to factors (previous shunts, septal defects, mechanical valves) suggesting a cardioembolic aetiology. These findings may inform surveillance and prevention strategies.
Exciton scattering via algebraic topology
Authors: Catanzaro Michael J. , Chernyak Vladimir Y. , Klein John R. 
Published: August 2017

This paper introduces an intersection theory problem for maps into a smooth manifold equipped with a stratification. We investigate the problem in the special case when the target is the unitary group [Formula: see text] and the domain is a circle. The first main result is an index theorem that equates a global intersection index with a finite sum of locally defined intersection indices. The local indices are integers arising from the geometry of the stratification. The result is used to study a well-known problem in chemical physics, namely, the problem of enumerating the electronic excitations (excitons) of a molecule equipped with scattering data.
Prototyping a query compiler using Coq (experience report)
Authors: Auerbach Joshua S. , Hirzel Martin , Mandel Louis , Shinnar Avraham , Siméon Jérôme 
Published: August 2017

Designing and prototyping new features is important in many industrial projects. Functional programming and formal verification tools can prove valuable for that purpose, but lead to challenges when integrating with existing product code or when planning technology transfer.
This article reports on our experience using the Coq proof assistant as a prototyping environment for building a query compiler intended for use in IBM's ODM Insights product. We discuss the pros and cons of using Coq for this purpose and describe our methodology for porting the compiler to Java, as required for product integration.
Parametric quantifiers for dependent type theory
Authors: Nuyts Andreas , Vezzosi Andrea , Devriese Dominique 
Published: August 2017

Polymorphic type systems such as System F enjoy the parametricity property: polymorphic functions cannot inspect their type argument and will therefore apply the same algorithm to any type they are instantiated on. This idea is formalized mathematically in Reynolds's theory of relational parametricity, which allows the metatheoretical derivation of parametricity theorems about all values of a given type. Although predicative System F embeds into dependent type systems such as Martin-Löf Type Theory (MLTT), parametricity does not carry over as easily. The identity extension lemma, which is crucial if we want to prove theorems involving equality, has only been shown to hold for small types, excluding the universe.
We attribute this to the fact that MLTT uses a single type former Π to generalize both the parametric quantifier ∀ and the type former → which is non-parametric in the sense that its elements may use their argument as a value. We equip MLTT with parametric quantifiers ∀ and ∃ alongside the existing Π and Σ, and provide relation type formers for proving parametricity theorems internally. We show internally the existence of initial algebras and final co-algebras of indexed functors both by Church encoding and, for a large class of functors, by using sized types.
We prove soundness of our type system by enhancing existing iterated reflexive graph (cubical set) models of dependently typed parametricity by distinguishing between edges that express relatedness of objects (bridges) and edges that express equality (paths). The parametric functions are those that map bridges to paths.
We implement an extension to the Agda proof assistant that type-checks proofs in our type system.
Gradual session types
Authors: Igarashi Atsushi , Thiemann Peter , Vasconcelos Vasco T. , Wadler Philip 
Published: August 2017

Session types are a rich type discipline, based on linear types, that lift the sort of safety claims that come with type systems to communications. However, web-based applications and micro services are often written in a mix of languages, with type disciplines in a spectrum between static and dynamic typing. Gradual session types address this mixed setting by providing a framework which grants seamless transition between statically typed handling of sessions and any required degree of dynamic typing.
We propose GradualGV as an extension of the functional session type system GV with dynamic types and casts. We demonstrate type and communication safety as well as blame safety, thus extending previous results to functional languages with session-based communication. The interplay of linearity and dynamic types requires a novel approach to specifying the dynamics of the language.
Neural Signatures of Spatial Statistical Learning: Characterizing the Extraction of Structure from Complex Visual Scenes
Authors: Karuza Elisabeth A. , Emberson Lauren L. , Roser Matthew E. , Cole Daniel , Aslin Richard N. , Fiser Jozsef 
Published: August 2017

Abstract
Behavioral evidence has shown that humans automatically develop internal representations adapted to the temporal and spatial statistics of the environment. Building on prior fMRI studies that have focused on statistical learning of temporal sequences, we investigated the neural substrates and mechanisms underlying statistical learning from scenes with a structured spatial layout. Our goals were twofold: (1) to determine discrete brain regions in which degree of learning (i.e., behavioral performance) was a significant predictor of neural activity during acquisition of spatial regularities and (2) to examine how connectivity between this set of areas and the rest of the brain changed over the course of learning. Univariate activity analyses indicated a diffuse set of dorsal striatal and occipitoparietal activations correlated with individual differences in participants' ability to acquire the underlying spatial structure of the scenes. In addition, bilateral medial-temporal activation was linked to participants' behavioral performance, suggesting that spatial statistical learning recruits additional resources from the limbic system. Connectivity analyses examined, across the time course of learning, psychophysiological interactions with peak regions defined by the initial univariate analysis. Generally, we find that task-based connectivity with these regions was significantly greater in early relative to later periods of learning. Moreover, in certain cases, decreased task-based connectivity between time points was predicted by overall posttest performance. Results suggest a narrowing mechanism whereby the brain, confronted with a novel structured environment, initially boosts overall functional integration and then reduces interregional coupling over time.
Hearing Outcomes after Ossicular Reconstruction with Removal of the Malleus
Authors: Haberman Rex S. , Salapatas Anna M. 
Published: August 2017

Objectives(1) Evaluate hearing outcomes of patients after planned malleus removal during ossicular chain reconstruction. (2) Analyze hearing results for titanium (Ti) and hydroxyapatite (HA) total ossicular prostheses (TOPs) and partial ossicular prostheses (POPs). (3) Compare Ti and HA partial prostheses.Study DesignRetrospective case series with chart review.SettingTertiary health care organization.Subjects and MethodsA chart review was conducted of 139 consecutive patients who presented with chronic otitis media with perforation (with or without cholesteatoma) and were treated with initial‐stage tympanoplasty (with or without mastoidectomy) and managed with TOP (n = 22) or POP (n = 117) between July 2010 and July 2015. The malleus was completely removed in all cases. Hearing was assessed via bone and air conduction pretone averages (0.5, 1, 2 kHz) pre‐ and postoperatively. Air‐bone gap (ABG) and change in ABG (ΔABG) were analyzed. Pre‐ and postoperative values were compared.ResultsThe overall mean ABG decreased from 29.4 ± 12.3 dB to 18.2 ± 11.4 dB postoperatively (P <. 001) with a mean ΔABG of 14.5 dB (95% CI, 12.793‐16.203). Overall success was achieved by 69.1%. The POP group achieved higher success (70.9%) than the TOP group (59.1%; P =. 0001). Mean ABG decreased significantly within surgical groups (TOP and POP) and prosthesis material groups (Ti and HA; all P <. 001). Ti had statistically higher success than HA in both techniques: POP (P =. 0478) and TOP (P =. 0251). There was a 98% graft take rate.ConclusionPlanned malleus removal during ossicular chain reconstruction, regardless of disease extent, allows for simpler reconstruction and comparable favorable results to preservation of the malleus and should be considered during surgical planning.
Spasmodic Dysphonia: A Review. Part 2: Characterization of Pathophysiology
Authors: Hintze Justin M. , Ludlow Christy L. , Bansberg Stephen F. , Adler Charles H. , Lott David G. 
Published: August 2017

ObjectiveThe purpose of this review is to describe the recent advances in characterizing spasmodic dysphonia. Spasmodic dysphonia is a task‐specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. The pathophysiology is poorly understood, and there are diagnostic difficulties.Data SourcesPubMed, Google Scholar, and Cochrane Library.Review MethodsThe data sources were searched using the following search terms: (spasmodic dysphonia or laryngeal dystonia) and (etiology, aetiology, diagnosis, pathogenesis, or pathophysiology).ConclusionThe diagnosis of spasmodic dysphonia can be difficult due to the lack of a scientific consensus on diagnostic criteria and the fact that other voice disorders may present similarly. Confusion can arise between spasmodic dysphonia and muscle tension dysphonia. Spasmodic dysphonia symptoms are tied to particular speech sounds, whereas muscle tension dysphonia is not. With the advent of more widespread use of high‐speed laryngoscopy and videokymography, measures of the disruptions in phonation and delays in the onset of vocal fold vibration after vocal fold closure can be quantified. Recent technological developments have expanded our understanding of the pathophysiology of spasmodic dysphonia.Implications for PracticeA 3‐tiered approach, involving a questionnaire, followed by speech assessment and nasolaryngoscopy is the most widely accepted method for making the diagnosis in most cases. More experimental and invasive techniques such as electromyography and neuroimaging have been explored to further characterize spasmodic dysphonia and aid in diagnosing difficult cases.