bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Penicillin G in Preterm and Term Neonates
Authors: Padari Helgi , Metsvaht Tuuli , Germovsek Eva , Barker Charlotte I. , Kipper Karin , Herodes Koit , Standing Joseph F. , Oselin Kersti , Tasa Tõnis , Soeorg Hiie , Lutsar Irja 
Published: February 2018

ABSTRACT

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but have been poorly described for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We describe the PK of penicillin G in neonates with a gestational age (GA) of ≥32 weeks and a postnatal age of <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg of body weight every 12 h (q12h). At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, and 12 h after injection. Noncompartmental PK analysis was performed with WinNonlin software. With those data in combination with data from neonates with a GA of ≤28 weeks, we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with a GA of ≥32 weeks were included in noncompartmental analysis. The median volume of distribution (
V
) was 0.50 liters/kg (interquartile range, 0.42 to 0.57 liters/kg), the median clearance (CL) was 0.21 liters/h (interquartile range, 0.16 to 0.29 liters/kg), and the median half-life was 3.6 h (interquartile range, 3.2 to 4.3 h). In the population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 liters/70 kg and 29.8 liters/70 kg for
V
of the central and peripheral compartments, respectively, and 13.2 liters/h/70 kg for CL. Considering the fraction of unbound penicillin G to be 40%, the PTA of an unbound drug concentration that exceeds the MIC for 40% of the dosing interval was >90% for MICs of ≤2 mg/liter with doses of 25,000 IU/kg q12h. In neonates, regardless of GA, the PK parameters of penicillin G were similar. The dose of 25,000 IU/kg q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 h of life. (This study was registered with the EU Clinical Trials Register under EudraCT number 2012-002836-97.)
Mesoscopic Energy Minimization Drives Pseudomonas aeruginosa Biofilm Morphologies and Consequent Stratification of Antibiotic Activity Based on Cell Metabolism
Authors: Sheraton M. V. , Yam J. K. H. , Tan C. H. , Oh H. S. , Mancini E. , Yang L. , Rice S. A. , Sloot P. M. A. 
Published: February 2018

ABSTRACT

Segregation of bacteria based on their metabolic activities in biofilms plays an important role in the development of antibiotic resistance. Mushroom-shaped biofilm structures, which are reported for many bacteria, exhibit topographically varying levels of multiple drug resistance from the cap of the mushroom to its stalk. Understanding the dynamics behind the formation of such structures can aid in design of drug delivery systems, antibiotics, or physical systems for removal of biofilms. We explored the development of metabolically heterogeneous
Pseudomonas aeruginosa
biofilms using numerical models and laboratory knockout experiments on wild-type and chemotaxis-deficient mutants. We show that chemotactic processes dominate the transformation of slender and hemispherical structures into mushroom structures with a signature cap. Cellular Potts model simulation and experimental data provide evidence that accelerated movement of bacteria along the periphery of the biofilm, due to nutrient cues, results in the formation of mushroom structures and bacterial segregation. Multidrug resistance of bacteria is one of the most threatening dangers to public health. Understanding the mechanisms of the development of mushroom-shaped biofilms helps to identify the multidrug-resistant regions. We decoded the dynamics of the structural evolution of bacterial biofilms and the physics behind the formation of biofilm structures as well as the biological triggers that produce them. Combining
in vitro
gene knockout experiments with
in silico
models showed that chemotactic motility is one of the main driving forces for the formation of stalks and caps. Our results provide physicists and biologists with a new perspective on biofilm removal and eradication strategies.
High Microbial Diversity Promotes Soil Ecosystem Functioning
Authors: Maron Pierre-Alain , Sarr Amadou , Kaisermann Aurore , Lévêque Jean , Mathieu Olivier , Guigue Julien , Karimi Battle , Bernard Laetitia , Dequiedt Samuel , Terrat Sébastien , Chabbi Abad , Ranjard Lionel 
Published: February 2018

ABSTRACT

In soil, the link between microbial diversity and carbon transformations is challenged by the concept of functional redundancy. Here, we hypothesized that functional redundancy may decrease with increasing carbon source recalcitrance and that coupling of diversity with C cycling may change accordingly. We manipulated microbial diversity to examine how diversity decrease affects the decomposition of easily degradable (i.e., allochthonous plant residues) versus recalcitrant (i.e., autochthonous organic matter) C sources. We found that a decrease in microbial diversity (i) affected the decomposition of both autochthonous and allochthonous carbon sources, thereby reducing global CO
2
emission by up to 40%, and (ii) shaped the source of CO
2
emission toward preferential decomposition of most degradable C sources. Our results also revealed that the significance of the diversity effect increases with nutrient availability. Altogether, these findings show that C cycling in soil may be more vulnerable to microbial diversity changes than expected from previous studies, particularly in ecosystems exposed to nutrient inputs. Thus, concern about the preservation of microbial diversity may be highly relevant in the current global-change context assumed to impact soil biodiversity and the pulse inputs of plant residues and rhizodeposits into the soil.

IMPORTANCE
With hundreds of thousands of taxa per gram of soil, microbial diversity dominates soil biodiversity. While numerous studies have established that microbial communities respond rapidly to environmental changes, the relationship between microbial diversity and soil functioning remains controversial. Using a well-controlled laboratory approach, we provide empirical evidence that microbial diversity may be of high significance for organic matter decomposition, a major process on which rely many of the ecosystem services provided by the soil ecosystem. These new findings should be taken into account in future studies aimed at understanding and predicting the functional consequences of changes in microbial diversity on soil ecosystem services and carbon storage in soil.
Efficient and Scalable Precision Genome Editing in
Staphylococcus aureus
through Conditional Recombineering and CRISPR/Cas9-Mediated Counterselection
Authors: Penewit Kelsi , Holmes Elizabeth A. , McLean Kathryn , Ren Mingxin , Waalkes Adam , Salipante Stephen J. 
Published: February 2018

ABSTRACT

Staphylococcus aureus
is an important human pathogen, but studies of the organism have suffered from the lack of a robust tool set for its genetic and genomic manipulation. Here we report the development of a system for the facile and high-throughput genomic engineering of
S. aureus
using single-stranded DNA (ssDNA) oligonucleotide recombineering coupled with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated counterselection. We identify recombinase
EF2132
, derived from
Enterococcus faecalis
, as being capable of integrating single-stranded DNA oligonucleotides into the
S. aureus
genome. We found that
EF2132
can readily mediate recombineering across multiple characterized strains (3 of 3 tested) and primary clinical isolates (6 of 6 tested), typically yielding thousands of recombinants per transformation. Surprisingly, we also found that some
S. aureus
strains are naturally recombinogenic at measurable frequencies when oligonucleotides are introduced by electroporation, even without exogenous recombinase expression. We construct a temperature-sensitive, two-vector system which enables conditional recombineering and CRISPR/Cas9-mediated counterselection in
S. aureus
without permanently introducing exogenous genetic material or unintended genetic lesions. We demonstrate the ability of this system to efficiently and precisely engineer point mutations and large single-gene deletions in the
S. aureus
genome and to yield highly enriched populations of engineered recombinants even in the absence of an externally selectable phenotype. By virtue of utilizing inexpensive, commercially synthesized synthetic DNA oligonucleotides as substrates for recombineering and counterselection, this system provides a scalable, versatile, precise, inexpensive, and generally useful tool for producing isogenic strains in
S. aureus
which will enable the high-throughput functional assessment of genome variation and gene function across multiple strain backgrounds.

IMPORTANCE
Engineering genetic changes in bacteria is critical to understanding the function of particular genes or mutations but is currently a laborious and technically challenging process to perform for the important human pathogen
Staphylococcus aureus
. In an effort to develop methods which are rapid, easy, scalable, versatile, and inexpensive, here we describe a system for incorporating synthetic, mutagenic DNA molecules into the
S. aureus
genome and for eliminating cells that lack the engineered mutation. This method allows efficient, precise, and high-throughput genetic engineering of
S. aureus
strains and will facilitate studies seeking to address a variety of issues about the function of particular genes and specific mutations.
De Novo
Assembly and Phasing of Dikaryotic Genomes from Two Isolates of
Puccinia coronata
f. sp.
avenae
, the Causal Agent of Oat Crown Rust
Authors: Miller Marisa E. , Zhang Ying , Omidvar Vahid , Sperschneider Jana , Schwessinger Benjamin , Raley Castle , Palmer Jonathan M. , Garnica Diana , Upadhyaya Narayana , Rathjen John , Taylor Jennifer M. , Park Robert F. , Dodds Peter N. , Hirsch Cory D. , Kianian Shahryar F. , Figueroa Melania 
Published: February 2018

ABSTRACT

Oat crown rust, caused by the fungus
Pucinnia coronata
f. sp.
avenae
, is a devastating disease that impacts worldwide oat production. For much of its life cycle,
P. coronata
f. sp.
avenae
is dikaryotic, with two separate haploid nuclei that may vary in virulence genotype, highlighting the importance of understanding haplotype diversity in this species. We generated highly contiguous
de novo
genome assemblies of two
P. coronata
f. sp.
avenae
isolates, 12SD80 and 12NC29, from long-read sequences. In total, we assembled 603 primary contigs for 12SD80, for a total assembly length of 99.16 Mbp, and 777 primary contigs for 12NC29, for a total length of 105.25 Mbp; approximately 52% of each genome was assembled into alternate haplotypes. This revealed structural variation between haplotypes in each isolate equivalent to more than 2% of the genome size, in addition to about 260,000 and 380,000 heterozygous single-nucleotide polymorphisms in 12SD80 and 12NC29, respectively. Transcript-based annotation identified 26,796 and 28,801 coding sequences for isolates 12SD80 and 12NC29, respectively, including about 7,000 allele pairs in haplotype-phased regions. Furthermore, expression profiling revealed clusters of coexpressed secreted effector candidates, and the majority of orthologous effectors between isolates showed conservation of expression patterns. However, a small subset of orthologs showed divergence in expression, which may contribute to differences in virulence between 12SD80 and 12NC29. This study provides the first haplotype-phased reference genome for a dikaryotic rust fungus as a foundation for future studies into virulence mechanisms in
P. coronata
f. sp.
avenae
.

IMPORTANCE
Disease management strategies for oat crown rust are challenged by the rapid evolution of
Puccinia coronata
f. sp.
avenae
, which renders resistance genes in oat varieties ineffective. Despite the economic importance of understanding
P. coronata
f. sp.
avenae
, resources to study the molecular mechanisms underpinning pathogenicity and the emergence of new virulence traits are lacking. Such limitations are partly due to the obligate biotrophic lifestyle of
P. coronata
f. sp.
avenae
as well as the dikaryotic nature of the genome, features that are also shared with other important rust pathogens. This study reports the first release of a haplotype-phased genome assembly for a dikaryotic fungal species and demonstrates the amenability of using emerging technologies to investigate genetic diversity in populations of
P. coronata
f. sp.
avenae
.
14-year case series of eyelid sebaceous gland carcinoma in Chinese patients and review of management
Authors: Lam Stacey C , Li Emmy Y M , Yuen Hunter K L 
Published: February 2018

AimsSebaceous gland carcinoma (SGC) of the eyelid is a rare but potentially deadly cancer. The purpose of this study was to determine whether the American Joint Committee on Cancer (AJCC) 7th Edition T category for SGC correlated with metastasis and survival in the Chinese population.MethodsThis was a retrospective, single-centre cohort study. Patients with surgically resected eyelid SGC between January 2001 and May 2015 at the Hong Kong Eye Hospital were reviewed. Tumours were staged using the AJCC criteria. The main outcome measures included local recurrence, metastasis and death. Disease-free survival (DFS) was measured from the completion of treatment; overall survival was measured from the date of initial diagnosis.ResultsThe study included 22 Chinese patients with a mean age of 65.4 years. The majority presented as a nodular lesion (91%) with 12 eyes (54.5%) initially misdiagnosed and a mean presentation time of 1 year. It was found that those with AJCC stage T2b or higher were significantly associated with lymph node metastasis (P=0.002) when compared with those with stage T2a. Older age at diagnosis (P=0.035) and no misdiagnosis (P=0.025) were associated with shorter DFS. Those with stage 3a or higher were associated with shorter DFS (P=0.007) and overall survival (P=0.024).ConclusionSimilar to previous reports, in this Chinese cohort, AJCC staging for SGC correlated with lymph node metastasis, DFS and overall survival. Those with stage 2b or higher on presentation will need closer surveillance for lymph node metastasis and may benefit from sentinel lymph node biopsy.
Gender differences in the use of anti-infective medications before and after widowhood: a register-based study
Authors: Santacroce Adriana , Wastesson Jonas W , Höhn Andreas , Christensen Kaare , Oksuzyan Anna 
Published: February 2018

BackgroundRecent findings suggest that bereavement due to spousal loss is associated with a decline in general immune functions, and thus to increased susceptibility to infections among widowed individuals. The present study aims to investigate whether spousal loss weakens immune defences more among men than among women using a 5% random sample of the total Danish population, and anti-infective medication use as a proxy for immune response.MethodsWe followed 6076 Danish individuals (67% women) aged ≥50 from 5 years before and up to 5 years after widowhood to examine changes in prescriptions of anti-infectives for systemic use.ResultsWomen used more anti-infective drugs both before and after spousal loss (women: OR= 1.31; 95% CI 1.21 to 1.42). The age-related changes in the use of anti-infective medications in the period before widowhood were similar to that in the period after widowhood among both men and women. Also, age-related changes in the use of anti-infective medications were similar in both genders.ConclusionsThe present study shows that individuals are more likely to use anti-infective medication after being widowed than before being widowed, but this change is likely to be related to increasing age and it is similar in both genders.
Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients
Authors: Lefebvre Mathilde , Dieux-Coeslier Anne , Baujat Geneviève , Schaefer Elise , Judith Saint-Onge , Bazin Anne , Pinson Lucile , Attie-Bitach Tania , Baumann Clarisse , Fradin Melanie , Pierquin Genevieve , Julia Sophie , Quélin Chloé , Doray Bérénice , Berg Sylvie , Vincent-Delorme Catherine , Lambert Laetitia , Bachmann Nadine , Lacombe Didier , Isidor Bertrand , Laurent Nicole , Joelle Roume , Blanchet Patricia , Odent Sylvie , Kervran Dominique , Leporrier Nathalie , Abel Carine , Segers Karine , Guiliano Fabienne , Ginglinger-Fabre Emmanuelle , Selicorni Angelo , Goldenberg Alice , El Chehadeh Salima , Francannet Christine , Demeer Benedicte , Duffourd Yannis , Thauvin-Robinet Christel , Verloes Alain , Cormier-Daire Valerie , Riviere Jean Baptiste , Faivre Laurence , Thevenon Julien 
Published: February 2018

BackgroundSegmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV.Patients and methodsWe used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3,MESP2,LFNG,HES7andTBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients.ResultsTen diagnoses, including four biallelic variants inTBX6, two biallelic variants inLFNGandDLL3, and one inMESP2andHES7, were made with the gene panel, and two diagnoses, including biallelic variants inFLNBand one variant inMEOX1,were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%).ConclusionAfter negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.
Tobacco industry misappropriation of American Indian culture and traditional tobacco
Authors: D’Silva Joanne , O’Gara Erin , Villaluz Nicole T 
Published: February 2018

ObjectiveDescribe the extent to which tobacco industry marketing tactics incorporated American Indian culture and traditional tobacco.MethodsA keyword search of industry documents was conducted using document archives from the Truth Tobacco Documents Library. Tobacco industry documents (n=76) were analysed for themes.ResultsTobacco industry marketing tactics have incorporated American Indian culture and traditional tobacco since at least the 1930s, with these tactics prominently highlighted during the 1990s with Natural American Spirit cigarettes. Documents revealed the use of American Indian imagery such as traditional headdresses and other cultural symbols in product branding and the portrayal of harmful stereotypes of Native people in advertising. The historical and cultural significance of traditional tobacco was used to validate commercially available tobacco.ConclusionsThe tobacco industry has misappropriated culture and traditional tobacco by misrepresenting American Indian traditions, values and beliefs to market and sell their products for profit. Findings underscore the need for ongoing monitoring of tobacco industry marketing tactics directed at exploiting Native culture and counter-marketing tactics that raise awareness about the distinction between commercial and traditional tobacco use. Such efforts should be embedded within a culturally sensitive framework to reduce the burden of commercial tobacco use.
Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women
Authors: Balder Jan-Willem , Rimbert Antoine , Zhang Xiang , Viel Martijn , Kanninga Roan , van Dijk Freerk , Lansberg Peter , Sinke Richard , Kuivenhoven Jan Albert 
Published: February 2018

Background:
Atherosclerosis starts in childhood but low-density lipoprotein cholesterol (LDL-C), a causal risk factor, is mostly studied and dealt with when clinical events have occurred. Women are usually affected later in life than men and are underdiagnosed, undertreated, and understudied in cardiovascular trials and research. This study aims at a better understanding of lifestyle and genetic factors that affect LDL-C in young women.

Methods:
We randomly selected for every year of age 8 women with LDL-C ≤1st percentile (≤50 mg/dL) and 8 women with LDL-C ≥99th percentile (≥186 mg/dL) from 28 000 female participants aged between 25 to 40 years of a population-based cohort study. The resulting groups include 119 and 121 women, respectively, of an average 33 years of age. A gene-sequencing panel was used to assess established monogenic and polygenic origins of these phenotypes. Information on lifestyle was extracted from questionnaires. A healthy lifestyle score was allocated based on a recently developed algorithm.

Results:
Of the women with LDL-C ≤1st percentile, 19 (15.7%) carried mutations that are causing monogenic hypocholesterolemia and 60 (49.6%) were genetically predisposed to low LDL-C on the basis of an extremely low weighted genetic risk score. In comparison with control groups, a healthier lifestyle was not associated with low LDL-C in women without genetic predispositions. Among women with LDL-C ≥99th percentile, 20 women (16.8%) carried mutations that cause familial hypercholesterolemia, whereas 25 (21%) were predisposed to high LDL-C on the basis of a high-weighted genetic risk score. The women in whom no genetic origin for hypercholesterolemia could be identified were found to exhibit a significantly unfavorable lifestyle in comparison with controls.

Conclusions:
This study highlights the need for early assessment of the cardiovascular risk profile in apparently healthy young women to identify those with LDL-C ≥99th percentile for their age: first, because, in this study, 17% of the cases were molecularly diagnosed with familial hypercholesterolemia, which needs further attention; second, because our data indicate that an unfavorable lifestyle is significantly associated with severe hypercholesterolemia in genetically unaffected women, which may also need further attention.