bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overview of Systemic Candida Infections in Hospital Settings and Report of Candida After DMEK Successfully Treated With Antifungals and Partial Graft Excision
Authors: Doshi Himank , Pabon Sheila , Price Marianne O. , Feng Matthew T. , Price Francis W. 
Published: April 2018

Purpose:
To report novel surgical and medical management of intraocular and corneal infection with Candida glabrata that manifested 3 months after Descemet membrane endothelial keratoplasty (DMEK) and to review demographic reasons for increasing fungal contamination of donor tissue.

Methods:
Demographics, donor rim cultures, diagnostic tests, management, clinical course, outcomes, and donor mate outcomes are reported for a fungal infection after DMEK.

Results:
The fungal infection was treated for 3 weeks with a combination of intracameral and intracorneal voriconazole and intracameral and topical amphotericin B (off-label use). After initial improvement, the infection appeared to spread to the posterior chamber and the cornea decompensated. Pars plana vitrectomy was performed, and the fungal plaque and underlying area of the graft (approximately 3 mm2 area) were excised with the vitrector. After surgical intervention, the voriconazole and amphotericin B injections were discontinued, and oral posaconazole was prescribed for 2 months (off-label use). This combination of surgical and medical management successfully cleared the infection. Surprisingly, corneal edema completely resolved, and central DMEK endothelial cell density was 2506 cells/mm2 1 month after discontinuing the antifungal injections, which apparently caused reversible endothelial toxicity.

Conclusions:
The incidence of nosocomial fungal infections, particularly non-albicans Candida, is increasing, as are the rates of positive fungal cultures from corneal donor tissue and postkeratoplasty fungal infections. Prospective studies are needed to assess the value of routine donor cultures, compare the safety and efficacy of various prophylactic treatments, and evaluate addition of antifungals to cold storage media.
Population Pharmacokinetics of Intravenous Linezolid in Premature Infants
Authors: Thibault Céline , Kassir Nastya , Goyer Isabelle , Théorêt Yves , Litalien Catherine , Moussa Ahmed , Ovetchkine Philippe , Autmizguine Julie 
Published: April 2018

Background:
The emergence of coagulase-negative staphylococci with reduced vancomycin susceptibility in some neonatal intensive care units has resulted in an increase of linezolid use. Linezolid pharmacokinetics (PK) and safety in premature infants still need to be better established.

Methods:
This was a retrospective PK study. All infants who received intravenous linezolid and had linezolid plasma concentrations per standard of care were included. Linezolid concentrations were measured by high performance liquid chromatography. A population PK model was developed using nonlinear mixed effects modeling. Optimal dosing was determined based on achievement of the surrogate pharmacodynamics target for efficacy: a ratio of the area under the concentration–time curve to minimum inhibitory concentration >80. We assessed the occurrence of thrombocytopenia and lactic acidosis in relation with drug exposure.

Results:
A total of 78 plasma concentrations were collected from 26 infants, with a median postnatal age (PNA) of 24 days (8–88) and weight of 1423 g (810–3256). A 1-compartment model described linezolid data well. The final model included PNA and weight on clearance and weight on volume of distribution. Considering an MIC90 of 1 mg/L, all infants reached an area under the concentration–time curve/minimum inhibitory concentration > 80. Although thrombocytopenia and hyperlactatemia occurred frequently, they were not sustained and were not considered related to linezolid.

Conclusion:
and was well tolerated in critically ill premature infants. PNA was the main determinant of clearance.
Distribution of Visits for Chronic Conditions Between Primary Care and Specialist Providers in Medicare Shared Savings Accountable Care Organizations
Authors: Cole Evan S. , Leighton Cassandra , Zhang Yuting 
Published: April 2018

Background:
Medicare Shared Savings Program Accountable Care Organizations (ACOs) may focus more on primary care given ACO financial incentives. We examine variation in primary care treatment of 8 prevalent chronic conditions across ACOs and the factors affecting the variation, and compare the role of primary care in ACOs and non-ACOs.

Research Design:
We conduct regression models at the ACO-level to identify factors predicting higher proportions of chronic condition visits delivered by primary care providers (PCPs) using 2013 Medicare claims and enrollment data. We compare the distribution of visits to PCPs, specialists and advanced practice providers between ACO-attributed and non–ACO-attributed beneficiaries.

Results:
At the ACO-level, the proportion of patients who are white and of the local population who are college educated, the complexity of the patient population, and the supply of specialists were negatively associated with the proportion of chronic condition visits delivered by PCPs, whereas the percentage of contracted physicians within the ACO who were PCPs was positively associated. These results varied when subanalyses were conducted for each specific chronic condition. ACO care for chronic conditions was managed similar to that of care for non-ACO Medicare beneficiaries in 2013, but that some ACOs utilize PCPs to manage chronic conditions more than others.

Conclusions:
Many ACOs may underutilize PCPs, and thus could actively shift care to less expensive primary care for potential savings to payers. Barriers to that shift could include low numbers of PCPs contracted in the ACO, and existing referral patterns and patient relationships with specialists.
Non-Parametric Mixture Modelling and its Application to Disease Progression Modelling
Authors: Firth Nicholas C. , Oxtoby Neil P. , Primativo Silvia , Brotherhood Emilie , Young Alexandra L. , Yong Keir X.X. , Crutch Sebastian J. , Alexander Daniel C. 
Published: April 2018

AbstractDementia is characterised by its progressive degeneration of cognitive abilities. In research cohorts, detailed neuropsychological test batteries are often administered to better understand how cognition changes over time. Understanding cognitive changes in dementia is of great importance, particularly in determining how structural changes in the brain may affect cognition and in facilitating earlier detection of symptomatic changes. Disease progression models are often applied to these data to understand how a disease changes over time from cross-sectional data or to disease trajectories from large numbers of individuals. Previous disease progression models used to build longitudinal models from cross-sectional data have focused on brain imaging data; however, these models are not directly applicable to cognitive data. Here we use the novel, non-parametric, Kernel Density Estimation Mixture Modelling (KDEMM) approach and demonstrate accurate modelling of the progression of cognitive test data. We found that using KDEMM resulted in more accurate models of disease progression in simulated data compared to Gaussian Mixture Models (GMMs) for the majority of parameters used to simulate the data. When comparing KDEMM and GMM to cognitive data collected in different Alzheimers Disease subtypes, we found the KDEMM resulted in a model much more in line with clinical phenotype. We anticipate that the KDEMM will be used to integrate cognitive test data, and other non-normally distributed datasets into complex disease progression models.
Cascading Effects of Shrimp Trawling: Increased Benthic Biomass and Increase in Net Primary Production
Authors: Joseph John Luczkovich , Rebecca A Deehr , Hart Kevin J , Clough Lisa M , Johnson Jeffrey C 
Published: April 2018

AbstractTrawling has been shown to cause high mortality of discarded species (bycatch) and short-term ecological disturbance to bottom communities in coastal systems, resulting in lowered benthic biomass. Here we report evidence of a trawling-induced trophic cascade resulting in an increase in biomass of benthic polychaetes after the end of the shrimp trawling season in areas open to trawling in North Carolina (USA). Using comparative measurements of abundance of bycatch species and benthos in open and closed trawling management areas and Ecopath network modeling, we show that trawling in the open area has led to increases in deposit-feeding polychaetes and decreases in bycatch species (fish and crabs) that are benthic predators on the polychaetes. We conclude that proposed management actions to reduce the shrimp trawl fishery effort will influence other net and trap fisheries for southern flounder and blue crabs indirectly, as revealed by our network models, and the proposed trawling ban may lead to improvements in other valuable fisheries.
A generalized theory of somatic evolution
Authors: Rozhok Andrii , DeGregori James 
Published: April 2018

AbstractThe modern Multi-Stage Model of Carcinogenesis (MMC) was developed in the 1950s through the ‘70s and postulated carcinogenesis as a process of rounds of Darwinian selection favoring progressively more malignant cell phenotypes. Through this period, almost nothing was known about driver mutations in cancers. Also, stem cells and cellular tissue organization were poorly characterized. The general multi-stage process was later confirmed by experimental studies, and cancer risk and incidence has been explained as primarily a function of mutation occurrence. However, the MMC has never been formally tested for its ability to account for current knowledge about cancer evolution. In particular, different numbers of cancer drivers required for different cancers and vast discrepancies in the organization of stem cell compartments for different tissues appear inconsistent with the very similar age distribution of the vast majority of cancers. In this regard, the initial theoretical idea underlying MMC is often over-interpreted with little connection to modern evidence, and a general theory of somatic evolution still does not exist. In this study, we applied Monte Carlo modeling and demonstrated the effect of various parameters, such as mutation rate, mutation effects and cell division, on the MMC performance. Our modeling demonstrates that the MMC requires considerable modification in order to describe cancer incidence. We elucidate the required conditions for how somatic cell selection should operate within the MMC in order to explain modern data on stem cell clonality and cancer, and propose a generalized theory of somatic evolution based on these results.
Low nutrient levels reduce the fitness cost of MexCD-OprJ efflux pump overexpression in ciprofloxacin-resistant Pseudomonas aeruginosa
Authors: Lin Wenfang , Wan Kun , Zeng Jie , Li Jingjing , Li Xi , Yu Xin 
Published: April 2018

AbstractThe long-term persistence of antibiotic resistance in the environment is a public health concern. Expression of an efflux pump, an important mechanism of resistance to antibiotics, is usually associated with a fitness cost in bacteria. In this study, we aimed to determine why antibiotic resistance conferred by overexpression of an efflux pump persists in environments such as drinking and source water in which antibiotic selective pressure may be very low or even absent. Competition experiments between wild-type Pseudomonas aeruginosa and ciprofloxacin-resistant mutants revealed that the fitness cost of ciprofloxacin resistance (strains cip_1, cip_2, and cip_3) significantly decreased (P < 0.05) under low-nutrient (0.5 mg/l total organic carbon (TOC)) relative to high-nutrient (500 mg/l TOC) conditions. Mechanisms underlying this fitness cost were analyzed. MexD gene expression in resistant bacteria (cip_3 strain) was significantly lower (P < 0.05) in low-nutrient conditions, with 10 mg/l TOC (8.01 ± 0.82-fold), than in high-nutrient conditions, with 500 mg/l TOC (48.89 ± 4.16-fold). Moreover, rpoS gene expression in resistant bacteria (1.36 ± 0.13-fold) was significantly lower (P < 0.05) than that in the wild-type strain (2.78 ± 0.29-fold) under low-nutrient conditions (10 mg/l TOC), suggesting a growth advantage. Furthermore, the difference in metabolic activity between the two competing strains was significantly smaller (P < 0.05) in low-nutrient conditions (5 and 0.5 mg/l TOC). These results suggest that nutrient levels are a key factor in determining the persistence and spread of antibiotic resistance conferred by efflux pumps in the natural environment with trace amounts or no antibiotics.ImportanceThe widespread of antibiotic resistance has led to an increasing concern about the environmental and public health risks. Mechanisms associated with antibiotic resistance including efflux pumps often increase bacterial fitness cost. Our study showed that the fitness cost of ciprofloxacin resistance conferred by overexpression of MexCD-OprJ efflux pump significantly decreased under low-nutrient relative to high-nutrient conditions. The significance of our research is to reveal that nutrient levels are key factor in determining the persistence of antibiotic resistance conferred by efflux pumps under conditions with trace amounts or no antibiotics, which can be mediated by some mechanisms including MexD gene expression, SOURs differences, and rpoS gene regulation.
Over 2000-fold increased production of the leaderless bacteriocin garvicin KS by genetic engineering and optimization of culture conditions
Authors: Telke Amar A. , Ovchinnikov Kirill V. , Vuoristo Kiira S. , Mathiesen Geir , Thorstensen Tage , Diep Dzung B. 
Published: April 2018

AbstractThe leaderless bacteriocin Garvicin KS (GarKS) is a potent antimicrobial, being active against a wide range of important pathogens. GarKS production by the native producerLactococcus garvieaeKS1546 was however relatively low (80 BU/ml) under standard laboratory growth conditions (batch culture in GM17 at 30°C). To improve the production of GarKS, we systematically evaluated the impact of different media and media components on bacteriocin production. Based on the outcomes a new medium formulation was made to greatly improve bacteriocin production. The new medium composed of pasteurized milk and tryptone (PM-T), increased GarKS production about 60-fold compared to that achieved in GM17. GarKS production was increased further 4-fold (i.e., to 20,000 BU/ml) by increasing gene dose of the bacteriocin gene cluster (gak) in the native producer. Finally, a combination of the newly composed medium (PM-T), an increased gene dose and a cultivation at a constant pH 6 and a 50-60% dissolved oxygen level in growth medium, gave rise to a GarKS production of 164,000 BU/ml. This high production, which is about 2000-fold higher compared to that initially achieved in GM17, corresponds to a GarKS production of 1.2 g/L. To our knowledge, this is one of the highest bacteriocin production reported hitherto.ImportanceLow bacteriocin production is a well-known bottle-neck in developing bacteriocins into large-scaled and useful applications. The present study shows different approaches that significantly improve bacteriocin production. This is an important research field to better exploit the antimicrobial potential of bacteriocins, especially with regard to the decreasing effect of antibiotics in infection treatments due to the global emergence of antibiotic resistance.
Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis
Authors: Piton Jérémie , Vocat Anthony , Lupien Andréanne , Foo Caroline , Riabova Olga , Makarov Vadim , Cole Stewart T. 
Published: April 2018

ABSTRACTMacozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.
TNF-α induces reactivation of human cytomegalovirus independently of myeloid cell differentiation following post-transcriptional establishment of latency
Authors: Forte Eleonora , Swaminathan Suchitra , Schroeder Mark W. , Kim Jeong Yeon , Terhune Scott S. , Hummel Mary 
Published: April 2018

ABSTRACTWe used the Kasumi-3 model to study HCMV latency and reactivation in myeloid progenitor cells. Kasumi-3 cells were infected with HCMV strain TB40/Ewt-GFP, flow sorted for GFP+ cells, and cultured for various times to monitor establishment of latency, as judged by repression of viral gene expression (RNA/DNA ratio) and loss of virus production. We found that, in the vast majority of cells, latency was established post-transcriptionally in the GFP+ infected cells: transcription was initially turned on, and then turned off. We also found that some of the GFP-cells were infected, suggesting that latency might be established in these cells at the outset of infection. We were not able to test this hypothesis because some GFP-cells expressed lytic genes, and thus, it was not possible to separate them from GFP-quiescent cells. In addition, we found that the pattern of expression of lytic genes that have been associated with latency, including UL138, US28, and RNA2.7, was the same as that of other lytic genes, indicating that there was no preferential expression of these genes once latency is established. We confirmed previous studies showing that TNF-α induced reactivation of infectious virus, and by analyzing expression of the progenitor cell marker CD34 as well as myeloid cell differentiation markers in IE+ cells after treatment with TNF-α, we showed that TNF-α induced transcriptional reactivation of IE gene expression independently of differentiation. TNF-α-mediated reactivation in Kasumi-3 cells was correlated with activation of NF-κB, KAP-1 and ATM.IMPORTANCEHCMV is an important human pathogen that establishes lifelong latent infection in myeloid progenitor cells, and reactivates frequently to cause significant disease in immunocompromised people. Our observation that viral gene expression is first turned on, and then turned off to establish latency suggests that there is a host defense, which may be myeloid-specific, responsible for transcriptional silencing of viral gene expression. Our observation that TNF-α induces reactivation independently of differentiation provides insight into molecular mechanisms that control reactivation.
Epilepsy gene therapy using non-integrating lentiviral delivery of an engineered potassium channel gene
Authors: Snowball Albert , Chabrol Elodie , Wykes Robert C. , Lieb Andreas , Hashemi Kevan S. , Kullmann Dimitri M. , Walker Matthew C. , Schorge Stephanie 
Published: April 2018

AbstractRefractory focal neocortical epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon-optimized for human expression and mutated to accelerate the channels’ recovery from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a non-integrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled pre-clinical trial, the EKC lentivector robustly reduced seizure frequency in a rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as ready for clinical translation in the treatment of refractory focal epilepsy.
A cell-based probabilistic approach unveils the concerted action of miRNAs
Authors: Mahlab-Aviv Shelly , Linial Nathan , Linial Michal 
Published: April 2018

SummaryMature microRNAs (miRNAs) regulate most human genes through direct base-pairing with mRNAs. We investigate some underlying principles of such regulation. To this end, we overexpressed miRNAs in different cell types and measured the mRNA decay rate under transcriptional arrest. Parameters extracted from these experiments were incorporated into a computational stochastic framework which was developed to simulate the cooperative action of miRNAs in living cells. We identified gene sets that exhibit coordinated behavior with respect to all major miRNAs, over a broad range of overexpression levels. While a small set of genes is highly sensitive to miRNA manipulations, about 180 genes are insensitive to miRNA manipulations as measured by their degree of mRNA retention. The insensitive genes are associated with the translation machinery. We conclude that the stochastic nature of miRNAs reveals an unexpected robustness of gene expression in living cells. Moreover, the use of a systematic probabilistic approach exposes design principles of cells’ states and in particular, the translational machinery.HighlightsA probabilistic-based simulator assesses the cellular response to thousands of miRNA overexpression manipulationsThe translational machinery displays an exceptional resistance to manipulations of miRNAs.The insensitivity of the translation machinery to miRNA manipulations is shared by different cell typesThe composition of the most abundant miRNAs dominates cell identity