bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery
Authors: Lu Cheng , Zhang Yuyi , Chen Mingyu , Zhong Ping , Chen Yuancheng , Yu Jicheng , Wu Xiaojie , Wu Jufang , Zhang Jing 
Published: August 2016

ABSTRACT
Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.)
Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing
Authors: Castillo-Mancilla Jose , Seifert Sharon , Campbell Kayla , Coleman Stacey , McAllister Kevin , Zheng Jia-Hua , Gardner Edward M. , Liu Albert , Glidden David V. , Grant Robert , Hosek Sybil , Wilson Craig M. , Bushman Lane R. , MaWhinney Samantha , Anderson Peter L. 
Published: August 2016

ABSTRACT
New objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.)
A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants
Authors: Leroux Stéphanie , Roué Jean-Michel , Gouyon Jean-Bernard , Biran Valérie , Zheng Hao , Zhao Wei , Jacqz-Aigrain Evelyne 
Published: August 2016

ABSTRACT
Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.
Potent Activities of Novel Imidazoles Lanoconazole and Luliconazole against a Collection of Azole-Resistant and -Susceptible Aspergillus fumigatus Strains
Authors: Abastabar Mahdi , Rahimi Nooshin , Meis Jacques F. , Aslani Narges , Khodavaisy Sadegh , Nabili Mojtaba , Rezaei-Matehkolaei Ali , Makimura Koichi , Badali Hamid 
Published: August 2016

ABSTRACT

A collection of azole-susceptible (
n
= 141) and azole-resistant (
n
= 27)
Aspergillus fumigatus
isolates was tested against seven antifungal drugs, including the new imidazoles lanoconazole and luliconazole. The luliconazole and lanoconazole MIC
90
values for the azole-susceptible strains were 0.001 μg/ml and 0.008 μg/ml, and those for the azole-resistant strains were 0.016 μg/ml and 0.032 μg/ml.
Clinical Characteristics, Treatment Outcomes, and Resistance Mutations Associated with Macrolide-Resistant Mycobacterium avium Complex Lung Disease
Authors: Moon Seong Mi , Park Hye Yun , Kim Su-Young , Jhun Byung Woo , Lee Hyun , Jeon Kyeongman , Kim Dae Hun , Huh Hee Jae , Ki Chang-Seok , Lee Nam Yong , Kim Hong Kwan , Choi Yong Soo , Kim Jhingook , Lee Seung-Heon , Kim Chang Ki , Shin Sung Jae , Daley Charles L. , Koh Won-Jung 
Published: August 2016

ABSTRACT

Macrolide antibiotics are key components of the multidrug treatment regimen for treating lung disease (LD) due to
Mycobacterium avium
complex (MAC). Despite the emergence of macrolide resistance, limited data are available on macrolide-resistant MAC-LD. This study evaluated the clinical features and treatment outcomes of patients with macrolide-resistant MAC-LD and the molecular characteristics of the macrolide-resistant isolates. A retrospective review of the medical records of 34 patients with macrolide-resistant MAC-LD who were diagnosed between January 2002 and December 2014 was performed, along with genetic analysis of 28 clinical isolates. Nineteen (56%) patients had the fibrocavitary form of MAC-LD, and 15 (44%) had the nodular bronchiectatic form.
M. intracellulare
was the etiologic organism in 21 (62%) patients. Approximately two-thirds (22/34 [65%]) of the patients had been treated with currently recommended multidrug regimens that included macrolide, ethambutol, and rifamycin prior to the emergence of macrolide resistance, and none had been treated with macrolide monotherapy. The median duration of treatment after the detection of macrolide resistance was 23.0 months (interquartile range, 16.8 to 45.3 months). Treatment outcomes were poor after the development of macrolide resistance, with favorable treatment outcomes achieved in only five (15%) patients, including two patients who underwent surgical resection. One-, 3-, and 5-year mortality rates were 9, 24, and 47%, respectively. Molecular analysis of 28 clinical isolates revealed that 96% (27/28) had point mutations at position 2058 or 2059 of the 23S rRNA gene. Our analyses indicate that more effective therapy is needed to treat macrolide-resistant MAC-LD and prevent its development.
IncHI2 Plasmids Are the Key Vectors Responsible for
oqxAB
Transmission among Salmonella Species
Authors: Wong Marcus Ho-yin , Chan Edward Wai-chi , Xie Liqi , Li Ruichao , Chen Sheng 
Published: August 2016

ABSTRACT

This study reported and analyzed the complete sequences of two
oqxAB
-bearing IncHI2 plasmids harbored by a clinical
Salmonella enterica
serovar Typhimurium strain and an
S
. Indiana strain of animal origin, respectively. In particular, pA3T recovered from
S
. Indiana comprised the resistance determinants
oqxAB
,
aac(6′)Ib
-cr,
fosA3
, and
bla
CTX-M-14
. Further genetic screening of 63
oqxAB
-positive
Salmonella
isolates revealed that the majority carried IncHI2 plasmids, confirming that such plasmids play a pivotal role in dissemination of
oqxAB
in
Salmonella
spp.
Fur Represses Adhesion to, Invasion of, and Intracellular Bacterial Community Formation within Bladder Epithelial Cells and Motility in Uropathogenic Escherichia coli
Authors: Kurabayashi Kumiko , Agata Tomohiro , Asano Hirofumi , Tomita Haruyoshi , Hirakawa Hidetada 
Published: August 2016

ABSTRACT

Uropathogenic
Escherichia coli
(UPEC) is a major pathogen that causes urinary tract infections (UTIs). This bacterium adheres to and invades the host cells in the bladder, where it forms biofilm-like polymicrobial structures termed intracellular bacterial communities (IBCs) that protect UPEC from antimicrobial agents and the host immune systems. Using genetic screening, we found that deletion of the
fur
gene, which encodes an iron-binding transcriptional repressor for iron uptake systems, elevated the expression of type I fimbriae and motility when UPEC was grown under iron-rich conditions, and it led to an increased number of UPEC cells adhering to and internalized in bladder epithelial cells. Consequently, the IBC colonies that the
fur
mutant formed in host cells were denser and larger than those formed by the wild-type parent strain. Fur is inactivated under iron-restricted conditions. When iron was depleted from the bacterial cultures, wild-type UPEC adhesion, invasion, and motility increased, similar to the case with the
fur
mutant. The purified Fur protein bound to regions upstream of
fimA
and
flhD
, which encode type I fimbriae and an activator of flagellar expression that contributes to motility, respectively. These results suggest that Fur is a repressor of
fimA
and
flhD
and that its repression is abolished under iron-depleted conditions. Based on our
in vitro
experiments, we conclude that UPEC adhesion, invasion, IBC formation, and motility are suppressed by Fur under iron-rich conditions but derepressed under iron-restricted conditions, such as in patients with UTIs.
ABBV-399, a c-Met Antibody–Drug Conjugate that Targets Both MET–Amplified and c-Met–Overexpressing Tumors, Irrespective of MET Pathway Dependence
Authors: Wang Jieyi , Anderson Mark G. , Oleksijew Anatol , Vaidya Kedar S. , Boghaert Erwin R. , Tucker Lora , Zhang Qian , Han Edward K. , Palma Joann P. , Naumovski Louie , Reilly Edward B. 
Published: August 2016

Abstract
Purpose: Despite the importance of the MET oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with MET amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic.
Experimental Design: ADC ABBV-399 was generated with the c-Met–targeting antibody, ABT-700. Antitumor activity was evaluated in cancer cells with overexpressed c-Met or amplified MET and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate the risk of on-target toxicity.
Results: A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399–mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard-of-care chemotherapy.
Conclusions: ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met–overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met–expressing non–small cell lung cancer (NSCLC) patients. Clin Cancer Res; 23(4); 992–1000. ©2016 AACR.
Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept
Authors: Peyrode Caroline , Weber Valérie , Voissière Aurélien , Maisonial-Besset Aurélie , Vidal Aurélien , Auzeloux Philippe , Gaumet Vincent , Borel Michèle , Dauplat Marie-Mélanie , Quintana Mercedes , Degoul Françoise , Rédini Françoise , Chezal Jean-Michel , Miot-Noirault Elisabeth 
Published: August 2016

Abstract
To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [3H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo 99mTc-NTP 15-5 scintigraphic imaging of PGs, 1H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575–85. ©2016 AACR.
Prognostic Factors in Patients With Pulmonary Hypertension—A Nationwide Cohort Study
Authors: Chang Wei‐Ting , Weng Shih‐Feng , Hsu Chih‐Hsin , Shih Jhih‐Yuan , Wang Jhi‐Joung , Wu Chun‐Ying , Chen Zhih‐Cherng 
Published: August 2016

Background

Pulmonary hypertension (
PH
) is a rare but fatal condition. Large‐scale studies to examine the prognostic factors are lacking. In the present study, we aimed to investigate the factors associated with overall mortality in
PH
patients.

Methods and Results

Based on Taiwan's National Health Insurance Database, we identified 1092 newly identified
PH
patients between 1999 and 2011. These patients were matched with 8736 healthy subjects based on propensity score calculated with age, sex, and chronic cardiovascular risk factors. Overall mortality, death incidence rate ratio, and hazard ratio were calculated. Patients with
PH
had a higher mortality than controls (56.45 versus 18.51 per 1000 person‐years,
P
<0.0001), with hazard ratio at 3.3 (95%
CI
: 2.92–3.73,
P
<0.001). The long‐term survival rates of the
PH
patients at 1, 5, and 10 years were 87.9%, 72.5%, and 62.6%, respectively, which were significantly lower than controls with 98.4%, 90.8%, and 83.6% at 1, 5, and 10 years, respectively. Among patients with
PH
, the mortality rate was higher in the older and male patients. However, after stratifying by age and sex, the younger (<50 years) and female patients had a higher risk. Regarding different etiologies of
PH
, chronic obstructive pulmonary disease and pulmonary embolism led to most cases of mortality (adjusted hazard ratio: 3.2, 95%
CI
: 2.76–3.71 and 4.64, 95%
CI
: 2.74–7.87,
P
<0.05).

Conclusions

PH
has high mortality, especially in females, and patients with younger age and with chronic diseases. Chronic obstructive pulmonary disease and pulmonary embolism contributed to an increased risk of mortality in
PH
patients.
Reversing the Standard Neural Signature of the Word–Nonword Distinction
Authors: Graves William W. , Boukrina Olga , Mattheiss Samantha R. , Alexander Edward J. , Baillet Sylvain 
Published: August 2016

Abstract
The distinction between letter strings that form words and those that look and sound plausible but are not meaningful is a basic one. Decades of functional neuroimaging experiments have used this distinction to isolate the neural basis of lexical (word level) semantics, associated with areas such as the middle temporal, angular, and posterior cingulate gyri that overlap the default mode network. In two fMRI experiments, a different set of findings emerged when word stimuli were used that were less familiar (measured by word frequency) than those typically used. Instead of activating default mode network areas often associated with semantic processing, words activated task-positive areas such as the inferior pFC and SMA, along with multifunctional ventral occipitotemporal cortices related to reading, whereas nonwords activated default mode areas previously associated with semantics. Effective connectivity analyses of fMRI data on less familiar words showed activation driven by task-positive and multifunctional reading-related areas, whereas highly familiar words showed bottom–up activation flow from occipitotemporal cortex. These findings suggest that functional neuroimaging correlates of semantic processing are less stable than previously assumed, with factors such as word frequency influencing the balance between task-positive, reading-related, and default mode networks. More generally, this suggests that results of contrasts typically interpreted in terms of semantic content may be more influenced by factors related to task difficulty than is widely appreciated.
The Role of Anterior Cingulate Cortex in the Affective Evaluation of Conflict
Authors: Braem Senne , King Joseph A. , Korb Franziska M. , Krebs Ruth M. , Notebaert Wim , Egner Tobias 
Published: August 2016

AbstractAn influential theory of ACC function argues that this brain region plays a crucial role in the affective evaluation of performance monitoring and control demands. Specifically, control-demanding processes such as response conflict are thought to be registered as aversive signals by ACC, which in turn triggers processing adjustments to support avoidance learning. In support of conflict being treated as an aversive event, recent behavioral studies demonstrated that incongruent (i.e., conflict inducing), relative to congruent, stimuli can speed up subsequent negative, relative to positive, affective picture processing. Here, we used fMRI to investigate directly whether ACC activity in response to negative versus positive pictures is modulated by preceding control demands, consisting of conflict and task-switching conditions. The results show that negative, relative to positive, pictures elicited higher ACC activation after congruent, relative to incongruent, trials, suggesting that ACC's response to negative (positive) pictures was indeed affectively primed by incongruent (congruent) trials. Interestingly, this pattern of results was observed on task repetitions but disappeared on task alternations. This study supports the proposal that conflict induces negative affect and is the first to show that this affective signal is reflected in ACC activation.
The Neural Correlates of Similarity- and Rule-based Generalization
Authors: Milton Fraser , Bealing Pippa , Carpenter Kathryn L. , Bennattayallah Abdelmalek , Wills Andy J. 
Published: August 2016

Abstract
The idea that there are multiple learning systems has become increasingly influential in recent years, with many studies providing evidence that there is both a quick, similarity-based or feature-based system and a more effortful rule-based system. A smaller number of imaging studies have also examined whether neurally dissociable learning systems are detectable. We further investigate this by employing for the first time in an imaging study a combined positive and negative patterning procedure originally developed by Shanks and Darby [Shanks, D. R., & Darby, R. J. Feature- and rule-based generalization in human associative learning. Journal of Experimental Psychology: Animal Behavior Processes, 24, 405–415, 1998]. Unlike previous related studies employing other procedures, rule generalization in the Shanks–Darby task is beyond any simple non-rule-based (e.g., associative) account. We found that rule- and similarity-based generalization evoked common activation in diverse regions including the pFC and the bilateral parietal and occipital lobes indicating that both strategies likely share a range of common processes. No differences between strategies were identified in whole-brain comparisons, but exploratory analyses indicated that rule-based generalization led to greater activation in the right middle frontal cortex than similarity-based generalization. Conversely, the similarity group activated the anterior medial frontal lobe and right inferior parietal lobes more than the rule group did. The implications of these results are discussed.