bluuebunny/crossref_metadata_2025_split huggingface dataset:
Limited Effect of Later-Generation Fluoroquinolones in the Treatment of Ofloxacin-Resistant and Moxifloxacin-Susceptible Multidrug-Resistant Tuberculosis
Authors: Lee Hyun , Ahn Soohyun , Hwang Na Young , Jeon Kyeongman , Kwon O Jung , Huh Hee Jae , Lee Nam Yong , Kim Chang-Ki , Koh Won-Jung 
Published: December 2017

ABSTRACT

Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant, moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used for all patients. Overall, 171 patients (82%) had ofloxacin-susceptible, moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group), and 37 (18%) had ofloxacin-resistant, moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a history of MDR-TB treatment (
P
< 0.001) and cavitary lesions on chest radiography (
P
< 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have resistance to the drugs pyrazinamide (
P
= 0.003), streptomycin (
P
= 0.015), prothionamide (
P
< 0.001), and para-aminosalicylic acid (
P
< 0.001). Favorable outcomes were more frequently achieved for the ofloxacin-susceptible group than for the ofloxacin-resistant group (91% [156/171] versus 57% [21/37], respectively [
P
< 0.001]). In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval, 1.55 to 18.53) times more likely than the ofloxacin-resistant group (
P
< 0.001) to have favorable outcomes. Despite
in vitro
moxifloxacin susceptibility, the frequency of favorable treatment outcomes for ofloxacin-resistant MDR-TB was significantly lower than that for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more-aggressive therapies may be needed for ofloxacin-resistant MDR-TB.
Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease
Authors: Jhun Byung Woo , Moon Seong Mi , Kim Su-Young , Park Hye Yun , Jeon Kyeongman , Kwon O Jung , Huh Hee Jae , Ki Chang-Seok , Lee Nam Yong , Chung Myung Jin , Lee Kyung Soo , Shin Sung Jae , Daley Charles L. , Koh Won-Jung 
Published: December 2017

ABSTRACT

Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic (NB)
Mycobacterium avium
complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent noncavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (
n
= 26) or intermittent therapy (
n
= 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared to the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent noncavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent noncavitary NB MAC lung disease.
Evaluation of Activity and Emergence of Resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae
Authors: Diep John K. , Sharma Rajnikant , Ellis-Grosse Evelyn J. , Abboud Cely S. , Rao Gauri G. 
Published: December 2017

ABSTRACT

ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing
Klebsiella pneumoniae
and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MIC of polymyxin B[MIC
PMB
], 0.5 mg/liter; MIC of fosfomycin [MIC
FOF
], 32 mg/liter) and BRKP67 (MIC
PMB
, 8 mg/liter; MIC
FOF
, 32 mg/liter) at an initial inoculum of 10
7
CFU/ml, were evaluated over 168 h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5-mg/kg loading dose as a 2 h-infusion followed by 1.5-mg/kg dose every 12 h [q12h] as a 1-h infusion) and fosfomycin (6 g q6h as a 1-h or 3-h infusion) regimens alone and in combination. Population analysis profiles (PAPs) and MIC testing were performed to assess emergence of resistance. Polymyxin B or fosfomycin monotherapy was ineffective and selected for resistance by 24 h. Polymyxin B plus a fosfomycin 1-h infusion demonstrated sustained bactericidal activity by 4 h, with undetectable colony counts beyond 144 h. Polymyxin B plus a fosfomycin 3-h infusion demonstrated bactericidal activity at 4 h, followed by regrowth similar to that of the control by 144 h. PAPs revealed resistant subpopulations by 120 h. The combination of polymyxin B and a fosfomycin 1-h infusion is a promising treatment option for KPC-producing
K. pneumoniae
and suppresses the emergence of resistance. Further evaluation of novel dosing strategies is warranted to optimize therapy.
In Vitro
and
In Vivo
Studies of the Trypanocidal Effect of Novel Quinolines
Authors: Nefertiti A. S. G. , Batista M. M. , Da Silva P. B. , Batista D. G. J. , Da Silva C. F. , Peres R. B. , Torres-Santos E. C. , Cunha-Junior E. F. , Holt E. , Boykin D. W. , Brun R. , Wenzler T. , Soeiro M. N. C. 
Published: December 2017

ABSTRACT

Therapies for human African trypanosomiasis and Chagas disease, caused by
Trypanosoma brucei
and
Trypanosoma cruzi
, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated
in silico
and by phenotypic studies using
in vitro
and
in vivo
models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition.
In vitro
screens against bloodstream forms of
T. cruzi
demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC
50
s) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing EC
50
s ranging from 0.6 to 0.1 μM. All quinolines were also highly active
in vitro
against African trypanosomes, showing EC
50
s of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in
in vivo
models. Results for DB2186 were promising in mice with
T. cruzi
and
T. brucei
infections, reaching a 70% reduction of the parasitemia load for
T. cruzi
, and it cured 2 out of 4 mice infected with
T. brucei
. DB2217 was also active
in vivo
and cured all 4 mice (100% cure rate) with
T. brucei
infection.
Pharmacodynamics of a Long-Acting Echinocandin, CD101, in a Neutropenic Invasive-Candidiasis Murine Model Using an Extended-Interval Dosing Design
Authors: Lepak Alexander J. , Zhao Miao , VanScoy Brian , Ambrose Paul G. , Andes David R. 
Published: December 2017

ABSTRACT

Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans, making it possible to design once-weekly dosing strategies. The present study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select
Candida albicans
(
n
= 4),
C. glabrata
(
n
= 3), and
C. parapsilosis
(
n
= 3) strains. The CD101 MIC ranged from 0.03 to 1 mg/liter. Plasma pharmacokinetic measurements were performed using uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 to 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days, at which time the organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC index) correlated well with efficacy (
R
2
, 0.74 to 0.93). The median stasis 24-h free-drug AUC/MIC targets were as follows: for
C. albicans
, 2.92; for
C. glabrata
, 0.07; and for
C. parapsilosis
, 2.61. The PK/PD targets for 1-log
10
kill endpoint were 2- to 4-fold higher. Interestingly, the aforementioned PK/PD targets of CD101 were numerically lower for all three species than those of other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent
in vivo
pharmacodynamic activity.
Distribution and Molecular Characterization of Acinetobacter baumannii International Clone II Lineage in Japan
Authors: Matsui Mari , Suzuki Masato , Suzuki Masahiro , Yatsuyanagi Jun , Watahiki Masanori , Hiraki Yoichi , Kawano Fumio , Tsutsui Atsuko , Shibayama Keigo , Suzuki Satowa 
Published: December 2017

ABSTRACT

Multidrug-resistant (MDR)
Acinetobacter
spp. have been globally disseminated in association with the successful clonal lineage
Acinetobacter baumannii
international clone II (IC II). Because the prevalence of MDR
Acinetobacter
spp. in Japan remains very low, we characterized all
Acinetobacter
spp. (
n
= 866) from 76 hospitals between October 2012 and March 2013 to describe the entire molecular epidemiology of
Acinetobacter
spp. The most prevalent species was
A. baumannii
(
n
= 645; 74.5%), with
A. baumannii
IC II (
n
= 245) accounting for 28.3% of the total. Meropenem-resistant isolates accounted for 2.0% (
n
= 17) and carried IS
Aba1-bla
OXA-23-like
(
n
= 10),
bla
IMP
(
n
= 4), or IS
Aba1-bla
OXA-51-like
(
n
= 3). Multilocus sequence typing of 110 representative
A. baumannii
isolates revealed the considerable prevalence of domestic sequence types (STs).
A. baumannii
IC II isolates were divided into the domestic sequence type 469 (ST469) (
n
= 18) and the globally disseminated STs ST208 (
n
= 14) and ST219 (
n
= 4). ST469 isolates were susceptible to more antimicrobial agents, while ST208 and ST219 overproduced the intrinsic AmpC β-lactamase.
A. baumannii
IC II and some
A. baumannii
non-IC II STs (e.g., ST149 and ST246) were associated with fluoroquinolone resistance. This study revealed that carbapenem-susceptible
A. baumannii
IC II was moderately disseminated in Japan. The low prevalence of acquired carbapenemase genes and presence of domestic STs could contribute to the low prevalence of MDR
A. baumannii
. A similar epidemiology might have appeared before the global dissemination of MDR epidemic lineages. In addition, fluoroquinolone resistance associated with
A. baumannii
IC II may provide insight into the significance of
A. baumannii
epidemic clones.
Bordetella pertussis Adenylate Cyclase Toxin Disrupts Functional Integrity of Bronchial Epithelial Layers
Authors: Hasan Shakir , Kulkarni Nikhil Nitin , Asbjarnarson Arni , Linhartova Irena , Osicka Radim , Sebo Peter , Gudmundsson Gudmundur H. 
Published: December 2017

ABSTRACTThe airway epithelium restricts the penetration of inhaled pathogens into the underlying tissue and plays a crucial role in the innate immune defense against respiratory infections. The whooping cough agent,Bordetella pertussis, adheres to ciliated cells of the human airway epithelium and subverts its defense functions through the action of secreted toxins and other virulence factors. We examined the impact ofB. pertussisinfection and of adenylate cyclase toxin-hemolysin (CyaA) action on the functional integrity of human bronchial epithelial cells cultured at the air-liquid interface (ALI).B. pertussisadhesion to the apical surface of polarized pseudostratified VA10 cell layers provoked a disruption of tight junctions and caused a drop in transepithelial electrical resistance (TEER). The reduction of TEER depended on the capacity of the secreted CyaA toxin to elicit cAMP signaling in epithelial cells through its adenylyl cyclase enzyme activity. Both purified CyaA and cAMP-signaling drugs triggered a decrease in the TEER of VA10 cell layers. Toxin-produced cAMP signaling caused actin cytoskeleton rearrangement and induced mucin 5AC production and interleukin-6 (IL-6) secretion, while it inhibited the IL-17A-induced secretion of the IL-8 chemokine and of the antimicrobial peptide beta-defensin 2. These results indicate that CyaA toxin activity compromises the barrier and innate immune functions ofBordetella-infected airway epithelia.
Takeaway meal consumption and risk markers for coronary heart disease, type 2 diabetes and obesity in children aged 9–10 years: a cross-sectional study
Authors: Donin Angela S , Nightingale Claire M , Owen Chris G , Rudnicka Alicja R , Cook Derek G , Whincup Peter H 
Published: December 2017

ObjectiveTo investigate associations between takeaway meal consumption and risk markers for coronary heart disease, type 2 diabetes and obesity risk markers in children.DesignA cross-sectional, school-based observational study.Setting85 primary schools across London, Birmingham and Leicester.Participants1948 UK primary school children in year 5, aged 9–10 years.Main outcome measuresChildren reported their frequency of takeaway meal consumption, completed a 24-hour dietary recall, had physical measurements and provided a fasting blood sample.ResultsAmong 1948 participants with complete data, 499 (26%) never/hardly ever consumed a takeaway meal, 894 (46%) did so <1/week and 555 (28%) did ≥1/week. In models adjusted for age, sex, month, school, ethnicity and socioeconomic status, more frequent takeaway meal consumption was associated with higher dietary intakes of energy, fat % energy and saturated fat % energy and higher energy density (all P trend <0.001) and lower starch, protein and micronutrient intakes (all P trend <0.05). A higher frequency of takeaway meal consumption was associated with higher serum total cholesterol and low-density lipoprotein (LDL) cholesterol (P trend=0.04, 0.01, respectively); children eating a takeaway meal ≥1/week had total cholesterol and LDL cholesterol 0.09 mmol/L (95% CI 0.01 to 0.18) and 0.10 mmol/L (95% CI 0.02 to 0.18) higher respectively than children never/hardly ever eating a takeaway meal; their fat mass index was also higher.ConclusionsMore frequent takeaway meal consumption in children was associated with unhealthy dietary nutrient intake patterns and potentially with adverse longer term consequences for obesity and coronary heart disease risk.
Effectiveness of preoperative medical consultations by internal medicine physicians: a systematic review
Authors: Pham Clarabelle T , Gibb Catherine L , Fitridge Robert A , Karnon Jonathan D 
Published: December 2017

ObjectiveClinics have been established to provide preoperative medical consultations, and enable the anaesthetist and surgeon to deliver the best surgical outcome for patients. However, there is uncertainty regarding the effect of such clinics on surgical, in-hospital and long-term outcomes. A systematic review of the literature was conducted to determine the effectiveness of preoperative medical consultations by internal medicine physicians for patients listed for elective surgery.DesignSystematic searches of MEDLINE, EMBASE, CINAHL, PubMed, Current Contents and the NHS Centre for Reviews and Dissemination were conducted up to 30 April 2017.SettingElective surgery.Study selectionRandomised controlled trials and non-randomised comparative studies conducted in adults.Outcome measuresLength of hospital stay, perioperative morbidity and mortality, costs and quality of life.ResultsThe one randomised trial reported that preadmission preoperative assessment was more effective than the option of an inpatient medical assessment in reducing the frequency of unnecessary admissions with significantly fewer surgical cancellations following admission for surgery. A small reduction in length of stay in patients was also observed. The three non-randomised studies reported increased lengths of stay, costs and postoperative complications in patients who received preoperative assessment. The timing and delivery of the preoperative medical consultation in the intervention group differed across the included studies.ConclusionFurther research is required to inform the design and implementation of coordinated involvement of physicians and surgeons in the provision of care for high-risk surgical patients. A standardised approach to perioperative decision-making processes should be developed with a clear protocol or guideline for the assessment and management of surgical patients.
The short-term health and economic burden of gestational diabetes mellitus in China: a modelling study
Authors: Xu Tingting , Dainelli Livia , Yu Kai , Ma Liangkun , Silva Zolezzi Irma , Detzel Patrick , Fang Hai 
Published: December 2017

ObjectivesGestational diabetes mellitus (GDM) is associated with a higher risk for adverse health outcomes during pregnancy and delivery for both mothers and babies. This study aims to assess the short-term health and economic burden of GDM in China in 2015.DesignUsing TreeAge Pro, an analytical decision model was built to estimate the incremental costs and quality-of-life loss due to GDM, in comparison with pregnancy without GDM from the 28th gestational week until and including childbirth. The model was populated with probabilities and costs based on current literature, clinical guidelines, price lists and expert interviews. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results.ParticipantsChinese population who gave birth in 2015.ResultsOn average, the cost of a pregnancy with GDM was ¥6677.37 (in 2015 international $1929.87) more (+95%) than a pregnancy without GDM, due to additional expenses during both the pregnancy and delivery: ¥4421.49 for GDM diagnosis and treatment, ¥1340.94 (+26%) for the mother’s complications and ¥914.94 (+52%) for neonatal complications. In China, 16.5 million babies were born in 2015. Given a GDM prevalence of 17.5%, the number of pregnancies affected by GDM was estimated at 2.90 million in 2015. Therefore, the annual societal economic burden of GDM was estimated to be ¥19.36 billion (international $5.59 billion). Sensitivity analyses were used to confirm the robustness of the results. Incremental health losses were estimated to be approximately 260 000 quality-adjusted life years.ConclusionIn China, the GDM economic burden is significant, even in the short-term perspective and deserves more attention and awareness. Our findings indicate a clear need to implement GDM prevention and treatment strategies at a national level in order to reduce the economic and health burden at both the population and individual levels.
APPLICATIONS OF THE HENDERSON-HASSELBALCH EQUATION TO SINGLE AND MIXED BUFFER SOLUTIONS
Authors: Birmingham Marion K. , Elliott K. A. C. 
Published: December 2017

On the basis of a review of recent literature the following constants for the bicarbonate and primary–secondary phosphate buffer systems seem to be the most reliable. pK′ for bicarbonate buffer in mammalian Ringer solution: 6.08 at 25°, 6.02 at 38°. pK′ for bicarbonate in Ringer–0.02 M phosphate–bicarbonate solution: 6.06 at 25°, 6.00 at 38°. pK′ for serum: 6.12 at 25°, 6.09 at 38°. pK′ for Ringer–phosphate solution: 6.8, scarcely changed by temperature. Solubility coefficient of carbon dioxide (αco2) in water, 0.76 at 25°, 0.54 at 38°; in Ringer solution, 0.74 at 25°, 0.53 at 38°. Methods for calculating pH and acid–base changes, carbon dioxide evolution and retention, and temperature effects, in single and mixed buffers have been presented. Examples of applications to Warburg manometric work are given which illustrate the effect of a second buffer on manometric determinations in bicarbonate buffered media.
Lymph Node Metastases in Colon Cancer Are Polyclonal
Authors: Ulintz Peter J. , Greenson Joel K. , Wu Rong , Fearon Eric R. , Hardiman Karin M. 
Published: December 2017

Abstract
Purpose: Recent studies have highlighted the existence of subclones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors, including colorectal cancer. We sought to understand the genetic origin of lymph node metastasis in colorectal cancer by evaluating the relationship between colorectal cancer subclones present in primary tumors and lymph nodes.
Experimental Design: A total of 33 samples from seven colorectal cancers, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of lymph node metastases. The computational method PyClone was used to define subclones within each tumor. The method Clonality Inference in Tumors Using Phylogeny (CITUP) was subsequently used to infer phylogenetic relationships among subclones.
Results: We found that there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal, and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor.
Conclusions: Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time. Clin Cancer Res; 24(9); 2214–24. ©2017 AACR.
See related commentary by Gerlinger, p. 2032