bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibilities of
Streptococcus pneumoniae
and
Haemophilus influenzae
to 10 Oral Antimicrobial Agents Based on Pharmacodynamic Parameters: 1997 U.S. Surveillance Study
Authors: Jacobs Michael R. , Bajaksouzian Saralee , Zilles Anne , Lin Gengrong , Pankuch Glenn A. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

The susceptibilities of
Streptococcus pneumoniae
(1,476 strains) and untypeable
Haemophilus influenzae
(1,676 strains) to various oral β-lactam, macrolide-azalide, and fluoroquinolone antimicrobial agents were determined by broth microdilution. Organisms were isolated from specimens obtained from outpatients in six geographic regions of the United States. MIC data were interpreted according to pharmacodynamically derived breakpoints applicable to the oral agents tested. Among
H. influenzae
strains, 41.6% were β-lactamase positive. Virtually all
H. influenzae
strains were susceptible to amoxicillin-clavulanate (98%), cefixime (100%), and ciprofloxacin (100%), while 78% were susceptible to cefuroxime, 57% were susceptible to amoxicillin, 14% were susceptible to cefprozil, 9% were susceptible to loracarbef, 2% were susceptible to cefaclor, and 0% were susceptible to azithromycin and clarithromycin. Among
S. pneumoniae
isolates, 49.6% were penicillin susceptible, 17.9% were intermediate, and 32.5% were penicillin resistant, with penicillin MICs for 50 and 90% of the isolates tested of 0.12 and 4 μg/ml, respectively. Overall, 94% of
S. pneumoniae
isolates were susceptible to amoxicillin and amoxicillin-clavulanate, 69% were susceptible to azithromycin and clarithromycin, 63% were susceptible to cefprozil and cefuroxime, 52% were susceptible to cefixime, 22% were susceptible to cefaclor, and 11% were susceptible to loracarbef. Although ciprofloxacin has marginal activity against
S. pneumoniae
, no high-level fluoroquinolone-resistant strains were found. Significant cross-resistance was found between penicillin and macrolides-azalides among
S. pneumoniae
isolates, with 5% of the penicillin-susceptible strains being macrolide-azalide resistant, compared with 37% of the intermediate isolates and 66% of the resistant isolates. Resistance was highest in
S. pneumoniae
isolates from patients younger than 10 years of age, middle ear and paranasal sinus specimens, and the southern half of the United States. With the continuing rise in resistance, judicious use of oral antimicrobial agents is necessary in all age groups.
Comparison of Glycopeptide-Resistant
Enterococcus faecium
Isolates and Glycopeptide Resistance Genes of Human and Animal Origins
Authors: Descheemaeker Patrick R. M. , Chapelle Sabine , Devriese Luc A. , Butaye Patrick , Vandamme Peter , Goossens Herman 
Published: October 2018

ABSTRACT

One hundred thirty-two glycopeptide-resistant
Enterococcus faecium
(GREF) isolates from different hospitals and pig and poultry farms in Belgium were compared on the basis of (i) their antibiotic susceptibilities, (ii) their
Sma
I pulsed-field gel electrophoresis (PFGE) patterns, and (iii) the organization of their Tn
1546
or related elements in order to detect possible phenotypic and genotypic relationships among both groups of isolates. Human and animal
vanA
-positive GREF isolates were found to have similar susceptibility patterns; they remained susceptible to gentamicin and were, in general, susceptible to ampicillin. PFGE demonstrated a very high degree of genomic heterogeneity in both groups of isolates. However, indistinguishable isolates were found within different farms or hospitals, and in two instances, epidemiologically unrelated pig and human isolates showed indistinguishable PFGE patterns. In total, eight different transposon types were identified, and all were related to the prototype transposon Tn
1546
. The two predominant types, Tn
1546
and type 2 transposons, which differed at three band positions, were present in both human and animal isolates. Type 2 transposons were significantly associated with pig isolates. The other types were seldom detected. These data suggest a possible exchange of glycopeptide resistance markers between animals and humans.
In Vitro Activities of Linezolid against Important Gram-Positive Bacterial Pathogens Including Vancomycin-Resistant Enterococci
Authors: Noskin Gary A. , Siddiqui Farida , Stosor Valentina , Hacek Donna , Peterson Lance R. 
Published: October 2018

ABSTRACTThe emergence of resistance in gram-positive bacteria has necessitated a search for new antimicrobial agents. Linezolid is an oxazolidinone, a new class of antibacterial agents with enhanced activity against pathogens. We compared the activity of linezolid to those of other antimicrobial agents against 3,945 clinical isolates. Linezolid demonstrated potent activity against all isolates tested. For all vancomycin-susceptible enterococci, staphylococci, and streptococci, the activity of linezolid was comparable to that of vancomycin. Against oxacillin-resistant staphylococci and vancomycin-resistant enterococci, linezolid was the most active agent tested. In summary, linezolid appears to be a promising new antimicrobial agent for the treatment of gram-positive infections.
The Structural Gene for Microcin H47 Encodes a Peptide Precursor with Antibiotic Activity
Authors: Rodríguez Eliana , Gaggero Carina , Laviña Magela 
Published: October 2018

ABSTRACT

Microcin H47 is a bactericidal antibiotic produced by a naturally occurring
Escherichia coli
strain isolated in Uruguay. The microcin genetic system is located in the chromosome and extends over a 10-kb DNA segment containing the genes required for microcin synthesis, secretion, and immunity. The smallest microcin synthesis gene,
mchB
, was sequenced and shown to encode a highly hydrophobic peptide. An
mchB-phoA
gene fusion, which directed the synthesis of a hybrid bifunctional protein with both PhoA and microcin H47-like activities, was isolated. The results presented herein lead us to propose that microcin H47 is indeed a ribosomally synthesized peptide antibiotic and that its peptide precursor already has antibiotic activity of the same specificity as that of mature microcin.
Randomized, Double-Blind Trial of an Antibiotic-Lock Technique for Prevention of Gram-Positive Central Venous Catheter-Related Infection in Neutropenic Patients with Cancer
Authors: Carratalà Jordi , Niubó Jordi , Fernández-Sevilla Alberto , Juvé Eulalia , Castellsagué Xavier , Berlanga Juan , Liñares Josefina , Gudiol Francesc 
Published: October 2018

ABSTRACT

The aim of the present study was to determine the efficacy of an antibiotic-lock technique in preventing endoluminal catheter-related infection with gram-positive bacteria in neutropenic patients with hematologic malignancies. Patients with nontunneled, multilumen central venous catheters were assigned in a randomized, double-blinded manner to receive either 10 U of heparin per ml (57 patients) or 10 U of heparin per ml and 25 μg of vancomycin per ml (60 patients), which were instilled in the catheter lumen and which were allowed to dwell in the catheter lumen for 1 h every 2 days. Insertion-site and hub swabs were taken twice weekly. The primary and secondary end points of the trial were significant colonization of the catheter hub and catheter-related bacteremia, respectively. Significant colonization of the catheter hub occurred in nine (15.8%) patients receiving heparin (seven patients were colonized with
Staphylococcus epidermidis
, one patient was colonized with
Staphylococcus capitis
, and one patient was colonized with
Corynebacterium
sp.), whereas the catheter hubs of none of the patients receiving heparin and vancomycin were colonized (
P
= 0.001). Catheter-related bacteremia developed in four (7%) patients receiving heparin (three patients had
S. epidermidis
bacteremia and one patient had
S. capitis
bacteremia), whereas none of the patients in the heparin and vancomycin group had catheter-related bacteremia (
P
= 0.05). The times to catheter hub colonization and to catheter-related bacteremia by the Kaplan-Meier method were longer in patients receiving heparin and vancomycin than in patients receiving heparin alone (
P
= 0.004 and
P
= 0.06, respectively). Our study shows that a solution containing heparin and vancomycin administered by using an antibiotic-lock technique effectively prevents catheter hub colonization with gram-positive bacteria and subsequent bacteremia during chemotherapy-induced neutropenia in patients with hematologic malignancy.
Oxfendazole Treatment of Sheep with Naturally Acquired Hydatid Disease
Authors: Dueger Erica L. , Moro Pedro L. , Gilman Robert H. 
Published: October 2018

ABSTRACT
A blinded, randomized placebo-controlled trial assessed the efficacy and safety of oxfendazole for the treatment of ovine hydatid disease. Cyst fertility and parasite viability were measured following daily, weekly, and monthly treatment schedules with 30 mg of oxfendazole per kg of body weight. The 12-week trial was conducted in 215 adult sheep in the central Peruvian Andes and was masked for both treatment group and scheduling. In this trial oxfendazole significantly reduced protoscolex viability relative to controls in all treatment groups. In the daily, weekly, and monthly groups, 100, 97, and 78% of sheep, respectively, were either cured or improved following treatment, compared to 35% cured or improved animals in the control group. However, daily dosing at 30 mg of oxfendazole per kg proved highly toxic to sheep, resulting in a 24% death rate in the daily group as compared to a 4 to 6% mortality rate in all other groups. If found safe in humans, oxfendazole may prove to be a useful and inexpensive treatment for cestode infections in humans. This study suggests that a staggered dosing regimen of oxfendazole, and possibly other benzimidazoles, may be as efficacious as daily treatment regimens for hydatidosis while decreasing both the cost and adverse effects associated with daily dosing.
Pharmacokinetics and Safety of High-Dose and Extended-Interval Regimens of Levofloxacin in Human Immunodeficiency Virus-Infected Patients
Authors: Piscitelli Stephen C. , Spooner Katherine , Baird Barbara , Chow Andrew T. , Fowler Cynthia L. , Williams Rex R. , Natarajan Jaya , Masur Henry , Walker Robert E. 
Published: October 2018

ABSTRACT
The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers.
Sicker patients account for the weekend mortality effect among adult emergency admissions to a large hospital trust
Authors: Sun Jianxia , Girling Alan J , Aldridge Cassie , Evison Felicity , Beet Chris , Boyal Amunpreet , Rudge Gavin , Lilford Richard J , Bion Julian 
Published: October 2018

ObjectiveTo determine whether the higher weekend admission mortality risk is attributable to increased severity of illness.DesignRetrospective analysis of 4 years weekend and weekday adult emergency admissions to a university teaching hospital in England.Outcome measures30-day postadmission weekend:weekday mortality ratios adjusted for severity of illness (baseline National Early Warning Score (NEWS)), routes of admission to hospital, transfer to the intensive care unit (ICU) and demographics.ResultsDespite similar emergency department daily attendance rates, fewer patients were admitted on weekends (mean admission rate 91/day vs 120/day) because of fewer general practitioner referrals. Weekend admissions were sicker than weekday (mean NEWS 1.8 vs 1.7, p=0.008), more likely to undergo transfer to ICU within 24 hours (4.2% vs 3.0%), spent longer in hospital (median 3 days vs 2 days) and less likely to experience same-day discharge (17.2% vs 21.9%) (all p values <0.001).The crude 30-day postadmission mortality ratio for weekend admission (OR=1.13; 95% CI 1.08 to 1.19) was attenuated using standard adjustment (OR=1.11; 95% CI 1.05 to 1.17). In patients for whom NEWS values were available (90%), the crude OR (1.07; 95% CI 1.01 to 1.13) was not affected with standard adjustment. Adjustment using NEWS alone nullified the weekend effect (OR=1.02; 0.96–1.08).NEWS completion rates were higher on weekends (91.7%) than weekdays (89.5%). Missing NEWS was associated with direct transfer to intensive care bypassing electronic data capture. Missing NEWS in non-ICU weekend patients was associated with a higher mortality and fewer same-day discharges than weekdays.ConclusionsPatients admitted to hospital on weekends are sicker than those admitted on weekdays. The cause of the weekend effect may lie in community services.
Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma
Authors: Job Sylvie , Draskovic Irena , Burnichon Nelly , Buffet Alexandre , Cros Jérôme , Lépine Charles , Venisse Annabelle , Robidel Estelle , Verkarre Virginie , Meatchi Tchao , Sibony Mathilde , Amar Laurence , Bertherat Jérôme , de Reyniès Aurélien , Londoño-Vallejo Arturo , Favier Judith , Castro-Vega Luis Jaime , Gimenez-Roqueplo Anne-Paule 
Published: October 2018

Abstract

Purpose:
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with SDHB- and FH-mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression.
Experimental Design: Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of TERT comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and ATRX mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.

Results:
Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in SDHB-mutated paragangliomas (P = 2.42e−09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group (P = 0.169), yet ATRX mutations were found preferentially in SDHB/FH-mutated metastatic tumors (P = 0.0014). Telomerase activation and ATRX mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; P = 6.50E−07 and 1.90E−07, respectively); OS (hazard ratio, 97.4 and 44.1; P = 4.30E−03 and 2.00E−03, respectively) and were associated with worse MFS and OS (log-rank tests P &lt; 0.0001).

Conclusions:
Assessment of telomerase activation and ATRX mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.
Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma
Authors: Gupta Sumati , Albertson Daniel J. , Parnell Timothy J. , Butterfield Andrew , Weston Alexis , Pappas Lisa M. , Dalley Brian , O’Shea John M. , Lowrance William T. , Cairns Bradley R. , Schiffman Joshua D. , Sharma Sunil 
Published: October 2018

Abstract
Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had ARID1A mutations. ARID1A mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant ARID1A-mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies ARID1A loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.
Polygenic Risk Score for Coronary Heart Disease Modifies the Elevated Risk by Cigarette Smoking for Disease Incidence
Authors: Hindy George , Wiberg Frans , Almgren Peter , Melander Olle , Orho-Melander Marju 
Published: October 2018

Background:
Coronary heart disease (CHD) is a multifactorial disease with both genetic and environmental components. Smoking is the most important modifiable risk factor for CHD. Our aim was to test whether the increased CHD incidence by smoking is modified by genetic predisposition to CHD.

Methods and Results:

Our study included 24 443 individuals from the MDCS (Malmö Diet and Cancer Study). A weighted polygenic risk score (PRS) was created by summing the number of risk alleles for 50 single-nucleotide polymorphisms associated with CHD. Individuals were classified as current, former, or never smokers. Interactions were primarily tested between smoking status and PRS and secondarily with individual single-nucleotide polymorphisms. Then, the predictive use of PRS for CHD incidence was tested among different smoking categories. During a median follow-up time of 19.4 years, 3217 incident CHD cases were recorded. The association between smoking and CHD was modified by the PRS (
P
interaction
=0.005). The magnitude of increased incidence of CHD by smoking was highest among individuals in the lowest tertile of PRS (odds ratio, 1.42; 95% confidence interval, 1.29–1.56 per smoking risk category) compared with the highest tertile (odds ratio, 1.20; 95% confidence interval, 1.11–1.30 per smoking risk category). This interaction was stronger among men (
P
interaction
=0.001) compared with women (
P
interaction
=0.44). The PRS provided a significantly better net reclassification and discrimination on top of traditional risk factors among never smokers compared with current smokers (
P
<0.001).

Conclusions:
Genetic predisposition to CHD modifies the associated increased CHD risk by smoking. The PRS has a better predictive use among never smokers compared with smokers.
Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults
Authors: Zhu Na , Gonzaga-Jauregui Claudia , Welch Carrie L. , Ma Lijiang , Qi Hongjian , King Alejandra K. , Krishnan Usha , Rosenzweig Erika B. , Ivy D. Dunbar , Austin Eric D. , Hamid Rizwan , Nichols William C. , Pauciulo Michael W. , Lutz Katie A. , Sawle Ashley , Reid Jeffrey G. , Overton John D. , Baras Aris , Dewey Frederick , Shen Yufeng , Chung Wendy K. 
Published: October 2018

Background:

Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although
BMPR2
mutations underlie ≈70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood.

Methods:
We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing.

RESULTS:

We observed similar frequencies of rare, deleterious
BMPR2
mutations in pediatric- and adult-onset patients: ≈55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of
TBX4
mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset), and
TBX4
carriers had younger mean age-of-onset compared with
BMPR2
carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene-damaging and predicted deleterious missense variants.

Conclusions:

Mutations in known PAH risk genes accounted for ≈70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in
TBX4
are enriched in pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases.
Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection
Authors: Kaadan M. Ihsan , MacDonald Carolyn , Ponzini Francesca , Duran Jessica , Newell Kelsey , Pitler Linda , Lin Angela , Weinberg Ido , Wood Malissa J. , Lindsay Mark E. 
Published: October 2018

Background:
Previous studies describing genetics evaluation in spontaneous coronary artery dissection (SCAD) have been retrospective in nature or presented as single case reports. As part of a dedicated clinical program, we evaluated patients in cardiovascular genetics clinic to determine the role of genetically triggered vascular disease and genetic testing in SCAD.

Methods and Results:

Patient data were entered prospectively into the Massachusetts General Hospital SCAD registry database from July 2013 to September 2017. Clinically indicated genetic testing was conducted based on patient imaging, family history, physical examination, and patient preference. Of the 107 patients enrolled in the registry, 73 underwent cardiovascular genetics evaluation at our center (average age, 45.3±9.4 years; 85.3% female), and genetic testing was performed for 44 patients. A family history of aneurysm or dissection was not a prevalent feature in the study population, and only 1 patient had a family history of SCAD. Six patients (8.2%) had identifiable genetically triggered vascular disease: 3 with vascular Ehlers–Danlos syndrome (
COL3A1
), 1 with Nail–patella syndrome (
LMX1B
), 1 with autosomal dominant polycystic kidney disease (
PKD1
), and 1 with Loeys–Dietz syndrome (
SMAD3
). None of these 6 had radiographic evidence of fibromuscular dysplasia.

Conclusions:
In this series, 8.2% of the SCAD patients evaluated had a molecularly identifiable disorder associated with vascular disease. The most common diagnosis was vascular Ehlers–Danlos syndrome. Patients with positive gene testing were significantly younger at the time of their first SCAD event. A low threshold for genetic testing should be considered in patients with SCAD.