[Show abstract][Hide abstract] ABSTRACT: Stenotrophomonas maltophilia causes serious infections in immunocompromised hosts. Here, we analyzed the clinical characteristics of S. maltophilia bloodstream infection (BSI) in patients with hematologic malignancies and evaluated in vitro synergistic effects of antimicrobial combinations.
We retrospectively reviewed all consecutive episodes of S. maltophilia BSIs in adult hematologic patients from June 2009 to May 2014, with in vitro susceptibility and synergy tests using high-throughput bioluminescence assay performed for available clinical isolates.
Among 11,004 admissions during 5-year period, 31 cases were identified as S. maltophilia BSIs. The incidence rate of S. maltophilia BSI was 0.134 cases/1,000 patient-days. Overall and attributable mortality of S. maltophilia BSI was 64.5% and 38.7%, respectively. Severe neutropenia (adjusted hazard ratio [HR] 5.24, p =0.013), shock at the onset of BSI (adjusted HR 6.05, p <0.001), and pneumonia (adjusted HR 3.15, p =0.017) were independent risk factors for mortality. In vitro susceptibilities to ceftazidime, levofloxacin, ticarcillin-clavulanic acid (TIM) and trimethoprim-sulfamethoxazole (SXT) were 11.1%, 44.0%, 40.7%, and 88.9%, respectively. MIC50/MIC90 for moxifloxacin and tigecycline were 1/4 mg/L and 4/8 mg/L. The 50% and 90% fractional inhibitory concentrations (FIC(50)/FIC(90)) of clinical isolates against a combination of SXT and TIM were 0.500/0.750. For SXT plus levofloxacin or moxifloxacin, FIC(50)/FIC(90) were 0.625/1.000 and 0.625/0.625, respectively.
S. maltophilia BSIs show high mortality, which is related to severe neutropenia, shock, and S. maltophilia pneumonia. Based upon drug susceptibility testing, the primary treatment of choice for S. maltophilia BSIs should be SXT in hematologic patients, rather than quinolones, with combination therapies including SXT serving as a feasible treatment option.
[Show abstract][Hide abstract] ABSTRACT: Human infection caused by Shewanella algae is rare, which usually occurred after direct contact with seawater or ingestion of raw seafood in the immunocompromised host. There have been anecdotal reports about Shewanella infections in human, but their pathogenic role and microbiologic data are limited. Here, we report a fatal case of spontaneous bacterial peritonitis with bacteremia due to S. algae in a 57-year-old male with liver cirrhosis who had no history of exposure to seawater or raw seafood. Polymicrobial infection with Streptococcus mitis and Escherichia coli was combined and the patient died in spite of early appropriate antimicrobial therapy and early goal-directed therapy for sepsis.
[Show abstract][Hide abstract] ABSTRACT: Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established.
In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L.
A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively).
While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.
[Show abstract][Hide abstract] ABSTRACT: AIM: The aim of this study was to investigate the genotypes of mupirocin-resistant methicillin-resistant Staphylococcus aureus (MR-MRSA) isolates in our neonatal intensive care unit (NICU) and their potential source. STUDY DESIGN: One hundred one MRSA isolates obtained from 59 inborn and 42 outborn infants were identified and their antimicrobial susceptibility determined. Using pulse-field gel electrophoresis (PFGE) analysis, MR-MRSA isolates obtained from the neonatal patients in the NICU were compared with those from adult hospitalized in the same hospital and with community-associated MRSA (CA-MRSA) isolates recovered from different hospitals in Korea. RESULTS: Overall, 47% of CA-MRSA and 79% of healthcare-associated MRSA isolates exhibited high-level mupirocin resistance (HLMR). Forty-five percent of the outborn infants were considered to have CA-MRSA at the time of admission to our NICU. Most HLMR-MRSA isolates from neonates were grouped into a single cluster by PFGE analysis, and which included CA-MRSA isolates with HLMR recovered from outborn infants who were already colonized when they were transferred to our NICU. They belonged to the same PFGE group as the community-genotype strains isolated from different hospitals in Korea. HLMR-MRSA isolates from adults patients were classified as different clones. None of the attending staff in the NICU were nasal carriers. CONCLUSION: Community-genotype strains of MRSA with HLMR may be imported to our NICU through obstetrics clinics and contribute to MRSA colonization or infection in facilities with a high rate of admission of outborn infants.
Early human development 05/2013; 89(9). DOI:10.1016/j.earlhumdev.2013.04.014 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Haemophilus influenzae frequently colonizes the nasopharynx of children and adults, which can lead to a variety of infections. We investigated H. influenzae carriage in the nasopharynx of 360 children, in terms of (1) the prevalence of strains with decreased susceptibility, and (2) the presence of amino acid substitutions in PBP3. One hundred twenty-three strains were isolated (34.2%, 123/360), 122 of which were classified as nontypable H. influenzae (NTHi). Of these, β-lactamase-nonproducing ampicillin-susceptible strains accounted for 26.2%, β-lactamase-producing-ampicillin-resistant strains for 9.0%, β-lactamase-nonproducing ampicillin-resistant (BLNAR) strains for 40.2%, and β-lactamase-producing amoxicillin-/clavulanic acid-resistant (BLPACR) for 24.6%, respectively. Pulsed field gel electrophoresis (PFGE) patterns were so diverse that they were clustered into 41 groups. The amino acid substitutions in the transpeptidase domain (292 amino acids) of ftsI in BLNAR isolates showed that group IIb accounted for 30.6%, IIc for 8.2%, IId for 16.3%, III for 32.7%, and the others for 12.2%. Moreover, groups IIb (56.7%; 17/30) and III (23.3%; 7/30) were prevalent among BLPACR strains. They were subclassified into more diverse sequence subtypes by analysis of the entire PBP3 (610 amino acids). Groups IIb, IIc, IId, and III exhibited 13, four, six, and four sequence subtypes, respectively. Such a genetic diversity is likely indicative of significant potential for decreased antimicrobial susceptibility in nasopharyngeal-colonizing NTHi strains.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has been increased not only in the hospital but also in the community worldwide. This study was aimed to characterize ESBL- producing E. coli isolates and to investigate the molecular epidemiology of community isolates in comparison with hospital isolates at a single center in Korea.
A total of 142 ESBL-producing E. coli isolates were collected at Daejeon St Mary's Hospital in Korea from January 2008 to September 2009. The ESBLs were characterized by PCR sequencing using specific primers. The genetic relatedness was determined by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST).
Of 142 isolates, 139 were positive for CTX-M type ESBLs; CTX-M-14 (n = 69, 49.6 %), CTX-M-15 (n = 53, 38.1 %) and both CTX-M-14 and -15 (n = 17, 12.2 %). CTX-M-14 and CTX-M-15 were detected in both community and hospital isolates whereas isolates producing both CTX-M14 and-15 were mainly identified in the hospital. CTX-M producing E. coli isolates were genetically heterogeneous, revealing 75 distinct PFGE types. By MLST, 21 distinctive STs including 5 major STs (ST131, ST405, ST38, ST10, and ST648) were identified. Major STs were distributed in both community and hospital isolates, and ST131 was the predominant clone regardless of the locations of acquisition. No specific major STs were confined to a single type of ESBLs. However, ST131 clones were significantly associated with CTX-M-15 and the majority of them were multidrug-resistant. Distinctively, we identified a hospital epidemic caused by the dissemination of an epidemic strain, ST131-PFGE type 10, characterized by multidrug resistance and co-producing both CTX-Ms with OXA-1 or TEM-1b.
The epidemiology of ESBL-producing E. coli is a complex and evolving phenomenon attributed to the horizontal transfer of genetic elements and clonal spread of major clones, predominantly ST131. The multidrug resistant ST131 clone producing CTX-M-15 has emerged as a major clone in both the community and hospital, suggesting the widespread of this epidemic clone in Korea.
[Show abstract][Hide abstract] ABSTRACT: Reduced vancomycin susceptibility in Staphylococcus aureus can cause serious problems relating to treatment failure and persistent infection. We investigated vancomycin susceptibility, genetic relationships and transcriptional changes of the accessory gene regulator (agr) in vancomycin-intermediate S. aureus (VISA) strains isolated from South Korea compared with vancomycin-susceptible S. aureus (VSSA) strains. Molecular characterization, population analysis profiling, agr sequencing and transcriptional profiling of RNAIII by real-time RT-PCR were performed. Of 16 VISA strains tested, eight exhibited ST5, agr II and type II SCCmec. The others exhibited ST239, agr I and type III SCCmec. A point mutation in AgrA (Asp8Gly or Ile238Lys) was found in only five VISA strains; no mutations were detected in the other strains. However, RNAIII levels markedly decreased in all VISA strains (mean of 1.39-fold change) compared with the VSSA strains (31.51-fold change) in late-exponential phases (P<0.0001). The downregulation of RNAIII could be an important genetic event in the VISA strains, regardless of the presence or absence of the agr mutation.
Journal of Medical Microbiology 03/2012; 61(Pt 3):345-52. DOI:10.1099/jmm.0.035204-0 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Monitoring the response to therapy for invasive aspergillosis (IA) is essential for the management of patients with hematologic diseases. We evaluated the correlation between the outcome of real-time nucleic acid sequence-based amplification (RTi-NASBA) for Aspergillus 18S rRNA and the clinical outcome of IA. A total of 157 serum samples from 29 patients with IA were tested for RTi-NASBA. The treatment response and mortality were compared with the NASBA outcome (whether the NASBA value was converted to negative or not) at 12 weeks after the start of antifungal therapy. At 12 weeks, there was a moderate correlation between the treatment failure and persistently positive NASBA (κ = 0.482; P = 0.019). Deaths attributable to IA were more prevalent in patients without negative conversion of NASBA than in those with negative conversion (50% vs 5%; P = 0.013). Significant factors of treatment failure at 12 weeks were the status of hematologic disease (nonremission; P = 0.041) and the NASBA outcome (failure of negative conversion; P = 0.024). Survival was significantly better in patients with negative conversion of NASBA than those with persistently positive values (P = 0.036). This study suggests that the serial monitoring of RTi-NASBA could be useful for prediction of the clinical outcome in hematologic patients with IA.
Journal of Korean medical science 01/2012; 27(1):10-5. DOI:10.3346/jkms.2012.27.1.10 · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the ability of infrequent restriction site-polymerase chain reaction (IRS-PCR) to perform molecular epidemiologic analysis of Community-Onset Extended Spectrum Beta-Lactamase (ESBL) producing Escherichia coli, and also assessed the use of PFGE as an alternative method.
[Show abstract][Hide abstract] ABSTRACT: Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species. However, despite its potential advantages, the occurrence of unpredictable toxicities might be critical in immunocompromised patients. The aim of this study was to analyze risk factors for voriconazole-related severe adverse events (SAEs).
This prospective observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009.
Of the 25 patients enrolled, eight (32%) showed voriconazole-related SAEs, which included hepatotoxicities (n=5), cardiac tachyarrhythmias (n=2), and neurotoxicity (n=1). Sex, age, underlying hematological malignancies, voriconazole dose, the co-administration of a proton pump inhibitor, and CYP2C19 genotype were not found to be related to the occurrence of SAEs. However, trough plasma concentrations of voriconazole were found to be significantly higher in the patients with an SAE: median 6.32 mg/l (interquartile range (IQR) 2.86-9.71 mg/l) vs. median 2.15 mg/l (IQR 0.92-4.00 mg/l); p=0.011. Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l (sensitivity 62.5% and specificity 94.1%). Furthermore, multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE.
This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 08/2011; 15(11):e753-8. DOI:10.1016/j.ijid.2011.06.004 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) isolated at 10 intensive care units (ICUs) in Korea. MRSA isolates from bacteremia and nasal colonization were collected prospectively from October 2008 through May 2009 at 10 University-affiliated hospital ICUs. A total of 83 and 175 MRSA strains were isolated from bacteremia and nasal colonization, respectively. Acquired group accounted for 69.9% (n = 58) of bacteremia and 73.1% (n = 128) of nasal colonization. Pulsed-field gel electrophoresis (PFGE) type B (SCCmec type II/ST5) was dominant in the acquired group followed by PFGE type D (SCCmec type IVA/ST72; a community genotype). Seven of 58 (12.1%) acquired bacteremia and 15 of 128 (11.8%) acquired nasal colonizations had SCCmec type IVA/ST72 genotype, which indicated that the community genotype had already emerged as a cause of ICU acquired MRSA infection or colonization. Antibiotic resistance rates to ciprofloxacin, tetracycline, clindamycin and trimethoprim/ sulfamethoxazole were 84.4%, 67.1%, 78.1%, and 12.0%, respectively. Susceptibility to ciprofloxacin best predicted a community genotype (sensitivity 96.5%; specificity 96.9%; odds ratio 861; 95% confidence interval 169-4,390, P < 0.001) and the positive predictive value was 90.2%. Among 23 nasal re-colonized strains, 7 MRSA strains (30.4%) were different from the originally colonized strains on the basis of PFGE types.
Journal of Korean medical science 05/2011; 26(5):604-11. DOI:10.3346/jkms.2011.26.5.604 · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the usefulness of infrequent-restriction-site polymerase chain reaction (IRS-PCR) compared with pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) on the molecular epidemiologic analysis of methicillin-resistant Staphylococcus aureus (MRSA).
[Show abstract][Hide abstract] ABSTRACT: We attempted to apply fluorescence resonance energy transfer technology to nucleic acid sequence-based amplification (FRET-NASBA) on the platform of the LightCycler system to detect Aspergillus species. Primers and probes for the Aspergillus 18S rRNA were newly designed to avoid overlapping with homologous sequences of human 18s rRNA. NASBA using molecular beacon (MB) showed non-specific results which have been frequently observed from controls, although it showed higher sensitivity (10(-2) amol) than the FRET. FRET-NASBA showed a sensitivity of 10(-1) amol and a high fidelity of reproducibility from controls. As FRET technology was successfully applied to the NASBA assay, it could contribute to diverse development of the NASBA assay. These results suggest that FRET-NASBA could replace previous NASBA techniques in the detection of Aspergillus.
Medical mycology: official publication of the International Society for Human and Animal Mycology 01/2011; 49(1):73-9. DOI:10.3109/13693786.2010.507604 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Staphylococcus aureus is one of the most important gram-positive pathogens in many clinical situations. Use of vancomycin against methicillin resistant S aureus (MRSA) has been anecdotally associated with treatment failure, which could be attributable to an inoculum effect (IE). Using a neutropenic mouse thigh infection model, we tried to evaluate the in vivo IE of vancomycin against S. aureus.
[Show abstract][Hide abstract] ABSTRACT: Over a 6-year period (March 2000-February 2006), there were 60 vancomycin-resistant Enterococcus faecium (VREF) bloodstream infections (BSIs) in a hematology unit, accounting for 83.3% of all VREF BSIs in the hospital. We investigated 49 VREF isolates causing BSIs in patients with neutropenia to understand the molecular epidemiology at this unit. All isolates had the vanA genotype. Pulsed-field gel electrophoresis typing revealed high clonal diversity (23 types with nine clusters comprising 35 isolates) and 1 predominant type, type A (14/49, 28.6%), persisted at this unit throughout the study period, suggesting the clonal spread of this endemic strain by cross-contamination. Tn1546 types were less heterogeneous, with five main Tn1546 types, two of which (types I and IV) accounted for 67.4% of isolates. This indicates that in addition to clonal spread, the horizontal transfer of Tn1546 played a major role in the nosocomial dissemination of vancomycin resistance. The genetic diversity of VREF increased over time, implying an increasing influx of new strains into the unit and genetic changes, possibly attributable to the horizontal transfer of diverse Tn1546 types. Despite such diversity, all the isolates belonged to clonal complex 17, which is the epidemic clone worldwide, enriched with the esp (35/49, 71.4%) and hyl (24/49, 48.9%) virulence genes. This hospital-adapted clone has become endemic and is well suited to causing BSIs in patients with neutropenia in this unit.
[Show abstract][Hide abstract] ABSTRACT: Community-associated methicillin resistant Staphylococcus aureus (CAMRSA) infections are increasing. Although gentamicin (GEN) is usually susceptible against CA-MRSA, GEN is rarely considered for treatment as monotherapy. We employed an in vitro pharmacodynamic model (IVPDM) to compare efficacies of GEN against CA-MRSA with two dosing regimens [thrice-daily (TD), once-daily (OD)].
Using two strains of CA-MRSA, we adopted IVPDM comprised of two-compartments with a surface-to-volume ratio of 5.34 cm(-1). GEN regimens were simulated with human pharmacokinetic data of TD and OD. Experiments were performed over 48 hours in triplicate for each strain and dosing regimen.
MICs of GEN for YSSA1 and YSSA15 were 1 and 2 mg/L, respectively. In OD, indices of peak/MIC were > 8.6 at least, in contrast to < 6.4 in TD. A > or = 3-log(10) reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD, and continued until 8 hours for both strains. However, reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001). During TD, resistance developed in YSSA1 and small colony variants (SCVs) were documented in YSSA15. No resistance or SCVs were observed during OD in both strains.
TD and OD showed the same killing slopes until 8 hours. After the 24 hours of experiments, OD of GEN would be advantageous not only in having more reductions in colony counts, but also suppressing the development of resistance or SCVs for 48 hours.
Yonsei medical journal 09/2010; 51(5):722-7. DOI:10.3349/ymj.2010.51.5.722 · 1.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the effects of peroxisome proliferator-activated receptor-γ (PPAR-γ) on the production of tumor necrosis factor-α (TNF-α) and expression of nuclear factor-κB (NF-κB) in stimulated THP-1 cells, a human monocyte cell line.
[Show abstract][Hide abstract] ABSTRACT: Meticillin-resistant Staphylococcus aureus (MRSA) strains harbouring staphylococcal cassette chromosome mec (SCCmec) type IVA are known to be more prevalent in South Korea than in other countries. Variations in the SCCmec IVA structure have been identified, including in sequence type (ST) 1 and ST72 strains. This study compared and investigated the genetic characteristics of two subtypes common in South Korea. Type IVA SCCmec of ST1 strains was characterized by type IV features with the linearized pUB110 at the junkyard (J) 3 region. However, that of ST72 strains carried a variant class B mec complex, ccrA2, with an identity of approximately 96 % and the linearized pUB110 at the J3 region. In SCCmec of ST72 strains, the organization of the class B variant and the J3 region may be more similar to that of type IA than to other types, but the ccr type and other J regions seemed to be derived from type IV. These genetic characteristics showed that type IVA appears to result from the dynamic genetic exchange and recombination of SCC DNA.
Journal of Medical Microbiology 08/2009; 58(Pt 10):1314-21. DOI:10.1099/jmm.0.009688-0 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) endocarditis has rarely been reported in healthy individuals without risk factors, such as skin and soft tissue infections, and intravenous drug abuse. We describe a case of infective endocarditis by CA-MRSA (ST72-PVL negative-SCCmec IVA) in previously healthy individuals with no underlying medical condition and CA-MRSA colonization in the family.
Yonsei medical journal 03/2009; 50(1):152-5. DOI:10.3349/ymj.2009.50.1.152 · 1.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains causing bloodstream infection (BSI) has not been studied in Korea.
We sought to determine the prevalence of CA-MRSA strains among isolates recovered from patients with MRSA BSIs and to explore epidemiological changes in Korea. We also sought to evaluate clinical characteristics relevant to the development of healthcare-associated BSIs.
We prospectively collected consecutive MRSA isolates from patients with BSI at 4 hospitals from July 1 through November 30, 2007, and we also included MRSA isolates recovered from culture of blood samples collected during a previous year (October 1, 2004 through September 30, 2005) at a different hospital. Molecular typing studies were performed, including pulsed-field gel electrophoresis (PFGE), multilocus sequence typing, Staphylococcus protein A (spa) typing, and staphylococcal cassette chromosome mec (SCCmec) typing. We compared the clinical characteristics and outcomes of patients with healthcare-associated BSI due to CA-MRSA strains with those of patients with healthcare-associated BSI due to healthcare-associated MRSA (HA-MRSA) strains.
There were 76 cases of MRSA BSI, of which 4 (5.3%) were community-associated and 72 (94.7%) were healthcare-associated. Among the 72 HA-MRSA BSIs, 18 (25%) were community onset, and 54 (75%) were hospital onset. PFGE type D-ST72-spa B-SCCmec type IVA MRSA, the predominant genotype of CA-MRSA in Korea, accounted for 19 (25%) of all 76 MRSA BSIs, including 17 (23.6%) of 72 HA-MRSA BSIs and 11 (20.8%) of 53 hospital-onset HA-MRSA BSIs. Patients with healthcare-associated BSIs due to CA-MRSA strains carrying SCCmec type IVA tended to have fewer healthcare-associated risk factors, compared with patients with healthcare-associated BSIs due to HA-MRSA strains carrying other SCCmec types. The presence of a central venous catheter or other invasive device was the only independent factor differentiating patients infected with hospital-associated genotype strains from patients infected with other strains. Clinical outcomes were similar between both groups.
CA-MRSA strains are emerging as a major cause of BSI in healthcare settings in Korea. This changing epidemiology of MRSA poses a challenge to public health and infection control in hospital settings.
Infection Control and Hospital Epidemiology 02/2009; 30(2):146-55. DOI:10.1086/593953 · 3.94 Impact Factor