Effect of 7 vs 14 Days of Antibiotic Therapy on Resolution of Symptoms Among Afebrile Men With Urinary Tract Infection: A Randomized Clinical Trial.

Importance: Determination of optimal treatment durations for common infectious diseases is an important strategy to preserve antibiotic effectiveness. Objective: To determine whether 7 days of treatment is noninferior to 14 days when using ciprofloxacin or trimethoprim/sulfamethoxazole to treat urinary tract infection (UTI) in afebrile men. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled noninferiority trial of afebrile men with presumed symptomatic UTI treated with ciprofloxacin or trimethoprim/sulfamethoxazole at 2 US Veterans Affairs medical centers (enrollment, April 2014 through December 2019; final follow-up, January 28, 2020). Of 1058 eligible men, 272 were randomized. Interventions: Participants continued the antibiotic prescribed by their treating clinician for 7 days of treatment and were randomized to receive continued antibiotic therapy (n = 136) or placebo (n = 136) for days 8 to 14 of treatment. Main Outcomes and Measures: The prespecified primary outcome was resolution of UTI symptoms by 14 days after completion of active antibiotic treatment. A noninferiority margin of 10% was selected. The as-treated population (participants who took ≥26 of 28 doses and missed no more than 2 consecutive doses) was used for the primary analysis, and a secondary analysis included all patients as randomized, regardless of treatment adherence. Secondary outcomes included recurrence of UTI symptoms and/or adverse events within 28 days of stopping study medication. Results: Among 272 patients (median [interquartile range] age, 69 [62-73] years) who were randomized, 100% completed the trial and 254 (93.4%) were included in the primary as-treated analysis. Symptom resolution occurred in 122/131 (93.1%) participants in the 7-day group vs 111/123 (90.2%) in the 14-day group (difference, 2.9% [1-sided 97.5% CI, -5.2% to ∞]), meeting the noninferiority criterion. In the secondary as-randomized analysis, symptom resolution occurred in 125/136 (91.9%) participants in the 7-day group vs 123/136 (90.4%) in the 14-day group (difference, 1.5% [1-sided 97.5% CI, -5.8% to ∞]) Recurrence of UTI symptoms occurred in 13/131 (9.9%) participants in the 7-day group vs 15/123 (12.9%) in the 14-day group (difference, -3.0% [95% CI, -10.8% to 6.2%]; P = .70). Adverse events occurred in 28/136 (20.6%) participants in the 7-day group vs 33/136 (24.3%) in the 14-day group. Conclusions and Relevance: Among afebrile men with suspected UTI, treatment with ciprofloxacin or trimethoprim/sulfamethoxazole for 7 days was noninferior to 14 days of treatment with regard to resolution of UTI symptoms by 14 days after antibiotic therapy. The findings support the use of a 7-day course of ciprofloxacin or trimethoprim/sulfamethoxazole as an alternative to a 14-day course for treatment of afebrile men with UTI. Trial Registration: ClinicalTrials.gov identifier: NCT01994538.

Predictive Value of the Cognitive Performance Test (CPT) for Staging Function and Fitness to Drive in People With Neurocognitive Disorders.

The Cognitive Performance Test (CPT) is a standardized occupational therapy assessment that examines cognitive integration with functioning in an instrumental activities of daily living context. Conventional cognitive measures provide diagnostic utility but do not fully address the functional implications. Ninety-one veterans diagnosed with cognitive impairment were evaluated. We compared the predictive value of the CPT with the Large Allen Cognitive Level Screen (LACLS), Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA) for the need to retire from driving versus ability to pass an on-road exam. Measures were also analyzed by diagnostic classification. CPT correctly classified a mild versus major neurocognitive disorder, whereas MMSE, MoCA, and LACLS did not differentiate the groups. A CPT cutoff score of <4.7/5.6 showed 89% sensitivity for failing the road exam and 75% specificity for ability to pass. CPT discriminated functional level in neurocognitive disorders and had better predictive value for fitness to drive compared with conventional cognitive measures.

Environmental Contamination in Households of Patients with Recurrent Clostridium difficile Infection.

Recurrent Clostridium difficile infection (R-CDI) is common and difficult to treat, potentially necessitating fecal microbiota transplantation (FMT). Although C. difficilespores persist in the hospital environment and cause infection, little is known about their potential presence or importance in the household environment. Households of R-CDI subjects in the peri-FMT period and of geographically matched and age-matched controls were analyzed for the presence ofC. difficile Household environmental surfaces and fecal samples from humans and pets in the household were examined. Households of post-FMT subjects were also examined (environmental surfaces only). Participants were surveyed regarding their personal history and household cleaning habits. Species identity and molecular characteristics of presumptive C. difficile isolates from environmental and fecal samples were determined by using the Pro kit (Remel, USA), Gram staining, PCR, toxinotyping, tcdC gene sequencing, and pulsed-field gel electrophoresis (PFGE). Environmental cultures detected C. difficile on ≥1 surface in 8/8 (100%) peri-FMT households, versus 3/8 (38%) post-FMT households and 3/8 (38%) control households (P= 0.025). The most common C. difficile-positive sites were the vacuum (11/27; 41%), toilet (8/30; 27%), and bathroom sink (5/29; 17%).C. difficile was detected in 3/36 (8%) fecal samples (two R-CDI subjects and one household member). Nine (90%) of 10 households with multiple C. difficile-positive samples had a single genotype present each. In conclusion,C. difficile was found in the household environment of R-CDI patients, but whether it was found as a cause or consequence of R-CDI is unknown. If household contamination leads to R-CDI, effective decontamination may be protective.

Intensity and Mechanisms of Fluoroquinolone Resistance within the H30 and H30Rx Subclones of Escherichia coli Sequence Type 131 Compared with Other Fluoroquinolone-Resistant E. coli.

The recent expansion of the H30 subclone of Escherichia coli sequence type 131 (ST131) and its CTX-M-15-associated H30Rx subset remains unexplained. Although ST131 H30 typically exhibits fluoroquinolone resistance, so do multiple other E. coli lineages that have not expanded similarly. To determine whether H30 isolates have more intense fluoroquinolone resistance than other fluoroquinolone-resistant E. coli isolates and to identify possible mechanisms, we determined the MICs for four fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, and norfloxacin) among 89 well-characterized, genetically diverse fluoroquinolone-resistant E. coli isolates (48 non-H30 and 41 H30 [23 H30Rx and 18 H30 non-Rx]). We compared the MICs with the H30 and H30Rx status, the presence/number of nonsynonymous mutations in gyrA, parC, and parE, the presence of aac(6')-1b-cr (an aminoglycoside/fluoroquinolone agent-modifying enzyme), and the efflux pump activity (measured as organic solvent tolerance [OST]). Among 1,518 recent E. coli clinical isolates, ST131 H30 predominated clonally, both overall and among the fluoroquinolone-resistant isolates. Among the 89 study isolates, compared with non-H30 isolates, H30 isolates exhibited categorically higher MICs for all four fluoroquinolone agents, higher absolute ciprofloxacin and norfloxacin MICs, more nonsynonymous mutations in gyrA, parC, and parE (specifically gyrA D87N, parC E84V, and parE I529L), and a numerically higher prevalence of (H30Rx-associated) aac(6')-1b-cr but lower OST scores. All putative resistance mechanisms were significantly associated with the MICs [for aac(6')-1b-cr: ciprofloxacin and norfloxacin only]. parC D87N corresponded with ST131 H30 and parE I529L with ST131 generally. Thus, more intense fluoroquinolone resistance may provide ST131 H30, especially H30Rx [if aac(6')-1b-cr positive], with subtle fitness advantages over other fluoroquinolone-resistant E. coli strains. This urges both parsimonious fluoroquinolone use and a search for other fitness-enhancing traits within ST131 H30.

Variation in resistance traits, phylogenetic backgrounds, and virulence genotypes among Escherichia coli clinical isolates from adjacent hospital campuses serving distinct patient populations.

Escherichia coli sequence type 13 (ST131), an emergent cause of multidrug-resistant extraintestinal infections, has important phylogenetic subsets, notably the H30 and H30Rx subclones, with distinctive resistance profiles and, possibly, clinical associations. To clarify the local prevalence of these ST131 subclones and their associations with antimicrobial resistance, ecological source, and virulence traits, we extensively characterized 233 consecutive E. coli clinical isolates (July and August 2013) from the University of Minnesota Medical Center-Fairview Infectious Diseases and Diagnostic Laboratory, Minneapolis, MN, which serves three adjacent facilities (a children's hospital and low- and high-acuity adult facilities). ST131 accounted for 26% of the study isolates (more than any other clonal group), was distributed similarly by facility, and was closely associated with ciprofloxacin resistance and extended-spectrum ß-lactamase (ESBL) production. The H30 and H30Rx subclones accounted for most ST131 isolates and for the association of ST131 with fluoroquinolone resistance and ESBL production. Unlike ST131 per se, these subclones were distributed differentially by hospital, being most prevalent at the high-acuity adult facility and were absent from the children's hospital. The virulence gene profiles of ST131 and its subclones were distinctive and more extensive than those of other fluoroquinolone-resistant or ESBL-producing isolates. Within ST131, bla CTX-M-15 was confined to H30Rx isolates and other bla CTX-M variants to non-Rx H30 isolates. Pulsed-field gel electrophoresis documented a predominance of globally distributed pulsotypes and no local outbreak pattern. These findings help clarify the epidemiology, ecology, and bacterial correlates of the H30 and H30Rx ST131 subclones by documenting a high overall prevalence but significant segregation by facility, strong associations with fluoroquinolone resistance and specific ESBL variants, and distinctive virulence gene associations that may confer fitness advantages over other resistant E. coli.

Extraintestinal Pathogenic and Antimicrobial-Resistant Escherichia coli Contamination of 56 Public Restrooms in the Greater Minneapolis-St. Paul Metropolitan Area.

How extraintestinal pathogenic Escherichia coli (ExPEC) and antimicrobial-resistant E. coli disseminate through the population is undefined. We studied public restrooms for contamination with E. coli and ExPEC in relation to source and extensively characterized the E. coli isolates. For this, we cultured 1,120 environmental samples from 56 public restrooms in 33 establishments (obtained from 10 cities in the greater Minneapolis-St. Paul, MN, metropolitan area in 2003) for E. coli and compared ecological data with culture results. Isolates underwent virulence genotyping, phylotyping, clonal typing, pulsed-field gel electrophoresis (PFGE), and disk diffusion antimicrobial susceptibility testing. Overall, 168 samples (15% from 89% of restrooms) fluoresced, indicating presumptive E. coli: 25 samples (2.2% from 32% of restrooms) yielded E. coli isolates, and 10 samples (0.9% from 16% of restrooms) contained ExPEC. Restroom category and cleanliness level significantly predicted only fluorescence, gender predicted fluorescence and E. coli, and feces-like material and toilet-associated sites predicted all three endpoints. Of the 25 E. coli isolates, 7 (28%) were from phylogenetic group B2(virulence-associated), and 8 (32%) were ExPEC. ExPEC isolates more commonly represented group B2 (50% versus 18%) and had significantly higher virulence gene scores than non-ExPEC isolates. Six isolates (24%) exhibited ≥3-class antibiotic resistance, 10 (40%) represented classic human-associated sequence types, and one closely resembled reference human clinical isolates by pulsed-field gel electrophoresis. Thus, E. coli, ExPEC, and antimicrobial-resistant E. coli sporadically contaminate public restrooms, in ways corresponding with restroom characteristics and within-restroom sites. Such restroom-source E. coli strains likely reflect human fecal contamination, may pose a health threat, and may contribute to population-wide dissemination of such strains.

Temporal trends in antimicrobial resistance and virulence-associated traits within the Escherichia coli sequence type 131 clonal group and its H30 and H30-Rx subclones, 1968 to 2012.

To identify possible explanations for the recent global emergence of Escherichia coli sequence type (ST) 131 (ST131), we analyzed temporal trends within ST131 O25 for antimicrobial resistance, virulence genes, biofilm formation, and the H30 and H30-Rx subclones. For this, we surveyed the WHO E. coli and Klebsiella Centre's E. coli collection (1957 to 2011) for ST131 isolates, characterized them extensively, and assessed them for temporal trends. Overall, antimicrobial resistance increased temporally in prevalence and extent, due mainly to the recent appearance of the H30 (1997) and H30-Rx (2005) ST131 subclones. In contrast, neither the total virulence gene content nor the prevalence of biofilm production increased temporally, although non-H30 isolates increasingly qualified as extraintestinal pathogenic E. coli (ExPEC). Whereas virotype D occurred from 1968 forward, virotypes A and C occurred only after 2000 and 2002, respectively, in association with the H30 and H30-Rx subclones, which were characterized by multidrug resistance (including extended-spectrum-beta-lactamase [ESBL] production: H30-Rx) and absence of biofilm production. Capsular antigen K100 occurred exclusively among H30-Rx isolates (55% prevalence). Pulsotypes corresponded broadly with subclones and virotypes. Thus, ST131 should be regarded not as a unitary entity but as a group of distinctive subclones, with its increasing antimicrobial resistance having a strong clonal basis, i.e., the emergence of the H30 and H30-Rx ST131 subclones, rather than representing acquisition of resistance by diverse ST131 strains. Distinctive characteristics of the H30-Rx subclone-including specific virulence genes (iutA, afa and dra, kpsII), the K100 capsule, multidrug resistance, and ESBL production-possibly contributed to epidemiologic success, and some (e.g., K100) might serve as vaccine targets.

Comparison of equations with estimate renal function to predict serum vancomycin concentration in patients with spinal cord injury--does the use of cystatin C improve accuracy?

BACKGROUND: Vancomycin dose selection is challenging in the spinal cord injury (SCI) population because of the difficulty in accurately estimating the renal function. Creatinine-based equations have been shown to be unreliable in this patient population. Adjusted equations designed for patients with SCI have not been well studied. Cystatin C is an alternative marker of renal function that is less affected by muscle mass and may offer improvement in estimating renal function leading to improved initial dose selection. OBJECTIVE: To compare the accuracy of serum creatinine- and serum cystatin C-based equations used in a pharmacokinetic (PK) model to predict steady-state serum vancomycin concentration in an SCI population. The rationale for this study is the need for an improved predictive model to guide initial vancomycin dose design before the availability of a measured steady-state serum concentration. METHODS: Patients with SCI receiving vancomycin with measured serum creatinine, cystatin C, and steady-state serum vancomycin concentration were identified. Serum creatinine- and cystatin C-based equations to estimate renal function were substituted into a population-based PK model to predict steady state-serum vancomycin concentration. Predictions using each equation in the model were compared with the measured steady-state serum vancomycin concentration. Predictive performances using each equation in the PK model were compared. RESULTS: The final study population included 37 patients with SCI. The Chronic Kidney Disease Epidemiology Collaboration cystatin C equation provided significantly less bias, greater precision, and superior accuracy when used in the PK model. CONCLUSIONS: In the SCI population, the use of Chronic Kidney Disease Epidemiology Collaboration cystatin C equation may improve initial vancomycin dosing. Further study into this potential is encouraged.

Brain amyloid-ß oligomers in ageing and Alzheimer's disease.

Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-ß aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-ß in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-ß aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-ß aggregates, including soluble amyloid-ß oligomers. Different soluble amyloid-ß oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-ß oligomers previously described in mouse models-amyloid-ß trimers, Aß*56 and amyloid-ß dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-ß trimers appear to be the fundamental amyloid-ß assembly unit of Aß*56 and are present in young mice prior to memory decline, amyloid-ß trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. Aß*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-ß dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between Aß*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between Aß*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-ß dimers or amyloid-ß trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-ß dimers, but the lowest levels of Aß*56 and amyloid-ß trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults Aß*56 increased ahead of amyloid-ß dimers or amyloid-ß trimers, and pathological tau proteins and postsynaptic proteins correlated with Aß*56, but not amyloid-ß dimers or amyloid-ß trimers. We propose that Aß*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

Association of stressful life events with incident falls and fractures in older men: the Osteoporotic Fractures in Men (MrOS) Study.

BACKGROUND: small, retrospective studies suggest that major life events and/or sudden emotional stress may increase fall and fracture risk. The current study examines these associations prospectively. METHODS: a total of 5,152 men aged ≥65 years in the Osteoporotic Fractures in Men study self-reported data on stressful life events for 1 year prior to study Visit 2. Incident falls and fractures were ascertained for 1 year after Visit 2. Fractures were centrally confirmed. RESULTS: a total of 2,932 (56.9%) men reported ≥1 type of stressful life event. In men with complete stressful life event, fall and covariate data (n = 3,949), any stressful life event was associated with a 33% increased risk of incident fall [relative risk (RR) 1.33, 95% confidence interval (CI) 1.19-1.49] and 68% increased risk of multiple falls (RR = 1.68, 95% CI = 1.40-2.01) in the year following Visit 2 after adjustment for age, education, Parkinson's disease, diabetes, stroke, instrumental activities of daily living (IADL) impairment, chair stand time, walk speed, multiple past falls, depressive symptoms and antidepressant use. Risk increased with the number of types of stressful life events. Though any stressful life event was associated with a 58% increased age-adjusted risk for incident fracture, this association was attenuated and no longer statistically significant after additional adjustment for total hip bone mineral density, fracture after age 50, Parkinson's disease, stroke and IADL impairment. CONCLUSIONS: in this cohort of older men, stressful life events significantly increased risk of incident falls independent of other explanatory variables, but did not independently increase incident fracture risk.

Internalizing disorder in adopted versus non-adopted adults: a NESARC based study.

The objective of the study consisted of comparing lifetime prevalence rates and odds ratios of anxiety, mood, and psychotic disorders in adopted-versus-non-adopted people in a nationally representative sample. The data were drawn from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). The main outcome measure was the prevalence of lifetime internalizing psychiatric disorders in adopted (n=378) versus non-adopted (n=42,503) individuals. Adoptees and non-adoptees were compared to estimate the odds of lifetime internalizing disorders using logistic regression analyses. Adoptees had higher prevalence rates of several lifetime mood and anxiety disorders compared with non-adoptees, with a 1.61-fold increase (95% CI 1.29-2.02) in the odds of any mood disorder and a 1.49-fold increase (95% CI 1.18-1.89) in the odds of any anxiety disorder compared with non-adoptees. Regarding specific mood and anxiety disorders, adoptees had increased odds of major depressive disorder, bipolar I disorder, panic disorder without agoraphobia, specific phobia, and generalized anxiety disorder. Disorders not differing between adoptees and non-adoptees included dysthymia, bipolar II disorder, panic disorder with agoraphobia, social phobia, and psychotic disorder. One adoption-specific risk factor was associated with lifetime mood disorder (i.e., Asian/Pacific Island). In conclusion, adoptees in a large sample from the general population had higher rates of mood and anxiety disorders compared to non-adoptees.

Soluble α-synuclein is a novel modulator of Alzheimer's disease pathophysiology.

Recent evidence has emphasized soluble species of amyloid-ß (Aß) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aß, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aß and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aß/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.

Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant pathogen among US veterans.

BACKGROUND: Escherichia coli sequence type 131 (ST131), typically fluoroquinolone-resistant (FQ-R) and/or extended-spectrum ß-lactamase (ESBL)-producing, has emerged globally. We assessed its prevalence and characteristics among US veterans. METHODS: In 2011, 595 de-identified E. coli clinical isolates were collected systematically within 3 resistance groups (FQ-susceptible [FQ-S], FQ-R, and ESBL-producing) from 24 nationally distributed Veterans Affairs Medical Centers (VAMCs). ST131 and its H30 subclone were detected by polymerase chain reaction and compared with other E. coli for molecular traits, source, and resistance profiles. RESULTS: ST131 accounted for 78% (184/236) of FQ-R and 64.2% (79/123) of ESBL-producing isolates, but only 7.2% (17/236) of FQ-S isolates (P < .001). The H30 subclone accounted for ≥95% of FQ-R and ESBL-producing, but only 12.5% of FQ-S, ST131 isolates (P < .001). By back-calculation, 28% of VAMC E. coli isolates nationally represented ST131. Overall, ST131 varied minimally in prevalence by specimen type, inpatient/outpatient source, or locale; was the most prevalent ST, followed distantly by ST95 and ST12 (13% each); and accounted for ≥40% (ß-lactams), >50% (trimethoprim-sulfamethoxazole , multidrug), or >70% (ciprofloxacin, gentamicin) of total antimicrobial resistance. FQ-R and ESBL-producing ST131 isolates had higher virulence scores than corresponding non-ST131 isolates. ST131 pulsotypes overlapped extensively among VAMCs. CONCLUSIONS: Among US veterans, ST131, primarily its H30 subclone, accounts for most antimicrobial-resistant E. coli and is the dominant E. coli strain overall. Possible contributors include multidrug resistance, extensive virulence gene content, and ongoing transmission. Focused attention to ST131, especially its H30 subclone, could reduce infection-related morbidity, mortality, and costs among veterans.

Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer.

BACKGROUND: Preclinical studies show that opioids stimulate angiogenesis and tumor progression through the mu opioid receptor (MOR). Although MOR is overexpressed in several human malignancies, the effect of chronic opioid requirement on cancer progression or survival has not been examined in humans. METHODS: We performed a retrospective analysis on 113 patients identified in the Minneapolis VA Tumor Registry (test cohort) and 480 patients from the national VA Central Cancer Registry (validation cohort) who had been diagnosed with stage IV prostate cancer between 1995 and 2010 to examine whether MOR expression or opioid requirement is associated with disease progression and survival. All opioids were converted to oral morphine equivalents for comparison. Laser scanning confocal microscopy was used to analyze MOR immunoreactivity in prostate cancer biopsies. The effects of variables on outcomes were analyzed in univariable and multivariable models. RESULTS: In patients with metastatic prostate cancer, MOR expression and opioid requirement were independently associated with inferior progression-free survival (hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.33-2.07, P<.001 and HR 1.08, 95% CI 1.03-1.13, P<.001, respectively) and overall survival (HR 1.55, 95% CI 1.20-1.99, P<.001 and HR 1.05, 95% CI 1.00-1.10, P = .031, respectively). The validation cohort confirmed that increasing opioid requirement was associated with worse overall survival (HR 1.005, 95% CI 1.002-1.008, P = .001). CONCLUSION: Higher MOR expression and greater opioid requirement are associated with shorter progression-free survival and overall survival in patients with metastatic prostate cancer. Nevertheless, clinical practice should not be changed until prospective randomized trials show that opioid use is associated with inferior clinical outcomes, and that abrogation of the peripheral activities of opioids ameliorates this effect.

Susceptibility to alternative oral antimicrobial agents in relation to sequence type ST131 status and Coresistance phenotype among recent Escherichia coli isolates from U.S. veterans.

The rising prevalence of resistance to first-line antimicrobial agents in Escherichia coli, which has paralleled the emergence of E. coli sequence type ST131, has created a need for alternative oral options for use in treating outpatients with infections such as cystitis and chronic prostatitis. Accordingly, we determined susceptibility to six alternative oral agents (azithromycin, chloramphenicol, doxycycline, fosfomycin, minocycline, and rifampin) by Etest or disk diffusion for 120 recently obtained E. coli clinical isolates from Veterans Affairs Medical Centers across the United States. Isolates were randomly selected in three subgroups of 40 isolates each based on coresistance to fluoroquinolones with and without extended-spectrum cephalosporins (ESCs). Results were stratified according to trimethoprim-sulfamethoxazole (TMP-SMZ) phenotype. Overall, the prevalence of susceptible (or susceptible plus intermediate) isolates varied by agent, with rifampin being lowest (0%), fosfomycin highest (98 to 99%), and others in the mid-range (37 to 88%). Substantial proportions of isolates (15 to 27%) yielded intermediate results for azithromycin, chloramphenicol, doxycycline, and minocycline. Among isolates resistant (versus susceptible) to fluoroquinolones with or without ESCs, susceptibility to the above four agents declined significantly among non-ST131 isolates but not ST131 isolates. In contrast, in the presence of resistance to TMP-SMZ, susceptibility to azithromycin, doxycycline, and minocycline was significantly reduced among both ST131 and non-ST131 isolates. These findings identify potential alternative oral agents for use with E. coli isolates resistant to fluoroquinolones, ESCs, and/or TMP-SMZ and suggest that determination of ST131 status could help guide initial antimicrobial selection, pending susceptibility results.

Molecular epidemiology of Escherichia coli sequence type 131 and Its H30 and H30-Rx subclones among extended-spectrum-ß-lactamase-positive and -negative E. coli clinical isolates from the Chicago Region, 2007 to 2010.

We assessed Escherichia coli ST131 and its H30 and H30-Rx subclones for virulence genes, antimicrobial resistance, and extended-spectrum beta-lactamase (ESBL) type. Although both subclones were associated with ESBL production, H30-Rx isolates had higher resistance scores and were associated specifically with CTX-M-15. Three virulence genes (iha, sat, and iutA) were more prevalent among H30 than non-H30 ST131 isolates. Thus, the H30 and H30-Rx subclones are more antimicrobial resistant and have virulence profiles that are distinct from those of non-H30 ST131 isolates.

OxyR contributes to the virulence of a Clonal Group A Escherichia coli strain (O17:K+:H18) in animal models of urinary tract infection, subcutaneous infection, and systemic sepsis.

The oxidative stress response regulator OxyR was assessed as both a urinary and extra-urinary virulence factor in Escherichia coli strain UCB34 (O17:K+:H18), a representative of the emergent Clonal Group A (CGA). Compared to UCB34, the isogenic oxyR mutant exhibited increased H2O2 sensitivity, indistinguishable in vitro growth, and attenuated virulence in rodent models of urinary tract, subcutaneous infection, and systemic sepsis. Complemented mutants showed virulence levels comparable to parent strains in all models. These findings uniquely fulfill molecular Koch's postulates for a putative virulence factor of CGA, provide experimental evidence of an extra-urinary virulence promoting trait in CGA, and document a role for OxyR in local and systemic extra-urinary E. coli infections.

Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint.

OBJECTIVE: Many forms of arthritis are accompanied by significant chronic joint pain. This study was undertaken to investigate whether there is significant sprouting of sensory and sympathetic nerve fibers in the painful arthritic knee joint and whether nerve growth factor (NGF) drives this pathologic reorganization. METHODS: A painful arthritic knee joint was produced by injection of Freund's complete adjuvant (CFA) into the knee joint of young adult mice. CFA-injected mice were then treated systemically with vehicle or anti-NGF antibody. Pain behaviors were assessed, and at 28 days following the initial CFA injection, the knee joints were processed for immunohistochemistry analysis using antibodies against calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kd (NF200; sensory nerve fibers), growth-associated protein 43 (GAP-43; sprouted nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), CD31 (endothelial cells), or CD68 (monocyte/macrophages). RESULTS: In CFA-injected mice, there was a significant increase in the density of CD68+ macrophages, CD31+ blood vessels, and CGRP+, NF200+, GAP-43+, and TH+ nerve fibers in the synovium, as well as a significant increase in joint pain-related behaviors. None of these findings were observed in sham-injected mice. Administration of anti-NGF reduced these pain-related behaviors and the ectopic sprouting of nerve fibers, but had no significant effect on the increase in density of CD31+ blood vessels or CD68+ macrophages. CONCLUSION: These findings demonstrate that ectopic sprouting of sensory and sympathetic nerve fibers occurs in the painful arthritic joint and may be involved in the generation and maintenance of arthritic pain.

Virulence of Escherichia coli clinical isolates in a murine sepsis model in relation to sequence type ST131 status, fluoroquinolone resistance, and virulence genotype.

Escherichia coli sequence type ST131 (O25b:H4) has emerged over the past decade as a globally disseminated, multidrug-resistant pathogen. Unlike traditional antimicrobial-resistant E. coli, ST131 derives from virulence-associated phylogenetic group B2 and exhibits extraintestinal virulence factors. This, plus preliminary evidence of virulence in experimental animals, has suggested that ST131's epidemic emergence may be due to high virulence potential, compared with other E. coli types. To test this hypothesis, we compared a large number of matched ST131 and non-ST131 E. coli clinical isolates, both fluoroquinolone resistant and susceptible, plus isolates from classic extraintestinal pathogenic E. coli (ExPEC) sequence types (STs) and case report ST131 household transmission isolates, for virulence in a mouse subcutaneous sepsis model. Overall, in mice, the study isolates produced a wide range of lethality and clinical illness. However, neither ST131 status nor fluoroquinolone phenotype correlated with this diversity of illness severity, which occurred within each of the 6 study groups. In contrast, multiple known or suspected ExPEC virulence genes, including pap (P fimbriae), vat (vacuolating toxin), kpsM II (group 2 capsule), ibeA (invasion of brain endothelium), and clbB/N (colibactin synthesis), plus molecularly defined ExPEC status, were significantly associated with virulence. These findings point away from ST131 isolates as having higher virulence potential compared with other E. coli types in causing invasive extraintestinal infections and suggest instead that ST131's epidemiological success may reflect enhanced fitness for upstream steps in pathogenesis or in colonization and transmission. Additionally, the extensive within-ST virulence diversity suggests an opportunity to compare closely related strains to identify the responsible genetic determinants.

Pneumococcal pyomyositis: report of 2 cases and review of the literature.

Streptococcus pneumoniae is an uncommon cause of pyomyositis. It is unclear whether the clinical presentation and outcome of pneumococcal pyomyositis differ depending on the host's underlying immune status. We describe 2 patients with pneumococcal pyomyositis, review all published cases, and compare characteristics between apparently healthy hosts and at-risk hosts. A total of 35 cases of pneumococcal pyomyositis were identified, 11 in apparently healthy hosts and 24 in at-risk hosts. Two-thirds of the patients had an antecedent respiratory illness or meningitis. At-risk hosts tended to have a longer interval between the development of symptomatic muscle infection and the diagnosis of pyomyositis and a significantly higher risk of disseminated disease at presentation, as manifested by involvement of multiple noncontiguous muscles or presence of meningitis. Overall, other than 1 death, all patients recovered with antibiotics and surgical drainage, but as might be expected there was a significantly higher rate of complications among at-risk hosts.