Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125µg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9µM and a favorable profile in the anesthetized guinea pig model.

African American Clergy and Depression: What they know; What they want to know.

UNLABELLED: Nearly 40% of African Americans use clergy as their primary source of help with depression. However, less than half of African American clergy are trained in counseling. OBJECTIVES: 1) to examine how African American cler recognize depression and 2) identify what they need to more effectively identify and address depression in their congregants. DESIGN: This was a descriptive, quantitative study using a Personal Profile Questionnaire and a Mental Health Counseling Survey. RESULTS: Sixty-five clergy completed the data collection tools; approximately 50% had some training in counseling. The majority could identify signs of depression. Eighty-one percent stated they needed additional education about depression and access to referral resources. CONCLUSIONS: If clergy take an active role in addressing the issue of depression and establishing liaisons with mental health professionals the stigma associated with depression could be greatly reduced, and individuals might enter into treatment earlier thus improving their quality of life.

Exercise intervention for fatigue-related symptoms in Thai women with breast cancer: A pilot study.

The purpose of this pilot study was to preliminarily examine the effects of an exercise program on the symptoms of fatigue, sleep disturbance, mood disturbance, symptom distress, and physical fitness for Thai women with breast cancer. Twenty-three eligible women were randomly assigned to either an experimental group (n = 11) or to a control group (n = 12). Data were collected and analyzed at baseline and again at 4, 7, and 10 weeks. At each time point, fatigue was measured at an expected high point during treatment. Participants in the exercise group demonstrated a trend toward improving the symptoms with mean score changes. Using generalized estimating equations analysis, a significant decrease in mood disturbance was found in the exercise group compared with control at 10 weeks (ß = 0.03, P = 0.04). The participants exhibited significantly longer 12-minute walk distance at 10 weeks than those in the control group (t = 2.28, P = 0.04). These results indicate that exercise during adjuvant chemotherapy may be beneficial for Thai women with breast cancer.

Psychometric analysis of two new scales: the evidence-based practice nursing leadership and work environment scales.

BACKGROUND: Those in nursing have been charged with practicing to the full extent of their education and training by the Institute of Medicine. Therefore, evidence-based practice (EBP) has never been more important to nursing than in the current healthcare environment. Frequently the burden of EBP is the responsibility of the bedside practitioner, but has been found to be a process that requires leadership and organizational support. A key underlying component of a strong EBP environment includes effective communications and collaboration among staff and nursing leadership. AIMS: Developing measurement tools that examine the milieu and nursing leadership in which the staff nurse practices is an important component of understanding the factors that support or hinder EBP. The aim of this study is to report on the development and analysis of two new scales designed to explore leadership and organizational support for EBP. The EBP Nursing Leadership Scale (10 items) examines the staff nurses perception of support provided by the nurse manager for EBP, and the EBP Work Environment Scale (8 items) examines organizational support for EBP. METHODS: Staff nurses who worked at least .5 FTE in direct patient care, from two inner city hospitals (n = 422) completed the scales. The scales were evaluated for internal consistency reliability with the Cronbach alpha technique, content validity using a panel of experts, and construct validity by RESULTS: The content validity index computed from expert rankings was .78 to 1.0 with an average of.96. Cronbach's alpha was .96 (n = 422) for the EBP Nursing Leadership Scale and .86 (n = 422) for the EBP Work Environment Scale. Factor analysis confirmed that each scale measured a unidimensional construct (p < .000). LINKING EVIDENCE TO ACTION: The EBP Nursing Leadership Scale and the EBP Work Environment Scale are psychometrically sound instruments to examine organizational influences on EBP.

Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.

Improved training for disasters using 3-D virtual reality simulation.

The purpose of this study was to examine the effects of virtual reality simulation (VRS) on learning outcomes and retention of disaster training. The study used a longitudinal experimental design using two groups and repeated measures. A convenience sample of associate degree nursing students enrolled in a disaster course was randomized into two groups; both groups completed web-based modules; the treatment group also completed a virtually simulated disaster experience. Learning was measured using a 20-question multiple-choice knowledge assessment pre/post and at 2 months following training. Results were analyzed using the generalized linear model. Independent and paired t tests were used to examine the between- and within-participant differences. The main effect of the virtual simulation was strongly significant (p < .0001). The VRS effect demonstrated stability over time. In this preliminary examination, VRS is an instructional method that reinforces learning and improves learning retention.

Development and psychometric testing of the nursing culture assessment tool.

A valid and reliable nursing culture assessment tool aimed at capturing general aspects of nursing culture is needed for use in health care settings to assess and then reshape indicated troubled areas of the nursing culture. This article summarizes the Nursing Culture Assessment Tool's (NCAT) development and reports on a cross-sectional, exploratory investigation of its psychometric properties. The research aims were to test the tool's psychometric properties; discover its dimensionality; and refine the item structure to best represent the construct of nursing culture, an occupational subset of organizational culture. Empirical construct validity was tested using a sample of licensed nurses and nursing assistants (n = 340). Exploratory and confirmatory factor analysis (CFA) and logistical regression yielded a 6-factor, 19-item solution. Evidence supports the tool's validity for assessing nursing culture as a basis for shaping the culture into one that supports change, thereby accelerating, improving, and advancing nursing best practices and care outcomes.

Novice nurse productivity following workplace bullying.

PURPOSE: To determine the prevalence and effects of workplace bullying (WPB) on the work productivity of novice nurses (NNs). DESIGN: Internet-based descriptive cross-sectional survey design. METHODS: One hundred ninety seven NNs (91.4% female, 8.6% male) in practice less than 2 years completed the Healthcare Productivity Survey, Negative Acts Questionnaire, and a demographic survey. FINDINGS: The majority (72.6%, n= 147) of NNs reported a WPB event within the previous month, with 57.9% (n= 114) the direct targets and another 14.7% (n= 29) witnesses of WPB behaviors. Using a weighted Negative Acts Questionnaire score, 21.3% (n= 43) of NNs were bullied daily over a 6-month period. When asked if bullied over the past 6 months, approximately 44.7% (n= 88) of NNs reported repeated, targeted WPB, with 55.3% (n= 109) reporting no WPB. WPB acts were primarily perpetrated by more experienced nursing colleagues (63%, n= 126). Further, work productivity regression modeling was significant and NN productivity was negatively impacted by workplace bullying (r=-.322, p= .045). CONCLUSIONS: WPB continues in the healthcare environment and negatively affects bullied NNs' productivity by affecting cognitive demands and ability to handle or manage their workload. CLINICAL RELEVANCE: Healthcare facilities should continue to measure WPB in the work environment after policy implementation as well as eliminate negative behaviors through root-cause analysis to correct environmental factors associated with WPB.

The relationship between executive function, AD/HD, overeating, and obesity.

Attention-deficit/hyperactivity disorder (AD/HD) and obesity are complex, costly disorders affecting physical, emotional, and social well-being. Executive function (EF), the cognitive ability for self-understanding and regulation, is often impaired in AD/HD, yet rarely considered in treatment of obese individuals with AD/HD. The hypothesis for this study is that low EF is seen in individuals with 4 or more symptoms of adult AD/HD and is associated with overeating behaviors leading to obesity. A nonexperimental single group design was used. A volunteer convenience sample (n = 125) completed EF, AD/HD, eating, and BMI measures. Path analysis tested the hypothesized/ modified model. Chi square (χ(2) = 6.15, df = 6, p = .4) and RMSEA (0.014) indicated a very good fit for the data. Assessment of EF and AD/HD symptoms in obese individuals is supported. Further study is needed to more fully understand this relationship and to develop strategies to address overeating behaviors in obese individuals with AD/HD.

The discovery and structure-activity relationships leading to CE-156811, a difluorophenyl cyclopropyl fluoroether: a novel potent antibacterial analog derived from hygromycin A.

SAR studies and optimization of various modified Hygromycin A fluoroalkyl ethers, which led to the discovery of the highly potent 4'-(2-cyclopropyl-2-fluoroethyl ether) antibacterial CE-156811 (1) derived from truncation of the ribose ring and difluorination of the phenyl found in Hygromycin A, are discussed.

Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Reaching a better management model for military medicine.

Despite the attempt by some to condemn it because of the unfortunate experience of some service members at Walter Reed Army Medical Center, military medicine has long provided healthcare coverage to legions of soldiers during both war and peace. Since 1884, the U.S. Congress has also required that military medicine provide healthcare treatment free of charge to the families of officers and soldiers. The unforeseen consequence of this Congressional action is that today, military medicine provides medical care to a population of families and retirees that is 4 times larger than the active duty force that it supports. Unable to do so on its own, the Department of Defense hired managed-care support contractors to help create the TRICARE health plan to improve access to healthcare for these families and retirees and to take advantage of capabilities of the managed-care industry. By most accounts, TRICARE has been successful. It is, however, anchored by the military treatment facilities, Walter Reed among them, which need a revolution in management. This article explores these aspects of military medicine.

In vitro antibacterial activity of CE-156811, a novel analog derived from hygromycin A.

We evaluated a novel truncated hygromycin A analog in which the furanose ring was replaced with a 2-fluoro-2-cyclopropylethyl substituent for its activity against multidrug resistant gram-positive bacteria and compared its activity to the activities of linezolid, quinupristin-dalfopristin, and vancomycin. CE-156811 demonstrated robust in vitro activity against gram-positive bacteria that was comparable to that of linezolid.

Effectiveness of brief interventions after alcohol-related vehicular injury: A randomized controlled trial.

BACKGROUND: Because 40% of motor vehicle fatalities in the United States are alcohol-related, interventions delivered by trauma clinicians targeted to reduce drinking are of particular importance to public health. The objective of this study was to test the effectiveness of hospital-based brief intervention strategies to reduce alcohol consumption and other health-related outcomes in the year after an alcohol-related vehicular injury. Brief interventions are clinically based strategies including assessment and direct feedback about drinking alcohol, goal setting, behavioral modification techniques, and the use of a self-help manual. METHODS: The study was a randomized controlled trial of two types of brief intervention with a 12-month follow-up. Participants with alcohol-related vehicular injury who were admitted to Level I trauma centers were eligible for enrollment. Enrolled participants were randomized to a control, simple advice, or brief counseling condition. Primary outcome variables were alcohol consumption (standard drinks/month, binges/month), adverse driving events (driving citations, traffic crashes), and changes in health status (hospital and emergency department admissions). RESULTS: The study enrolled 187 participants at baseline and retained 100 across 12 months. Participants had a significant decrease in alcohol consumption and traffic citations at 12 months as compared with baseline. Mean standard drinks/month declined from 56.80 (SD 63.89) at baseline to 32.10 (SD 53.20) at 12 months. Mean binges/month declined from 5.79 (SD 6.98) at baseline to 3.21 (SD 6.17) at 12 months. There were no differences in alcohol consumption, adverse driving events, or health status by condition. CONCLUSIONS: Whether the reductions in alcohol consumption and traffic citations were a result of the crash, hospitalization for injury, screening for alcohol use, or combination of these factors is difficult to determine. Further work is needed to understand the mechanisms involved in reductions of health-related outcomes and the role of brief intervention in this population.

Crystal structure of nicotinic acid mononucleotide adenylyltransferase from Staphyloccocus aureus: structural basis for NaAD interaction in functional dimer.

Bacterial nicotinic acid mononucleotide adenylyltransferase (NaMNAT; EC 2.7.7.18) encoded by the nadD gene, is essential for cell survival and is thus an attractive target for developing new antibacterial agents. The NaMNAT catalyzes the transfer of an adenylyl group of ATP to nicotinic acid mononucleotide (NaMN) to form nicotinic acid dinucleotide (NaAD). Two independently derived, high-resolution structures of Staphylococcus aureus NaMNAT-NaAD complexes establish the conserved features of the core dinucleotide-binding fold with other adenylyltransferases from bacteria to human despite a limited sequence conservation. The crystal structures reveal that the nicotinate carboxylates of NaAD are recognized by interaction with the main-chain amides of Thr85 and Tyr117, a positive helix dipole and two bridged-water molecules. Unlike other bacterial adenylyltransferases, where a partially conserved histidine residue interacts with the nicotinate ring, the Leu44 side-chain interacts with the nicotinate ring by van der Waals contact. Importantly, the S. aureus NaMNAT represents a distinct adenylyltransferase subfamily identifiable in part by common features of dimerization and substrate recognition in the loop connecting beta5 to beta6 (residues 132-146) and the additional beta6 strand. The unique beta6 strand helps orient the residues in the loop connecting beta5 to beta6 for substrate/product recognition and allows the beta7 strand structural flexibility to make key dimer interface interactions. Taken together, these structural results provide a molecular basis for understanding the coupled activity and recognition specificity for S. aureus NaMNAT and for rational design of selective inhibitors.

Memory functioning in polysubstance dependent women.

BACKGROUND: The vast majority of studies on polysubstance abuse or dependence have utilized male participants; therefore, the specific neuropsychological effects of polysubstance dependence in women are relatively unknown. The goal of the present study is to examine the effects of polysubstance dependence on women's verbal and visual memory ability. METHODS: Data were collected from 109 women (46 controls and 63 polysubstance dependence women who were similar in ethnic identification, education, age, and verbal ability). A series of multiple regressions were run to test whether group membership significantly predicted performance on the Benton Visual Retention Test and the California Verbal Learning Test after controlling for important demographic characteristics. RESULTS: The primary results indicated that the polysubstance dependent women had significantly poorer verbal learning ability (ranging from p<.005 to .05) than the control group, while no differences were found in visual memory ability. Further, significant bivariate relationships were observed between frequency of alcohol and cocaine use and verbal learning, delayed recall, and recognition ability. CONCLUSIONS: The results confirm that polysubstance dependence is associated with deficient encoding of verbal information. In addition, past year frequent use of alcohol and cocaine was associated with more severe deficits in delayed recall and recognition ability among polysubstance dependent women at the bivariate level.

The effects of age and ethnicity on physical injury from rape.

OBJECTIVE: To determine whether postmenopausal (age 50 years or older) women would sustain significantly more injury after rape than women younger than 50 and to determine the role of skin pigmentation in the observance of genital injury. DESIGN AND SETTING: Registry data from a sexual assault forensic nurse examiners program. PARTICIPANTS: Based on date of examination, records from women of age 50 years or older (n = 40) were matched to two other participants: a premenopausal group younger than 40 years and a perimenopausal group of 40 to 49 years. The final sample consisted of 120 subjects. MAIN OUTCOME MEASURES: Number, type, and location of injuries. RESULTS: A series of exact conditional logistic regression analyses indicated no significant association between age and genital, nongenital, or head injury. A significant association between race (Black versus White) and genital injury (adjusted odds ratio = 4.30, 95% confidence interval = 1.09-25.98, p = .03) indicated that Whites were more than four times as likely as Blacks to have genital injury. CONCLUSION: Although the primary hypothesis was not supported, the role of racial/ethnic differences and their association with the observance of injury need further exploration to determine whether the standard forensic examination is appropriate for all women. Health disparities may exist if women of color are less likely than others to have genital injuries identified and treated. Alternatively, skin properties may explain racial/ethnic differences in injury prevalence.

Patterns of drinking four weeks prior to an alcohol-related vehicular crash.

OBJECTIVE: The primary objective of the study was to determine if drinking patterns on the days immediately prior to an alcohol-related motor vehicle crash (ARMVC) were significantly different than drinking patterns in the weeks prior to the crash. METHODS: Following ARMVC, 187 hospitalized non-alcohol dependent young-adults (43 females, 144 males) were enrolled. Mean age was 29.03 years, mean blood alcohol level was 165.18 mg/dL, and mean injury severity score was 10.50. When alcohol-free, subjects were interviewed by nurse clinicians to determine the quantity/frequency of alcohol consumption during the 28 days prior to the crash. Subjects reported the number of standard drinks using the Timeline Followback procedure. Total drinks/day were determined, with day 1 considered 4 weeks prior to the crash and day 28 the day of the crash. A random-intercepts general linear mixed model (GLMM) was used to test the effect of several covariates (segment 1 [days 1-26], segment 2 [days 27-28], age, sex, race, holiday/non-holiday period, driver/passenger status, and weekend/weekday crash) on the amount of standard drinks/day. RESULTS: There was no significant interaction among the covariates. The only significant predictors of drinks/day were segment 2 (b = .322, p < .0001) and gender (b = -.221, p = .016). The positive, statistically significant slope for segment 2 indicated an increase in consumption of drinks/day in the two-day period prior to the ARMVC and the negative slope for gender indicated greater consumption of drinks/day for men than women. CONCLUSION: Persons injured in an ARMVC had a significant increase in alcohol consumption on the day before and the day of vehicular crashes (days 27 and 28) as compared to the first 26 days in the 28-day period preceding the crash. When non-alcohol-dependent subjects are counseled to reduce their risk of traffic crashes, they should be alerted that when their patterns of drinking change, they are at higher risk than usual for a crash.

Violence or nonviolence: which do we choose?

A large mass of research on violence now exists, yet the utilitarian value of this vast amount of scientific endeavor may be rated as low, comparing it to the levels of violence at all levels abounding in the world today. The author calls for centralizing funding and work on violence at the national level in the United States, perhaps forming a separate National Institute for Violence. In addition to focusing on violence, nonviolence must be studied with more vigor for scientific work in this area to increase in utilitarian value.

A path model of risk factors for intimate partner violence among couples in the United States.

The present study was designed to identify the impact of drinking problems, impulsivity, and a history of childhood physical abuse on both male-to-female (MFIPV) and female-to-male intimate partner violence (FMIPV). The data were collected in 1995 from a representative national sample of couples living in the contiguous 48 states. Using a multistage probability sampling design, face-to-face interviews were conducted in respondent' homes, privately with each member of 1, 635 couples. A complex path model building on earlier work was tested for African American, Hispanic, and White couples separately. Multiple-group path analysis demonstrated that impulsivity, alcohol problems, and childhood physical abuse were differentially associated with reports of MFIPV and FMIPV as a function of ethnicity. This study suggests that a history of being physically harmed by parental figures during childhood, impulsivity, and drinking problems are all risk factors for intimate partner violence in the general household population in the United States.