Child Maltreatment, Relationship with Father, Peer Substance Use, and Adolescent Marijuana Use.

This longitudinal prospective study examined the relationship between child maltreatment as per reports to child protective services (CPS) and adolescent self-reported marijuana use, and the association between relationships with mothers and fathers and use of marijuana. The association between relationships with parents early in childhood (ages 6-8 years) and during adolescence with adolescent marijuana use were also probed. Another aim examined whether relationships with parents moderated the link between child maltreatment and youth marijuana use. The sample included 702 high risk adolescents from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN), a consortium of 5 studies related to maltreatment. Children were recruited at age 4 or 6 years together with their primary caregiver. Some were recruited due to their risk for child maltreatment, others were already involved with CPS, and children in one site had been placed in foster care. Logistic regression analysis was performed using youth self-report of marijuana use as the criterion variable and child maltreatment and the relationships with parents as predictor variables, controlling for youths' perceptions of peer substance use and parental monitoring, parental substance use, race/ethnicity, sex and study site. Approximately half the youth had used marijuana. Most of them described quite positive relationships with their mothers and fathers. Participant marijuana Use was associated with a poorer quality of relationship with mother during adolescence, and with peer and parental substance use. A better relationship with father, but not mother, during adolescence attenuated the connection between Child Maltreatment and youth Marijuana Use.

Timing and chronicity of child neglect and substance use in early adulthood.

BACKGROUND: Neglect is the most common form of child maltreatment with consequences that appear to be as serious as for abuse. Despite this, the problem has received less than its due attention. OBJECTIVE: To examine the relationship between the timing and chronicity of neglect during childhood and substance use in early adulthood. PARTICIPANTS AND SETTING: The sample consisted of a subset of 475 participants from the prospective Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) consortium from five geographic areas around the U.S. METHOD: Neglect was assessed using abstracted information from CPS reports (birth-18) and self-reports of neglect (12-18). Participants completed a follow-up online survey (mean age of 24 years) that probed their use of substances. RESULTS: The prevalence of substance use during the past year was comparable in this high-risk sample to the general population. Latent class analysis supported the presence of three groups related to the presence and timing of neglect: Chronic Neglect, Late Neglect and Limited Neglect. Late Neglect was the pattern most strongly linked to substance use in early adulthood. CONCLUSIONS: High-risk youth experiencing neglect beginning in mid- adolescence are especially vulnerable to later substance use. Those working with such youth and their families can play a valuable role helping ensure their basic needs are adequately met, and recognizing early signs of substance use and abuse.

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria.

The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 µg/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli, respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically <10-8 against E. coli and A. baumannii at concentrations equivalent to 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC50], >100 µM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.

Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors.

There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.

In vitro biological evaluation of novel broad-spectrum isothiazolone inhibitors of bacterial type II topoisomerases.

OBJECTIVES: To evaluate the in vitro biological properties of a novel class of isothiazolone inhibitors of the bacterial type II topoisomerases. METHODS: Inhibition of DNA gyrase and topoisomerase IV activity was assessed using DNA supercoiling and decatenation assays. MIC and MBC were determined according to CLSI guidelines. Antibacterial combinations were assessed using a two-dimensional chequerboard MIC method. Spontaneous frequency of resistance was measured at various multiples of the MIC. Resistant mutants were generated by serial passage at subinhibitory concentrations of antibacterials and genetic mutations were determined through whole genome sequencing. Mammalian cytotoxicity was evaluated using the HepG2 cell line. RESULTS: Representative isothiazolone compound REDX04957 and its enantiomers (REDX05967 and REDX05990) showed broad-spectrum bactericidal activity against the ESKAPE organisms, with the exception of Enterococcus spp., as well as against a variety of other human bacterial pathogens. Compounds retained activity against quinolone-resistant strains harbouring GyrA S83L and D87G mutations (MIC ≤4 mg/L). Compounds inhibited the supercoiling activity of wild-type DNA gyrase and the decatenation function of topoisomerase IV. Frequency of resistance of REDX04957 at 4× MIC was <9.1 × 10(-9). Against a panel of recent MDR isolates, REDX05967 demonstrated activity against Acinetobacter baumannii with MIC50 and MIC90 of 16 and 64 mg/L, respectively. Compounds showed a lack of cytotoxicity against HepG2 cells at 128 mg/L. CONCLUSIONS: Isothiazolone compounds show potent activity against Gram-positive and -negative pathogens with a dual targeting mechanism-of-action and a low potential for resistance development, meriting their continued investigation as broad-spectrum antibacterial agents.

Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV.

OBJECTIVES: The objective of this study was to characterize the in vitro and in vivo biological properties of a novel series of small-molecule bacterial type IIA topoisomerase inhibitors. METHODS: Bacterial susceptibility testing was performed by broth microdilution. Resistance frequencies were determined by plating bacteria onto agar containing test compound and enumerating mutants. Bacteria were passaged using subinhibitory concentrations of antibacterials to generate resistance. Target enzyme inhibition was determined by exposure to antibacterials and DNA; topoisomers were visualized by gel electrophoresis. Oral and intravenous pharmacokinetic profiles were determined in mice. In vivo efficacy was determined using a mouse model of septicaemia and thigh infection with MSSA and MRSA, respectively. RESULTS: Representative compounds REDX04139, REDX05604 and REDX05931 demonstrated in vitro potency against a range of Gram-positive and fastidious Gram-negative pathogens. Clinical isolate testing revealed REDX04139 and REDX05931 had MIC90 values of 0.25 and 0.5 mg/L, respectively, for MRSA and MIC90 values of 2 mg/L for streptococci. REDX04139 was bactericidal in vitro against Staphylococcus aureus at 8× MIC over 6 h. Pharmacokinetic profiling of REDX04139 and REDX05604 in mice revealed low clearance and excellent bioavailability (≥71%). REDX04139 provided 100% survival against S. aureus in a mouse septicaemia model, while REDX05604 reduced bacterial load by up to 3.7 log units in the MRSA mouse thigh infection model. CONCLUSIONS: Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria.

Adversity, Maltreatment, and Resilience in Young Children.

BACKGROUND: Much of the research on children in high risk environments, particularly those who have been maltreated, has focused on negative outcomes. Yet, much can be learned from some of these children who fare relatively well. The objective was to examine resilience in high-risk preschoolers, and to probe contributors to their adaptive functioning. METHODS: The sample of 943 families was from the Longitudinal Studies of Child Abuse and Neglect, a consortium of 5 sites, prospectively examining the antecedents and outcomes of maltreatment. Most of the families were at high risk for maltreatment, and many had been reported to Child Protective Services (CPS) by the time the children were aged 4 years. Standardized measures were used at ages 4 and 6 to assess the children's functioning in behavioral, social and developmental domains, and parental depressive symptoms and demographic characteristics. Maltreatment was determined on the basis of CPS reports. Logistic regressions were conducted to predict resilience, defined as competencies in all 3 domains, over time. RESULTS: Forty-eight percent of the sample appeared resilient. This was associated with no history of maltreatment (odds ratio = 1.50; 95% confidence interval [CI], 1.02-2.20; P = .04), a primary caregiver reporting few depressive symptoms (odds ratio = 2.19; 95% CI, 1.63-2.94; P < .001), (P = .014), and fewer children in the home (P = .03). CONCLUSIONS: Almost half of the sample appeared resilient during this important developmental period of transition to school. This enables clinicians to be cautiously optimistic in their work with high-risk children and their families. However, more than half the sample was not faring well. Child maltreatment and caregiver depressive symptoms were strongly associated with poor outcomes. These children and families deserve careful attention by pediatric practitioners and referral for prevention and early intervention services.

Characteristics of Child Maltreatment and Adolescent Marijuana Use: A Prospective Study.

There has been increasing acceptance of marijuana use in the United States in recent years, and rates among adolescents have risen. At the same time, marijuana use during adolescence has been linked to an array of health and social problems. Maltreated children are at risk for marijuana use, but the relationships among characteristics of maltreatment and marijuana use are unclear. In this article, we examine how the type and the extent of maltreatment are related to the level of adolescent marijuana use. Data analyses were conducted on a subsample of maltreated adolescents (n = 702) from the Longitudinal Studies of Child Abuse and Neglect project. Approximately half the sample had used marijuana, and maltreatment was associated with its use. Multivariate regression models showed that being male, extensive maltreatment, and peer marijuana use were associated with heavy use of marijuana. These findings suggest the importance of comprehensively assessing children's maltreatment experiences and their peers' drug use to help prevent or address possible marijuana use in these high-risk adolescents.

Comparison of hybrid and completely online RN-to-BSN curricula: aspects of program structure that lead to success.

The large increase in the number of RN-to-BSN programs has occurred in the context of the expansion of Internet-based resources. This article expands on an earlier reported evaluation of a program based on community-derived needs. Several dimensions were identified that appear to contribute to student success in a blended-hybrid and completely online curricula. Students move through a synchronous cohort curriculum. The graduation rate for both programs was above the national average for all programs (80%), and graduation rate for the blended-hybrid program (92%) exceeded the online program (88%). Social support theory framed the important factors in a way that paralleled the factors reported by students as leading to their success.

Using a modified lag task to measure adult age differences in working memory.

Four groups of adults, ages 40 to 70+ years, took the Modified Lag Task which requires that participants remember lists of words and subsequently recall the first, second, or third word from the end of the list. Previously, the task showed convergent validity with the operation span (a complex span measure) and a divergent validity with the digit span (a simple span measure). To establish predictive validity, the present study was designed to assess if this task could separate four age groups in working memory performance. The present study found support for the validity of the Modified Lag Task; however, additional research is warranted to further develop the construct validity of this task.

A hybrid classroom-online curriculum format for RN-BSN students: cohort support and curriculum structure improve graduation rates.

As more registered nurses (RNs) return to school to obtain a bachelor of science in nursing (BSN), innovative ways must be found to support them in this endeavor. Barriers for RNs who return to school include scheduling of coursework and fear of failure. One school of nursing with a traditional BSN program reviewed its RN-BSN track, with its low retention and graduation rates. With input from nursing leaders and nurses in the community, the school applied for and was awarded a 3-year Health Resources and Services Administration grant to redesign the RN-BSN program. A hybrid classroom-online curriculum is offered in a structured, sequential format so that the RNs are admitted once a year and must complete the courses as a group, in a cohort. Data collected from evaluations showed that program support, technology support, and social support from peers encouraged the RNs to "stay the course," and 100% completed the requirements to graduate.

Do children "DRM" like adults? False memory production in children.

The Deese/Roediger-McDermott (DRM) paradigm was used to investigate developmental trends in accurate and false memory production. In Experiment 1, DRM lists adjusted to be more consistent with children's vocabulary were used with 2nd graders, 8th graders, and college students. Accurate and false recall and recognition increased with age, but semantic information appeared to be available to all age groups. Experiment 2 created a set of child-generated lists based on the free associations by a group of 3rd graders to critical items. The child-generated associates were different from those generated by adults; long and short versions of the child-generated lists were therefore presented to 2nd, 5th, and 8th graders and college students in Experiment 3. Second graders exhibited few false memories, whereas 5th graders were similar to adults in low-demand conditions and more similar to younger children in high-demand conditions. Findings are discussed in terms of developmental changes in automatic and effortful processing and the use of semantic networks.

A group-administered lag task as a measure of working memory.

The purpose of the present studies was to evaluate the utility of a group-administered version of the n-back, or lag task. Experiments 1 and 2 describe the construction of the task and reveal that the modified lag task (MLT) produces the same performance trends as have been observed in individually administered versions of the lag task; performance decreased significantly as lag conditions increased in difficulty. Experiments 3 and 4 established convergent validity by comparing the MLT to another common working memory task, the operation-word span task, as well as the updated version of this task, the automatic operation span task. The results showed that MLT performance was significantly correlated to scores on both measures. These experiments provide important details about the MLT as a measure of working memory, in a group- or individual-administration setting.

Children's susceptibility to misidentifying a familiar bystander from a lineup: When younger is better.

Children from 5 to 12 years of age (N = 779) were shown a videotape where a preschool teacher has money stolen from her wallet. Children were shown a lineup, and for children in the bystander condition, the lineup contained a familiar bystander without the thief. Children in the control condition viewed the same lineup but they had not seen the bystander in the videotape. Among the 11-12-year olds, participants in the bystander condition were significantly more likely than control participants to misidentify the familiar bystander. This effect was not found in children from 5 to 10 years of age. When children in the control condition were shown a lineup that contained the thief without the bystander, the 11-12-year olds were significantly more likely than the younger children to correctly identify the thief. These findings demonstrate that age can both increase and decrease the accuracy of children's lineup identification accuracy depending on the task at hand and the content of a lineup.

American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome.

BACKGROUND: Response to neoadjuvant chemotherapy is used as an intermediate endpoint for breast cancer relapse and survival. Most breast cancer response classification systems use pathologic complete response, either alone or in conjunction with clinical assessments, to categorize response. We examined the ability of the revised 2003 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system, which considers both the number of involved axillary lymph nodes and the extent of tumor in the breast to predict patient survival after neoadjuvant chemotherapy for breast cancer. METHODS: We assessed the pathologic stage of residual tumor in 132 patients with nonmetastatic breast cancer after they had undergone neoadjuvant chemotherapy and examined the association between AJCC TNM stage and subsequent distant disease-free survival and overall survival. All statistical tests were two-sided. RESULTS: At a median follow-up of 5 years, pathologic stage in the surgical specimens after neoadjuvant chemotherapy using the revised AJCC system was strongly associated with both distant disease-free survival and overall survival. A higher pathologic stage of residual tumor after neoadjuvant chemotherapy was associated with a statistically significant lower rate of distant disease-free survival (stage 0: 95%, stage I: 84%, stage II: 72%, and stage III: 47%; Ptrend < .001). The 5-year distant disease-free survival for patients with residual stage IIIC tumors was only 18% (95% CI = 0% to 36%). CONCLUSION: Classification of residual tumor in the breast and axillary surgical specimens after neoadjuvant chemotherapy using the revised AJCC TNM system is useful for predicting distant relapse and survival.

Central nervous system metastases in women after multimodality therapy for high risk breast cancer.

BACKGROUND: Central nervous system (CNS) relapse is increasing in breast cancer. This increase may reflect altered failure patterns from adjuvant therapy, more effective systemic therapy with improved control in non-CNS sites, or a resistant breast cancer subtype. METHODS: To determine the factors associated with clinical CNS relapse, we examined response to neoadjuvant chemotherapy (chemosensitivity), time to relapse and sites of relapse in a cohort of 140 patients without evidence of metastasis at presentation. RESULTS: At 5 years (interquartile range 3-6 years), 44 (31%) patients developed distant metastases, including 13 with CNS metastases. CNS relapse was early (median 24 months after diagnosis) and associated with relapse in bone and liver, suggesting hematogenous dissemination. Those with CNS relapse were younger at diagnosis (40 versus 49 years) and more likely to have lymphovascular invasion in the primary tumor compared with non-CNS metastases. Response to neoadjuvant chemotherapy was not different (69% versus 73% response rate) between the two groups. Extent of residual disease after chemotherapy was strongly associated with relapse outside the CNS but not CNS relapses. The CNS was an isolated or dominant site of metastasis in 8 of 13. Despite treatment, most patients with CNS involvement died of neurologic causes a median of 6 months later. CONCLUSION: Breast cancers that develop CNS metastases differ from those that develop metastases elsewhere. Both tumor behavior and reduced chemotherapy accessibility to the CNS may contribute to increased CNS involvement in breast cancer patients treated with multimodality therapy.

High-resolution axillary ultrasound is a poor prognostic test for determining pathologic lymph node status in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of high-resolution axillary ultrasound in detecting axillary lymph node metastases after neoadjuvant chemotherapy in patients with locally advanced breast cancer. METHODS: Fifty-three patients with stage II or III breast cancer undergoing neoadjuvant chemotherapy who had a physical examination, high-resolution axillary ultrasound, and axillary lymph node dissection from January 1999 to September 2003 were included in this study. RESULTS: The positive predictive value of the postchemotherapy ultrasound for predicting pathologic nodal involvement was 83%, but the negative predictive value was only 52%. Postchemotherapy physical examination was also poor at predicting pathologic nodal involvement with a positive predictive value of 93% and a negative predictive value of only 58%. CONCLUSIONS: A negative post-neoadjuvant chemotherapy high-resolution axillary ultrasound or physical examination does not predict pathologic node status, and this test has limited value in this setting.