Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions.

The estrogen receptor (ER), glucocorticoid receptor (GR), and forkhead box protein 1 (FoxA1) are significant factors in breast cancer progression. FoxA1 has been implicated in establishing ER-binding patterns though its unique ability to serve as a pioneer factor. However, the molecular interplay between ER, GR, and FoxA1 requires further investigation. Here we show that ER and GR both have the ability to alter the genomic distribution of the FoxA1 pioneer factor. Single-molecule tracking experiments in live cells reveal a highly dynamic interaction of FoxA1 with chromatin in vivo. Furthermore, the FoxA1 factor is not associated with detectable footprints at its binding sites throughout the genome. These findings support a model wherein interactions between transcription factors and pioneer factors are highly dynamic. Moreover, at a subset of genomic sites, the role of pioneer can be reversed, with the steroid receptors serving to enhance binding of FoxA1.

Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing.

Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within ± 50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings.

A retrospective review of patient outcomes in the pediatric HEROES weight management program.

Pediatric obesity is a public health concern in the U.S. The purpose of this study was to describe the impact of a pediatric stage 3 and 4 weight management program. Program aims measured: change in biometric values using BMI z-scores; intervention attrition rate; and health-related quality of life (HRQOL) from admission through the initial six months of the program. The program evaluation included a retrospective review of 884 electronic records. Of the 698 children that met the inclusion criteria, 468 completed at least one follow-up visit within the baseline to 6 month time period. Overall 66.38% of the 468 maintained program involvement at the 6 month evaluation. Of the 468 who completed the 6 months, 192 children/families participated in the clinic only program and 276 participated both in the clinic and a 12 week contract education/fitness and exercise intervention. The completion rate for the contract intervention was 7.3%. All children demonstrated a decrease in BMI z-scores. There were no statistically significant differences (p = 0.276) in the BMI z-change scores from baseline to 6 months in the clinic only program; those who did not complete the education/fitness and exercise intervention, and those who completed the education/fitness and exercise intervention. Children demonstrated a statistically significant improvement in their overall HRQOL scale score (p = 0.001) from baseline to the 6 month evaluation. The results indicate the impact of attrition and HRQOL in weight management programs. Further research is needed to develop and strengthen the effectiveness of weight management interventions.

Bridging the gap from screening assays to estrogenic effects in fish: potential roles of multiple estrogen receptor subtypes.

This study seeks to delineate the ligand interactions that drive biomarker induction in fish exposed to estrogenic pollutants and provide a case study on the capacity of human (h) estrogen receptor (ER)-based in vitro screening assays to predict estrogenic effects in aquatic species. Adult male Japanese medaka (Oryzias latipes) were exposed to solutions of singular steroidal estrogens or to the estrogenic extract of an anaerobic swine waste lagoon. All exposure concentrations were calibrated to be equipotent based on the yeast estrogen screen (YES), which reports activation of hERα. These exposures elicited significantly different magnitudes of hepatic vitellogenin and choriogenin gene induction in the male medaka. Effects of the same YES-calibrated solutions in the T47D-KBluc assay, which reports activation of hERα and hERß, generally recapitulated observations in medaka. Using competitive ligand binding assays, it was found that the magnitude of vitellogenin/choriogenin induction by different estrogenic ligands correlated positively with preferential binding affinity for medaka ERß subtypes, which are highly expressed in male medaka liver prior to estrogen exposure. Results support emerging evidence that ERß subtypes are critically involved in the teleost estrogenic response, with the ERα:ERß ratio being of particular importance. Accordingly, incorporation of multiple ER subtypes into estrogen screening protocols may increase predictive value for the risk assessment of aquatic systems, including complex estrogenic mixtures.

Construct validity and reliability of the Handover Evaluation Scale.

AIMS AND OBJECTIVES: To examine the psychometric properties of the Handover Evaluation Scale using exploratory and confirmatory factor analysis. BACKGROUND: Handover is a fundamental component of clinical practice and is essential to ensure safe patient care. Research indicates a number of problems with this process, with high variability in the type of information provided. Despite the reported deficits with handover practices internationally, guidelines and standardised tools for its conduct and evaluation are scarce. Further work is required to develop an instrument that measures the effectiveness of handover in a valid and reliable way. DESIGN: Secondary analysis of data collected between 2006-2008 from nurses working on 24 wards across a large Australian healthcare service. METHODS: A sample of 299 nurses completed the survey that included 20 self-report items which evaluated the effectiveness of handover. Data were analysed using exploratory factor analysis and confirmatory factor analysis supported by structural equation modelling. RESULTS: Analyses resulted in a 14-item Handover Evaluation Scale with three subscales: (1) quality of information (six items), (2) interaction and support (five items) and (3) efficiency (three items). A fourth subscale, patient involvement (three items), was removed from the scale as it was not a good measure of handover. CONCLUSIONS: The scale is a self-report, valid and reliable measure of the handover process. It provides a useful tool for monitoring and evaluating handover processes in health organisations, and it is recommended for use and further development. RELEVANCE TO CLINICAL PRACTICE: Monitoring handover is an important quality assurance process that is required to meet healthcare standards. This reliable and valid scale can be used in practice to monitor the quality of handover and provide information that can form the basis of education and training packages and guidelines to improve handover policies and processes.

Factors associated with transfers from healthcare facilities among readmitted older adults with chronic illness.

OBJECTIVE: Because chronic illness accounts for a considerable proportion of Australian healthcare expenditure, there is a need to identify factors that may reduce hospital readmissions for patients with chronic illness. The aim of the present study was to examine a range of factors potentially associated with transfer from healthcare facilities among older adults readmitted to hospital within a large public health service in Melbourne, Australia. METHODS: Data on readmitted patients between June 2006 and June 2011 were extracted from hospital databases and medical records. Adopting a retrospective case-control study design, a sample of 51 patients transferred from private residences was matched by age and gender with 55 patients transferred from healthcare facilities (including nursing homes and acute care facilities). Univariate and multivariate logistic regression analyses were used to compare the two groups, and to determine associations between 46 variables and transfer from a healthcare facility. RESULTS: Univariate analysis indicated that patients readmitted from healthcare facilities were significantly more likely to experience relative socioeconomic advantage, disorientation on admission, dementia diagnosis, incontinence and poor skin integrity than those readmitted from a private residence. Three of these variables remained significantly associated with admission from healthcare facilities after multivariate analysis: relative socioeconomic advantage (odds ratio (OR) 11.30; 95% confidence interval (CI) 2.62-48.77), incontinence (OR 7.18; 95% CI 1.19-43.30) and poor skin integrity (OR 18.05; 95% CI 1.85-176.16). CONCLUSIONS: Older adults with chronic illness readmitted to hospital from healthcare facilities are significantly more likely to differ from those readmitted from private residences in terms of relative socioeconomic advantage, incontinence and skin integrity. The findings direct efforts towards addressing the apparent disparity in management of patients admitted from a facility as opposed to a private residence.

Construct validity and reliability of the Single Checking Administration of Medications Scale.

Research indicates that single checking of medications is as safe as double checking; however, many nurses are averse to independently checking medications. To assist with the introduction and use of single checking, a measure of nurses' attitudes, the thirteen-item Single Checking Administration of Medications Scale (SCAMS) was developed. We examined the psychometric properties of the SCAMS. Secondary analyses were conducted on data collected from 503 nurses across a large Australian health-care service. Analyses using exploratory and confirmatory factor analyses supported by structural equation modelling resulted in a valid twelve-item SCAMS containing two reliable subscales, the nine-item Attitudes towards single checking and three-item Advantages of single checking subscales. The SCAMS is recommended as a valid and reliable measure for monitoring nurses' attitudes to single checking prior to introducing single checking medications and after its implementation.

Use of a Pteridine Moiety to Track DNA Uptake in Cells.

Fluorescence labeled oligonucleotides have a long history of being used to monitor nucleic acid transport and uptake. However, it is not known if the fluorescent moiety itself physically limits the number of pathways that can be used by the cell due to steric, hydrophobic, or other chemical characteristics. Here, we report a method for comparing the uptake kinetics of oligonucleotides labeled either with the fluorescent pteridine, 3-methyl-8-(2-deoxy-ß-D-ribofuranosyl) isoxanthopterin (3MI), or the common fluorophore 5-carboxyfluorescein (5-FAM). We use a multiphoton microscopic technique to monitor nucleic acid uptake LLC-PK1, a pig renal tubular cell line that is known to have multiple uptake pathways. We find that the two fluorophores enter the cells at different rates, suggesting that choice of fluorescent moiety influences the uptake pathway used by a cell. Finally, we reconstituted an LLC-PK1 membrane channel that is selective for nucleic acids in planar lipid bilayers, and tested the ability of the labeled nucleic acids to permeate the channel. We find that 3MI, and not 5-FAM labeled oligonucleotides can traverse the plasma membrane through the channel. These results have implications for future studies aimed at delivering pteridine moieties to cells and for tracking nucleic acid transport into tissues.

Referrals to hospital emergency departments from residential aged care facilities: stuck in a time warp.

This research aimed to describe the number and type of residents admitted to emergency departments (EDs) over 2 years; and to explore nurses' perceptions of the reasons why residential aged care facility (RACF) residents are referred to EDs. The research objective was addressed in a retrospective exploratory study using data on admissions to EDs from RACFs (N = 3,094) at the participating organisation over a 2-year period, and interview data on seven RACF and four ED nurses' perceptions of the issues involved. Most residents presenting at EDs required urgent medical attention. Major themes identified by RACF and ED nurses included issues related to staff competency, availability of general practitioners, lack of equipment in RACFs, residents and family members requesting referrals, communication difficulties, and poor attitudes towards RACF staff. There is a need to use strategies to detect residents whose conditions are deteriorating and treat them promptly in RACFs.

Community-based participatory research to guide adoption of culturally responsive trauma-informed HIV care throughout Nashville, Tennessee.

Background: Psychological trauma is a highly prevalent driver of poor health among people with HIV (PWH) in the Southern United States (U.S.). Trauma-informed care (TIC) has potential to advance national Ending the HIV Epidemic (EHE) goals, but formative research is needed to tailor TIC implementation to complex and interdependent HIV networks. Methods: We applied a community-based participatory research (CBPR) approach to iteratively engage personnel from high volume HIV care institutions in Nashville, Tennessee. Current practices and potential implementation determinants were identified through participatory process mapping (PM) and key informant interviews. The Consolidated Framework for Implementation Research (CFIR) was applied to deductively code interview data. Personnel attending a dissemination summit developed a network-wide implementation plan. Results: Data were collected with personnel from five institutions (e.g., community-based organizations, primary care clinics, public health department), for PM (n=48), interviews (n=35), and the summit (n=17). Results suggest there are limited trauma screenings, assessments, and services across the network. Relevant Characteristics of Individuals included a trauma-sensitive workforce committed to continuous learning and TIC adoption. Relevant Inner Setting Factors were networks and communications, with strong tension for change, high compatibility with TIC, and need for advancing cultural responsiveness. Relevant Outer Setting Factors included patient needs and resources and cosmopolitanism, with need for better leveraged mental health services. Relevant Process domains were champions and leadership, with need to diversify championship among leaders. Relevant Intervention Characteristics included relative advantage and complexity, with need for personnel wellness initiatives and increased engagement with the community as service designers. Four recommendations included development of shared communication systems, personnel wellness campaigns, routine evaluations to inform practices, and culturally responsive care initiatives. Conclusion: Modifiable TIC determinants were identified, and a community-created implementation plan was developed to guide adoption. Future research will focus on city-wide implementation and strengthening pre-implementation research in other settings.

The relationship between positive development and psychopathology during the transition to adulthood: a person-centred approach.

The transition to adulthood is characterised by potential for both positive development and problem outcomes such as psychopathology, yet little is known about relationships between the two. Given the diversity of pathways observed during this transition period, there is likely to be significant heterogeneity in young people's experiences of these outcomes. Drawing on data from 1158 19-20 year olds in the Australian Temperament Project and using latent profile analysis, we identified six subgroups. For most, higher positive development was associated with lower psychopathology and vice versa. One group (33.6%) was high across all positive development measures and low on psychopathology, and another (47.7%) average in both areas. The remaining four groups were low on positive development but differentiated by average psychopathology (4.7%), high internalising (5.5%), and moderate (7.2%) and severe (1.3%) externalising problems. Tailored intervention strategies that address both the promotion of competence and prevention of problem outcomes are needed.

The longitudinal prediction of alcohol consumption-related harms among young adults.

This study explores the longitudinal pathways by which risk and protective factors influence the development of alcohol-related harms in a representative community sample of 941 young adults (19-20 years) from Victoria, Australia, focusing on the role of concurrent risky drinking. Impulsivity at 15-16 years, alcohol-related harms at 15-16 years and 17-18 years, frequency of intoxication at 17-18 years, and antisocial behavior, friends' drinking and living arrangements at 19-20 years were directly related to alcohol-related harms, as well as indirectly related to harms through increased risky drinking. Paternal drinking at 17-18 years was directly related to alcohol-related harms. Friends' drinking at 19-20 years and alcohol-related harms at age 17-18 interacted with risky drinking to increase the likelihood of alcohol-related harms. Implications for intervention efforts are discussed.

Carers' perspectives of respite care in Australia: an evaluative study.

Caring for someone with dementia is burdensome and challenging. In Australia, respite services help carers to cope with these demands. In this descriptive study, 62 carers of people with dementia provided information on their use of respite care, its effectiveness and their satisfaction with services provided during the preceding 12 months. Results indicated that carers used day centre, in-home, residential, regular outings and cottage care. The main reasons for use were to assist with managing care, take a break, or attend to health problems. Although 78% of carers rated respite as beneficial to their care recipients, most suggested areas that required attention. Improvements included the need for more time and flexibility, better quality and more permanent staff, improved communication, bureaucracy, administration and affordability. Respite providers need to recognize these limitations and develop strategies to improve the delivery of diverse respite care for carers of people with dementia.

Assessing the Prevalence and Determinants of Exposure-Influenced HIV Testing among a Sample of Pre- and Post-Exposure Prophylaxis-Naïve Young Men Who Have Sex with Men in the United States.

Self-initiated Human Immunodeficiency Virus (HIV) testing after potential sexual exposure to HIV (i.e., exposure-influenced HIV testing) has high utility in detecting individuals with the highest probabilities of HIV seroconversion. We conducted a cross-sectional study among a sample of sexually active, pre/post-exposure prophylaxis (PrEP/PEP)-naïve young men who have sex with men (YMSM) in two US cities to assess the determinants (e.g., demographic, psychosocial, sexual, substance use, and HIV prevention characteristics) of exposure-influenced HIV testing (never/rarely vs. mostly/always) in their lifetime. Of 261 YMSM, only 26.5% reported mostly/always seeking exposure-influenced prior to the study. Multivariable analyses showed that younger age, sexual orientation non-disclosure, perceived HIV stigma, internalized homophobia, lower general resilience, and lower social support were associated with a lower likelihood of mostly/always seeking exposure-influenced HIV testing. YMSM who never/rarely sought exposure-influenced HIV testing were more likely to use recreational drugs before sex, binge alcohol, and have group sex; while less likely to be aware of PrEP, test for sexually transmitted infections, or use condoms compared to those mostly/always seeking exposure-influenced HIV testing. Exposure-influenced HIV testing is suboptimal among YMSM with elevated risk for HIV. Our findings provide important implications for designing targeted interventions to promote exposure-influenced HIV testing among high-risk YMSM.

Differentiating three conceptualisations of the relationship between positive development and psychopathology during the transition to adulthood.

The transition to adulthood is characterised by both great potential for positive change and a relatively high incidence of problem outcomes. A multidimensional model of positive development during the transition to adulthood (at 19-20 years) has recently been proposed. However, an unresolved question regarding the nature of positive development during this time is how best to conceptualise its relationship to psychopathology. We drew on data from 1158 participants in the Australian Temperament Project, a large longitudinal community-based study that has followed young people's psychosocial adjustment from infancy to early adulthood. Using structural equation modelling, we compared three models reflecting different conceptualisations of the relationship between positive development and psychopathology. The results suggest that positive development and psychopathology are best modelled as separate but correlated constructs. Hence, development in one domain is likely to influence the other, although separate and specific developmental pathways are also likely to be operating.

Stability and change in positive development during young adulthood.

Calls have been made for a greater focus on successful development and how positive functioning can be conceptualized in theory and empirical research. Drawing on a large Australian community sample (N = 890; 61.7% female), this article examines the structure and stability of positive development at two time points during young adulthood. Previously, we developed and empirically tested a model of positive development at 19-20 years comprised of five first-order constructs (civic action and engagement, trust and tolerance of others, trust in authorities and organisations, social competence, and life satisfaction) and a second-order positive development construct. In the current study, we replicated this model at 23-24 years and found that it was again a good fit for the data, and was equally applicable for young men and women. Hence, positive development can be conceptualized according to five important dimensions at both ages. While variable-oriented tests suggested continuity in levels of positive development, person-oriented analyses revealed four distinct patterns of positive development over time-two reflecting stability (stable high [34.5%] and stable very low [11.6%]) and two characterized by change (low/average increasing [30.4%] and average decreasing [23.5%]). There were significant differences in the gender composition of these groups, with young women overrepresented in the more favourable groups. Thus, despite mean level stability, positive development is characterized by change for many young people, suggesting the importance of identifying factors that support young people's capacity for positive functioning over this transitional period. The current findings contribute to our understanding of the nature and course of positive development over this important period.

Predictors of positive development in emerging adulthood.

This article responds to recent calls for a focus on successful development in young people and examination of its developmental precursors, in order to identify potentially modifiable targets for interventions. The current study examined child and adolescent precursors of positive functioning in emerging adulthood, including individual characteristics, relationship factors, and connections to the community, using a multidimensional positive development measure at 19-20 years. The sample consisted of 511 males and 647 females who were participants in the Australian Temperament Project, a population based longitudinal study that has followed young people's psychosocial adjustment from infancy to early adulthood. Higher levels of positive development in emerging adulthood were associated with stronger family and peer relationships, better adjustment to the school setting, higher family socioeconomic status, and better emotional control. Some significant gender differences were observed, with emotional control, family relationships, and community orientation all being stronger predictors of males' than of females' positive development. The findings provide possible targets for child and adolescent interventions to promote positive development in early adulthood.

Leveraging Expertise from Community Resources to Improve the Role of the Pharmacist in HIV Testing and Counseling.

The human immunodeficiency virus (HIV) epidemic continues to be a major global public health issue. Moreover, disparities continue to persist in HIV among racial and ethnic minority populations, with the highest rates of new diagnoses in Black/African American and Hispanic/Latino men who have sex with men in the United States. Pharmacists are one of the most accessible and trusted health care professionals. Therefore, it is imperative that student pharmacists are educated on culturally-competent HIV testing and risk behaviors counseling. This study describes the development of a partnership between a pharmacy school and a community-based organization to offer an HIV counseling and testing training program to help develop skills in delivering HIV testing services. The HIV counseling and testing training program contains learning modules that provide a wide array of in-depth information about HIV patient care in the community. The partnership allows for the enjoyment of a myriad of benefits for students, the pharmacy program, the community-based organization, and the public health of the community-at-large. Students feel more prepared and comfortable working with patients in discussing HIV transmission risk factors and test results as a result of this training. Such partnerships support the pharmacist's role in the public health arena. A successful and durable relationship between a community partner and a school of pharmacy is a feasible strategy for pharmacy progress in public health.

Conformational heterogeneity and quasi-static self-quenching in DNA containing a fluorescent guanine analogue, 3MI or 6MI.

Two different microenvironments in the DNA sequence 5'-act aGa gat ccc tca gac cct ttt agt cag tGt gga-3' (in both single- and double-stranded forms) are explored using two similar fluorescent nucleoside analogues, 3MI and 6MI. Each probe was evaluated in two environments, one strand with the probe flanked by thymines (PTRT) and the other by adenines (PTRA) with positions indicated by G's in the sequence. Both time-resolved anisotropies and lifetimes of the probes depend upon local interactions, and these are altered by duplex formation. Integrals of lifetime curves compared with quantum yields reveal that each probe displays a "dark" component (below detection limits, with a lifetime of <70 ps). For 6MI in PTRA, this QSSQ "quasi-static self-quenching" or "dark" component represents approximately half the molecules, whether in single- or double-stranded form. In PTRT, 6MI displays an unusual increase in the quantum yield upon formation of the double strand (from 0.107 to 0.189) apparently the result of escape from QSSQ which simultaneously declines from 66 to 33%. This is also accompanied by doubling of steady-state anisotropy. Only 6MI in the PTRT duplex displays a rotational correlation time of >7 ns. In other words, the DS 6MI PTRA environment fails to constrain local motion and QSSQ remains the same as in the single strand; in contrast, the flanking T duplex environment restricts local motion and halves QSSQ. We collected both steady-state and time-resolved fluorescence quenching titrations of 3MI and 6MI in solution with the mononucleotides AMP, CMP, GMP, and TMP. The dynamic quenching rank of the free probes (quenching constant, kq: T > A > G > C) is totally different from that of incorporated probes. We hypothesize the production of weak 3MI.C or 6MI.C complexes that are somehow rendered less subject to dynamic quenching by collision with subsequent C molecules.

Implementing a journal club in a palliative care setting: a link in the chain of evidence-based practice.

This paper describes the implementation and evaluation of a journal club in a privately funded palliative care unit. Journal club meetings were initiated as part of a quality improvement process to foster the uptake of evidence-based practice. Nurses were presented with research articles each month and discussions were conducted focussing on methodological considerations of the research and implications of the research for patient care. The maximum number of attendees at any one meeting was nine and the minimum number was four. Overall, evaluations were positive about all aspects of the meetings. Attendees found that the selected articles were relevant, providing new information, stimulated discussion and reflection on clinical practice and encouraged further reading. One of the positive aspects of the meetings identified by participants was the facilitation style that enabled discussion in a safe and supportive environment. An important outcome of the meetings is the potential to explore evidence-based practices relevant to palliative care and to implement new practices or revise existing ones. As part of this process practice changes and clinical guidelines have been implemented. A dedicated facilitator with university links and a supportive organisational culture promoted club meetings as a practical way to provide clinical nurses with the opportunity to explore evidence-based research in the area of palliative care.