Pragmatic Trial of Hospitalization Rate in Chronic Kidney Disease.

BACKGROUND: Despite the availability of effective therapies for patients with chronic kidney disease, type 2 diabetes, and hypertension (the kidney-dysfunction triad), the results of large-scale trials examining the implementation of guideline-directed therapy to reduce the risk of death and complications in this population are lacking. METHODS: In this open-label, cluster-randomized trial, we assigned 11,182 patients with the kidney-dysfunction triad who were being treated at 141 primary care clinics either to receive an intervention that used a personalized algorithm (based on the patient's electronic health record [EHR]) to identify patients and practice facilitators to assist providers in delivering guideline-based interventions or to receive usual care. The primary outcome was hospitalization for any cause at 1 year. Secondary outcomes included emergency department visits, readmissions, cardiovascular events, dialysis, and death. RESULTS: We assigned 71 practices (enrolling 5690 patients) to the intervention group and 70 practices (enrolling 5492 patients) to the usual-care group. The hospitalization rate at 1 year was 20.7% (95% confidence interval [CI], 19.7 to 21.8) in the intervention group and 21.1% (95% CI, 20.1 to 22.2) in the usual-care group (between-group difference, 0.4 percentage points; P = 0.58). The risks of emergency department visits, readmissions, cardiovascular events, dialysis, or death from any cause were similar in the two groups. The risk of adverse events was also similar in the trial groups, except for acute kidney injury, which was observed in more patients in the intervention group (12.7% vs. 11.3%). CONCLUSIONS: In this pragmatic trial involving patients with the triad of chronic kidney disease, type 2 diabetes, and hypertension, the use of an EHR-based algorithm and practice facilitators embedded in primary care clinics did not translate into reduced hospitalization at 1 year. (Funded by the National Institutes of Health and others; ICD-Pieces ClinicalTrials.gov number, NCT02587936.).

Accounting for quality improvement during the conduct of embedded pragmatic clinical trials within healthcare systems: NIH Collaboratory case studies.

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines. QI initiatives often co-occur with ePCTs and address the same high-impact health questions, and this co-occurrence may dilute or confound the ability to detect change as a result of the ePCT intervention. During the design, pilot, and conduct phases of the large-scale NIH Collaboratory Demonstration ePCTs, many QI initiatives occurred at the same time within the HCSs. Although the challenges varied across the projects, some common, generalizable strategies and solutions emerged, and we share these as case studies. KEY LESSONS: Study teams often need to monitor, adapt, and respond to QI during design and the course of the trial. Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care.

Incidence of statin use in older adults with and without cardiovascular disease and diabetes mellitus, January 2008- March 2018.

BACKGROUND: Data from randomized controlled trials and observational studies on older adults who take statins for primary prevention of atherosclerotic cardiovascular disease are limited. To determine the incidence of statin use in older adults with and without cardiovascular disease (CVD) and/or diabetes (DM), we conducted a descriptive observational study. METHODS: The cohort consisted of health plan members in the NIH Collaboratory Distributed Research Network aged >75 years who had continuous drug and medical benefits for ≥183 days during the study period, January 1, 2008- March 31, 2018. We defined DM and CVD using diagnosis codes, and identified statins using dispensing data. Statin use was considered incident if a member had no evidence of statin exposure in the claims during the previous 183 days, and the use was considered long-term if statins were supplied for ≥180 days. Incidence rates were reported among members with and without CVD and/or diabetes, and stratified by year, sex, and age group. RESULTS: Among 757,569 eligible members, 109,306 older adults initiated statins and 54,624 became long-term users. Health plan members with CVD had the highest incidence of statin use (143.9 initiators per 1,000 member-years for CVD & DM; 114.5 initiators per 1,000 member-years for CVD & No DM). Among health plan members without CVD, those with DM had rates of statin use that were over two times higher than members without DM (76.1 versus 34.5 initiators per 1,000 member-years, respectively). Statin initiation remained steady throughout 2008-2016, was slightly higher in males, and declined with increasing age. CONCLUSION: Incidence of statin use varied by CVD and DM comorbidity, and was lowest among those without CVD. These results highlight the potential clinical equipoise to conduct large pragmatic clinical trials to generate evidence that could be used to inform future blood cholesterol guidelines.

Addressing guideline and policy changes during pragmatic clinical trials.

While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.

Community pharmacists and mental illness: a survey of service provision, stigma, attitudes and beliefs.

Background Half of Americans experience mental illness during their lifetime. Significant opportunity exists for community pharmacists to deliver services to these patients; however, personal and practice-related barriers may prevent full engagement. Objective To assess the demographics, practice characteristics, service provision, stigma, attitudes and beliefs of a national sample of community pharmacists towards individuals with mental illness. Setting National random sample of 3008 community pharmacists in the USA. Method 101-item cross-sectional mailed survey questionnaire on: (1) demographics, (2) knowledge and practice characteristics, (3) provision of clinical pharmacy services, and (4) comparative opinions. Main outcome measure Scaled measures of service provision (comfort, confidence, willingness and interest) and comparative opinions (stigma, attitudes and beliefs) of mental illness, four linear regression models to predict service provision. Results A total of 239 responses were received (response rate 7.95%). Across pharmacy services, ratings for willingness/interest were higher than those for comfort/confidence. Pharmacists who reported providing medication therapy management (MTM) services for patients reported higher comfort (18.36 vs. 17.46, p < 0.05), confidence (17.73 vs. 16.01, p < 0.05), willingness (20.0 vs. 18.62, p < 0.05) and interest (19.13 vs. 17.66, p < 0.05). Pharmacists with personal experience with mental illness also resulted in higher scores across all four domains of service provision, lower levels of stigma (18.28 vs. 20.76, p < 0.05) and more positive attitudes (52.24 vs. 50.53, p < 0.01). Regression analyses demonstrated increased frequency of MTM service delivery and more positive attitudes as significantly predictive across all four models for comfort, confidence, willingness and interest. Increased delivery of pharmacy services was significantly associated with both willingness and interest to provide mental illness-specific services. Conclusion Despite willingness/interest to provide services to patients with mental illness, decreased levels of comfort/confidence remain service-related barriers for community pharmacists.

How well does early-career investigators' cardiovascular outcomes research training align with funded outcomes research?

BACKGROUND: Outcomes research training programs should prepare trainees to successfully compete for research funding. We examined how early-career investigators' prior and desired training aligns with recently funded cardiovascular (CV) outcomes research. METHODS: We (1) reviewed literature to identify 13 core competency areas in CV outcomes research; (2) surveyed early-career investigators to understand their prior and desired training in each competency area; (3) examined recently funded grants commonly pursued by early-career outcomes researchers to ascertain available funding in competency areas; and (4) analyzed alignment between investigator training and funded research in each competency area. We evaluated 185 survey responses from early-career investigators (response rate 28%) and 521 funded grants from 2010 to 2014. RESULTS: Respondents' prior training aligned with funded grants in the areas of clinical epidemiology, observational research, randomized controlled trials, and implementation/dissemination research. Funding in community-engaged research and health informatics was more common than prior training in these areas. Respondents' prior training in biostatistics and systematic review was more common than funded grants focusing on these specific areas. Respondents' desired training aligned similarly with funded grants, with some exceptions; for example, desired training in health economics/cost-effectiveness research was more common than funded grants in these areas. Restricting to CV grants (n=132) and National Heart, Lung, and Blood Institute-funded grants (n=170) produced similar results. CONCLUSIONS: Identifying mismatch between funded grants in outcomes research and early-career investigators' prior/desired training may help efforts to harmonize investigator interests, training, and funding. Our findings suggest a need for further consideration of how to best prepare early-career investigators for funding success.

Training cardiovascular outcomes researchers: A survey of mentees and mentors to identify critical training gaps and needs.

BACKGROUND: Many young investigators are interested in cardiovascular (CV) outcomes research; however, the current training experience of early investigators across the United States is uncertain. METHODS: From April to November 2014, we surveyed mentees and mentors of early-stage CV outcomes investigators across the United States. We contacted successful grantees of government agencies, members of professional organizations, and trainees in CV outcomes training programs. RESULTS: A total of 185 (of 662) mentees and 76 (of 541) mentors completed the survey. Mentees were equally split by sex; most had completed training >3 years before completing the survey and were clinicians. Mentors were more likely women, mostly ≥20 years posttraining, and at an associate/full professor rank. Mentors reported devoting more time currently to clinical work than when they were early in their career and mentoring 2-4 people simultaneously. More than 80% of mentees started training to become academicians and completed training with the same goal. More than 70% of mentees desired at least 50% research time in future jobs. More than 80% of mentors believed that future investigators would need more than 50% time dedicated to research. Most mentees (80%) were satisfied with their relationship with their mentor and reported having had opportunities to develop independently. Mentors more frequently than mentees reported that funding cutbacks had negatively affected mentees' ability to succeed (84% vs 58%). Across funding mechanisms, mentees were more optimistic than mentors about securing funding. Both mentees and mentors reported greatest preparedness for job/career satisfaction (79% for both) and publications (84% vs 92%) and least preparedness for future financial stability (48% vs 46%) and work-life balance (47% vs 42%). CONCLUSIONS: Survey findings may stimulate future discourse and research on how best to attract, train, and retain young investigators in CV outcomes research. Insights may help improve existing training programs and inform the design of new ones.

Priorities for Cardiovascular Outcomes Research: A Report of the National Heart, Lung, and Blood Institute's Centers for Cardiovascular Outcomes Research Working Group.

The Centers for Cardiovascular Outcomes Research (CCORs) held a meeting to review how cardiovascular outcomes research had evolved in the decade since the National Heart, Lung, and Blood Institute 2004 working group report and to consider future directions. The conference involved representatives from governmental agencies, outcomes research thought leaders, and public and private healthcare partners. The main purposes of this meeting were to (1) advance collaborative high-yield, high-impact outcomes research; (2) identify priorities and barriers to important cardiovascular outcomes research; and (3) define future needs for the field. This report highlights the key topics covered during the meeting, including an examination of the recent history of outcomes research, an evaluation of the current academic climate, and a vision for the future of cardiovascular outcomes research.

ACC/AHA Special Report: Clinical Practice Guideline Implementation Strategies: A Summary of Systematic Reviews by the NHLBI Implementation Science Work Group: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

BACKGROUND: In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity. OBJECTIVES: Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. METHODS: This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review. RESULTS: Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews). CONCLUSION: The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation.

ACC/AHA Special Report: Clinical Practice Guideline Implementation Strategies: A Summary of Systematic Reviews by the NHLBI Implementation Science Work Group: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

BACKGROUND: In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity. OBJECTIVES: Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. METHODS: This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review. RESULTS: Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews). CONCLUSION: The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation.

Future directions for cardiovascular disease comparative effectiveness research: report of a workshop sponsored by the National Heart, Lung, and Blood Institute.

Comparative effectiveness research (CER) aims to provide decision makers with the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart, Lung, and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address 8 clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.

Applying the PRECIS criteria to describe three effectiveness trials of weight loss in obese patients with comorbid conditions.

OBJECTIVES: To characterize Practice-Based Opportunities for Weight Reduction (POWER) trials along the pragmatic-explanatory continuum. SETTINGS: The POWER trials consist of three individual studies that target obesity treatment in primary care settings. DESIGN: Using the PRagmatic Explanatory Continuum Indicator Summary (PRECIS) criteria, nine reviewers independently scored each trial. METHODS: Average and median ratings, inter-rater reliability, and relationships to additional ratings of the extent to which study designs were explanatory (i.e., efficacy) versus pragmatic (i.e., practical) and related to external validity were determined. PRINCIPAL FINDINGS: One trial was consistently rated as being significantly more pragmatic than the others (R(2) =0.43, p< .001), although all three were in the moderate range on the PRECIS scales. Ratings varied across PRECIS dimensions, being most pragmatic on comparison condition and primary outcome. Raters, although undergoing training and using identical definitions, scored their own study as more pragmatic than the other studies/interventions. CONCLUSIONS: These results highlight the need for more comprehensive reporting on PRECIS and related criteria for research translation. The PRECIS criteria provide a richer understanding of the POWER studies. It is not clear whether the original criteria are sufficient to provide a comprehensive profile.

Age-related differences in idiom production in adulthood.

To investigate whether idiom production was vulnerable to age-related difficulties, we asked 40 younger (ages 18-30) and 40 older healthy adults (ages 60-85) to produce idiomatic expressions in a story-completion task. Younger adults produced significantly more correct idiom responses (73%) than did older adults (60%). When older adults generated partially correct responses, they were less likely than younger participants to eventually produce the complete target idiom (old: 32%; young: 70%); first-word cues after initial failure to retrieve an idiom resulted in more correct idioms for older (24%) than younger (15%) participants. Correlations between age and idiom correctness were positive for the young group and negative for the older group, suggesting mastery of familiar idioms continues into adulthood. Within each group, scores on the Boston Naming Test correlated with performance on the idiom task. Findings for retrieving idiomatic expressions are thus similar to those for retrieving lexical items.

Extracellular domain dependence of PTPalpha transforming activity.

Two isoforms of the transmembrane protein tyrosine phosphatase PTPalpha, which differ by nine amino acids in their extracellular regions, are expressed in a tissue-specific manner. Over-expression of the shorter isoform transforms rodent cells, and it has previously been reasonable to assume that this was a direct consequence of its dephosphorylation and activation of Src. Transformation by the longer wild-type isoform has not previously been studied. We tested the activities of both isoforms in NIH3T3 cells and found that, while both dephosphorylated and activated Src similarly, only the shorter isoform induced focus formation or anchorage-independent growth. Differences in phosphorylation of PTPalpha at its known regulatory sites, Grb2 binding to PTPalpha, phosphorylation level of focal adhesion kinase by PTPalpha, or overall localization were excluded as possible explanations for the differences in transforming activities. The results suggest that transformation by PTPalpha involves at least one function other than, or in addition to, its activation of Src and that this depends on PTPalpha's extracellular domain. Previous studies have suggested that PTPalpha might be a useful target in breast and colon cancer therapy, and the results presented here suggest that it may be advantageous to develop isoform-specific therapeutic reagents.

Independent but coordinated trials: insights from the practice-based Opportunities for Weight Reduction Trials Collaborative Research Group.

BACKGROUND: The National Heart, Lung, and Blood Institute (NHLBI) funded three institutions to conduct effectiveness trials of weight loss interventions in primary care settings. Unlike traditional multi-center clinical trials, each study was established as an independent trial with a distinct protocol. Still, efforts were made to coordinate and standardize several aspects of the trials. The three trials formed a collaborative group, the 'Practice-based Opportunities for Weight Reduction (POWER) Trials Collaborative Research Group.' PURPOSE: We describe the common and distinct features of the three trials, the key characteristics of the collaborative group, and the lessons learned from this novel organizational approach. METHODS: The Collaborative Research Group consists of three individual studies: 'Be Fit, Be Well' (Washington University in St. Louis/Harvard University), 'POWER Hopkins' (Johns Hopkins), and 'POWER-UP' (University of Pennsylvania). There are a total of 15 participating clinics with ~1100 participants. The common primary outcome is change in weight at 24 months of follow-up, but each protocol has trial-specific elements including different interventions and different secondary outcomes. A Resource Coordinating Unit at Johns Hopkins provides administrative support. RESULTS: The Collaborative Research Group established common components to facilitate potential cross-site comparisons. The main advantage of this approach is to develop and evaluate several interventions, when there is insufficient evidence to test one or two approaches, as would be done in a traditional multi-center trial. LIMITATIONS: The challenges of the organizational design include the complex decision-making process, the extent of potential data pooling, time intensive efforts to standardize reports, and the additional responsibilities of the DSMB to monitor three distinct protocols.

ACCP white paper: Essential components of a faculty development program for pharmacy practice faculty.

Prospective, ongoing faculty development programs are important in the initial orientation and short- and long-term development of faculty in higher education. Pharmacy practice faculty are likely to benefit from a comprehensive faculty development program due to the complex nature of their positions, incomplete training in select areas, and multiple demands on their time. The need for faculty development programs is supported by the increased need for pharmacy practice faculty due to the increased number of colleges and schools of pharmacy, expanding enrollment in existing colleges and schools, and loss of existing senior faculty to retirement or other opportunities within or outside the academy. This White Paper describes a comprehensive faculty development program that is designed to enhance the satisfaction, retention, and productivity of new and existing pharmacy practice faculty. A comprehensive faculty development program will facilitate growth throughout a faculty member's career in pertinent areas. The structure of such a program includes an orientation program to provide an overview of responsibilities and abilities, a mentoring program to provide one-on-one guidance from a mentor, and a sustained faculty development program to provide targeted development based on individual and career needs. The content areas to be covered in each component include the institution (e.g., culture, structure, roles, responsibilities), student-related activities, teaching abilities, scholarship and research abilities, practice abilities and the practice site, and professional abilities (e.g., leadership, career planning, balancing responsibilities). A general framework for a comprehensive pharmacy practice faculty development program is provided to guide each college, school, department, and division in the design and delivery of a program that meets the needs and desires of the institution and its faculty.

Environmental enrichment attenuates cue-induced reinstatement of sucrose seeking in rats.

This study examined the effect of environmental enrichment on sucrose seeking in rats made abstinent from sucrose for 1 month, as measured by response for a tone+light cue previously associated with 10% sucrose self-administration. Rats were either enriched throughout the study (experiment 1) or only after sucrose self-administration training (experiment 2). Enrichment consisted of either housing the rats in pairs or grouping four rats (ENR4) in a large environment, both with novel objects. Controls (CON) were singly housed without novel objects. In experiment 1, ENR4 rats responded less to the sucrose-paired cue versus CON rats, but this difference was not statistically significant. In contrast, the decrease in response of ENR4 rats versus CON rats in experiment 2 was dramatic and significant. These findings, along with findings from other laboratories, support a hypothesis that the enrichment may provide individuals with a greater ability to discriminate the availability of reward. This may impart a decreased vulnerability to relapse behavior. Therefore, these results are relevant to both eating disorder and drug addiction - disorders characterized by relapse.

Generation and use of primary rat cultures for studies of the effects of ethanol.

In vivo studies are ideal for identifying the phenomenology of ethanol toxicity and teratology. They are limited in being able to explore cellular and molecular mechanisms of action. Two types of culture models have proven to be very instructive: monolayer primary cultures of dissociated cells and organotypic slice cultures. Dissociated cell preparations have the advantage of being enriched populations of cells, whereas the organotypic cultures have the advantage of providing normal cell associations. Details for the methods used to generate these preparations are described. As ethanol is a volatile liquid, the success of a culture model depends upon stabilizing the ethanol content in the culture medium. A method to maintain the ethanol concentration is described.

Foxg1 haploinsufficiency reduces the population of cortical intermediate progenitor cells: effect of increased p21 expression.

Foxg1 is a transcription factor that is critical for forebrain development. Foxg1(+/Cre) mice were used to test the hypotheses 1) that the subventricular zone (SZ) generates supragranular neurons, 2) that Foxg1-regulated activities define the output from the SZ, and 3) that Foxg1 is involved in the suppression of p21-initiated cell-cycle exit. Foxg1(+/Cre) mice have thinner neocortices than wild-type controls, specifically in the supragranular layers, as detected by Brn2 immunostaining. Cell proliferation in the ventricular zone (VZ) and SZ was examined to investigate the reduction in upper layer neurons. The number of cycling VZ cells was similar in Foxg1(+/+) and Foxg1(+/Cre) brains. Interestingly, cell proliferation in the SZ and intermediate progenitor cell (IPC) production (noted by Tbr2-immunostaining) was reduced in Foxg1(+/Cre) brains. These decreases coincided with increased expression of the cell-cycle inhibitor p21 in the VZ and SZ. Furthermore, colocalization of p21 with markers of cell proliferation and IPCs indicated that p21 was temporally expressed to influence the proliferative fate of IPCs. Thus, the present data are consistent with the above hypotheses, particularly, that during corticogenesis, Foxg1-regulated activities enable the expansion of the IPC population likely through suppression of p21-dependent cell-cycle exit.