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The protein phosphatase Phlpp1 is an essential enzyme for proper chondrocyte function. Altered Phlpp1 levels are associated with cancer and degenerative diseases such as osteoarthritis. While much is known about the post-transcriptional mechanisms controlling Phlpp1 levels, transcriptional regulation of the Phlpp1 gene locus is underexplored. We previously showed that CpG methylation of the PHLPP1 promoter is lower in osteoarthritic cartilage than in normal cartilage, and indirectly correlates with gene expression. Here we further defined the effects of DNA methylation on PHLPP1 promoter activity in chondrocytes. We cloned a 1791 bp fragment of the PHLPP1 promoter (−1589:+202) and found that the first 500 bp were required for maximal promoter activity. General methylation of CpG sites within this fragment significantly blunts transcriptional activity, whereas site-specific methyltransferases HhaI or HpaII decreases transcriptional activation by approximately 50%. We located putative FoxO consensus sites within the PHLPP1 promoter region. Inhibition of DNA methylation by incorporation of 5-azacytidine increases Phlpp1 mRNA levels, but FoxO inhibition abolishes this induction. To determine which FoxO transcription factor mediates Phlpp1 expression, we performed overexpression and siRNA-mediated knock down experiments. Overexpression of FoxO3a, but not FoxO1, increases Phlpp1 levels. Likewise, siRNAs targeting FoxO3a, but not FoxO1, diminished Phlpp1 levels. Lastly, FoxO inhibition increases glycosaminoglycan staining of cultured chondrocytes and leads to concomitant increases in FGF18 and HAS2 expression. Together, these data demonstrate that CpG methylation and FoxO3a regulate PHLPP1 expression.

Phlpp protein phosphatases are abnormally abundant within human osteoarthritic articular chondrocytes and may contribute to the development of osteoarthritis. Mice lacking Phlpp1 were previously shown to be resistant to post-traumatic osteoarthritis. Here a small molecule with therapeutic properties that inhibits Phlpp1 and Phlpp2 was tested for its ability to slow post-traumatic OA in mice and to stimulate anabolic pathways in human articular cartilage from OA joints. PTOA was induced in male C57Bl/6 mice by surgically destabilizing the meniscus. Seven weeks after surgery, mice received a single intra-articular injection of the Phlpp inhibitor NSC117079 or saline. Mechanical allodynia was measured with von Frey assays, mobility was tracked in an open field system, and cartilage damage was assessed histologically. A single intra-articular injection of the Phlpp inhibitor NSC117079 attenuated mechanical allodynia and slowed articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor 7 weeks after injury maintained normal activity levels, while those in the control group traveled shorter distances and were less active 3 months after the joint injury. NSC117079 also increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2, and PKC) in human articular chondrocytes. Our results indicate that Phlpp inhibitor NSC117079 is a novel osteoarthritis disease modifying drug candidate that may have palliative affects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1487-1497, 2018.

Objective To understand how health care providers and social services providers coordinate their work in communities that achieve relatively low health care utilization and costs for older adults. Study Setting Sixteen Hospital Service Areas (HSAs) in the United States. Study Design We conducted a qualitative study of HSAs with performance in the top or bottom quartiles nationally across three key outcomes: ambulatory care sensitive hospitalizations, all-cause risk-standardized readmission rates, and average reimbursements per Medicare beneficiary. We selected 10 higher performing HSAs and six lower performing HSAs for inclusion in the study. Data Collection To understand patterns of collaboration in each community, we conducted site visits and in-depth interviews with a total of 245 representatives of health care organizations, social service agencies, and local government bodies. Principal Findings Organizations in higher performing communities regularly worked together to identify challenges faced by older adults in their areas and responded through collective action—in some cases, through relatively unstructured coalitions, and in other cases, through more hierarchical configurations. Further, hospitals in higher performing communities routinely matched patients with needed social services. Conclusions The collaborative approaches used by higher performing communities, if spread, may be able to improve outcomes elsewhere.

Long bone formation is a complex process that requires precise transcriptional control of gene expression programs in mesenchymal progenitor cells. Histone deacetylases (Hdacs) coordinate chromatin structure and gene expression by enzymatically removing acetyl groups from histones and other proteins. Hdac inhibitors are used clinically to manage mood disorders, cancers, and other conditions but are teratogenic to the developing skeleton and increase fracture risk in adults. In this study, the functions of Hdac3, one of the enzymes blocked by current Hdac inhibitor therapies, in skeletal mesenchymal progenitor cells were determined. Homozygous deletion of Hdac3 in Prrx1-expressing cells prevented limb lengthening, altered pathways associated with endochondral and intramembranous bone development, caused perinatal lethality, and slowed chondrocyte and osteoblast differentiation in vitro. Transcriptomic analysis revealed that Hdac3 regulates vastly different pathways in mesenchymal cells expressing the Prxx1-Cre driver than those expressing the Col2-CreERT driver. Notably, Fgf21 was elevated in Hdac3-CKOPrrx1 limbs as well as in chondrogenic cells exposed to Hdac3 inhibitors. Elevated expression of Mmp3 and Mmp10 transcripts was also observed. In conclusion, Hdac3 regulates distinct pathways in mesenchymal cell populations and is required for mesenchymal progenitor cell differentiation and long bone development. © 2017 American Society for Bone and Mineral Research.

Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone-derived factors that reduce RANKL (receptor activator of NF-kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1-expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3-deficient mice on a high fat diet. Thus, Hdac3-depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.

Gray wolves (Canis lupus) were extirpated from the northern Rocky Mountains (NRM) of the United States by the 1930s. Dispersing wolves from Canada naturally recolonized Montana and first denned there in 1986. In 1995 and 1996, the United States Fish and Wildlife Service reintroduced 66 wolves into central Idaho and Yellowstone National Park. By 2008, there were ≥1,655 wolves in ≥217 packs, including 95 breeding pairs in the NRM. From 1993–2008, we captured and radio-collared 1,681 wolves and documented 297 radio-collared wolves dispersing as lone individuals. We monitored dispersing wolves to determine their pack characteristics (i.e., pack size and surrounding pack density) before and after dispersal, their reproductive success, and eventual fate. We calculated summary statistics for characteristics of wolf dispersal (i.e., straight-line distance, age, time of year, sex ratio, reproduction, and survival), and we tested these characteristics for differences between sexes and age groups. Approximately, 10% of the known wolf population dispersed annually. The sex ratio of dispersals favored males (169 M, 128 F), but fewer dispersed males reproduced (28%, n = 47) than females (42%, n = 54). Fifty-nine percent of all dispersers of known age were adults (n = 156), 37% were yearlings (n = 99), and 4% were pups (n = 10). Mean age at dispersal for males (32.8 months) was not significantly different (P = 0.88) than for females (32.1 months). Yellowstone National Park had a significant positive effect on dispersal rate. Pack density in a wolf's natal population had a negative effect on dispersal rate when the entire NRM population was considered. The mean NRM pack size (6.9) from 1993 to 2008 was smaller than the mean size of packs (10.0) from which wolves dispersed during that time period (P 300 km. On average, dispersal distance decreased later in the study (P = 0.006). Sex, survival rate in the natal population, start date, dispersal distance, and direction were not significant predictors of dispersal rate or successful dispersal. Wolves that formed new packs were >11 times more likely to reproduce than those that joined packs and surrounding pack density had a negative effect on successful dispersal. Dispersal behavior seems to be innate in sexually mature wolves and thereby assures that genetic diversity will remain high and help conserve the NRM wolf population. © 2017 The Wildlife Society.

In 2011, 1.65 million individuals with terminal illnesses received hospice services, and 44.6% of all decedents in the United States had been under the care of a hospice.1 Hospice users and their primary caregivers are typically older adults. In 2013, an estimated 84% of hospice users were aged 65 and older and 41% were aged 85 and older.2 Primary caregivers, who help make decisions for terminally ill individuals, are most often their spouses or adult children who are aged 60 and older.3 Although most family members of individuals in hospice who die recover from initial reactions of acute grief and return to preloss functioning,4 an estimated 11% develop the mental health disorders of complicated grief (CG) and depression, with prevalence increasing slightly with increasing age.5–7 CG is characterized by symptoms of reactive distress to the death (e.g., disbelief or bitterness) and disruption in social relationships or identity.8 Criteria for major depressive disorder (depression) are well established,8 but diagnosis of depression after bereavement has recently undergone a significant change. The Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition, allows diagnosis of depression within 2 weeks of bereavement, replacing the DSM, Fourth Edition, requirement that depression not be diagnosed until 2 months after bereavement.8 This change expands the population of individuals who might benefit from screening and treatment. In older adults, depression and CG are associated with greater risk of morbidity for most of the common diseases of later life, including chronic functional impairment, hypertension, sleep impairment, and suicidal ideation.9–18 For example, the risk of hypertension is 10 times as high in older widowed adults who meet consensus criteria for CG as in those who do not.19 As the U.S. population continues to age, it is likely that the impairment associated with depression and CG will create an even greater societal burden. Well-validated measures and effective individual and group psychotherapeutic treatments for CG and depression in older adults have been developed,20–22 yet older adults are less likely to seek bereavement support than younger adults,23 in part because of a cohort-specific stigma about the acceptability of using mental health care.24 Because hospices care for people before and during death, they are uniquely positioned to offer screening and referral services for CG and bereavement-related depression in older family caregivers. Receiving bereavement support in a setting to which older adults are already connected may make it use more likely.25 Moreover, Medicare, the primary payer for hospice care (providing coverage to 84% of people in hospice)1 requires that hospices offer bereavement services to family members for at least a year after the person in hospice dies in order to receive reimbursement under the Medicare Hospice Benefit.1 Although hospice provision of bereavement services has been described in detail,26–29 previous publications have not focused specifically on screening and referral practices for CG or depression. Accordingly, the current study used data from the National Hospice Survey to estimate the extent to which hospices nationally provide screening and referral services that address the mental health needs of family members of individuals who die in hospice. The associations between organizational and staff factors and the likelihood of offering screening and referral for CG and depression were also examined. Organizational theory posits that organizational structure can affect the type and quality of care provided.30 In this analysis, organizational factors considered included hospice profit status, chain affiliation, size, and geographical region. In keeping with previous work, it was hypothesized that larger hospice size would be associated with higher likelihood of conducting screening and referral.29 Because previous analyses did not find consistent associations between profit status, chain affiliation, region, and bereavement service intensity more generally,29 it was not expected to that any association would be found with these variables in the analyses. It was also hypothesized that the extent to which hospices provide screening and referral or bereavement-related mental health conditions would be associated with provider- level factors, such as level of provider training, volunteer availability, and interdisciplinary team meeting involvement. Consistent with theories that participation of and interactions among providers of a variety of backgrounds can enhance care,31–33 research has demonstrated that social worker and volunteer involvement, and interdisciplinary collaboration more broadly, are associated with better quality of care for people in hospice.22,34,35 Training requirements have also been associated with quality of bereavement care provision specifically,36 but these associations have not been adequately studied for hospice bereavement care. As previous findings and existing theory predicted, it was hypothesized that lengthier training requirements, interdisciplinary team attendance from a large range of providers, and a lower ratio of volunteer hours to number of individuals in hospice would be associated with higher likelihood of conducting CG and depression screening and referral. Findings from this study can provide a more-complete picture of how hospices may be screening for important bereavement-related mental health problems and helping family caregivers connect to appropriate care after the death. This information can inform future work to identify strategies to improve mental health screening or therapy in hospices, as well as in other settings with a large bereaved population.

Wolf (Canis lupus) predation on livestock and management methods used to mitigate conflicts are highly controversial and scrutinized especially where wolf populations are recovering. Wolves are commonly removed from a local area in attempts to reduce further depredations, but the effectiveness of such management actions is poorly understood. We compared the effects of 3 management responses to livestock depredation by wolf packs in Montana, Idaho, and Wyoming: no removal, partial pack removal, and full pack removal. We examined the effectiveness of each management response in reducing further depredations using a conditional recurrent event model. From 1989 to 2008, we documented 967 depredations by 156 packs: 228 on sheep and 739 on cattle and other stock. Median time between recurrent depredations was 19 days following no removal (n = 593), 64 days following partial pack removal (n = 326), and 730 days following full pack removal (n = 48; recurring depredations were made by the next pack to occupy the territory). Compared to no removal, full pack removal reduced the occurrence of subsequent depredations by 79% (hazard ratio [HR] = 0.21, P

BACKGROUND: Improving hospital discharge has become a national priority for teaching hospitals, yet little is known about physician perspectives on factors limiting the quality of discharge care. OBJECTIVES: To describe the discharge process from the perspective of housestaff physicians, and to generate hypotheses about quality-limiting factors and key strategies for improvement. METHODS: Qualitative study with in-depth, in-person interviews with a diverse sample of 29 internal medicine housestaff, in 2010–2011, at 2 separate internal medicine training programs, including 7 different hospitals. We used the constant comparative method of qualitative analysis to explore the experiences and perceptions of factors affecting the quality of discharge care. RESULTS: We identified 5 unifying themes describing factors perceived to limit the quality of discharge care: (1) competing priorities in the discharge process; (2) inadequate coordination within multidisciplinary discharge teams; (3) lack of standardization in discharge procedures; (4) poor patient and family communication; and (5) lack of postdischarge feedback and clinical responsibility. CONCLUSIONS: Quality-limiting factors described by housestaff identified key processes for intervention. Establishment of clear standards for discharge procedures, including interdisciplinary teamwork, patient communication, and postdischarge continuity of care, may improve the quality of discharge care by housestaff at teaching hospitals. Journal of Hospital Medicine 2012; © 2012 Society of Hospital Medicine

Introduction: Reproductive health problems are the leading cause of women's morbidity and mortality worldwide. In the United States, officially sponsored refugee women continue to face challenges in accessing reproductive health programs despite having access to health insurance. Methods: The objective of this study was to explore the reproductive health experiences of 1 such population—Somali Bantu women in Connecticut—to identify potential barriers to care experienced by marginalized populations. The study was qualitative, consisting of key informant interviews, a focus group session, and a semistructured survey. Results: Although all the women in the study reported having access to reproductive health care services, they also reported having unmet health needs resulting from barriers to care that included ethnic distinction/language barriers, passive acceptance of incorrect care, cultural discordance in family planning services, patient-provider sex discordance, and desire but limited scope for ownership in health care outcomes. The root cause of the various types of patient-provider discordance was the lack of recognition that the Somali Bantu are distinct in culture, language, and solidarity from ethnic Somalis, resulting in Language Line translation services being conducted in a Somali language that the Somali Bantu women did not understand. Discussion: The results of the study primarily highlight the larger issue of information asymmetry within the health care system that, if left unaddressed, will persist as new vulnerable populations of refugees arrive in the United States.

Although genetic evidence has demonstrated a role for Wnt5b during cartilage and limb development, little is known about the mechanisms underlying Wnt5b-regulated chondrocyte differentiation. We observed that Wnt5b inhibited chondrocyte hypertrophy and expression of type X collagen. In addition, Wnt5b regulated the overall size of chondrogenic cultures, suggesting that Wnt5b regulates other processes involved in cartilage development. We therefore investigated the signaling pathways by which Wnt5b influences differentiation. Wnt5b activated known calcium-dependent signaling pathways and JNK, a component of the planar cell polarity pathway. Since the planar cell polarity pathway regulates process such as cell migration and cell aggregation that are involved in limb development, we assayed for effects of Wnt5b on these processes. We observed a marked increase chondroprogenitor cell migration with Wnt5b expression. This effect was blocked by inhibition of JNK, but not by inhibition of other Wnt5b-responsive factors. Expression of Wnt5b also disrupted the cellular aggregation associated with mesenchymal condensation. Decreased aggregation was associated with reduced cadherin expression as well as increased cadherin receptor turnover. This increase in cadherin receptor turnover was associated with an increase in Src-dependent beta-catenin phosphorylation downstream of Wnt5b. Our data demonstrate that not only does Wnt5b inhibit chondrocyte hypertrophy, but document a novel role for Wnt5b in modulating cellular migration through the JNK-dependent and cell adhesion through an activation of Src and subsequent cadherin receptor turnover.

Amid persistent evidence that many patients do not receive guideline-based care, national quality campaigns have developed to motivate widespread adoption of evidence-based practices to improve quality of care. Recent examples include the 100,000 Lives and 5 Million Lives Campaigns sponsored by the Institute for Healthcare Improvement (Gosfield and Reinertsen 2005; Berwick et al. 2006; McCannon, Hackbarth, and Griffin 2007; American Heart Association; 2009), and the Door-to-Balloon (D2B) Alliance for Quality led by the American College of Cardiology (Krumholz et al. 2008). Although there is some debate regarding the magnitude of impact (Wachter and Pronovost 2006), evidence (Berwick et al. 2006; McCannon et al. 2006; Bradley et al. 2009a;) suggests that these campaigns can have measurable impact in increased adherence to guidelines and potentially marked reductions in preventable deaths. Despite the widespread participation by hospitals in such national quality campaigns, we know little about users' perspectives about what makes such campaigns more effective or less effective. Previous research has reported views of network sponsors and researchers concerning characteristics of effective learning networks (Ovretveit 2002; Ovretveit et al. 2002; Wilson, Berwick, and Cleary 2003; Ayers et al. 2005; McCannon and Perla 2009;), but these reports have not examined participant views. Nevertheless, participant views are important for understanding the characteristics of campaigns that enhance their effectiveness, for identifying why campaigns might be effective, and for describing the conditions under which campaigns may be more effective or less effective. This deeper understanding of campaigns may shed light into the process of effective dissemination of evidence-based practices to promote quality of care. Accordingly, we sought to understand the influence of a national quality campaign, the D2B Alliance, from the participants' perspective. The D2B Alliance was a national quality campaign, sponsored by the American College of Cardiology and 38 other professional organizations and agencies, to disseminate evidence-based practices in reducing delays to between-hospital presentation and percutaneous coronary intervention (PCI), or balloon angioplasty, for patients with ST-segment elevation myocardial infarction (STEMI). The D2B Alliance was an open and free campaign that enrolled more than 1,000 U.S. hospitals in its first year (Krumholz et al. 2008). Hospitals enrolled by having a letter signed by the senior administrator committing to the goal of the D2B Alliance, which was for 75 percent of patients with STEMI treated with PCI to receive therapy within 90 minutes of hospital arrival, the D2B time target set by national guidelines. The D2B Alliance promoted the implementation of evidence-based strategies (Bradley et al. 2006; Bradley et al. 2009a) for reducing D2B time by disseminating a toolkit and a change package as well as providing open access to webinars, an online community, and a mentor network. We addressed the following questions pertinent to national quality campaigns with our research. What characteristics of the campaign are viewed by participants as most effective? What are the mechanisms by which the campaign influences outcomes? And what are the contextual factors that modify the effectiveness of the campaign? Such information can be used by researchers, policy makers, and practitioners to anticipate the circumstances under which campaigns might be effective dissemination strategies and to include design features based on evidence about what participants view as most effective.

Through health sector reform in developing countries, Ministries of Health have sought to enhance health care through greater community governance and improved management effectiveness in their public hospitals. In this paper, we present a partnership-mentoring model for enhancing management capacity that has been piloted in Ethiopia and may be useful in other developing countries. The model included needs assessment and baseline evaluation using a hospital management indicator checklist, deployment of 24 Fellows (US and international hospital administrators) for 1 year to work as mentors with hospital management teams in 14 Ethiopian hospitals, continuing didactic and practical training in quality improvement methods for hospital management teams, and 24 management improvement projects to be completed during the year with plans for replication more broadly as appropriate. Surveys of Fellows and Ethiopian managers within the first quarter of onsite activity found high levels of trust in one another's abilities and intent to implement changes. The partnership-mentoring model promotes sustainability and may provide other countries with approaches for improving the quality of hospital care through improved hospital management.

While M-CSF-mediated MEK/ERK activation promotes osteoclast survival, the signaling pathway by which M-CSF activates MEK/ERK is unresolved. Functions for PI3K, Ras, and Raf have been implicated in support of osteoclast survival, although interaction between these signaling components has not been examined. Therefore, the interplay between PI3K, Ras and Raf in M-CSF-promoted MEK/ERK activation and osteoclast survival was investigated. M-CSF activates Ras to coordinate activation of PI3K and Raf/MEK/ERK, since Ras inhibition decreased PI3K activation and PI3K inhibition did not block M-CSF-mediated Ras activation. As further support for Ras-mediated signaling, constitutively active (ca) Ras promoted MEK/ERK activation and osteoclast survival, which was blocked by inhibition of PI3K or Raf. Moreover, PI3K-selective or Raf-selective caRas were only partially able to promote osteoclast survival when compared to parental caRas. We then examined whether PI3K and Raf function linearly or in parallel downstream of Ras. Expression of caPI3K increased MEK/ERK activation and promoted osteoclast survival downstream of M-CSF, supporting this hypothesis. Blocking Raf did not decrease osteoclast survival and MEK/ERK activation promoted by caPI3K. In addition, PI3K-selective Ras-mediated survival was not blocked by Raf inhibition. Taken together, our data support that Raf signaling is separate from Ras/PI3K signaling and PI3K signaling is separate from Ras/Raf signaling. These data therefore support a role for Ras in coordinate activation of PI3K and Raf acting in parallel to mediate MEK/ERK-promoted osteoclast survival induced by M-CSF.

Managers of recovering wolf (Canis lupus) populations require knowledge regarding the potential impacts caused by the loss of territorial, breeding wolves when devising plans that aim to balance population goals with human concerns. Although ecologists have studied wolves extensively, we lack an understanding of this phenomenon as published records are sparse. Therefore, we pooled data (n = 134 cases) on 148 territorial breeding wolves (75 M and 73 F) from our research and published accounts to assess the impacts of breeder loss on wolf pup survival, reproduction, and territorial social groups. In 58 of 71 cases (84%), ≥1 pup survived, and the number or sex of remaining breeders (including multiple breeders) did not influence pup survival. Pups survived more frequently in groups of ≥6 wolves (90%) compared with smaller groups (68%). Auxiliary nonbreeders benefited pup survival, with pups surviving in 92% of cases where auxiliaries were present and 64% where they were absent. Logistic regression a...

OBJECTIVES: To describe the Hospital Elder Life Program (HELP) across dissemination sites, to detail adaptations, and to summarize advantages across sites. DESIGN: Cross-sectional survey. SETTING: HELP sites in acute care hospitals. PARTICIPANTS: Thirteen sites that enrolled 11,344 patients. MEASUREMENTS: Seventy-five closed- and open-ended questions describing details of the HELP site, procedures, staffing, outcomes tracked, and advantages. RESULTS: As of July 1, 2005, HELP had been fully implemented in 13 sites, with a median duration of 24 months (range 6.0–38.0). Although a high degree of fidelity to the original model was maintained, variations existed in staffing patterns, outcome tracking, and recommended HELP procedures. Adaptations were made across multiple domains, including enrollment criteria at 15.4% of sites, screening and assessment tools at 61.5%, and individual intervention protocols at 15.4% to 30.8%. Local circumstances drove these adaptations, with the most common reasons being lack of adequate staffing and logistical constraints. All sites conducted regular HELP staff meetings; other recommended quality assurance procedures were conducted at 46.2% to 92.3% of sites. Reported advantages of HELP included providing an educational resource at 100% of sites, improving hospital outcomes (e.g., delirium and functional decline) at 100%, providing nursing education and improving retention at 100%, enhancing patient and family satisfaction with care at 92.3%, raising visibility for geriatrics at 92.3%, and improving quality of care at 84.6%. CONCLUSION: This report describes the real-world implementation of HELP across 13 sites, documents their local adaptations and successes, and provides insight into how motivated institutions can create change to improve quality of care for older persons.

Managing wolf (Canis lupus) depredation on livestock is expensive and controversial; therefore, managers seek to improve and develop new methods to mitigate conflicts. Determining which factors put ranches at higher risk to wolf depredation may provide ideas for ways to reduce livestock and wolf losses. We sampled cattle pastures in Montana and Idaho that experienced confirmed wolf depredations (n = 34) from 1994–2002 and compared landscape and selected animal husbandry factors with cattle pastures on nearby ranches where depredations did not occur (n=62). Pastures where depredations occurred were more likely to have elk (Cervus elaphus) present, were larger in size, had more cattle, and grazed cattle farther from residences than pastures without depredations. Using classification tree analysis, we found that a higher percentage of vegetation cover also was associated with depredated pastures in combination with the variables above. We found no relationship between depredations and carcass dispos...

Successful nonlethal management of livestock predation is important for conserving rare or endangered carnivores. In the northwestern United States, wolves (Canis lupus) have been translocated away from livestock to mitigate conflicts while promoting wolf restoration. We assessed predation on livestock, pack establishment, survival, and homing behavior of 88 translocated wolves with radiotelemetry to determine the effectiveness of translocation in our region and consider bow it may be improved. More than one-quarter of translocated wolves preyed on livestock after release. Most translocated wolves (67%) never established or joined a pack, although eight new packs resulted from translocations. Translocated wolves had lower annual survival (0.60) than other radio-collared wolves (0.73), with government removal the primary source of mortality. In northwestern Montana, where most wolves have settled in human-populated areas with livestock, survival of translocated wolves was lowest (0.41) and more wolves proportionally failed to establish packs (83%) after release. Annual survival of translocated wolves was highest in central Idaho (0.71) and more wolves proportionally established packs (44%) there than in the other two recovery areas. Translocated wolves showed a strong homing tendency; most of those that failed to home still showed directional movement toward capture sites. Wolves that successfully returned to capture sites were more likely to be adults, hard (immediately) rather than soft (temporarily held in enclosure) released, and translocated shorter distances than other wolves that did not return home. Success of translocations varied and was most affected by the area in which wolves were released. We suggest managers translocating wolves or other large carnivores consider soft releasing individuals (in family groups, if social) when feasible because this may decrease homing behavior and increase release-site fidelity.

Objectives To examine key factors that influence sustainability in the diffusion of the Hospital Elder Life Program (HELP) as an example of an evidence-based, multifaceted, innovative program to improve care for hospitalized older adults. Design Longitudinal, qualitative study between November 2000 and November 2003 based on 102 in-depth interviews every 6 months during HELP implementation. Setting Thirteen hospitals implementing HELP. Participants Forty-two hospital staff members (physician, nursing, volunteer, and administrative staff) implementing HELP, conducted 102 interviews. Measurements Staff experiences sustaining the program, including challenges and strategies that they viewed as successful in addressing these challenges. Results Of the 13 hospitals studied, 10 were sustaining HELP at the end of the study period; three terminated the program (after 24 months, 12 months, and 6 months). Critical factors were identified as influencing whether the program was sustained: the presence of clinical leadership, the ability and willingness to adapt the original HELP protocols to local hospital circumstances and constraints, and the ability to obtain longer-term resources and funding for HELP. Conclusion Recognizing the need for sustained clinical leadership and funding as well as the inevitable modifications required to sustain innovative programs can promote more-realistic goals and expectations for health services researchers, clinicians, and policy makers in their laudable efforts to translate research into practice.

Quality improvement (QI) efforts aimed at optimizing adherence to coronary artery disease quality indicators are helping to bridge the serious gaps in the quality of care for this population. Motivation for these initiatives is prompted by a number of sources, including the public reporting of hospitals' adherence to these indicators found on the Center for Medicare and Medicaid Services Web site. Although complex barriers challenge QI efforts, results of recent studies demonstrate that the use of five key success factors reduces these barriers and accelerates improvement. Integral components of this model include administrative support that cultivates a blameless culture that strives for perfection; committed and respected champions; goals that are shared within the organization; the use of timely, credible data at the organizational and individual levels; and implementation of a QI initiative tailored to the complexity of the project. In this review article, the authors discuss how quality of care is measured, provide examples of successful QI programs, and describe how the use of a QI model composed of five key success factors can accelerate QI efforts and optimize the care of patients hospitalized with coronary artery disease.

Objectives: To examine the adequacy of caregiver-patient communication in serious illness and its relationship to caregiver burden. Design: Cross-sectional cohort study. Setting: Participants' homes. Participants: One hundred ninety-three persons aged 60 and older seriously ill with cancer, congestive heart failure, or chronic obstructive pulmonary disease and their caregivers. Measurements: Communication concerns, measured in terms of agreement with statements regarding desire for and difficulty with communication about the patient's illness. Caregiver burden, measured using a 10-item subset of the Zarit Burden Inventory, with scores ranging from 0 to 40 and higher scores indicating greater burden. Results: Of caregivers, 39.9% desired more communication, and 37.3% reported that communication was difficult. Of patients, 20.2% desired more communication, and 22.3% reported that communication was difficult. Disagreement regarding communication concerns was frequent in caregiver-patient pairs; of caregivers who desired more communication, 83.1% of patients did not, and of patients who desired more communication, 66.7% of caregivers did not. Caregivers who desired more communication had significantly higher caregiver burden scores than did caregivers who did not (9.2 vs 4.7, P

Objectives: To describe the process of adoption of an evidence-based, multifaceted, innovative program into the hospital setting, with particular attention to issues that promoted or impeded its implementation. This study examined common challenges faced by hospitals implementing the Hospital Elder Life Program (HELP) and strategies used to address these challenges. Design: Qualitative study design based on in-depth, open-ended telephone interviews. Setting: Nine hospitals implementing HELP throughout the United States. Participants: Thirty-two key staff members (physician, nursing, volunteer, and administrative staff) who were directly involved with the HELP implementation. Measurements: Staff experiences implementing the program, including challenges and strategies they viewed as successful in overcoming challenges of implementation. Results: Six common challenges faced hospital staff: (1) gaining internal support for the program despite differing requirements and goals of administration and clinical staff, (2) ensuring effective clinician leadership, (3) integrating with existing geriatric programs, (4) balancing program fidelity with hospital-specific circumstances, (5) documenting positive outcomes of the program despite limited resources for data collection and analysis, and (6) maintaining the momentum of implementation in the face of unrealistic time frames and limited resources. Strategies perceived to be successful in addressing each challenge are described. Conclusion: Translating research into clinical practice is challenging for staff across disciplines. Developing strategies to address common challenges identified in this study may facilitate the adoption of innovative programs within healthcare organizations.

Objectives: To determine predictors of recommendation adherence and goal attainment of family caregivers of patients at a geriatric assessment center. Design: One-year prospective cohort study. Setting: Outpatient geriatric assessment center in Connecticut. Participants: Two hundred consecutive new patients and their family caregivers. Measurements: Family caregivers were interviewed after geriatric assessment to ascertain their treatment goals for the patient. Medical records were reviewed to identify treatment recommendations. Family caregivers were interviewed 1 year later to assess adherence to recommendations and attainment of goals. Results: Follow-up interviews were completed with 176 (88%) family caregivers. Common recommendations pertained to physician referral (71%), medications (46%), counseling/education (31%), diagnostic tests (30%), residential planning (26%), healthcare planning (21%), and community services (21%). Goal attainment was reported in 44% to 67% of the patient cases, depending on goal category. Caregiver agreement with recommendations predicted adherence to recommendations (adjusted relative risk (ARR)=1.99, 95% confidence interval (CI)=1.04–5.92) after adjusting for available clinical and demographic factors. In addition, adherence to recommendations predicted goal attainment in adjusted analyses (ARR=1.70, 95% CI=1.09–2.64). Conclusion: This study revealed a broad range of treatment recommendations in geriatric assessment and suggests that agreeing with recommendations can promote adherence and that adherence can promote goal attainment. Taken together, the results imply that articulating shared treatment recommendations may improve the quality of health care.

Objectives: To examine agreement between patients, caregivers, and clinicians regarding prognosis communication and to examine patients' and caregivers' desire for prognostic information. Design: Cross-sectional survey. Setting: Participants' homes. Participants: Two hundred fourteen persons aged 60 and older with a limited life expectancy secondary to cancer, congestive heart failure, or chronic obstructive pulmonary disease; caregivers; and clinicians. Measurements: Patient–clinician and caregiver–clinician agreement about the occurrence of prognosis discussions and patient and caregiver desire for prognostic information. Results: In 46% of patient/clinician and 34% of caregiver/clinician pairs, the clinician reported saying that the patient could die of the underlying disease, whereas the patient or caregiver reported no discussion. In 23% of patient/clinician and 30% of patient/caregiver pairs, the clinician reported discussing an approximate life expectancy, whereas the patient or caregiver reported no discussion. Of 205 patients who reported no life expectancy discussion, 40% did not want this discussion. Whereas 83% of those believing they had 1 year or less to live wanted to discuss prognosis, 79% of those believing they had 1 to 2 years, 53% of those believing they had 2 to 5 years, and 50% of those believing they had more than 5 years or who were unwilling to answer wanted this discussion (P=.007). Conclusion: Although clinicians report that they are discussing prognosis, patients and caregivers frequently do not corroborate these reports. Furthermore, many patients do not want prognostic information. Despite previous reports concluding that patients want full disclosure about their illness, many seriously ill older persons and caregivers may not be ready or able to receive prognostic information.

Purpose: To describe characteristics, attitudes, and communications of nurses regarding hospice and caring for terminally ill patients. Design: A cross-sectional study of randomly selected nurses (n=180) from six randomly selected Connecticut community hospitals was conducted in 1998 and 1999. Methods: Hospice-related training, knowledge and attitudes, demographic and practice characteristics, and personal experience with hospice were assessed with a self-administered questionnaire (response rate=82%). Logistic regression was used to model the effects of hospice-related training, knowledge, and attitudes on these outcomes, adjusting for personal experience and other characteristics of nurses. Findings: Characteristics associated with discussion of hospice with both patients and families included greater religiousness, having a close family member or friend who had used hospice, and reporting satisfaction with hospice caregivers. Greater self-rated knowledge was significantly associated with discussion of hospice with patients. Attitudinal scores indicating greater comfort with initiating discussion and greater perceived added benefit of hospice were significantly associated with discussion with patients' families. Conclusions: Nurses' discussion of hospice with terminally ill patients and their families are related to the potentially modifiable factors of self-rated knowledge and attitudes revealing comfort with discussion and perceived benefit of hospice care.

We have examined highly purified osteoclasts that were generated in vitro from murine co-culture of marrow precursors with stromal support cells and have found evidence of activation of the MEK/ERK and AKT/NFkappaB survival pathways. Many mature marrow-derived osteoclasts survived for at least 48 h in culture whether or not they are maintained with stromal cells. Moreover, supplementing purified osteoclasts with RANKL and/or M-CSF had no impact on their survival pattern. In addition, spleen-derived osteoclasts generated with RANKL and M-CSF treatment exhibited a similar survival pattern. Blocking MEK, AKT, or NFkappaB activity resulted in apoptosis of many, but not all, of the osteoclasts in purified marrow-derived osteoclasts, marrow-derived osteoclasts co-cultured with stromal cells, and spleen-derived osteoclasts maintained with RANKL and M-CSF. These data support that both the MEK/ERK and AKT/NFkappaB pathways contribute to osteoclast survival. Since PI3K has been shown to activate either of these pathways, we have examined its role in osteoclast survival. PI3K inhibition caused apoptosis of nearly all osteoclasts in purified and co-cultured marrow-derived osteoclasts and spleen-derived osteoclasts maintained with RANKL and M-CSF. Interestingly, in marrow-derived co-cultures, the apoptotic response was restricted to osteoclasts as there was no evidence of stromal support cell apoptosis. PI3K inhibition also blocked MEK1/2, ERK1/2, and AKT phosphorylation and NFkappaB activation in purified osteoclasts. Simultaneous blockage of both AKT and MEK1/2 caused rapid apoptosis of nearly all osteoclasts, mimicking the response to PI3K inhibition. These data reveal that PI3K coordinately activates two distinct survival pathways that are both important in osteoclast survival.

Use of long-term care services among minority elders is an important topic of research in light of the changing age and ethnic composition of the U.S. population. By 2030, the number of persons older than age 65 in the U.S. is projected to comprise 20 percent of the population (U.S. Census Bureau 2001). By the year 2050, the proportion of persons older than age 65 who are nonwhite will more than double, from 14 percent in 2000 to nearly 30 percent by 2050 (U.S. Census Bureau, 2001). Because rates of disability and chronic illness increase with age and are greater for minority than for white elders (Gibson and Jackson 1987; Clark 1997; Jones, LaVeist, and Lillie-Blanton 1991), these demographic trends suggest that long-term care needs, especially by minority groups, will become increasingly important in the next decades. Increased attention has been directed at the use of long-term care services by minority and nonminority groups in the health services literature in recent years. The vast majority of these rely on a single conceptual model of service use: the Andersen and Newman Behavioral Model of Health Service Use (Andersen and Newman 1973; Andersen 1995). Our research objectives were: (1) to augment this model in ways that may enhance its explanatory power when applied to empirical studies of race/ethnicity and long-term care, and (2) to suggest factors that may vary by race/ethnicity and have not previously been incorporated into empirical research in this area. Most research on the role of race/ethnicity in long-term care use focuses on nursing home and home care services. Less attention has been paid to other forms of long-term care, including adult day care and assisted living, due to the relative newness of these services and the smaller proportion of public resources expended on such services. Accordingly, this brief review focuses on nursing home and home care use. Studies of nursing home use generally conclude that African-American and Hispanic elders are less likely than white elders to use nursing homes (Mui and Burnette 1994; Greene and Ondrich 1990; Wallace et al. 1998). In most studies, the race/ethnicity effect persists even after adjusting for disability, socioeconomic status, living arrangement, and availability of formal services. Findings regarding home care use are less consistent. Studies using national data generally have not found significant differences in formal home care use by minority and nonminority groups (Miller et al. 1996; Clark 1997). Conversely, other studies suggest that differences in use do exist by race/ethnicity. Some of this research has demonstrated that minority elders are more likely than white elders to use home care services (Kemper 1992; Greene and Monahan 1984; Mui and Burnette 1994; Mitchell and Krout 1998); other studies have found that minority elders are less likely than their white counterparts to use home care services (Wallace, Levy-Storms, and Ferguson 1995; Morrow-Howell and Proctor 1994; Tennstedt and Chang 1998). The Andersen model (1973; Andersen 1995), developed to study determinants of acute care health services use, has been used frequently in studies of long-term care and race/ethnicity (Mui, Choi, and Monk 1998). The model posits that health services use is determined by societal factors, health services system factors, and individual factors. Individual factors, the focus of many empirical studies, are categorized as need, enabling factors, and predisposing factors. Need includes individuals' perceived and evaluated functional capacity, symptoms, and general state of health. Enabling factors encompass family and community resources and accessibility of those resources. Predisposing factors include age, sex, marital status, education, race/ethnicity, and occupation, as well as a set of beliefs (e.g., attitudes toward health services, knowledge about disease, and values). We argue that two aspects of the model can be enhanced to better guide future investigations regarding long-term care use because it may vary by racial/ethnic groups. First, although the Andersen and Newman model includes “beliefs,” which include attitudes toward health services, knowledge about disease, and values (Andersen and Newman 1973), limited attention has focused on psychosocial factors. “Beliefs” as described by Andersen and Newman may not adequately capture the breadth of psychosocial factors germane to race/ethnicity-related variations in long-term care use. These factors may be more important for long-term versus acute care because long-term care involves assistance with routine personal tasks (e.g., cooking, shopping, hygiene maintenance, dressing, bathing, and toileting), about which individuals may have specific knowledge and strong attitudes. Second, although the Andersen model (1995) identifies predisposing, enabling, and need factors as determinants of service use, it does not explore fully how these three domains, or their measures, are interrelated. For example, the model combines race/ethnicity with other demographic characteristics included as predisposing factors. Although these predisposing characteristics are similar in that they have low mutability (Andersen 1995; Aday and Awe 1997), each variable may interrelate with the other factors in different ways. This is potentially problematic in studies of race/ethnicity, in which omission of such interrelationships may oversimplify the role of race/ethnicity in service use.

Egypt has seen an increase in overweight and obesity over the last two decades. This study aims to identify current prevalence and associated risk factors for an intra-household double burden of ov...

In order to assess the prevalence of obesity in families of extremely obese individuals, we conducted a mail survey of a national obesity organization. Thirty-nine percent (N=981) of the questionnaires were completed and returned. Respondents were excluded from further analysis if they were adopted, male, their gender could not be determined, provided incomplete information about their parents or their own height and weight, or were less than 22 or greater than 63 years of age. The analyses included 729 probands and their families. Both the prevalence and the extent of obesity were high in the families members. The average family members' body mass index (BMI=kg/m2 was 30, and 78% of the families studied had at least one other obese (BM1>30 kg/m2) first-degree relative (parent, sibling, or child). Although obesity was common in the families, survey respondents were generally the heaviest members of their families, having an average BMI of 47 kg/m2. Correlations among first- degree relatives were similar to those found for average weight groups, suggesting that obesity and BMI are similarly influenced by family genetic factors in this extremely obese population.

The affects of differences in amino acid sequence on the temperature stability of the three-dimensional structure of the small beta-sheet protein, rubredoxin (Rd), was revealed when a set of homology models was subjected to molecular dynamics simulations at relatively high temperatures. Models of Rd from the hyperthermophile, Pyrococcus furiosus (Pf), an organism that grows optimally at 100 degrees C, were compared to three mesophilic Rds of known X-ray crystal structure. Simulations covering the limits of known Rd thermostabilities were carried out at temperatures of 300 K, 343 K, 373 K, and 413 K. They suggest that Rd stability is correlated with structural dynamics. Because the dynamic behavior of three Pf Rd models was consistently different from the dynamic behavior of the three mesophilic Rd structures, detailed analysis of the temperature-dependent dynamic behavior was carried out. The major differences between the models of the protein from the hyperthermophile and the others were: (1) an obvious temperature-dependent transition in the mesophilic structures not seen with the Pf Rd models, (2) consistent AMBER energy for the Pf Rd due to differences in nonbonded interaction terms, (3) less variation in the average conformations for the Pf Rd models with temperature, and (4) the presence of more extensive secondary structure for the Pf Rd models. These unsolvated dynamics simulations support a simple, general hypothesis to explain the hyperthermostability of Pf Rd. Its structure simplifies the conformational space to give a single minimum accessible over an extreme range of temperatures, whereas the mesophilic proteins sample a more complex conformational space with two or more minima over the same temperature range.

The three-dimensional structure of rubredoxin from the hyperthermophilic archaebacterium, Pyrococcus furiosus, has been modeled from the X-ray crystal structures of three homologous proteins from Clostridium pasteurianum, Desulfovibrio gigas, and Desulfovibrio vulgaris. All three homology models are similar. When comparing the positions of all heavy atoms and essential hydrogen atoms to the recently solved crystal structure (Day, M. W., et al., 1992, Protein Sci. 1, 1494-1507) of the same protein, the homology model differ from the X-ray structure by 2.09 A root mean square (RMS). The X-ray and the zinc-substituted NMR structures (Blake, P. R., et al., 1992b, Protein Sci. 1, 1508-1521) show a similar level of difference (2.05 A RMS). On average, the homology models are closer to the X-ray structure than to the NMR structures (2.09 vs. 2.42 A RMS).