Enhancing Care for Long-Term Care Residents Approaching End-of-Life: A Mixed-Methods Study Assessing a Palliative Care Transfer Form.

BACKGROUND: Many barriers exist in providing quality end-of-life care in long-term care (LTC), including transitions of care between acute care and LTC. Transfer forms can be beneficial in ensuring resident's end-of-life care needs are coordinated between different settings. The NYGH-LTC Transfer Form is a newly developed tool created to enhance care for residents transferred from acute care back to their LTC home for end-of-life. STUDY AIM: Assess the perceived ease of use, usefulness, and care-enhancing potential of the NYGH-LTC Transfer Form by interprofessional LTC staff. METHODS: The study population included interprofessional staff members at 2 LTC homes in Toronto, Canada. Quantitative data was obtained through surveys and qualitative data was obtained through focus groups. RESULTS: There were a total of 34 participants. 79.4% of participants agreed the form was easy to use and 82.4% agreed it would improve care. Subgroup analysis demonstrated that participants with greater than 20 years experience were less likely to agree that it would improve care (p = 0.01). Qualitative analysis generated 4 themes: 1) Strengths, 2) Areas of Improvement, 3) Information Sharing, and 4) Communication. CONCLUSIONS: The NYGH-LTC Transfer Form was overall well-evaluated. The form was seen as most useful for those with less experience or less confidence in palliative care. Communication was identified as a major barrier to successful transitions of care and increased bidirectional verbal communication is needed in addition to the form.

Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production.

Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, "alternatively activated" macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes.

Orally administered ß-glucan attenuates the Th2 response in a model of airway hypersensitivity.

ß-Glucan is a polysaccharide that can be extracted from fungal cell walls. Wellmune WGP(®), a preparation of ß-1,3/1,6-glucans, is a dietary supplement that has immunomodulating properties. Here we investigated the effect WGP had on a mouse model of asthma. OVA-induced asthma in mice is characterized by infiltration of eosinophils into the lung, production of Th2 cytokines and IgE. Daily oral administration of WGP (400 µg) significantly reduced the influx of eosinophils into the lungs of OVA-challenged mice compared to control mice. In addition, WGP inhibited pulmonary production of Th2 cytokines (IL-4, IL-5, IL-13), however serum IgE levels were unaffected by WGP treatment. These data indicate that WGP could potentially be useful as an oral supplement for some asthma patients, however, it would need to be combined with therapies that target other aspects of the disease such as IgE levels. As such, further studies that examine the potential of WGP in combination with other therapies should be explored.

Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification.

Coronary artery calcification (CAC) is a heritable and definitive morphologic marker of atherosclerosis that strongly predicts risk for future cardiovascular events. To search for genes involved in CAC, we used an integrative transcriptomic, genomic, and protein expression strategy by using next-generation DNA sequencing in the discovery phase with follow-up studies using traditional molecular biology and histopathology techniques. RNA sequencing of peripheral blood from a discovery set of CAC cases and controls was used to identify dysregulated genes, which were validated by ClinSeq and Framingham Heart Study data. Only a single gene, TREML4, was upregulated in CAC cases in both studies. Further examination showed that rs2803496 was a TREML4 cis-eQTL and that the minor allele at this locus conferred up to a 6.5-fold increased relative risk of CAC. We characterized human TREML4 and demonstrated by immunohistochemical techniques that it is localized in macrophages surrounding the necrotic core of coronary plaques complicated by calcification (but not in arteries with less advanced disease). Finally, we determined by von Kossa staining that TREML4 colocalizes with areas of microcalcification within coronary plaques. Overall, we present integrative RNA, DNA, and protein evidence implicating TREML4 in coronary artery calcification. Our findings connect multimodal genomics data with a commonly used clinical marker of cardiovascular disease.

A qualitative analysis of information sharing for children with medical complexity within and across health care organizations.

BACKGROUND: Children with medical complexity (CMC) are characterized by substantial family-identified service needs, chronic and severe conditions, functional limitations, and high health care use. Information exchange is critically important in high quality care of complex patients at high risk for poor care coordination. Written care plans for CMC are an excellent test case for how well information sharing is currently occurring. The purpose of this study was to identify the barriers to and facilitators of information sharing for CMC across providers, care settings, and families. METHODS: A qualitative study design with data analysis informed by a grounded theory approach was utilized. Two independent coders conducted secondary analysis of interviews with parents of CMC and health care professionals involved in the care of CMC, collected from two studies of healthcare service delivery for this population. Additional interviews were conducted with privacy officers of associated organizations to supplement these data. Emerging themes related to barriers and facilitators to information sharing were identified by the two coders and the research team, and a theory of facilitators and barriers to information exchange evolved. RESULTS: Barriers to information sharing were related to one of three major themes; 1) the lack of an integrated, accessible, secure platform on which summative health care information is stored, 2) fragmentation of the current health system, and 3) the lack of consistent policies, standards, and organizational priorities across organizations for information sharing. Facilitators of information sharing were related to improving accessibility to a common document, expanding the use of technology, and improving upon a structured communication plan. CONCLUSIONS: Findings informed a model of how various barriers to information sharing interact to prevent optimal information sharing both within and across organizations and how the use of technology to improve communication and access to information can act as a solution.

Rapid point-of-care HIV testing in youth: a systematic review.

PURPOSE: This review examines the literature surrounding acceptability of, and preference for, rapid point-of-care (POC) human immunodeficiency virus (HIV) testing in youth, documents notification rates when youth were offered rapid POC testing, and identifies the sociodemographic factors associated with testing. METHODS: The reviewers searched the scholarly literature indexed in MEDLINE, Embase, CINAHL, and PsycInfo using a set of keywords related to youth and rapid POC HIV testing. A total of 14 articles were included in the review. RESULTS: Four themes were identified: (1) Youth will accept rapid POC testing, particularly if offered; (2) youth prefer rapid POC testing to traditional testing; (3) youth receive their rapid POC HIV test results; and (4) older youth and those with HIV risk factors or a concurrent genitourinary diagnosis are more likely to accept rapid POC HIV testing when it is offered. CONCLUSIONS: Evidence shows that youth accept and prefer rapid POC HIV tests when offered. The routine use of rapid POC HIV tests in emergency departments and adolescent primary care clinics should be considered because of higher uptake in these environments. Youth receive their rapid POC test results more frequently and sooner than traditional test results. However, further work is needed to develop HIV testing programs that target younger adolescents.

Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.

DNAX-activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT-PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12-coupled receptors, in particular TREM-1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid-binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild-type mice, but when these mice were re-derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP, lymphocytes from the DAP12-deficient mice housed in the two facilities proliferated and produced opposite profiles of pro-inflammatory and anti-inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.

LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing ß-catenin activation in dendritic cells.

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2-/- mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear ß-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2-/- DCs. Accordingly, Lat2-/- DCs directed reduced Th1 polarization in vitro and Lat2-/- mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and ß-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance.

Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis.

The triggering receptor expressed on myeloid cells (TREM)-1 plays a crucial role during the onset of sepsis by amplifying the host immune response. The TREM-like transcript-1 (TLT-1) belongs to the TREM family, is selectively expressed on activated platelets, and is known to facilitate platelet aggregation through binding to fibrinogen. In this study, we show that a soluble form of TLT-1 is implicated in the regulation of inflammation during sepsis by dampening leukocyte activation and modulating platelet-neutrophil crosstalk. A 17-aa sequence of the TLT-1 extracellular domain (LR17) is responsible for this activity through competition with the TREM-1 ligand. Whereas early or late LR17 treatment of septic mice improves survival, treml-1(-/-) animals are highly susceptible to polymicrobial infection. The present findings identify platelet-derived soluble TLT-1 as a potent endogenous regulator of sepsis-associated inflammation and open new therapeutic perspectives. We anticipate soluble TLT-1 to be important in regulating leukocyte activation during other noninfectious inflammatory disorders.

Pseudotumors associated with total hip arthroplasty.

Pseudotumors are a rare but important complication occurring with all types of hip replacements.The true prevalence of pseudotumors is debated.Potential causes of pseudotumors may include foreign-body reaction, hypersensitivity, and wear debris.The conduct of clinical trials on the incidence, causes, and treatments of pseudotumors has been inadequate as few investigators have used a randomized controlled design to compare various implant types.

The use of registered nurses to perform flexible sigmoidoscopy procedures in ontario: a cost minimization analysis.

RATIONALE: Rates of colorectal cancer (CRC) are on the rise in Canada. Flexible sigmoidoscopy (FS) is an initial screening test for CRC primarily used in adults aged 50 years and older at average risk for the disease. Physicians and registered nurses have been shown to have the same effectiveness in performing a FS procedure. This paper presents an analysis of the use of registered nurses (RN) compared to physicians in Ontario to assess costs to the healthcare system. OBJECTIVES: To evaluate whether FS performed by RNs is a less costly alternative to increase access to CRC screening capacity in Ontario. METHODOLOGY: A cost minimization analysis was conducted from a health system perspective. DISCUSSION: RN-performed FS is a viable alternative for increasing CRC screening capacity in Ontario. Remuneration schedules for on-call physicians must be taken into consideration if policies are developed for the implementation of RN screening procedures. RESULTS: The findings suggest that the use of RNs may be cost saving compared to physician-performed FS procedures, depending on physician remuneration.

CONTEXTE : Au Canada, les taux de cancer colorectal (CCR) sont à la hausse. La sigmoïdoscopie flexible (SF) est un test initial de dépistage du CCR principalement utilisé chez les adultes de 50 ans et plus qui présentent un risque moyen de développer la maladie. Il a été démontré que les médecins et les infirmières autorisées présentent la même efficacité pour effectuer les procédés de FS. Cet article présente une analyse de comparaison entre les infirmière autorisées et les médecins en Ontario afin d'en évaluer les coûts pour le système de santé. OBJECTIFS : Évaluer dans quelle mesure la SF effectuée par les infirmières autorisées est un choix moins coûteux pour accroître l'accès au dépistage du CCR en Ontario. MÉTHODOLOGIE : Une analyse de minimisation des coûts a été effectuée selon l'angle du système de santé. DISCUSSION : La FS effectuée par les infirmières autorisées afin d'accroître les capacités de dépistage du CCR en Ontario est une option viable. Les barèmes de rémunération des médecins sur appel doivent être reconsidérés si on souhaite élaborer des politiques de mise en place de procédés de dépistage par les infirmières autorisées. RÉSULTATS : Les résultats font voir que, par rapport aux médecins, l'utilisation des infirmières autorisées pour effectuer les procédés de SF peut permettre des économies, dépendamment de la rémunération des médecins.

Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance.

X-linked SCID patients are deficient in functional IL-2Rgamma(c) leading to the loss of IL-2/IL-4/IL-7/IL-9/IL-15/IL-21 signaling and a lack of NK and mature T cells. Patients treated with IL-2Rgamma(c) gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2Rgamma(c)(-/-) mice reconstituted with IL-2Rgamma(c) developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2Rgamma(c) signaling. Given the shift toward self-inactivating long terminal repeats with weaker promoters to control the risk of leukemia, we assessed NK and T cell numbers and function in IL-2Rgamma(c)(-/-) mice reconstituted with limiting amounts of IL-2Rgamma(c). Reconstitution resulted in lower IL-2/-15-mediated STAT5 phosphorylation and proliferation in NK and T cells. However, TCR costimulation restored cytokine-driven T cell proliferation to wild-type levels. Vector modifications that improved IL-2Rgamma(c) levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2Rgamma(c) levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2Rgamma(c) are reduced compared with wild-type cells, the reduction in NK cell half-live is much more severe than in T cells. Collectively, these data indicate different IL-2Rgamma(c) signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2Rgamma(c) reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2Rgamma(c) signaling by the TCR.

The linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) regulates triggering receptor expressed on myeloid cells (TREM)-2 signaling and macrophage inflammatory responses independently of the linker for activation of T cells.

Triggering receptor expressed on myeloid cells-2 (TREM-2) is rapidly emerging as a key regulator of the innate immune response via its regulation of macrophage inflammatory responses. Here we demonstrate that proximal TREM-2 signaling parallels other DAP12-based receptor systems in its use of Syk and Src-family kinases. However, we find that the linker for activation of T cells (LAT) is severely reduced as monocytes differentiate into macrophages and that TREM-2 exclusively uses the linker for activation of B cells (LAB encoded by the gene Lat2(-/-)) to mediate downstream signaling. LAB is required for TREM-2-mediated activation of Erk1/2 and dampens proximal TREM-2 signals through a novel LAT-independent mechanism resulting in macrophages with proinflammatory properties. Thus, Lat2(-/-) macrophages have increased TREM-2-induced proximal phosphorylation, and lipopolysaccharide stimulation of these cells leads to increased interleukin-10 (IL-10) and decreased IL-12p40 production relative to wild type cells. Together these data identify LAB as a critical, LAT-independent regulator of TREM-2 signaling and macrophage development capable of controlling subsequent inflammatory responses.

Primary total hip arthroplasty with a porous-coated acetabular component. A concise follow-up, at a minimum of twenty years, of previous reports.

We previously reported the seven and fifteen-year results of the use of a porous-coated acetabular metal shell inserted without cement in a consecutive series of 204 primary total hip arthroplasties. In the present study, we evaluated the longer-term outcomes of these arthroplasties at a minimum follow-up time of twenty years. One hundred and fourteen (92%) of the 124 hips available for study had retained the original acetabular metal shell. A total of five acetabular components had been revised for aseptic loosening or had radiographic evidence of definite loosening. Fourteen hips with well-fixed acetabular shells required a change of the modular acetabular liner because of excessive wear and/or for the treatment of osteolysis, and liner changes have been recommended for another eight hips. The twenty-year rate of survival of the metal shell, with failure defined as revision because of loosening or radiographic evidence of loosening, was 96% (95% confidence interval, 94% to 98%). Cementless acetabular reconstruction continues to provide durable fixation at twenty years postoperatively. Wear-related complications continue to be the major mode of failure.

Survey design in orthopaedic surgery: getting surgeons to respond.

We provide an overview of survey design and implementation strategies in orthopaedic surgery. Health-care surveys are vital for obtaining information on the beliefs, patterns of practice, attitudes, and behaviors of orthopaedic surgeons. It is important to obtain a high response rate from administered surveys to reduce bias due to nonresponse. Researchers should follow the guidelines provided by this review to increase the response rate of orthopaedic surgeons to surveys. When designing these surveys, the researcher must consider length, format, and aesthetics. In addition, the types of questions that are included, the wording of these questions, and the order in which the questions are presented within the survey need to be carefully considered. Surveys can be administered by telephone, mail, facsimile (fax), and electronically by e-mail or Internet. The use of a mixed-mode method is recommended to improve the response rate. To increase the response rate to surveys that are directed at health professionals, a number of strategies have been suggested, including using cover letters, personalizing the cover letter and survey package, pretesting the cover letter and survey, contacting the surgeons prior to administration of the survey, contacting the surgeons multiple times, using stamped return envelopes in mail surveys, using appropriate survey packaging styles, providing incentives, and ensuring that the orthopaedic surgeon recognizes the sender of the survey. The costs associated with each administration method are briefly discussed, and ethical considerations are reviewed.

TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans.

Triggering receptor expressed on myeloid cells-like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte alpha-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1-/- mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1-/- mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1-/- mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation.

Revision of the acetabular component without cement. A concise follow-up, at twenty to twenty-four years, of a previous report.

We previously reported the results of the use of a cementless acetabular shell for revision total hip arthroplasty in 138 hips at a minimum of three, seven, and fifteen years postoperatively. The current report presents the long-term outcomes of this group at a minimum follow-up of twenty years. Since the last report, two additional hips required repeat revision, both for infection; no additional acetabular shell was loose. In the entire series to date, repeat acetabular revision was performed in twenty-one (15%) of the original 138 hips. Twenty of the twenty-one shells were well fixed at the time of repeat revision, and one had become aseptically loose. The most common reasons for repeat revision were infection (eight hips) and recurrent instability (eight hips). In the metal shells that were well fixed, an isolated liner change for polyethylene wear and/or osteolysis was performed in a total of six hips; four of these liner exchanges were performed since the time of our last report. A liner change had been recommended because of severe wear in four additional hips; thus, 18% of the fifty-six unrevised metal shells were associated with polyethylene wear-related problems. Survivorship, with revision of the shell for aseptic loosening or radiographic evidence of loosening as the end point, was 95% at twenty years (95% confidence interval, 83% to 98%). Reoperations for wear and osteolysis were first seen at approximately twelve years postoperatively. At the time of the present long-term follow-up, the reoperation rate for polyethylene wear and/or osteolysis had increased. We continue to use a hemispherical, titanium metal shell with multiple screws for fixation in the majority of acetabular revisions.

In vivo expression of signaling proteins in reconstituted NK cells.

Natural Killer cells are cells of the innate immune system that are important for the recognition and clearance of virally infected cells or tumors. Examination of the development and signaling of these cells has been severely hampered due to an inability to over-express proteins in these cells. We developed a novel technique to generate NK cells in vivo, all of which express a gene of interest. IL2Rgamma(c)(-/-)/Rag2(-/-) mice do not develop NK cells due to the lack of IL15 signaling. We infected bone marrow from IL2Rgamma(c)(-/-)/Rag2(-/-) mice with a retroviral construct encoding EGFP and IL2Rgamma(c) connected by an IRES. NK cells selectively developed through expression of IL2Rgamma(c) and 100% of these NK cells were found to be EGFP(+). In order to test the utilization of this method to examine the function of biologically relevant proteins, constitutively active PI3K p110gamma and p110delta isoforms were over-expressed in this system. Constitutively active p110gamma revealed profound effects on NK cell development and function in vivo while p110delta had little effect.

Emotional and sexual infidelity offline and in cyberspace.

This study investigated how men and women perceive online and offline sexual and emotional infidelity. Undergraduates from a large university in Northern Ireland participated in the study. It was found that men, when forced to decide, were more upset by sexual infidelity and women by emotional infidelity. It was also found that men were more likely to believe that women have sex when in love and that women believe that men have sex even when they are not in love. It was not, however, found that either men or women believed that having cybersex implied the other was also in love or that being in love online implied they were having cybersex. These results are explained through a social-cognitive lens.