Defining the Core Skills and Activities of the Attending Physician in Post-Acute and Long-Term Care.

The American Board of Post-Acute and Long-Term Care Medicine (ABPLM) contracted with a psychometric firm to perform a 3-phase Job Analysis following best practices. Literature was reviewed, a task force of subject matter experts was convened, a survey was developed and sent via Survey Monkey to attending physicians practicing in post-acute and long-term care settings (PALTC). The task force refined a comprehensive list of the tasks, knowledge, and medical knowledge needed in the role of attending physician in PALTC. These items were written as statements and edited until consensus was reached on their accuracy, conciseness, and lack of overlap. Task statements described distinct, identifiable, and specific practice-related activities relevant across multiple care settings. Knowledge statements described previously acquired information considered necessary to effectively perform such tasks. The survey consisted of 260 items, including 21 demographic questions, 115 task statements, 73 knowledge statements, and 72 medical knowledge statements. The survey was disseminated via e-mail invitations to Society for Post-Acute and Long-Term Care (AMDA) members and through an online link available through ABPLM's website. A total of 389 respondents participated. Survey data were analyzed with statistical analysis software SPSS. For each task and knowledge statement, an Overall Task Rating and Knowledge Rating were developed by combining the importance rating weighted at 65% and (for task) the frequency rating or (for knowledge) the cognitive level weighted at 35%. One task statement and 1 medical knowledge statement had a mean importance rating lower than 2.5 and were dropped from further review, resulting in a final count of 114 task, 73 knowledge, and 71 medical knowledge statements (258 total). The results of this Job Analysis highlight the unique and specific nature of medical care provided by attending physicians across a range of PALTC settings. These findings lay a foundation for Focused Practice Designation or Subspecialty in PALTC and changes in practice and policy.

Creation of a PDMS Polymer Brush on SiO2-Based Nanoparticles by Surface-Initiated Ring-Opening Polymerization.

The incorporation of nanoparticles into soft matrices opens a broad spectrum of novel property combinations. However, one of the major challenges for these systems remains the compatibilization of particles with the surrounding matrix by proper surface functionalization. For silicon-based systems or liquid crystalline phases, polydimethylsiloxane (PDMS) brushes at the surface of particles increase the stability against particle agglomeration in such systems. Here, we report a novel approach for the functionalization of particles with a polysiloxane brush by surface-initiated ring-opening polymerization of a cyclosiloxane. For this purpose, surface hydroxy groups of silica and silica-coated hematite particles are used as initiators in combination with phosphazene bases as catalysts. The ring-chain equilibrium of a model-based solution polymerization is investigated in detail to find the appropriate reaction parameters. The corresponding molar masses are determined and compared by 1H-NMR and SEC measurements to confirm the underlying mechanism. In the resulting hybrid nanostructures, a covalently bound PDMS fraction is achieved up to 47 mass %.

The use of structured imagery and dispositional measurement to assess situational use of mindfulness skills.

The recent proliferation of studies on mindfulness produced varying theoretical models, each based in part on how mindfulness is assessed. These models agree, however, that mindfulness encompasses moment-to-moment or situational experiences. Incongruence between dispositional and situational assessment would be problematic for theory and empirical research. In particular, it remains to be established whether situational measurement is an accurate method for mindfulness assessment and whether dispositional measures are able to accurately detect mindfulness skills in various situations. The association between dispositional and situational mindfulness processes (i.e., situational attention awareness and emotion acceptance) was examined in two studies. In Study 1 (N = 148), independent groups who reported high and low levels of dispositional mindfulness skills were compared on a continuous measure of situational mindfulness skills. In Study 2 (N = 317), dispositional mindfulness questionnaires were used to predict situational use of mindfulness skills. Results suggest not only that situational measures accurately detect use of mindfulness skills, but also that dispositional measures can predict one's use of situational mindfulness skills. Findings from both studies were consistent across both positive and negative situations. Moreover, neither neuroticism nor extraversion was shown to have a moderating effect on the relationship between dispositional and situational use of mindfulness skills. The implications of these findings for clinical practice and future investigations pertaining to measurement validity in this area are discussed.

Intrahepatic application of suicide gene-armed measles virotherapeutics: a safety study in transgenic mice and rhesus macaques.

Abstract Oncolytic viruses such as measles virus (MV) represent a new class of therapeutic agents that might help to overcome current limitations in cancer therapy. Although MV-based virotherapeutics already have entered clinical testing for various tumor entities, the preclinical safety of MV virotherapeutics so far has not been elucidated for particular regimens with high medical need, such as (1) direct injection into hepatic tumor sites, (2) employing high doses ibidem, and (3) concurrent usage of arming with cytotoxic genes required to further enhance oncolytic efficiency. Here, we assessed the safety and pharmacokinetics of suicide gene-armed vector MV-SCD when administered intrahepatically in two animal models, IFNAR(tm)-CD46(Ge) (interferon-α receptor deficient and CD46 MV receptor knock-in) transgenic mice and rhesus macaques (Macaca mulatta). Clinically, singular direct intrahepatic applications of MV-SCD were found to be well tolerated. Quantitative RT-PCR demonstrated the transient presence of viral RNA in various organs, whereas no shedding of infectious virus particles was observed at any time point. Histological analyses of organs did not exhibit adverse effects attributable to the test article. Blood parameters including liver enzymes revealed no deviations from normal. In both species an antiviral humoral immune response was mounted shortly after virus administration. Surprisingly, daily repeated systemic applications of MV-SCD under concomitant prodrug administration resulted in side effects in IFNAR(tm)-CD46(Ge) mice, but were less pronounced than in a 5-fluorouracil standard therapy control cohort. Taken together, these data indicate that "single shot" direct intrahepatic injections of MV-SCD in conjunction with systemic prodrug administration are safe and could be used in future virotherapeutic treatments of liver cancers.

Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus.

Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133(+) tumor cells. Both viruses exerted strong antitumoral effects on human hepatocellular carcinoma growing subcutaneously or multifocally in the peritoneal cavity of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Notably, the CD133-targeted viruses were more effective in prolonging survival than the parental MV-NSe, which is currently assessed as oncolytic agent in clinical trials. Interestingly, target receptor overexpression or increased spreading kinetics through tumor cells were excluded as being causative for the enhanced oncolytic activity of CD133-targeted viruses. MV-141.7 was also effective in mouse models of orthotopic glioma tumor spheres and primary colon cancer. Our results indicate that CD133-targeted measles viruses selectively eliminate CD133(+) cells from tumor tissue, offering a key tool for research in tumor biology and cancer therapy.

T-cell receptor gene transfer exclusively to human CD8(+) cells enhances tumor cell killing.

Transfer of tumor-specific T-cell receptor (TCR) genes into patient T cells is a promising strategy in cancer immunotherapy. We describe here a novel vector (CD8-LV) derived from lentivirus, which delivers genes exclusively and specifically to CD8(+) cells. CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase. Strikingly, T cells genetically modified with CD8-LV killed melanoma cells reproducibly more efficiently than CD8(+) cells transduced with a conventional lentiviral vector. Neither TCR expression levels, nor the rate of activation-induced death of transduced cells differed between both vector types. Instead, CD8-LV transduced cells showed increased granzyme B and perforin levels as well as an up-regulation of CD8 surface expression in a small subpopulation of cells. Thus, a possible mechanism for CD8-LV enhanced tumor cell killing may be based on activation of the effector functions of CD8(+) T cells by the vector particle displaying OKT8-derived CD8-scFv and an increase of the surface density of CD8, which functions as coreceptor for tumor-cell recognition. CD8-LV represents a powerful novel vector for TCR gene therapy and other applications in immunotherapy and basic research requiring CD8(+) cell-specific gene delivery.

Long-term effects of brief acceptance and commitment therapy for psychosis.

A previous report explored the impact of a brief (four session) acceptance and commitment therapy (ACT) intervention as compared with treatment as usual (TAU) on rehospitalization over 4 months in a sample of 80 inpatients with psychosis. The present study extended the follow-up period to 1 year and used a more sophisticated survival analysis to take previous hospitalization and length of the current hospitalization into account. Those in the ACT condition showed reduced hospitalization as compared to those in TAU at 4 months post discharge and again at 1 year post discharge. A test of proportionality of hazard showed that survival curves continued to diverge in the 5- to 12-month postdischarge period after adjusting for differences in the 0 to 4 month period. Future directions are discussed.

Vaccination with Abeta-displaying virus-like particles reduces soluble and insoluble cerebral Abeta and lowers plaque burden in APP transgenic mice.

In transgenic animal models, humoral immunity directed against the beta-amyloid peptide (Abeta), which is deposited in the brains of AD patients, can reduce Abeta plaques and restore memory. However, initial clinical trials using active immunization with Abeta1-42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Abeta. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Abeta (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Abeta retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Abeta retroparticles evoked high and long-lived Abeta-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Abeta plaque load to approximately 60% of controls and lowered both insoluble Abeta40 as well as Abeta42 in APP23 brain, but also significantly reduced cerebral soluble Abeta species. In summary, Abeta retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer's disease.

Working with families in long-term care.

Effective communication with families can improve clinical process and outcomes in long-term care. Such communication may be challenging to long-term care clinicians, who may feel they lack requisite skills or are uncomfortable with potentially charged and negative emotions that may result. These barriers can be overcome by using models of family behavior and of physician involvement in family counseling to foster understanding and organize family meetings. We present such models in this article. The first of these, the Pearlin Stress Process Model offers a framework for understanding family adaptation to long-term care. Within the Pearlin model, family function is a critical intervening variable. Structural Family Systems Theory is therefore examined next to guide to recognition of family characteristics that impact communication. We focus on translation of these theories to long-term care practice through clinical case vignettes. Applying the Levels of Physician Involvement in family oriented care to long-term care, we then suggest an organizing, stepwise process for the family meeting itself. We conclude with strategies for conflict management and a discussion of the importance of the interdisciplinary team in family care.

Vesicular stomatitis virus glycoprotein displaying retrovirus-like particles induce a type I IFN receptor-dependent switch to neutralizing IgG antibodies.

Vesicular stomatitis virus (VSV) infection rapidly induces IFN-alphabeta that confers initial survival, whereas long-term protection is mediated by neutralizing IgG responses. Because coadministration of IFN-alphabeta can enhance Ab responses against soluble Ags, we addressed whether virus-induced IFN-alphabeta also had an impact on the induction of neutralizing Ab responses. To this end, we generated apathogenic retrovirus-like particles (VLP) displaying the VSV gp (VLP-VSV). Reminiscent of live VSV, VLP-VSV induced VSV-neutralizing IgM responses that switched to IgG in a T help-dependent manner. In type I IFN receptor-deficient (IFNAR(-/-)) mice, VLP-VSV injection elicited neutralizing IgM, whereas the IgG switch was absent. The lack of subclass switch was associated with a reduced germinal center reaction. Conditional knockout mice with a lymphocyte-specific IFNAR ablation showed normal Ab responses against VLP-VSV, as well as against live VSV. Thus, IFNAR triggering critically promoted the T help-dependent subclass switch of virus-neutralizing Ab responses against VLP-VSV. Interestingly, in the context of VLP-VSV as well as VSV immunization, IFNAR triggering of B lymphocytes did not play a critical role.

Prion protein-specific antibodies for therapeutic intervention of transmissible spongiform encephalopathies.

Prion diseases, also called transmissible spongiform encephalopathies, are a group of fatal neurodegenerative conditions that affect humans and a wide variety of animals. There is no therapeutic or prophylactic approach against prion diseases available at present. The causative infectious agent is the prion, also termed PrPSc, which is a pathological conformer of the cellular prion protein PrPC. Passive immunisation studies with PrPC-specific antibodies indicated that immunotherapeutic strategies directed against PrPC can prevent prion disease. In this review, putative mechanisms of antibody-mediated prion inactivation, as well as active immunisation strategies, are discussed. Special attention is given to the problem of immunological self-tolerance against PrP.

Vaccination against prion diseases.

Prion diseases are a group of fatal neurodegenerative conditions that affect humans and a wide variety of animals. To date there is no therapeutic or prophylactic approach against prion diseases available. The causative infectious agent is the prion, also termed PrP(Sc), which is a pathological conformer of the cellular prion protein PrP(C). As passive immunization studies with PrP(C)-specific antibodies indicated that immunotherapeutic strategies can prevent prion replication, researchers are now aiming at the development of active prion vaccines.

Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice.

Beta-secretase (BACE1) is the rate-limiting protease for the generation of the amyloid beta-peptide (Abeta) in Alzheimer disease. Mice in which the bace1 gene is inactivated are reported to be healthy. However, the presence of a homologous gene encoding BACE2 raises the possibility of compensatory mechanisms. Therefore, we have generated bace1, bace2, and double knockout mice. We report here that BACE1 mice display a complex phenotype. A variable but significant number of BACE1 offspring died in the first weeks after birth. The surviving mice remained smaller than their littermate controls and presented a hyperactive behavior. Electrophysiologically, subtle alterations in the steady-state inactivation of voltage-gated sodium channels in BACE1-deficient neurons were observed. In contrast, bace2 knockout mice displayed an overall healthy phenotype. However, a combined deficiency of BACE2 and BACE1 enhanced the bace1-/- lethality phenotype. At the biochemical level, we have confirmed that BACE1 deficiency results in an almost complete block of Abeta generation in neurons, but not in glia. As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to Abeta generation in the brains of Alzheimer disease and, in particular, Down syndrome patients. In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity.

Circumventing tolerance to the prion protein (PrP): vaccination with PrP-displaying retrovirus particles induces humoral immune responses against the native form of cellular PrP.

Passive immunization with antibodies directed against the cellular form of the prion protein (PrPC) can protect against prion disease. However, active immunization with recombinant prion protein has so far failed to induce antibodies directed against native PrPC expressed on the cell surface. To develop an antiprion vaccine, a retroviral display system presenting either the full-length mouse PrP (PrP209) or the C-terminal 111 amino acids (PrP111) fused to the transmembrane domain of the platelet-derived growth factor receptor was established. Western blot analysis and immunogold electron microscopy of the retroviral display particles revealed successful incorporation of the fusion proteins into the particle membrane. Interestingly, retroviral particles displaying PrP111 (PrPD111 retroparticles) showed higher incorporation efficiencies than those displaying PrP209. Already 7 days after intravenous injection of PrPD111 retroparticles, PrPC-deficient mice (Prnp(o/o)) showed high immunoglobulin M (IgM) and IgG titers specifically binding the native PrPC molecule as expressed on the surface of T cells isolated from PrPC-overexpressing transgenic mice. More importantly, heterozygous Prnp(+/o) mice and also wild-type mice showed PrPC-specific IgM and IgG antibodies upon vaccination with PrPD111 retroparticles, albeit at considerably lower levels. Bacterially expressed recombinant PrP, in contrast, was unable to evoke IgG antibodies recognizing native PrPC in wild-type mice. Thus, our data show that PrP or parts thereof can be functionally displayed on retroviral particles and that immunization with PrP retroparticles may serve as a novel promising strategy for vaccination against transmissible spongiform encephalitis.

The use of acceptance and commitment therapy to prevent the rehospitalization of psychotic patients: a randomized controlled trial.

The present study examined the impact of a brief version of an acceptance-based treatment (acceptance and commitment therapy; ACT) that teaches patients to accept unavoidable private events; to identify and focus on actions directed toward valued goals; and to defuse from odd cognition, just noticing thoughts rather than treating them as either true or false. Eighty inpatient participants with positive psychotic symptoms were randomly assigned to treatment as usual (TAU) or to 4 sessions of ACT plus TAU. ACT participants showed significantly higher symptom reporting and lower symptom believability and a rate of rehospitalization half that of TAU participants over a 4-month follow-up period. The same basic pattern of results was seen with all participant subgroups except delusional participants who denied symptoms.

Prescription privileges for psychologists: constituencies and conflicts.

The pros and cons of the proposal to link prescription privileges specifically to psychological training vary from the point of view of the constituencies involved. The present article analyzes those differences. Two surprising facts are noted. First, it is scientist-practitioners who are resisting the move toward prescription privileges, not so much the basic science organizations. Second, while the practice-based organizations have been avid in their support of prescription privileges, the same cannot be said for rank and file private practitioners. On closer examination, the costs, benefits, and views of the different constituencies make sense of these anomalies. The resistance to prescription privileges is not arbitrary or unreasonable and it is not likely to go away any time soon.