Exploring key components and factors that influence the use of clinical decision- support tools for prescribing to older patients with kidney disease: the perspective of healthcare providers.

BACKGROUND: Clinical decision-support (CDS) tools are systems that provide healthcare providers (HCPs) with recommendations based on knowledge and patient-specific factors to facilitate informed decisions. OBJECTIVES: To identify the key components of a CDS tool that are most important to HCPs in caring for older adults with kidney disease, and to understand the facilitators and barriers toward using CDS tools in daily clinical practice. METHODS: Design: A cross-sectional survey of Canadian HCPs was undertaken. DATA COLLECTION: Participants affiliated with a provincial college, nephrology organization, or advocacy body were contacted. The survey was conducted between August and October 2021. INSTRUMENT: A 59-item questionnaire was developed and divided into five main domains/themes. Analysis was done descriptively. RESULTS: Sixty-three participants completed the questionnaire. Physicians (60%) and pharmacists (22%) comprised the majority of the participants. Most of the participants were specialized in nephrology (65%). The most important components in a CDS tool for prescribing to older patients with kidney disease were the safety and efficacy of the medication (89%), the goal of therapy (89%), and patient's quality of life (87%). 90% were willing to use CDS tools and 57% were already using some CDS tools for prescribing. The majority of the participants selected the validation of CDS tools (95%), accompanying the recommendations by the supporting evidence (84%), and the affiliation of the tools with known organizations (84%), as factors that facilitate the use of CDS tools. CONCLUSION: CDS tools are being used and are accepted by HCPs and have value in their assistance in engaging patients in making well-informed decisions.

Economic analysis of healthcare-associated infection prevention and control interventions in medical and surgical units: systematic review using a discounting approach.

Nosocomial or healthcare-associated infections (HCAIs) are associated with a financial burden that affects both patients and healthcare institutions worldwide. The clinical best care practices (CBPs) of hand hygiene, hygiene and sanitation, screening, and basic and additional precautions aim to reduce this burden. The COVID-19 pandemic has confirmed these four CBPs are critically important prevention practices that limit the spread of HCAIs. This paper conducted a systematic review of economic evaluations related to these four CBPs using a discounting approach. We searched for articles published between 2000 and 2019. We included economic evaluations of infection prevention and control of Clostridioides difficile-associated diarrhoea, meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and carbapenem-resistant Gram-negative bacilli. Results were analysed with cost-minimization, cost-effectiveness, cost-utility, cost-benefit and cost-consequence analyses. Articles were assessed for quality. A total of 11,898 articles were screened and seven were included. Most studies (4/7) were of overall moderate quality. All studies demonstrated cost effectiveness of CBPs. The average yearly net cost savings from the CBPs ranged from $252,847 (2019 Canadian dollars) to $1,691,823, depending on the rate of discount (3% and 8%). The average incremental benefit cost ratio of CBPs varied from 2.48 to 7.66. In order to make efficient use of resources and maximize health benefits, ongoing research in the economic evaluation of infection control should be carried out to support evidence-based healthcare policy decisions.

Dexras1/AGS-1, a steroid hormone-induced guanosine triphosphate-binding protein, inhibits 3',5'-cyclic adenosine monophosphate-stimulated secretion in AtT-20 corticotroph cells.

Dexras1 is a novel GTP-binding protein that shares structural similarity with the Ras family of small molecular weight GTPases and is strongly and rapidly induced during treatment with dexamethasone. The function of Dexras1 and its contribution to glucocorticoid-dependent signaling in the corticotroph cell are unknown. The present study was undertaken to examine the potential role of Dexras1 in the regulation of peptide hormone secretion in the AtT-20 corticotroph cell line. To determine the effects of Dexras1 expressed independently of glucocorticoid treatment, expression plasmids for wild-type and constitutively active mutant Dexras1 proteins were cotransfected with human GH (hGH), which provides an ectopic marker for the stimulus-coupled secretory pathway. GTP binding properties and the GTP to GDP ratio of wild-type and mutant Dexras1 proteins were examined in transiently transfected AtT-20 and COS-7 cells. Stimulated and constitutive components of secretion were assessed after 2-h incubations with 5 mM 8-Br-cAMP or control. cAMP treatment led to a 2-fold increase in hGH secretion relative to control. Cotransfection of wild-type Dexras1 had no effect on cAMP-stimulated hGH secretion, but a constitutively active mutant, Dexras[A178V], attenuated stimulated secretion by 86% (P < 0.01). A double-mutant containing a deletion of the carboxyl terminus isoprenylation site, Dexras[A178V/C277term], did not inhibit cAMP-stimulated hGH secretion, indicating that the effect is prenylation dependent. These findings suggest that activation of Dexras1 has important functional consequences leading to inhibition of stimulus-secretion coupling in corticotroph cells. Because Dexras1 messenger RNA is strongly and rapidly induced during glucocorticoid treatment, these results raise the possibility that Dexras1 may participate in the signal transduction pathways that govern the rapid regulatory effects of glucocorticoids on peptide hormone secretion in corticotroph cells.

A longitudinal study of the effects of graduate medical education on hospital operating costs.

OBJECTIVE: To examine the effect of graduate medical education sponsorship on hospital operating costs over a seven-year period, to test for a longitudinal association between teaching intensity and cost, and to determine whether the indirect medical education (IME) payment adjustments made under Medicare's Prospective Payment System are appropriate. DATA SOURCES: Medicare cost and payment data from the Hospital Cost Report Information System and other related HCFA files, from FFY 1989 through 1995. The study population consists of all short-stay hospitals (approximately 5,000) participating in Medicare and receiving case payments by diagnosis-related groups. STUDY DESIGN: The original cost functions used to develop indirect medical education payment adjustments under PPS are re-estimated with panel data. Specification changes are included based on findings from critiques of the original hospital cost model. Additional variations on the model are explored to test for differences by hospital status, to control for the effect of additional disproportionate share and outlier payments, and to isolate the effects of improved case-mix measurement on model results. PRINCIPAL FINDINGS: Fixed effects regression produces no evidence of a significant within-hospital association between increased sponsorship of medical residents and increased cost per case. In models designed to capture a cross-sectional association, operating costs are positively related to teaching activity, but the association shows a decline in strength over time. In all years, the strength of the association is significantly greater among hospitals eligible for disproportionate share adjustments and among major teaching hospitals. Controlling for secular trends of increased teaching intensity results in a pattern of declining cross-sectional teaching coefficients that supports a theory that observed teaching effects are the result of unmeasured case severity. CONCLUSIONS: A significant but declining cost differential is observed between teaching and nonteaching hospitals. The association appears to be related to hospital and patient characteristics that cannot be controlled using currently available case-mix and wage indices. Longitudinal models do not provide evidence to support a payment adjustment formula that allows individual hospitals to recompute their IME adjustment rates as their teaching ratios rise or fall from year to year. Cross-sectional findings suggest that re-estimations of the teaching effect may be appropriate when significant improvements occur in Medicare case-mix measurement.

Beneficiary survey-based feedback on new Medicare informational materials.

In response to the Balanced Budget Act (BBA) of 1997, the Center for Medicare & Medicaid Services (CMS) initiated a massive information and education campaign to promote effective health plan decision-making. Early results suggest that the pilot version of the Medicare & You handbook and other new Medicare informational materials were viewed favorably overall. Despite their limitations, most beneficiaries found the information useful. The longer, more comprehensive materials were not perceived to be more useful than the shorter, less complicated version. Additional research is needed to determine which subgroups of beneficiaries may need more and, possibly less, information.

Inter-organizational relationships of seven Veterans Affairs Medical Centers and their affiliated medical schools: results of a multiple-case-study investigation.

PURPOSE: This study describes the costs and and value added to Veterans Affairs Medical Centers (VAMCs) through their affiliations with medical schools. The study also creates a conceptual framework for evaluating the critical dimensions across which these affiliations vary. METHOD: Case studies of seven VAMCs' affiliations with medical schools, ranging from two highly affiliated VAMCs to one with only one funded residency position, were conducted in 1997 and 1998 using a survey and in-depth interviews with 78 key individuals at the institutions. The qualitative data were then used to develop a conceptual framework for evaluating these affiliations. RESULTS: The results are reported in two stages. In stage one, three organizing themes emerged from the data that formed the conceptual framework for evaluating affiliations: (1) the characteristics of each VAMC and its environment, (2) the characteristics of the relationships between each VAMC and its medical school affiliates, and (3) the costs and value that medical school affiliations add to VAMCs. The affiliations that were most beneficial to VAMCs were characterized by a relationship of trust, extensively shared education and research programs, and a high degree of physician interaction. The achievement of these characteristics is influenced by the distance between the VAMCs and their affiliated medical schools, the VAMCs' levels of organizational complexity, the degree of managed care penetration, and the continuity and academic orientation of leadership at the VAMCs. In stage two, study data were used to create a conceptual framework to evaluate the characteristics of VAMCs and their affiliations with medical schools. CONCLUSIONS: The study supplied data to construct a conceptual framework that describes many of the relationships among the different affiliations in the study. The framework offers a tool for evaluating the dimensions across which affiliations vary and how these differences influence the costs and value of medical school affiliations to VAMCs.

High-affinity monoclonal antibodies to PED/PEA-15 generated using 5 microg of DNA.

Class-switched, affinity-matured murine monoclonal antibody (MAb) producing cell lines reactive with PED/PEA-15 were generated and isolated in less than 4 weeks following polynucleotide immunizations using only 5 microg of DNA in conjunction with the Powderject gene gun. Somatic fusions of peripheral lymph node cells were performed 13 days after initiating delivery of DNA encoding the target antigen. The data presented demonstrates the rapid production, identification, and characterization of class-switched, affinity-matured MAbs that bind PED/PEA-15. The reported strategy enabled the rapid development of MAbs that are useful in enzyme-linked immunoadsorbent assay (ELISA), Western blotting, and immunoprecipitations.

Monoclonal antibodies generated against recombinant ATM support kinase activity.

We report on the rapid generation of two monoclonal antibodies, ATM A16.35 and ATM D16.11, that bind to the kinase domain of mutated ataxia telangiectasia (ATM). These antibodies were generated against E. coli-expressed recombinant protein using the RIMMS strategy. We show that ATM A16.35 binds ATM by Western blot analysis, and ATM D16.11 forms immune complexes with native ATM in immunoprecipitations without neutralizing kinase activity.

GRID: a novel Grb-2-related adapter protein that interacts with the activated T cell costimulatory receptor CD28.

Adapter proteins such as Grb2 play a central role in the formation of signaling complexes through their association with multiple protein binding partners. These interactions are mediated by specialized domains such as the well-characterized Src homology SH2 and SH3 motifs. Using yeast three-hybrid technology, we have identified a novel adapter protein, expressed predominantly in T lymphocytes, that associates with the activated form of the costimulatory receptor, CD28. The protein is a member of the Grb2 family of adapter proteins and contains an SH3-SH2-SH3 domain structure. A unique glutamine/proline-rich domain (insert domain) of unknown function is situated between the SH2 and N-terminal SH3 domains. We term this protein GRID for Grb2-related protein with insert domain. GRID coimmunoprecipitates with CD28 from Jurkat cell lysates following activation of CD28. Using mutants of CD28 and GRID, we demonstrate that interaction between the proteins is dependent on phosphorylation of CD28 at tyrosine 173 and integrity of the GRID SH2 domain, although there are also subsidiary stabilizing contacts between the PXXP motifs of CD28 and the GRID C-terminal SH3 domain. In addition to CD28, GRID interacts with a number of other T cell signaling proteins, including SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa), p62dok, and RACK-1 (receptor for activated protein kinase C-1). These findings suggest that GRID functions as an adapter protein in the CD28-mediated costimulatory pathway in T cells.

Development of class-switched, affinity-matured monoclonal antibodies following a 7-day immunization schedule.

Previously we reported making high-affinity monoclonal antibodies (MAbs) 13 days after the onset of Repetitive Immunizations Multiple Sites (RIMMS) strategy. The Ig subclass variety and affinity of these antibodies suggested that maturational processes had already begun within draining lymph nodes. We now demonstrate that this diversity can in fact be captured as early as Day 7. In the work reported here, somatic fusion of immune lymphocytes isolated from peripheral lymph nodes resulted in the isolation of affinity-matured MAbs reactive with cytosine deaminase. This model further demonstrates and substantiates at a cellular level the rapid development and maturation of T-cell-dependent B-cell responses occurring within draining lymph nodes following antigen challenge.

Shorter development of immunoassay for drugs: application of the novel RIMMS technique enables rapid production of monoclonal antibodies to ranitidine.

High affinity, specific murine monoclonal antibodies have been produced for ranitidine using the novel RIMMS (repetitive immunizations, multiple sites) technique. We demonstrate that this technique can be employed to produce high affinity monoclonal antibodies to drug haptens in approximately 1 month; whereas, conventional techniques typically require 3-9 months. Polyclonal antiserum development typically requires at least 6 months. Consequently, RIMMS has a clear impact allowing reagent antibodies to be available earlier in the drug development process. Isotyping studies demonstrated that the developed antibodies are either IgG1 or IgG2b immunoglobulins which confirms that the technique produces class-switched, affinity matured reagent antibodies. The most promising monoclonal antibody for quantitative applications afforded similar sensitivity, by competitive ELISA, to the established sheep polyclonal anti-ranitidine sera. The calibration range, estimated as the limits between the asymptotic regions of calibration graphs, is 0.5-41.2 ng ranitidine per well. Specificity studies indicated that the monoclonal antibody afforded superior selectivity, yielding only 4.1% cross-reactivity with the ranitidine sulphoxide metabolite; the corresponding value for the antiserum was 8.6%. Both reagents had similar cross-reactivities with the N-oxide metabolite.

Identification of tyrosine phosphorylated adhesion proteins in human cancer cells.

Tyrosine phosphorylation is a form of signal transduction that regulates cell growth, differentiation, migration, and survival. This knowledge has promoted much interest in the role of tyrosine kinases and phosphatases in regulating cell behavior during development and tumorigenesis. However, it is generally less well appreciated that tyrosine phosphorylated proteins are enriched within sites of cell adhesion, particularly in transformed cells. To identify these, we developed a panel of monoclonal antibodies specific for tyrosine phosphorylated proteins in breast cancer cells, using extensive modifications of existing technologies for immunization, somatic fusion, and antibody screening. Mice were immunized with a complex mixture of phosphotyrosine containing proteins using the newly developed RIMMS method. By increasing the sensitivity of antigen recognition, we isolated reagents specific for a wide diversity of tyrosine phosphorylated adhesion proteins in breast cancer cells.

Potential mediators of post-traumatic stress disorder in child witnesses to domestic violence.

OBJECTIVE: The aim was to examine variables that might mediate the incidence of Post-Traumatic Stress Disorder (PTSD) in child witnesses to domestic violence. These variables included age, gender, locus of control, self-blame, perception of threat, active versus palliative coping style, maternal emotional health plus aspects of the violence witnessed (intensity, frequency, age of child when first witnessing violence, and time since the last violent episode). METHOD: Following screening for other PTSD inducing experiences, a sample of 20 child witnesses to domestic violence, 15 matched control children, and their mothers were assessed using the following tools: The Straus Conflict Tactics Scale; the Child Post-Traumatic Stress Reaction Index; the Nowicki-Strickland Locus of Control Scale; the General Health Questionnaire, and a Screening Questionnaire designed to elicit qualitative information from both children and mothers including data about any other potential PTSD inducing stressor the subject child may have been exposed to. RESULTS: None of the factors under examination were found to contribute significantly to the severity levels of Post-Traumatic Stress Disorder in relation to witness status. CONCLUSION: The small sample size of the study necessitates that the results be interpreted with caution. Nevertheless the findings indicate that the impact of witnessing domestic violence, in terms of PTSD, is not mediated by factors such as maternal emotional well-being, age and gender of the child, or the child's style of coping with parental conflict. Evidence that variables specifically related to the violence witnessed did not mediate the impact suggests that all domestic violence may have severe and long-term impact on child witnesses.

Inhibition of establishment of primary and micrometastatic tumors by a urokinase plasminogen activator receptor antagonist.

Tumor establishment and metastasis are dependent on extracellular matrix proteolysis, tumor cell migration, and angiogenesis. Urokinase plasminogen activator (uPA) and its receptor are essential mediators of these processes. The purpose of this study was to investigate the effect of a recombinant human uPAR antagonist on growth, establishment, and metastasis of tumors derived from human cancer cell lines. A noncatalytic recombinant protein, consisting of amino acids 1-137 of human uPA and the CH2 and CH3 regions of mouse IgG1 (uPA-IgG), was expressed, purified, and shown to bind specifically to human uPAR and to saturate the surface of human tumor cells which express uPAR. Daily i.p. administration of uPA-IgG to nude mice extended latencies of unstaged tumors derived from Lox melanoma and SW48 colon carcinoma cells by 7.7 and 5.5 days, respectively. uPA-IgG treatment did not affect the growth of Lox or KB tumors staged to 200 mg before antagonist treatment commenced. The effect of uPA-IgG on the establishment of micrometastases was assessed in SCID mice. KB head/neck tumor cells were injected in the tail vein and allowed to seed for 48 h before initiation of daily i.p. injections of uPA-IgG for 24 days. The number of lung colonies ranged between 5 and 30% of vehicle-treated mice in two separate experiments. Furthermore, a single 800 microg dose of uPA-IgG administered 1 h prior to tail vein injection of KB cells reduced lung colony formation to just 3.5% of vehicle-treated SCID mice. These data demonstrate that antagonism of uPAR arrested metastasis and inhibited the establishment of primary tumors and micrometastases. Thus, small molecule uPAR antagonists may serve as useful adjuvant agents in combination with existing cancer chemotherapy.

Gene gun delivered DNA-based immunizations mediate rapid production of murine monoclonal antibodies to the Flt-3 receptor.

Class-switched, affinity-matured murine monoclonal antibody (MAb)-producing cell lines were generated against the Flt-3 receptor in less than 4 weeks following polynucleotide immunizations, used in conjunction with repetitive immunizations, multiple sites (RIMMS). Plasmid DNA encoding Flt-3/Fc was coated onto gold particles, which were subsequently propelled into the epidermis of mice using biolistic particle bombardment using the Accell gene gun. Pools of immune peripheral lymph node cells were somatically fused 13 days after the onset of delivery of DNA encoding the target antigen. To determine if early responses could be augmented, DNA-encoding murine GM-CSF was delivered 3 days prior to the Flt-3/Fc DNA immunizations. The data presented demonstrates the successful identification and characterization of class-switched, affinity-matured MAbs that bind to the Flt-3 receptor. When compared to conventional methodologies or intramuscular targeted DNA-based immunization for the generation of MAbs, use of the gene gun in conjunction with RIMMS allows for a more rapid production of affinity-matured MAb-producing cell lines.

Post-traumatic stress disorder in child witnesses to domestic violence.

A sample of children aged 6-12, of whom 20 had witnessed domestic violence and and 15 had not, was examined for symptoms of post-traumatic stress disorder (PTSD), and witness status was found to be a significant predictor of PTSD. Implications for clinical intervention are discussed.