Geographical assignment of hospitalists in an urban teaching hospital: feasibility and impact on efficiency and provider satisfaction.

OBJECTIVE: To evaluate whether implementation of a geographic model of assigning hospitalists is feasible and sustainable in a large hospitalist program and assess its impact on provider satisfaction, perceived efficiency and patient outcomes. METHODS: Pre (3 months) - post (12 months) intervention study conducted from June 2014 through September 2015 at a tertiary care medical center with a large hospitalist program caring for patients scattered in 4 buildings and 16 floors. Hospitalists were assigned to a particular nursing unit (geographic assignment) with a goal of having over 80% of their assigned patients located on their assigned unit. Satisfaction and perceived efficiency were assessed through a survey administered before and after the intervention. RESULTS: Geographic assignment percentage increased from an average of 60% in the pre-intervention period to 93% post-intervention. The number of hospitalists covering a 32 bed unit decreased from 8-10 pre to 2-3 post-intervention. A majority of physicians (87%) thought that geography had a positive impact on the overall quality of care. Respondents reported that they felt that geography increased time spent with patient/caregivers to discuss plan of care (p < 0.001); improved communication with nurses (p = 0.0009); and increased sense of teamwork with nurses/case managers (p < 0.001). Mean length of stay (4.54 vs 4.62 days), 30-day readmission rates (16.0% vs 16.6%) and patient satisfaction (79.9 vs 77.3) did not change significantly between the pre- and post-implementation period. The discharge before noon rate improved slightly (47.5% - 54.1%). CONCLUSIONS: Implementation of a unit-based model in a large hospitalist program is feasible and sustainable with appropriate planning and support. The geographical model of care increased provider satisfaction and perceived efficiency; it also facilitated the implementation of other key interventions such as interdisciplinary rounds.

Physician communication coaching effects on patient experience.

BACKGROUND: Excellent communication is a necessary component of high-quality health care. We aimed to determine whether a training module could improve patients' perceptions of physician communication behaviors, as measured by change over time in domains of patient experience scores related to physician communication. STUDY DESIGN: We designed a comprehensive physician-training module focused on improving specific "etiquette-based" physician communication skills through standardized simulations and physician coaching with structured feedback. We employed a quasi-experimental pre-post design, with an intervention group consisting of internal medicine hospitalists and residents and a control group consisting of surgeons. The outcome was percent "always" scores for questions related to patients' perceptions of physician communication using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey and a Non-HCAHPS Physician-Specific Patient Experience Survey (NHPPES) administered to patients cared for by hospitalists. RESULTS: A total of 128 physicians participated in the simulation. Responses from 5020 patients were analyzed using HCAHPS survey data and 1990 patients using NHPPES survey data. The intercept shift, or the degree of change from pre-intervention percent "always" responses, for the HCAHPS questions of doctors "treating patients with courtesy" "explaining things in a way patients could understand," and "overall teamwork" showed no significant differences between surgical control and hospitalist intervention patients. Adjusted NHPPES percent excellent survey results increased significantly post-intervention for the questions of specified individual doctors "keeping patient informed" (adjusted intercept shift 9.9% P = 0.019), "overall teamwork" (adjusted intercept shift 11%, P = 0.037), and "using words the patient could understand" (adjusted intercept shift 14.8%, p = 0.001). CONCLUSION: A simulation based physician communication coaching method focused on specific "etiquette-based" communication behaviors through a deliberate practice framework was not associated with significantly improved HCAHPS physician communication patient experience scores. Further research could reveal ways that this model affects patients' perceptions of physician communication relating to specific physicians or behaviors.

Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics.

An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed.

A comparison of the ability of the human IgG1 allotypes G1m3 and G1m1,17 to stimulate T-cell responses from allotype matched and mismatched donors.

The immunogenicity of clinically administered antibodies has clinical implications for the patients receiving them, ranging from mild consequences, such as increased clearance of the drug from the circulation, to life-threatening effects. The emergence of methods to engineer variable regions resulting in the generation of humanised and fully human antibodies as therapeutics has reduced the potential for adverse immunogenicity. However, due to differences in sequence referred to as allotypic variation, antibody constant regions are not homogeneous within the human population, even within sub-classes of the same immunoglobulin isotype. For therapeutically administered antibodies, the potential exists for an immune response from the patient to the antibody if the allotype of patient and antibody do not match. Allotypic distribution in the human population varies within and across ethnic groups making the choice of allotype for a therapeutic antibody difficult. This study investigated the potential of human IgG1 allotypes to stimulate responses in human CD4(+) T cells from donors matched for homologous and heterologous IgG1 allotypes. Allotypic variants of the therapeutic monoclonal antibody trastuzumab were administered to genetically defined allotypic matched and mismatched donor T cells. No significant responses were observed in the mismatched T cells. To investigate the lack of T-cell responses in relation to mismatched allotypes, HLA-DR agretopes were identified via MHC associated peptide proteomics (MAPPs). As expected, many HLA-DR restricted peptides were presented. However, there were no peptides presented from the sequence regions containing the allotypic variations. Taken together, the results from the T-cell assay and MAPPs assay indicate that the allotypic differences in human IgG1 do not represent a significant risk for induction of immunogenicity.

Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics.

PURPOSE: Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics. METHODS: Monoclonal chimeric (rituximab) and humanized (trastuzumab) antibodies were subjected to fine-tuned stress conditions to achieve low levels (<3% of total protein) of sub-visible aggregates. The effect of stimulating human dendritic cells (DC) and CD4(+) T cells with the aggregates was measured in vitro using cytokine secretion, proliferation and confocal microscopy. RESULTS: Due to its intrinsic high clinical immunogenicity, aggregation of rituximab had minimal effects on DC activation and T cell responses compared to monomeric rituximab. However, in the case of trastuzumab (low clinical immunogenicity) small quantities of aggregates led to potent CD4(+) T cell proliferation as a result of strong cytokine and co-stimulatory signals derived from DC. Consistent with this, confocal studies showed that stir-stressed rituximab was rapidly internalised and associated with late endosomes of DC. CONCLUSIONS: These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub-visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity.

Reducing patient placement errors in emergency department admissions: right patient, right bed.

INTRODUCTION: Because lack of inpatient capacity is associated with emergency department (ED) crowding, more efficient bed management could potentially alleviate this problem. Our goal was to assess the impact of involving a patient placement manager (PPM) early in the decision to hospitalize ED patients. The PPMs are clinically experienced registered nurses trained in the institution-specific criteria for correct unit and bed placement. METHODS: We conducted two pilot studies that included all patients who were admitted to the adult hospital medicine service: 1) 10/24 to 11/22/2010 (30 days); and 2) 5/24 to 7/4/2011 (42 days). Each pilot study consisted of a baseline control period and a subsequent study period of equal duration. In each pilot we measured: 1) the number of "lateral transfers" or assignment errors in patient placement, 2) median length of stay (LOS) for "all" and "admitted" patients and 3) inpatient occupancy. In pilot 2, we added as a measure code 44s, i.e. status change from inpatient to observation after patients are admitted, and also equipped all emergency physicians with portable phones in order to improve the efficiency of the process. RESULTS: In pilot 1, the number of "lateral transfers" (incorrect patient placement assignments) during the control period was 79 of the 854 admissions (9.3%) versus 27 of 807 admissions (3.3%) during the study period (P<0.001). We found no statistically significant differences in inpatient occupancy or ED LOS for "all" or for "admitted" patients. In pilot 2, the number of "lateral transfers" was 120 of 1,253 (9.6%) admissions in the control period and 42 of 1,229 (3.4%) admissions in the study period (P<0.001). We found a 49-minute (352 vs. 401 minutes) decrease in median LOS for "admitted" ED patients during the study period compared with the control period (P=0.04). The code 44 rates, median LOS for "all" patients and inpatient occupancy did not change. CONCLUSION: Inclusion of the PPM in a three-way handoff conversation between emergency physicians and hospitalist providers significantly decreased the number of "lateral transfers." Moreover, adding status determination and portable phones for emergency physicians improved the efficiency of the process and was associated with a 49 (12%) minute decrease in LOS for admitted patients.

Prediction of immunogenicity of therapeutic proteins: validity of computational tools.

Most protein therapeutics have the potential to induce undesirable immune responses in patients. Many patients develop anti-therapeutic antibodies, which can affect the safety and efficacy of the therapeutic protein, particularly if the response is neutralizing. There are a variety of factors that influence the immunogenicity of protein therapeutics and, in particular, the presence of B- and T-cell epitopes is considered to be of importance. In silico tools to identify the location of both B- and T-cell epitopes and to assess the potential for immunogenicity have been developed, and such tools provide an alternative to more complex in vitro or in vivo immunogenicity assays. This article reviews computational epitope prediction methods and also the use of manually curated databases containing experimentally derived epitope data. However, due to the complexities of the molecular interactions involved in epitope recognition by the immune system, the heterogeneity of key proteins in human populations and the adaptive nature of the immune response, in silico methods have not yet achieved a level of accuracy that enables them to be used as stand-alone tools for predicting clinical immunogenicity. Computational methods, particularly with regard to T-cell epitopes, only consider a limited number of events in the process of epitope formation and therefore routinely over-predict the number of epitopes within a molecule. Epitope databases such as the Immune Epitope Database (IEDB) and the proprietary T Cell Epitope Database (TCED) have reached a size and level of organization that increases their utility; however, they are not exhaustive. These methods have greatest utility as an adjunct to in vitro assays where they can be used either to reduce the amount and complexity of the in vitro screening, or they can be used as tools to analyze the sequence of the identified epitope in order to locate amino acids critical for its properties.

Immunogenicity of protein therapeutics: The key causes, consequences and challenges.

The immunogenicity of protein therapeutics has so far proven to be difficult to predict in patients, with many biologics inducing undesirable immune responses directed towards the therapeutic resulting in reduced efficacy, anaphylaxis and occasionally life threatening autoimmunity. The most common effect of administrating an immunogenic protein therapeutic is the development of a high affinity anti-therapeutic antibody response. Furthermore, it is clear from clinical studies that protein therapeutics derived from endogenous human proteins are capable of stimulating undesirable immune responses in patients, and as a consequence, the prediction and reduction of immunogenicity has been the focus of intense research. This review will outline the principle causes of the immunogenicity in protein therapeutics, and describe the development of pre-clinical models that can be used to aid in the prediction of the immunogenic potential of novel protein therapeutics prior to administration in man.

The anti-CD20 antibody rituximab augments the immunospecific therapeutic effectiveness of an anti-CD19 immunotoxin directed against human B-cell lymphoma.

The chimaeric anti-CD20 antibody rituximab (Rituxan) sensitises lymphoma cells to small molecule cytotoxic drugs and to protein toxins. We have explored the augmentive effect of rituximab on the anti-CD19 immunotoxin BU12-SAPORIN in a model of human lymphoma. Intact rituximab and its F(ab)2 derivative both augmented the immunospecific protein synthesis inhibitory effects of BU12-SAPORIN in a complement-independent manner. A combination of rituximab + BU12-SAPORIN completely abolished the proliferation of Ramos cells in vitro and also induced a significantly greater degree of apoptosis in these cells. Treatment with rituximab, BU12-SAPORIN or a combination of both induced poly(ADPribose) polymerase and caspase 3 cleavage, although this was always consistently greater in combination-treated cells. zVAD almost completely inhibited apoptosis in rituximab- or BU12-SAPORIN-treated cells but only partially in combination-treated cells. In severe combined immunodeficient (SCID)-Ramos mice the combination of rituximab + BU12-SAPORIN was significantly better therapeutically than either single agent. The immunological fidelity of the therapeutic effect because of combination treatment was demonstrated through the failure of rituximab to augment an irrelevant anti-CD7 immunotoxin. The therapeutic efficacy of rituximab and combination treatment was reduced in SCID-Ramos mice depleted of serum complement while natural killer cell depletion failed to show any convincing role for antibody-dependent cellular cytotoxicity. This study shows a clear therapeutic advantage from using rituximab to immunospecifically augment immunotoxin cytotoxicity warranting further investigation.