Hospitalized Patients with Delirium and 28-Day Unplanned Hospital Readmissions: A Longitudinal Retrospective Cohort Study.

OBJECTIVE: To establish the predictors of 28-day unplanned hospital readmissions (28D-UHR) in older adults (aged >65 years) with delirium during index hospital admission. DESIGN: Retrospective longitudinal cohort study. SETTING AND PARTICIPANTS: 1634 patients (aged >65 years) admitted to a Melbourne quaternary hospital with delirium during index admission. METHODS: Delirium during hospital admission was defined by the inclusion of one of the following International Classification of Diseases, Tenth Revision, codes F05.0, F05.1, F05.8, or F05.9 in the hospital medical discharge summary. Descriptive statistics were obtained for baseline characteristics. Multivariate logistic regression model was developed to assess predictors of 28D-UHR. RESULTS: A total of 1634 patients with delirium during their inpatient admission were included, with 9.8% (160 patients) incidence of 28D-UHR. For patients who were readmitted, a shorter length of stay [odds ratio (OR) 0.98, 95% CI 0.96-0.99], higher number of medications on discharge from index admission (OR 1.10, 95% CI 1.06-1.14), and residing in a nursing home preadmission (OR 1.35, 95% CI 1.04-1.75) were associated with 28D-UHR. CONCLUSIONS AND IMPLICATIONS: This study found that nursing home residence pre index admission, shorter length of stay (LOS), and polypharmacy were predictors of 28D-UHR. Further research into strategies to minimize 28D-UHR is required. Exploration of predischarge pharmacy-driven deprescribing programs and hospital-based postdischarge support for nursing home staff are important areas for future intervention.

Development of the European Organisation for Research and Treatment of Cancer quality of life questionnaire module for older people with cancer: The EORTC QLQ-ELD15.

BACKGROUND AND AIM: There is a lack of instruments that focus on the specific health-related quality of life (HRQOL) issues that affect older people with cancer. The aim of this study was to develop a HRQOL questionnaire module to supplement the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire, the EORTC QLQ-C30 for older (>70years) patients with cancer. METHODS: Phases 1-3 were conducted in seven countries following modified EORTC Quality of Life Group guidelines for module development. Phase 1: potentially relevant issues were identified by a systematic literature review, a questionnaire survey of 17 multi-disciplinary health professionals and two rounds of qualitative interviews. The first round included 9 patients aged >70. The second round was a comparative series of interviews with 49 patients >70years with a range of cancer diagnoses and 40 patients aged 50-69years matched for gender and disease site. In Phase 2 the issues were formulated into a long provisional item list. This was administered in Phase 3 together with the QLQ-C30 to two further groups of cancer patients aged >70 (n=97) or 50-69years (n=85) to determine the importance, relevance and acceptability of each item. Redundant and duplicate items were removed; issues specific to the older group were selected for the final questionnaire. RESULTS: In Phase 1, 75 issues were identified. These were reduced in Phase 2 to create a 45 item provisional list. Phase 3 testing of the provisional list led to the selection of 15 items with good range of response, high scores of importance and relevance in the older patients. This resulted in the EORTC QLQ-ELD15, containing five conceptually coherent scales (functional independence, relationships with family and friends, worries about the future, autonomy and burden of illness). CONCLUSION: The EORTC QLQ-ELD15 in combination with the EORTC QLQ-C30 is ready for large-scale validation studies, and will assess HRQOL issues of most relevance and concern for older people with cancer across a wide range of cancer sites and treatment stages.

Clonal relationships between thyroid-stimulating hormone receptor-stimulating antibodies illustrate the effect of hypermutation on antibody function.

Graves' disease is characterized by production of agonist antibodies to the thyroid-stimulating hormone receptor (TSHR), but knowledge of the genetic and somatic events leading to their aberrant production is limited. We describe the genetic analysis of two monoclonal antibodies (mAbs) with thyroid-stimulating activity (TSAb) obtained from a single mouse with experimental Graves' disease. The mAbs were class switched, but used the same rearrangement of immunoglobulin heavy chain, variable region (IGHV) and immunoglobulin light chain, variable region (IGLV) germline genes, implying a clonal relationship and derivation from a single precursor B-cell clone. The IGHV-region genes of the two mAbs underwent high degrees of somatic hypermutation by sharing numerous mutations before diverging, while the IGLV genes evolved separately. Interestingly, the mutations were present in both the complementarity-determining regions (CDRs) and the framework regions. The cloned IGHV and IGLV genes were confirmed to have TSAb properties in experiments in which they were expressed as recombinant Fabs (rFabs). In other experiments, we swapped the IGLV genes with IGHV genes by constructing chimeric rFabs and showed that the chimeras retained TSAb activities, confirming the close functional relatedness of the V-region genes. Importantly, the IGLV genes in chimeric rFabs had a dominant stimulatory effect at low concentrations, while the IGHV genes had a dominant effect at higher concentrations. Our findings demonstrate that, in experimentally immunized mice, multiple pathogenic antibodies to TSHR can arise from a single clone by a series of somatic mutations in the V-region genes and may give an insight into how such antibodies develop spontaneously in autoimmune Graves' disease.

Treatment of Graves' disease with rituximab specifically reduces the production of thyroid stimulating autoantibodies.

Treatment of Graves' disease (GD) with the B-lymphocyte depleting agent rituximab in addition to standard methimazole-therapy prolongs remission. Paradoxically, it does not mediate a reduction in thyrotropin receptor antibody (TRAb) levels over that of methimazole monotherapy. Using a bioassay involving Chinese hamster ovary cells transfected with the human thyrotropin receptor, we found that the stimulatory capacity of TRAbs was reduced markedly, by 66+/-22%, upon treatment with rituximab and methimazole for 21 days (p<0.0001), compared to an increase by 33% on average (NS) in patients receiving methimazole alone (p=0.04 between groups). The overall levels of TRAbs decreased by around 15% in both groups. Within one year of follow-up, rituximab therapy mediated specific decreases in thyroid-peroxidase antibody- and IgM levels, whereas IgG levels were unaffected. The data indicate that rituximab therapy has differential effects on pathogenic and non-pathogenic autoantibodies, even when directed against the same antigen. The possible mechanisms underlying this hitherto unappreciated phenomenon are discussed.

A systematic review of the use and validation of health-related quality of life instruments in older cancer patients.

AIM: The aim of this paper is to systematically review the use and validation of HRQOL instruments in older cancer patients. METHOD: A systematic review of 5 databases and 3 research registers identified studies reporting the use and validation of HRQOL instruments in cancer patients aged over 65 years from 1995 to mid 2007. RESULTS: Thirty-one studies reported the use of HRQOL measures in older people, using a range of generic and disease-specific instruments. Little work was reported in patients aged over 80 years. All studies exhibited methodological limitations. Fourteen studies were identified with variable evidence on the psychometric properties and clinical usefulness of identified instruments. CONCLUSION: Our review identified that the development, validation and use of HRQOL instruments often ignore the specific needs of older people. This review highlights the need for a HRQOL instrument specifically designed to capture the issues and concerns most relevant to older cancer patients.

Application of new therapies in Graves' disease and thyroid-associated ophthalmopathy: animal models and translation to human clinical trials.

Most current approaches for treating Graves' disease are based essentially upon regimes developed nearly 50 years ago. Moreover, therapeutic approaches for complications such as thyroid-associated ophthalmopathy (TAO) and dermopathy are singularly dependent on conventional approaches of nonspecific immunosuppression. The recent development of an induced model of experimental Graves' disease, although incomplete as it lacks the extrathyroidal manifestations, provided opportunities to investigate immune intervention strategies, including influence upon the autoreactive B and T cell players in the autoimmune process. These major advances are generating new possibilities for therapeutic interventions for patients with Graves' disease and TAO.

Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity-prone HLA-DRB1*0301 transgenic mice.

We have examined the induction of autoimmunity and the maintenance of sustained hyperthyroidism in autoimmunity-prone human leucocyte antigen (HLA) DR3 transgenic non-obese diabetic (NOD) mice following chronic stimulation of the thyrotropin receptor (TSHR) by monoclonal thyroid-stimulating autoantibodies (TSAbs). Animals received weekly injections over the course of 9 weeks of monoclonal antibodies (mAbs) with strong thyroid-stimulating properties. Administration of the mAbs KSAb1 (IgG2b) or KSAb2 (IgG2a), which have similar stimulating properties but different TSH-binding blocking activity, resulted in significantly elevated serum thyroxine (T(4)) levels and thyroid hyperplasia. After the first injection, an initial surge then fall in serum T(4) levels was followed by sustained elevated levels with subsequent injections for at least 63 days. Examination of KSAb1 and KSAb2 serum bioactivity showed that the accumulation of the TSAbs in serum was related to their subclass half-lives. The thyroid glands were enlarged and histological examination showed hyperplastic follicles, with minimal accompanying thyroid inflammation. Our results show that chronic in vivo administration of mAbs with strong thyroid-stimulating activity resulted in elevated T(4) levels, suggesting persistent stimulation without receptor desensitization, giving a potential explanation for the sustained hyperthyroid status in patients with Graves' disease. Moreover, despite the presence of HLA disease susceptibility alleles and the autoimmune prone NOD background genes, chronic stimulation of the thyroid gland did not lead to immune cell-mediated follicular destruction, suggesting the persistence of immunoregulatory influences to suppress autoimmunity.

Treatment of autoimmune hyperthyroidism in a murine model of Graves' disease with tumor necrosis factor-family ligand inhibitors suggests a key role for B cell activating factor in disease pathology.

Hyperthyroid Graves' disease is a common autoimmune disorder mediated by agonistic antibodies to the TSH receptor, termed thyroid stimulating antibodies (TSAbs). Recently members of the TNF superfamily, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), have been identified along with their receptors, B cell maturation antigen and transmembrane activator and calcium-modulator and cyclophilin ligand interactor, and the BAFF-specific receptor. BAFF is a fundamental B cell survival/maturation factor, and both BAFF and APRIL have been implicated in antibody production. We investigated the effect of interfering with BAFF- and APRIL-mediated signals in an induced model of Graves' disease by blockade of these factors using soluble decoy receptors. In a therapeutic setting in mice with established hyperthyroidism, we show that blockade of BAFF or BAFF+APRIL with BAFF-specific receptor-Fc and B cell maturation antigen-Fc, respectively, leads to significant reductions in the induced hyperthyroidism. This was supported by a parallel pattern of declining TSAbs in the responding animals. Histopathological analysis of splenic sections from treated animals revealed marked reductions in the B cell follicle regions, but staining with anti-CD138 revealed the persistence of plasma cells. Thus, the reductions in TSAbs in the treated animals were not related to overall plasma cell numbers in the secondary lymphoid organs. Our results are the first to demonstrate attenuation of established hyperthyroidism by therapeutic intervention aimed at autoreactive B cells and indicate that both BAFF and APRIL appear to play important roles in the development and survival of the autoantibody producing cells in this model.

Monoclonal pathogenic antibodies to the thyroid-stimulating hormone receptor in Graves' disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signaling pathways.

The thyroid target Ag for disease-inducing autoantibodies in Graves' disease is the receptor for thyroid-stimulating hormone (TSH), but little is known about the molecular basis of this pathogenic Ab response. We describe the characteristics of two high- affinity mAbs developed from an experimental murine model of hyperthyroid Graves' disease that exhibit potent thyroid-stimulating activity. Nanogram concentrations of the IgG mAbs KSAb1 and KSAb2 and their Fab induce full stimulation of the TSH receptor that is matched by the ligand TSH and, thus, act as full agonists for the receptor. However, KSAb1 and KSAb2 display differential activities in their ability to block TSH-mediated stimulation of the receptor, indicating subtle differences in their biological properties. In displacement studies, IgG and Fabs of KSAb1 and KSAb2 compete with Graves' disease autoantibodies as well as thyroid-blocking Abs present in some hypothyroid patients, indicating a close relationship between these autoimmune determinants on the receptor. In passive transfer studies, single injections of microgram quantities of KSAb1 or KSAb2 IgG led to rapid elevation of serum thyroxine and a hyperthyroid state that was maintained for a number of days. The thyroid glands showed evidence of cell necrosis, but there was no accompanying mononuclear cell infiltrate. In studying their receptor activation pathways, both KSAb1 and KSAb2 provoked phosphorylation of the intracellular ERK1/2 pathway in primary thyrocytes, indicating that multiple signaling pathways may participate in the pathogenesis of Graves' disease. In summary, our findings emphasize the similarities of the experimental mouse model in reproducing the human disorder and provide improved means for characterizing the molecular basis of this pathogenic response.

Dynamics of thyroid-stimulating and -blocking antibodies to the thyrotropin receptor in a murine model of Graves' disease.

Graves' disease is characterized by the presence of autoantibodies to the TSH receptor (TSHR). There are multiple antibodies to the TSHR, with thyroid-stimulating antibodies (TSAbs) and TSH-stimulating blocking antibodies (TSBAbs), which in patients can fluctuate over time, resulting in changes in disease activity. Recently, animal models of Graves' disease have been developed, but it is not known whether the induced TSAbs and TSBAbs change spontaneously with time to influence disease. We used fibroblasts expressing major histocompatability complex (MHC) class II and human TSHR murine model to study anti-TSHR antibody patterns in serial bleeds of 23 animals. Anti-TSHR antibody responses were first detectable after 7-8 wk of first immunization. Moreover, the pattern of the TSAbs or TSBAbs was selected early in the response. The majority of the animals showed anti-TSHR antibodies that were either TSAb or TSBAb responses and were maintained throughout the course of 17-24 wk of the experiment. Remarkably, a proportion of mice (13%) displayed presence of antibodies with both TSAbs and TSBAbs, which appeared to cycle over time and thus mimic the fluctuations described in some hyperthyroid patients. Analyses of the linear epitopes to TSHR by peptide scanning showed that there was no early restricted epitope response. Thus, despite using an inbred strain, the initial response appears to target different regions of the receptor in different animals. Our data show that anti-TSHR antibody epitopes in the model display heterogeneity in TSHR epitopes, which vary in individual animals as well as in their regulation.