Network geometry of evidence from randomised controlled trials addressing donor selection and source of haematopoietic progenitor cells used in allogeneic transplantation: a systematic scoping review.

BACKGROUND AND METHODS: A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of donor for allogeneic haematopoietic cell transplantation (HCT) was performed to create a network of best evidence that allows us to identify new potential indirect comparisons for the strategic development of future studies that connect to the existing evidence network. RESULTS: A total of 19 eligible RCTs (2589 total patients) were identified. Nine studies (1566 patients) compared clinical outcomes following the use of peripheral blood progenitor cells (PBPCs) with bone marrow (BM) from matched related donors (eight studies) or matched unrelated donors (one study). The remaining studies compared BM or PBPCs with various methods of BM stimulation or manipulation (six studies), compared different methods of surface molecule-based selection and/or depletion of grafts (two studies) or compared the optimal number of units for paediatric cord blood transplantation (two studies). No published RCTs compared different types of donors. The geometry of the evidence network was analysed to identify opportunities for potential novel indirect comparisons and to identify opportunities to expand the network. Few indirect comparisons are currently feasible due to small sample size and heterogeneity in patient diagnoses and demographics between treatment nodes in the network. CONCLUSION: More RCTs that enrol greater numbers of similar patients are needed to leverage the current evidence network concerning donor choice and source of cells used in allogeneic HCT.

Costs of the in-home patients affected by dementia.

In 2000, Alzheimer's disease (AD) and other dementias were the third most expensive health conditions in the USA and in 2005 their annual costs amounted to more than $148 billion. An observational, non-randomized study aimed to evaluate direct costs of demented patients in their homes. Two hundred thirty-six informal caregivers have been enrolled. A financial support, represented by a disability living allowance (15.3%) or attendance allowance (3.4%), was presented in just 19.7% of the cases. Patients receiving assistance from an employed carer were 39% with a mean cost of 800 Euro/month. Receiving assistance from an employed carer is not correlated with cognitive and functional impairment, with the age of the caregiver and with the duration of the disease (t=1.03; t=-0.86; t=1.41; t=-0.16, respectively). The informal caregivers declared that they thoughts about the possibility of institutionalize the patient were 20.9%. The present study underlines the discrepancy between subjects having assistance from an employed caregiver and subjects receiving financial supports. It often happens that patients not reaching the minimum requisites for social assistant or financial support, need at least a supervision.

Depressive symptoms and quality of life in elderly patients with exacerbation of chronic obstructive pulmonary disease or cardiac heart failure: preliminary data of a randomized controlled trial.

Aim of the study was to evaluate mortality and functional, cognitive, affective status in elderly patients (>or=75 years) with exacerbation of chronic obstructive pulmonary disease (COPD) or acute congestive heart failure (CHF) admitted to the emergency department (ED) of S. Giovanni Battista Hospital of Torino and randomly assigned to the geriatric home hospitalization service (GHHS) or to a general medical ward (GMW). All patients were evaluated on admission, on discharge and at 6 months, using a standardized study protocol. We excluded patients with unstable medical conditions. The total sample included 73 patients: 35 with COPD exacerbation (19 GHHS, 16 GMW) and 38 with CHF (19 GHHS, 19 GMW). Mean age was 81.7+/-8.0 years. At baseline, no significant differences in demographic, social and clinical conditions were found between the two groups of patients. 56.7% of COPD patients had a severe exacerbation, according to Anthonisen criteria; 65% of CHF patients were NYHA-III and 35% NYHA-IV (according to the criteria of the New York Heart Association) (FE<35% in 40% of patients). On admission all patients were partially dependent in ADLs and IADLs, with a moderate impairment of depression score and a fairly good quality of life. On discharge depression score and quality of life were significantly better only in GHHS patients. Mortality was similar in the two setting of care. Patients managed at home had a significantly longer length of treatment. At 6-month follow-up we did not observe a difference in mortality, but we observed a higher readmission rate in patients previously treated in hospital. In conclusion, our study indicates that home-treated patients with COPD or CHF have better depressive scores and quality of life and a lower rate of hospital readmission after six months.

Degradation signals in ErbB-2 dictate proteasomal processing and immunogenicity and resist protection by cis glycine-alanine repeat.

ErbB-2 is ubiquitinated and degraded when dissociated from its membrane chaperone or bound by specific antibody. Reagents which induce such degradation have demonstrated antitumor activity and may impact ErbB-2 immunogenicity. To further understand ErbB-2 degradation and immunogenicity, a glycine-alanine repeat (GAr) or the reverse proline-alanine repeat (PAr) which protects certain proteins from proteasome degradation, was inserted after amino acid 5 (GAr5/PAr5) or 55 (GAr55/PAr55) of ErbB-2. When dissociated from the membrane with geldanamycin, E2-GAr5 and E2-PAr5 were not protected and still ubiquitinated and degraded by the proteasome, despite the presence of GAr. Insertional mutagenesis with GAr sequences at a.a. 55 of E2 enhanced proteasome degradation rendering E2-GAr55 and E2-PAr55 unstable on the membrane, but rescued in the cytosol by proteasome inhibitors. Immunization with E2-GAr induced antitumor immunity and CTL which lysed tumor cells expressing chimeric E2-GAr or wild-type E2 proteins, demonstrating efficient presentation through MHC I pathway. Improved understanding of the strong degradation signals in ErbB-2 may facilitate the development of anticancer agents or vaccines.

Vaccination with cytoplasmic ErbB-2 DNA protects mice from mammary tumor growth without anti-ErbB-2 antibody.

Wild-type ErbB-2 (E2) positive D2F2/E2 tumors are rejected by active vaccination with ErbB-2 DNA. However, anti-ErbB-2 Ab response can cause cardiac toxicity or interfere with cellular immunity. It will be advantageous to induce only cellular immunity by active vaccination. A panel of E2 DNA vaccines were constructed, and their vaccination efficacy was ranked as E2 > tyrosine kinase-deficient ErbB-2 (E2A) > full-length ErbB-2 targeted to the cytoplasm (cytE2) > tyrosine kinase-deficient cytE2 (cytE2A). E2A is a tyrosine kinase-deficient mutant containing a single residue substitution. CytE2 or cytE2A encodes a full-length protein that is targeted to and rapidly degraded in the cytosol by the proteasomes. Covaccination with cytE2A and GM-CSF or IL-2 DNA resulted in equivalent anti-tumor activity as E2. However, anti-ErbB-2 Ab was induced by E2 or E2A, but not cytE2 or cytE2A. Therefore, cytE2A appears to induce anti-tumor immunity without an Ab response. ErbB-2-specific CTL were detected in mice immunized with cytE2A and GM-CSF and have rejected tumor challenge. Depletion of CD8, but not CD4 T cells reduced anti-tumor immunity, indicating CTL as the effector cells. Covaccination with E2A and cytE2A induced synergistic anti-tumor activity, supporting enhanced peptide presentation from cytE2A, which was further evidenced by superior CTL activation using APCs expressing cytE2 vs E2. Taken together, cytoplasmic ErbB-2 DNA induced anti-tumor CTL, but not humoral response, demonstrating the feasibility of eliciting individual effector mechanism by targeted DNA vaccine.

Complementary antitumor immunity induced by plasmid DNA encoding secreted and cytoplasmic human ErbB-2.

A plasmid DNA was constructed to encode the N-terminal 505 aa of human ErbB-2 (E2, HER-2/neu) and designated as secreted ErbB-2 (secE2). Recombinant secE2 protein was detected in the transfected cells and was secreted as an 80-kDa glycoprotein. Vaccination of BALB/c mice with secE2 DNA induced both IgG1 and IgG2a ErbB-2-specific Abs and protected approximately 90% of mice against mouse mammary tumor D2F2, which expressed human ErbB-2 (D2F2/E2). The efficacy of secE2 vaccine was comparable with that of wild-type ErbB-2 DNA, which encodes the entire 1258 aa of ErbB-2 protein, induced only IgG2a E2-specific Abs, and stimulated greater CTL activity. Immune lymphocytes were stimulated in vitro with irradiated 3T3 cells, which expressed ErbB-2, K(d), and B7.1. CTL activity was measured by the lysis of E2-positive target cells and by intracellular IFN-gamma production. To enhance CTL activation, mice were immunized with a combination of secE2 and cytoplasmic E2 (cytE2); the latter encodes the 1258-aa ErbB-2 protein that was released into the cytoplasm upon synthesis. Significant increase in CTL activity was demonstrated after mice were immunized with the combined vaccines and all mice were protected from D2F2/E2 tumor growth. Therefore, secE2, which induced Th2 Ab and weak CTL, conferred similar protection as E2, which induced Th1 Ab and strong CTL. Combined vaccination with secE2 and cytE2 resulted in Th2 Ab, strong CTL, and the most effective protection against tumor growth. The strategy of coimmunization with DNA that direct Ags to different subcellular compartments may be adapted as appropriate to optimize immune outcome.

Neural network and linear regression models in residency selection.

For many years, multiple linear regression models have been used at a residency program to generate preliminary rank lists of residency applicants. These lists are then used by the admissions committee as an aid in developing a final ranking to submit to the National Residency Match Program (NRMP). A study was undertaken to compare predictions made using linear regression with those generated by a newer technique, an artificial neural network. A prospective cohort design was used. Seventy-four applicants to an emergency medicine program were evaluated by faculty and resident interviewers with regard to medical school grades, autobiography, interviews, letters of recommendation, and National Board scores. Normalization of these scores (by linear transformation of interviewer means) was used to correct for differences among interviewers. Multivariate linear regression and neural network models were developed using data from the previous 5 years' applicants. These models were used to forecast provisional rank orderings of the candidates. These rankings were combined into a single hybrid list that was used by the admissions committee as the starting point for development of the final rank list by consensus. Each model's predictions were tested for goodness of fit against the final NRMP rank using Wilks' test. Using the final submitted NRMP rank order as the dependent variable, the neural network yielded a correlation coefficient of 0.77 and an R2 of 59.4%. The linear regression model exhibited a correlation coefficient of 0.74 and an R2 of 54.0%. No significant difference was found (chi 2 = 1.08, P = .7). A neural network performs as well as a linear regression model when used for forecasting the rank order of residency applicants.