Feasibility Test of the MedaCube

Poor adherence is a significant barrier to achieve better patient outcomes. Rates of non-adherence approach 40% resulting in 10% of all emergency department visits and 23% of admissions into skilled nursing facilities. Many factors contribute to medication non-adherence including psychological and memory disorders, aging and pill burden. The MedaCube is a medication management system intended to help solve unintentional medication non-adherence. The device is designed to dispense scheduled and as-needed oral medications. The MedaCube provides audio and visual prompts alerting subjects to administer their medications. Caregivers receive notification of missed doses, late doses and refill requests. The null hypothesis is that use of the MedaCube results in no difference in medication adherence when compared with six month prior adherence in individual subjects

CTL Escape Mediated by Proteasomal Destruction of an HIV-1 Cryptic Epitope

Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes

Impact of hydrogen partial pressure on coal liquefaction. Final technical report

This program was conducted to determine the effects of hydrogen partial pressure on the SRC-I direct coal liquefaction process and SRC-I Demonstration Plant design. A native solvent was produced in quantity and slurried with Kentucky number 9 Mulford coal in a series of coal liquefaction runs under varying hydrogen gas rates, temperatures, residence times, and hydrogen partial pressures. The results showed that hydrogen partial pressure significantly affected product distribution; the magnitude of the effect was comparable to changes in temperature and residence time. Also, the impact of hydrogen partial pressure was enhanced by increases in both temperature and residence time. Operating at low hydrogen partial pressure did not show any apparent advantage; it reduced coal conversion, reduced oil yield, and had a detrimental effect on the yield distribution of other products. An increase in hydrogen partial pressure had the following effects: increased coal conversion; increased conversion of asphaltenes and preasphaltenes to lighter products; significantly increased the oil yield; increased light gas yields; decreased sulfur content in the SRC; increased hydrogen content of the recycle solvent; and increased hydrogen consumption. This study strongly suggests that further studies should be conducted to optimize the effects of hydrogen partial pressure on the process, both within and, preferably, beyond the constraints of the current basic SRC-I design, considering the major impact of this variable on the process. 10 references, 37 figures, 10 tables

Feasibility Test of the MedaCube

Poor adherence is a significant barrier to achieve better patient outcomes. Rates of non-adherence approach 40% resulting in 10% of all emergency department visits and 23% of admissions into skilled nursing facilities. Many factors contribute to medication non-adherence including psychological and memory disorders, aging and pill burden. The MedaCube is a medication management system intended to help solve unintentional medication non-adherence. The device is designed to dispense scheduled and as-needed oral medications. The MedaCube provides audio and visual prompts alerting subjects to administer their medications. Caregivers receive notification of missed doses, late doses and refill requests. The null hypothesis is that use of the MedaCube results in no difference in medication adherence when compared with six month prior adherence in individual subjects

R5 Human Immunodeficiency Virus Type 1 (HIV-1) Replicates More Efficiently in Primary CD4(+) T-Cell Cultures Than X4 HIV-1

In this report, we present evidence that R5 human immunodeficiency virus type 1 (HIV-1) replicates more efficiently in primary CD4(+) T cells than X4 HIV-1. By comparing CD3/CD28-costimulated CD4(+) T-cell cultures infected by several X4 and R5 HIV-1 strains, we determined that R5-infected CD4(+) T cells produce more virus over time than X4-infected CD4(+) T cells. In the first comparison, we found that more cells were infected by the X4-tropic strain LAI than by the R5-tropic strain JR-CSF and yet that higher levels of viral production were detected in the R5-infected cultures. The differential viral production was partially due to the severe cytopathic effects of the X4 virus. We also compared cultures infected with the isogenic HIV-1 strains NL4-3 (X4) and 49.5 (R5). We found that fewer cells were infected by the R5 strain, and yet similar levels of viral production were detected in both infected cultures. Cell death played less of a role in the differential viral production of these strains, as the cell viability remained comparable in both X4- and R5-infected cultures over time. The final comparison involved the primary R5-tropic isolate KP1 and the primary dual-tropic isolate KP2. Although both strains infected similar numbers of cells and induced comparable levels of cytopathicity, viral production was considerably higher in the R5-infected culture. In summary, these data demonstrate that R5 HIV-1 has an increased capacity to replicate in costimulated CD4(+) T cells compared to X4 HIV-1