Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single-Ascending-Dose Studies

Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.     

Feasibility and Acceptability of a Pilot Housing Transition Program for Homeless Adults with Mental Illness and Substance Use

The purpose of this study was to determine if a housing transition program was feasible and acceptable to homeless clients with mental illness and substance use histories. Ten male residents of a homeless shelter participated in the 3-week housing intervention. The intervention used a DVD format with instructional videos, graphics, and opportunities for hands-on practice of functional skills in a simulated apartment environment. Outcome measures included goal attainment scale scores (GAS), satisfaction surveys, and case manager reports. Six of the 10 participants completed the program and achieved GAS scores at a greater level than expected at baseline (T > 50). Participants reported the intervention to be engaging and enhanced their knowledge of the housing transition process. The intervention appears to have assisted the participants in the attainment of housing skills and warrants further study.     

Recommended Immunological Strategies to Screen for Botulinum Neurotoxin-Containing Samples

Botulinum neurotoxins (BoNTs) cause the life-threatening neurological illness botulism in humans and animals and are divided into seven serotypes (BoNT/A–G), of which serotypes A, B, E, and F cause the disease in humans. BoNTs are classified as “category A” bioterrorism threat agents and are relevant in the context of the Biological Weapons Convention. An international proficiency test (PT) was conducted to evaluate detection, quantification and discrimination capabilities of 23 expert laboratories from the health, food and security areas. Here we describe three immunological strategies that proved to be successful for the detection and quantification of BoNT/A, B, and E considering the restricted sample volume (1 mL) distributed. To analyze the samples qualitatively and quantitatively, the first strategy was based on sensitive immunoenzymatic and immunochromatographic assays for fast qualitative and quantitative analyses. In the second approach, a bead-based suspension array was used for screening followed by conventional ELISA for quantification. In the third approach, an ELISA plate format assay was used for serotype specific immunodetection of BoNT-cleaved substrates, detecting the activity of the light chain, rather than the toxin protein. The results provide guidance for further steps in quality assurance and highlight problems to address in the future.     

A Case Study of Unusual Etiology of Anterior Uveitis with Ocular Hypertension-Iris Metastasis of Primary Lung Adenocarcinoma

This is a case of anterior uveitis in a 50 year-old man caused by lung adenocarcinoma metastasis to the iris. The patient was initially worked up for pneumonia and was discovered to have multiple lung lesions on computed tomography scan. Prior to discharge, the patient began complaining of ocular redness, pain, photophobia and decreased visual acuity. The patient was given an initial diagnosis of anterior uveitis with uveitic glaucoma, which was later confirmed to be secondary to lung adenocarcinoma metastasis to the iris. Metastasis to the iris is a particularly rare cause of anterior uveitis and may inadvertently be left out of a physician''s differential diagnosis. This case illustrates a rare, but clinically important cause of anterior uveitis with intraocular hypertension, which should be considered in all cases of ocular redness and pain.     

Student and Faculty Member Perspectives on Lecture Capture in Pharmacy Education

Objectives. To examine faculty members’ and students’ use and perceptions of lecture recordings in a previously implemented lecture-capture initiative.Methods. Patterns of using lecture recordings were determined from software analytics, and surveys were conducted to determine awareness and usage, effect on attendance and other behaviors, and learning impact.Results. Most students and faculty members were aware of and appreciated the recordings. Students’ patterns of use changed as the novelty wore off. Students felt that the recordings enhanced their learning, improved their in-class engagement, and had little effect on their attendance. Faculty members saw little difference in students’ grades or in-class engagement but noted increased absenteeism.Conclusion. Students made appropriate use of recordings to support their learning, but faculty members generally did not make active educational use of the recordings. Further investigation is needed to understand the effects of lecture recordings on attendance. Professional development activities for both students and faculty members would help maximize the learning benefits of the recordings.     

Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis

Activated in response to chemotherapy, senescence is a tumor suppressive mechanism that induces a permanent loss of proliferation. However, in response to treatment, it is not really known how cells can escape senescence and how irreversible or incomplete this pathway is. We have recently described that cells that escape senescence are more transformed than non-treated parental cells, they resist anoikis and rely on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that Akt was activated as a feedback pathway during the early step of senescence. The inhibition of the kinase prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 downregulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. The inactivation of Noxa prevented apoptosis and increased the number of emergent cells. Using either RNA interference or p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its downregulation improved treatment efficacy through apoptosis induction. Therefore, although senescence is an efficient suppressive mechanism, it also generates more aggressive cells as a consequence of apoptosis inhibition. We therefore propose that senescence-inducing therapies should be used sequentially with drugs favoring cell death such as Akt inhibitors. This should reduce cell emergence and tumor relapse through a combined induction of senescence and apoptosis.     

How Well Do Patients Understand Written Instructions?: Health Literacy Assessment in Rural and Urban Rheumatology Outpatients

The aim of this study was to assess health literacy (word recognition and comprehension) in patients at a rural rheumatology practice and to compare this to health literacy levels in patients from an urban rheumatology practice.Inclusion criteria for this cross-sectional study were as follows: ≥18-year-old patients at a rural rheumatology practice (Mid-North Coast Arthritis Clinic, Coffs Harbour, Australia) and an urban Sydney rheumatology practice (Combined Rheumatology Practice, Kogarah, Australia). Exclusion criteria were as follows: ill-health precluding participation; poor vision/hearing, non-English primary language. Word recognition was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). Comprehension was assessed using the Test of Functional Health Literacy in Adults (TOFHLA). Practical comprehension and numeracy were assessed by asking patients to follow prescribing instructions for 5 common rheumatology medications.At the rural practice (Mid-North Coast Arthritis Clinic), 124/160 patients agreed to participate (F:M 83:41, mean age 60.3 ± 12.2) whereas the corresponding number at the urban practice (Combined Rheumatology Practice) was 99/119 (F:M 69:30, mean age 60.7 ± 17.5). Urban patients were more likely to be born overseas, speak another language at home, and be employed. There was no difference in REALM or TOFHLA scores between the 2 sites, and so data were pooled. REALM scores indicated 15% (33/223) of patients had a reading level ≤Grade 8 whereas 8% (18/223) had marginal or inadequate functional health literacy as assessed by the TOFHLA. Dosing instructions for ibuprofen and methotrexate were incorrectly understood by 32% (72/223) and 21% (46/223) of patients, respectively.Up to 15% of rural and urban patients had low health literacy and <1/3 of patients incorrectly followed dosing instructions for common rheumatology drugs.There was no significant difference in word recognition, functional health literacy, and numeracy between rural and urban rheumatology patients.