Trimethoprim‐Sulfamethoxazole Activity and Pharmacodynamics against Glycopeptide‐Intermediate Staphylococcus aureus

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90392/1/phco.22.12.983.33599.pd

Work‐Related Outcomes After a Myocardial Infarction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90385/1/phco.24.16.1515.50946.pd

Health‐Related Quality of Life in Patients 7 Months After a Myocardial Infarction: Factors Affecting the Short Form‐12

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90293/1/phco.22.17.1616.34121.pd

Validation of Electronic Data Capture of the Irritable Bowel Syndrome—Quality of Life Measure, the Work Productivity and Activity Impairment Questionnaire for Irritable Bowel Syndrome and the EuroQol

ABSTRACTObjectivesTo assess the comparability, reliability, and subject acceptability of electronic data capture (EDC) versions of Irritable Bowel Syndrome—Quality of Life (IBS-QOL), EuroQoL (EQ-5D) and Work Productivity and Activity Impairment (WPAI:IBS) instruments.MethodsComparability of EDC and paper questionnaires was evaluated in 72 subjects with IBS who completed a baseline EDC or paper questionnaire, a crossover questionnaire 24 hours later, and a retest of the crossover version at 1 week. The EDC version was presented on a hand-held device. Comparability was assessed using paired t-test statistics, intraclass correlation coefficients (ICC) and tests for internal consistency (Cronbach's alpha).ResultsNo significant differences were found between scores obtained by paper questionnaire and EDC at the baseline and crossover assessments. ICCs between baseline and crossover assessments ranged from 0.83 to 0.96 for the IBS-QOL scores, 0.82 to 0.96 for the WPAI:IBS scores, and 0.77 to 0.82 for the EQ-5D. Internal consistency was comparable for the two data collection methods for the IBS-QOL overall score (0.96) and subscales and the EQ-5D Index (0.70 vs. 0.74). Retest statistics (ICC) were generally comparable between the EDC and paper versions for all scores. Ease of use was comparable for the two modes of administration, but more patients preferred EDC (47.2%) than the paper questionnaire (23.6%).ConclusionsEDC versions of the IBS-QOL, EQ-5D, and WPAI:IBS are comparable to paper questionnaires in internal consistency and test–retest reliability, and have greater patient acceptability

Deep sequencing analysis of the developing mouse brain reveals a novel microRNA

Extent: 15p.Background: MicroRNAs (miRNAs) are small non-coding RNAs that can exert multilevel inhibition/repression at a post-transcriptional or protein synthesis level during disease or development. Characterisation of miRNAs in adult mammalian brains by deep sequencing has been reported previously. However, to date, no small RNA profiling of the developing brain has been undertaken using this method. We have performed deep sequencing and small RNA analysis of a developing (E15.5) mouse brain. Results: We identified the expression of 294 known miRNAs in the E15.5 developing mouse brain, which were mostly represented by let-7 family and other brain-specific miRNAs such as miR-9 and miR-124. We also discovered 4 putative 22-23 nt miRNAs: mm_br_e15_1181, mm_br_e15_279920, mm_br_e15_96719 and mm_br_e15_294354 each with a 70-76 nt predicted pre-miRNA. We validated the 4 putative miRNAs and further characterised one of them, mm_br_e15_1181, throughout embryogenesis. Mm_br_e15_1181 biogenesis was Dicer1-dependent and was expressed in E3.5 blastocysts and E7 whole embryos. Embryo-wide expression patterns were observed at E9.5 and E11.5 followed by a near complete loss of expression by E13.5, with expression restricted to a specialised layer of cells within the developing and early postnatal brain. Mm_br_e15_1181 was upregulated during neurodifferentiation of P19 teratocarcinoma cells. This novel miRNA has been identified as miR-3099. Conclusions: We have generated and analysed the first deep sequencing dataset of small RNA sequences of the developing mouse brain. The analysis revealed a novel miRNA, miR-3099, with potential regulatory effects on early embryogenesis, and involvement in neuronal cell differentiation/function in the brain during late embryonic and early neonatal development.King-Hwa Ling, Peter J Brautigan, Christopher N Hahn, Tasman Daish, John R Rayner, Pike-See Cheah, Joy M Raison, Sandra Piltz Jeffrey R Mann, Deidre M Mattiske, Paul Q Thomas, David L Adelson and Hamish S Scot

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

AN ANALYSIS OF THE COST OF ADVERSE EVENTS ASSOCIATED WITH THE USE OF HMG-COA REDUCTASE INHIBITORS

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72431/1/j.1524-4733.2001.40202-77.x.pd

Economic Considerations in the Prescribing of Third-Generation Antidepressants

A comprehensive, multinational literature search was conducted of all articles published from 1993 to 2003 regarding the cost effectiveness of antidepressant drugs, with special emphasis on comparing third-generation antidepressants (TGAs) with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Information from the collected articles was entered into a database and then analysed to assess the different approaches to cost effectiveness comparisons for the various classes of antidepressants. Factors examined included direct and indirect costs, treatment endpoints, healthcare cost burden and productivity gains for patients successfully treated for depression. Most model-based studies published between 1993 and 2003 supported the cost effectiveness of TGAs compared with TCAs or SSRIs. While the purchase price of TGAs may be greater, cost savings in terms of direct and indirect costs were realised because of the reduced adverse effects of TGAs and subsequent improved patient compliance. Studies based on patient level cost data, however, were less conclusive about the economic benefits of TGAs compared with SSRIs or TCAs. While it may be premature to conclude that TGAs have a significant net economic benefit compared with other antidepressant classes, prescribers and payers may find it helpful when choosing antidepressants for depressed patients to consider that the higher drug prices for TGAs may be offset by savings, in terms of their greater compliance and resultant therapeutic success rates compared with TCAs or SSRIs. Additional research is needed to clarify how cost effectiveness is assessed in different patient populations, such as geriatric patients - who commonly have more co-morbidities and higher total healthcare costs than other patient populations.Antidepressants, Cost-effectiveness, Depression, Mirtazapine, Nefazodone, Reboxetine, Venlafaxine

Economic Evaluation of Rivastigmine in Patients with Parkinson's Disease Dementia

Background: The positive results of a randomised clinical trial of rivastigmine in patients with dementia associated with Parkinson's disease have been published recently. Patient-level healthcare utilisation data were also collected, and this report is the economic evaluation based on these data. Objective: To determine the cost effectiveness of rivastigmine 3-12 mg/day in patients in whom mild to moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease. Methods: A cost-effectiveness analysis was performed by applying Canadian and UK cost weights (year 2004 values) to healthcare utilisation data collected prospectively during a randomised, double-blind, multinational, 24-week trial of rivastigmine 3-12 mg/day (n = 362) versus placebo (n = 179). Patients were >=50 years of age, had a Mini-Mental State Examination (MMSE) score of between 20 and 24 and had contact with a responsible caregiver at least 3 days a week. Quality-adjusted survival time, transformed from MMSE scores, was the measure of effectiveness. Caregiver costs included paid and unpaid time, and direct costs included concomitant medications, outpatient care, hospitalisations, long-term care and study medications. Analysis was conducted from a societal perspective with a time horizon of 24 weeks. Results: Consistent with the improvement in clinical outcomes, there was an observed increase in quality-adjusted survival time in the rivastigmine arm of 2.81 quality-adjusted life-days (two-sided p-value 0.13 [90% CI -0.243, 5.86]). Using Canadian price weights, there was an observed increase in cost in the rivastigmine arm of $Can55.76 (two-sided p-value 0.98 [90$Can7429 per QALY. Using UK price weights, there was an observed decrease in cost in the rivastigmine arm of Lstg 26.18 (two-sided p-value 0.99 [90% CI -2407, 2355]). Conclusion: Although no between-treatment differences in cost were seen, the small sample size, highly variable cost distributions and short time horizon prevent us from making strong conclusions with regard to the effect of rivastigmine on total costs and, by inference, on cost effectiveness.Cost-utility, Dementia, Parkinson's-disease, Rivastigmine