An Observational Cohort Study to Evaluate the Impact of a Tailored Medicines Optimisation Service on Medication Use, Accident and Emergency Department Visits, and Admissions Among Patients Identified with Medication Support Needs in Secondary Care.

Purpose: Quantifying the impact of pharmacy interventions, such as tailored medicines optimisation, can be challenging owing to the sometimes-indirect nature of their effect on patient outcomes such A&E (Accident & Emergency) attendance, hospital admission and length of stay. This study aimed to assess the impact of the, Lewisham Integrated Medicines Optimisation Service (LIMOS) on medicines self-management, A&E attendances and hospital admissions. Patients and Methods: The study was conducted as a retrospective and prospective observational evaluation of patients referred to LIMOS at University Hospital Lewisham between April and September 2016. Only patients with an appropriate referral that received a LIMOS intervention within the study period were considered eligible. The main outcomes examined pre- and post-LIMOS included medicines self-management, A&E attendance, number of admissions, as well as length of stay. Results: Data were collected for a total of 193 patients. Over half (56.4%, n = 109) identified as female with a mean age of 78 years at the time of referral. The number of hospital admissions decreased significantly post-LIMOS (-0.36 ± 1.87, 95% CI -0.63-0.10). Furthermore, the mean reduction in length of stay was significant and decreased by over a week (19.58 vs 11.09 days post-LIMOS, -7.67 ± 48.57, 95% CI -14.57--0.78). There was a significant increase in A&E visits observed post-intervention (0.78 ± 1.93, 95% CI 0.50-1.06); however, the majority (63%, n =165/261) occurred over 90 days post-intervention. There was a significant reduction in the number of patients self-managing medication post-LIMOS, with the number of patients receiving additional support with their medication increasing (-0.38 ± 0.50, 95% CI -0.45--0.31). LIMOS, therefore, successfully identified patients who were unable to manage their medicines. Conclusion: Specialist pharmacy interventions, which include support with medicines management, have a positive impact on admission avoidance and length of hospital stay.

Isogenic human cell lines for drug discovery: regulation of target gene expression by engineered zinc-finger protein transcription factors.

Isogenic cell lines differing only in the expression of the protein of interest provide the ideal platform for cell-based screening. However, related natural lines differentially expressing the therapeutic target of choice are rare. Here the authors report a strategy for drug screening employing isogenic human cell lines in which the expression of the target protein is regulated by a gene-specific engineered zinc-finger protein (ZFP) transcription factor (TF). To demonstrate this approach, a ZFP TF activator of the human parathyroid hormone receptor 1 (PTHR1) gene was identified and introduced into HEK293 cells (negative for PTHR1). Following induction of ZFP TF expression, this cell line produced functional PTHR1 protein, resulting in a robust and ligand-specific cyclic adenosine monophosphate (cAMP) response. Reciprocally, the natural expression of PTHR1 observed in SAOS2 cells was dramatically reduced by the introduction of the appropriate PTHR1-specific ZFP TF repressor. Moreover, this ZFP-driven PTHR1 repression selectively eliminated the functional cAMP response invoked by known ligands of PTHR1. These data establish ZFP TF-generated isogenic lines as a general approach for the identification of therapeutic agents specific for the target gene of interest.

Zinc-finger protein-targeted gene regulation: genomewide single-gene specificity.

Zinc-finger protein transcription factors (ZFP TFs) can be designed to control the expression of any desired target gene, and thus provide potential therapeutic tools for the study and treatment of disease. Here we report that a ZFP TF can repress target gene expression with single-gene specificity within the human genome. A ZFP TF repressor that binds an 18-bp recognition sequence within the promoter of the endogenous CHK2 gene gives a >10-fold reduction in CHK2 mRNA and protein. This level of repression was sufficient to generate a functional phenotype, as demonstrated by the loss of DNA damage-induced CHK2-dependent p53 phosphorylation. We determined the specificity of repression by using DNA microarrays and found that the ZFP TF repressed a single gene (CHK2) within the monitored genome in two different cell types. These data demonstrate the utility of ZFP TFs as precise tools for target validation, and highlight their potential as clinical therapeutics.