Harnessing experience: exploring the gap between evidence-based medicine and clinical practice.

RATIONALE, AIMS AND OBJECTIVES: There is mounting evidence of a gap between Evidence-based Medicine (EBM) and physician clinical practice, in part because EBM is averaged global evidence gathered from exogenous populations which may not be relevant to local circumstances. Local endogenous evidence, collected in particular and 'real world' patient populations may be more relevant, convincing and timely for clinical practice. Evidence Farming (EF) is a concept to provide such local evidence through the systematic collection of clinical experience to guide more effective practice. METHODS: We report on the findings of a pilot study of 29 individual and three focus group (n = 10) interviews exploring physicians' evaluations how they use multiple sources of information in clinical decision making and their thoughts on EF. RESULTS: Physicians recognize a gap in translating EBM to practice. Physicians reported that when making clinical decisions, they more often rely on clinical experience, the opinions of colleagues and EBM summarizing electronic clinical resources rather than refer directly to EBM literature. Confidence in making decisions based on clinical experience increases over time, yet few physicians reported having systems for tracking their clinical experience in designing treatment plans and patient outcomes. Most physicians saw EF as a promising way to track experience, thereby making scientific evidence more relevant to their own clinical practices. CONCLUSION: Clinical experience is relatively neglected by the EBM movement, but if that experience were systematically gathered through an approach such as EF, it would meet a need left unfulfilled by EBM.

What ever happened to N-of-1 trials? Insiders' perspectives and a look to the future.

CONTEXT: When feasible, randomized, blinded single-patient (n-of-1) trials are uniquely capable of establishing the best treatment in an individual patient. Despite early enthusiasm, by the turn of the twenty-first century, few academic centers were conducting n-of-1 trials on a regular basis. METHODS: The authors reviewed the literature and conducted in-depth telephone interviews with leaders in the n-of-1 trial movement. FINDINGS: N-of-1 trials can improve care by increasing therapeutic precision. However, they have not been widely adopted, in part because physicians do not sufficiently value the reduction in uncertainty they yield weighed against the inconvenience they impose. Limited evidence suggests that patients may be receptive to n-of-1 trials once they understand the benefits. CONCLUSIONS: N-of-1 trials offer a unique opportunity to individualize clinical care and enrich clinical research. While ongoing changes in drug discovery, manufacture, and marketing may ultimately spur pharmaceutical makers and health care payers to support n-of-1 trials, at present the most promising resuscitation strategy is stripping n-of-1 trials to their essentials and marketing them directly to patients. In order to optimize statistical inference from these trials, empirical Bayes methods can be used to combine individual patient data with aggregate data from comparable patients.

Zinc enhancement of nonviral salivary gland transfection.

Gene transfer to exocrine glands, including the major salivary glands, presents an attractive method to deliver proteins for therapeutic applications. Previous efforts using nonviral gene delivery to these glands have resulted in limited success. In this report, zinc and other divalent transitions were coadministered with plasmid DNA in an effort to improve nonviral salivary gland transfection efficiency. The inclusion of zinc into plasmid DNA solutions resulted in a 20-fold enhancement in transgene expression without noticeable inflammation compared to a solution of plasmid DNA only. This observed enhancement in transgene expression was dependent upon the DNA dose and correlated with the accumulation of plasmid DNA by salivary gland tissues.

Synthesis and estrogen receptor affinity of a 4-hydroxytamoxifen-labeled ligand for diagnostic imaging.

A 10-step synthesis of a novel 4-hydroxytamoxifen-DTPA ligand (HOTam-DTPA) is reported. Tamoxifen and its primary metabolite 4-hydroxytamoxifen are common estrogen receptor ligands. Consequently, tamoxifen has found utility as the targeting component of various diagnostic agents for selective imaging of estrogen receptor-rich tissue, specifically breast cancer. An L-aspartic acid-derived DTPA analogue was attached to the ethyl side chain of 4-hydroxy-tamoxifen using N,N'-dimethylethylenediamine as a hydrophilic linker. A competitve estrogen receptor binding assay using [3H]-17beta-estradiol was performed to determine the effect of the ethyl side chain modification on estrogen receptor affinity. The results show that while the relative affinity of HOTam-DTPA for the estrogen receptor is approximately 10-fold lower than that of tamoxifen, it still remains a potent ligand at relatively low concentrations.

A versatile linker for nontoxic polyamine-mediated DNA transfection.

Low levels of transfection efficacy and lipid-associated cytotoxicity have complicated the use of cationic lipids to facilitate transfer of exogenous DNA to eukaryotic cells. To address these issues, we synthesized a panel of six tetraester polyamines that were designed to minimize cytotoxicity by using pentaerythritol to link the hydrophobic and the DNA-binding domains. We conducted this study to probe the effects of structural modifications around pentaerythritol as a linker on transfection activity and cell viability. We compared polyamines against commercial lipid reagents using luciferase and green fluorescent protein transfection assays in both CHO and NIH3T3 cells. Measurement of transfection activity and cytotoxicity using flow cytometry showed that the more active polyamine analogs exhibited activities comparable to LipofectAMINE PLUS and TransFast. Flow cytometry analyses revealed that all the pentaerythritol-based polyamines were uniformly nontoxic, whereas transfection activity was dependent on headgroup and sidechain composition. These results demonstrate that pentaerythritol is a useful core material for the development of active, nontoxic transfection agents.