Successful Implementation of Clinical Information Technology: Seven Key Lessons from CPOE.

OBJECTIVES: To identify and describe the most critical strategic and operational contributors to the successful implementation of clinical information technologies, as deployed within a moderate sized system of U.S. community hospitals. BACKGROUND AND SETTING: CHRISTUS Health is a multi-state system comprised of more than 350 services and 60 hospitals with over 9 000 physicians. The Santa Rosa region of CHRISTUS Health, located in greater San Antonio, Texas is comprised of three adult community hospital facilities and one Children's hospital each with bed capacities of 142-180. Computerized Patient Order Entry (CPOE) was first implemented in 2012 within a complex market environment. The Santa Rosa region has 2 417 credentialed physicians and 263 mid-level allied health professionals. METHODS: This report focuses on the seven most valuable strategies deployed by the Health Informatics team in a large four hospital CHRISTUS region to achieve strong CPOE adoption and critical success lessons learned. The findings are placed within the context of the literature describing best practices in health information technology implementation. RESULTS: While the elements described involved discrete de novo process generation to support implementation and operations, collectively they represent the creation of a new customer-centric service culture in our Health Informatics team, which has served as a foundation for ensuring strong clinical information technology adoption beyond CPOE. CONCLUSION: The seven success factors described are not limited in their value to and impact on CPOE adoption, but generalize to - and can advance success in - varied other clinical information technology implementations across diverse hospitals. A number of these factors are supported by reports in the literature of other institutions' successful implementations of CPOE and other clinical information technologies, and while not prescriptive to other settings, may be adapted to yield value elsewhere.

Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis.

Endometriosis is a benign, though aggressive, disease of the female reproductive tract that consists of endometrial stromal and epithelial cells growing at an extrauterine site. Although it is widely accepted that the majority of cases of endometriosis result from the ectopic implantation of refluxed menstrual tissue, the precise mechanisms by which this disease becomes established are not well understood. Matrix metalloproteinases (MMPs), enzymes which are important for extracellular matrix turnover, have recently been implicated in the development of endometriosis. MMPs appear to be overexpressed in endometriotic lesions, but expression levels decrease following successful medical therapy. Intriguingly, although transforming growth factor-beta (TGF-beta) mediates progesterone suppression of specific endometrial MMPs, this growth factor is overexpressed in women with endometriosis. In the current study, we used an established experimental model of endometriosis to explore MMP regulation by TGF-beta. Our findings indicate that blocking the action of TGF-beta opposes progesterone-mediated suppression of MMPs and blocks the ability of this steroid to prevent experimental endometriosis. However, we also show that the action of TGF-beta does not lead to a sustained suppression of MMPs as observed following progesterone treatment. Taken together, our data suggest that in the absence of a normal progesterone response, common in ectopic lesions of endometriosis, sensitivity to TGF-beta may be altered, resulting in a failure to regulate MMPs.

Propofol modulation of [3H]flunitrazepam binding to GABAA receptors in guinea pig cerebral cortex.

Binding of the radioligand [3H]flunitrazepam to membranes prepared from the cerebral cortex of adult, male guinea pigs under equilibrium and non-equilibrium conditions was used to investigate the allosteric interaction between the intravenous general anesthetic propofol and the benzodiazepine site of the GABAA receptor. Propofol induced a potentiation of [3H]flunitrazepam binding with an EC50 of 9+/-4 microM. Propofol increased the affinity for [3H]flunitrazepam binding with no change in maximal binding. Propofol did not change the rate constant of association for [3H]flunitrazepam binding to cerebral cortical membranes. In contrast, the rate constant for dissociation of [3H]flunitrazepam was significantly decreased in the presence of propofol. These data demonstrate that propofol increases the affinity of the benzodiazepine site of the GABAA receptor via a selective decrease in the rate constant for dissociation, and suggest a mechanism for the allosteric interaction between propofol and benzodiazepines at the GABAA receptor.

Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice.

Matrix metalloproteinases of the stromelysin family are expressed in the human endometrium as a consequence of cellular events during the menstrual cycle that require extracellular matrix remodeling. We have recently documented the presence of these enzymes in lesions of endometriosis, a benign disease that presents as persistent ectopic sites of endometrial tissue, usually within the peritoneal cavity. Endometriosis can develop after retrograde menstruation of endometrial tissue fragments, and establishment of ectopic sites within the peritoneal cavity requires breakdown of extracellular matrix. To examine whether matrix metalloproteinases might contribute to the steroid-dependent epidemiology and cellular pathophysiology of endometriosis, we have developed an experimental model of endometriosis using athymic nude mice as recipients of human endometrial tissue. Our results demonstrate that estrogen treatment of human endometrial tissue in organ culture maintains secretion of matrix metalloproteinases, and promotes establishment of ectopic peritoneal lesions when injected into recipient animals. In contrast, suppressing metalloproteinase secretion in vitro with progesterone treatment, or blocking enzyme activity with a natural inhibitor of metalloproteinases, inhibits the formation of ectopic lesions in this experimental model.

The unliganded mineralocorticoid receptor is associated with heat shock proteins 70 and 90 and the immunophilin FKBP-52.

The human mineralocorticoid receptor (MR) is a member of the steroid-thyroid hormone receptor superfamily, which includes receptors for retinoic acid, vitamin D, and other steroids, such as the glucocorticoids (which bind the glucocorticoid receptor, GR). MR and GR, the corticosteroid receptors, share significant homology and are activated by steroid binding, resulting in a conformational change, nuclear translocation, and DNA binding. Despite these similarities with GR, the MR remains less well characterized. However, protein components known to be present in the unliganded GR are also likely to be components of the heteromeric MR complex. In the current study, we investigated whether or not hsp70, hsp90, and the immunophilin FKBP-52 are present in the nonsteroid-bound MR complex, because these proteins are known to be present in the unliganded GR complex. The unliganded MR complex was assembled in vitro using reticulocyte lysate and in vivo using the baculovirus overexpression system and Spodoptera frugiperda (Sf9) cells. Western blot analysis revealed the presence of hsp70, hsp90, and FKBP-52 in the unliganded complexes, but hsp90 and FKBP-52 were not detected following exposure to aldosterone. Electrophoretic mobility shift analysis demonstrated that DNA binding of MR occurred only after treatment with aldosterone. These studies indicate that proteins associated with the unliganded GR are also present in the unliganded MR complex, and that hsp90 and FKBP-52 dissociate prior to DNA binding in a manner similar to that described for GR. Finally, the stoichiometric analysis of the proteins present within the heteromeric MR complex suggests a divergence between this receptor and the GR.

Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium.

Unlike most normal adult tissues, cyclic growth and tissue remodeling occur within the uterine endometrium throughout the reproductive years. The matrix metalloproteinases (MMPs), a family of structurally related enzymes that degrade specific components of the extracellular matrix are thought to be the physiologically relevant mediators of extracellular matrix composition and turnover. Our laboratory has identified MMPs of the stromelysin family in the cycling human endometrium, implicating these enzymes in mediating the extensive remodeling that occurs in this tissue. While the stromelysins are expressed in vivo during proliferation-associated remodeling and menstruation-associated endometrial breakdown, none of the stromelysins are expressed during the progesterone-dominated secretory phase of the cycle. Our in vitro studies of isolated cell types have confirmed progesterone suppression of stromal MMPs, but a stromal-derived paracrine factor was found necessary for suppression of the epithelial-specific MMP matrilysin. In this report, we demonstrate that transforming growth factor beta (TGF-beta) is produced by endometrial stroma in response to progesterone and can suppress expression of epithelial matrilysin independent of progesterone. Additionally, we find that an antibody directed against the mammalian isoforms of TGF-beta abolishes progesterone suppression of matrilysin in stromal-epithelial cocultures, implicating TGF-beta as the principal mediator of matrilysin suppression in the human endometrium.

Induction of mutations by replication of malondialdehyde-modified M13 DNA in Escherichia coli: determination of the extent of DNA modification, genetic requirements for mutagenesis, and types of mutations induced.

The mutagenicity of the lipid peroxidation product, malondialdehyde (MDA), was measured in the lacZ alpha forward mutation assay using a recombinant M13 phage, M13MB102. Single-stranded M13MB102 DNA was reacted with MDA at neutral pH and the modified DNA was transformed into strains of Escherichia coli induced for the SOS response. Increasing concentrations of MDA led to an increase in lacZ alpha-mutations coincident with an increase in the level of the major MDA-deoxyguanosine adduct. Spontaneous and MDA-induced M13MB102 mutants were collected and the lacZ alpha target region was subjected to automated DNA sequence analysis. The most common sequence changes induced by MDA were base-pair substitutions (76%). Of these, 43% (29/68) were transversions, most of which were G-->T (24/29). Transitions account for 57% of the base-pair substitutions (39/68) and were comprised exclusively of C-->T (22/39) and A-->G (17/39). Frameshift mutations were identified in 16% of the induced mutants and were comprised of mainly single base additions occurring in runs of reiterated bases (11/14). The diversity of base-pair substitution and frameshift mutations induced by MDA at low levels of adduction suggests it may be an important contributor to endogenous mutagenesis and carcinogenesis in aerobic organisms.

Assessment of the reproductive system of the male ruminant.

Physical examination requires very little equipment or expense and is an effective means of obtaining valuable information concerning fertility. Thorough evaluation of the reproductive system provides important information often unattainable by any other means. Disease processes, congenital abnormalities, injuries, management errors, and many other factors can be identified. No segment of the examination should be overlooked, as each part is important. The time invested in evaluating the male reproductive system is rewarded with a more complete and accurate assessment of the breeding male.

Ancillary tests for assessment of the reproductive system.

Ancillary tests applied to the male reproductive system include semen evaluation, ultrasonography, and testicular biopsy. Venereal disease testing and karyotyping are conducted on both male and female animals. The ancillary tests conducted on the female ruminant include culture, biopsy, cytology, and lavage; oviduct patency; and progesterone analysis. The application and interpretation of these tests as adjuncts to the physical examination of the reproductive system are discussed.

Mutation spectrum and sequence alkylation selectivity resulting from modification of bacteriophage M13mp18 DNA with S-(2-chloroethyl)glutathione. Evidence for a role of S-(2-N7-guanyl)ethyl)glutathione as a mutagenic lesion formed from ethylene dibromide.

The major DNA adduct (greater than 95% total) resulting from the bioactivation of ethylene dibromide by conjugation with GSH is S-(2-(N7-guanyl)ethyl)GSH. The mutagenic potential of this adduct has been uncertain, however, because the observed mutagenicity might be caused by other adducts present at much lower levels, e.g. S-(2-N1-adenyl)ethyl)GSH. To assess the formation of other potential adducts, S-(2-(N3-deoxycytidyl)ethyl)GSH, S-(2-(O6-deoxyguanosyl)ethyl)GSH, and S-(2-(N2-deoxyguanosyl)ethyl)GSH were prepared and used as standards in the analysis of calf thymus DNA modified by treatment with [1,2-14C]ethylene dibromide and GSH in the presence of rat liver cytosol; only minor amounts (less than 0.2%) were found. A forward mutation assay in (repair-deficient) Salmonella typhimurium TA100 and sequence analysis were utilized to determine the type, site, and frequency of mutations in a portion of the lacZ gene resulting from in vitro modification of bacteriophage M13mp18 DNA with S-(2-chloroethyl)GSH, an analog of the ethylene dibromide-GSH conjugate. An adduct level of approximately 8 nmol (mg DNA)-1 resulted in a 10-fold increase in mutation frequency relative to the spontaneous level. The spectrum of spontaneous mutations was quite varied, but the spectrum of S-(2-chloroethyl)GSH-induced mutations consisted primarily of base substitutions of which G:C to A:T transitions accounted for 75% (70% of the total mutations). All available evidence implicates S-(2-(N7-guanyl)ethyl)GSH as the cause of these mutations inasmuch as the levels of the minor adducts are not consistent with the mutation frequency observed in this system. The sequence selectivity of alkylation was determined by treatment of end-labeled lac DNA fragments with S-(2-chloroethyl)GSH, cleavage of the DNA at adduct sites, and electrophoretic analysis. Comparison of the sequence selectivity with the mutation spectrum revealed no obligate relationship between the extent of adduct formation and the number of mutations which resulted at different sites. We suggest that the mechanism of mutagenesis involves DNA sequence-dependent alterations in the interaction of the polymerase with the (modified) template and incoming nucleotide.

Neighboring nucleotide interactions during DNA sequencing gel electrophoresis.

Electrophoretic separation of oligonucleotides in denaturing polyacrylamide gels is primarily a function of length-dependent mobility. The 3' terminal nucleotide sequence of the oligonucleotide is a significant, secondary determinant of mobility and separation. Oligomers with 3'-ddT migrate more slowly than expected on the basis of length alone, and thus are better separated from the preceding, shorter oligomers in the sequencing ladder. Oligomers with 3'-ddC are relatively faster than expected, and are therefore less separated. At the 3' penultimate position, -dC- increases and -dT- reduces separation. Purines at the 3' terminal or penultimate positions of oligonucleotides affect separation less than the pyrimidines. These results suggest specific interactions among neighboring nucleotides with important effects on the conformation of oligonucleotides during electrophoresis. These interactions are compared to compression artifacts, which represent more extreme anomalies of length-dependent separation of oligonucleotides. Knowledge of base-specific effects on electrophoretic behavior of DNA oligomers supplements the usual information available for determination of sequences; additionally it provides an avenue to thermodynamic and hydrodynamic investigations of DNA structure.

The thymus as primary site for antigen-specific T suppressor cells in neonatally induced tolerance to bovine serum albumin.

The ontogeny of antigen-specific T suppressor cells in thymus and spleen was analyzed in CBA/Ca mice which were rendered tolerant as neonates by subimmunogenic doses of bovine serum albumin (low-zone tolerance). Activity of T suppressor cells from those mice was assessed by an assay in which spleen cells from animals primed with fluorescein-conjugated human gamma globulin can be stimulated in vitro to produce IgG anti-fluorescein antibodies when cultured in the presence of fluorescein-conjugated bovine serum albumin. Carrier-specific T suppressor cells appear first in the thymus (day 10), and much later (day 30) in the spleen. The data are discussed in connection with the possible role of T suppressor cells during induction of tolerance in newborn mice.

Evaluation of a pneumatic-tube system for delivery of blood specimens to the blood bank.

This study evaluated the suitability of delivering patient blood specimens to the blood bank by a hospital pneumatic-tube system. No significant discrepancies were found between duplicate pneumatic-tube and hand-carried specimens in ABO and Rh typing, Du and direct Coombs' testing, rouleaux formation, and antibody screening and identification. There were no significant differences in titers or scores of unexpected erythrocytic antibodies in duplicate pneumatic-tube and hand-carried specimens. No significant differences in antibody strength were detected between specimens from partially-filled and nearly full clot tubes delivered by pneumatic-tube. Our pneumatic-tube system may be safely used to transport patient blood specimens for routine type and crossmatch. Slight hemolysis in some pneumatic-tube specimens makes our pneumatic-tube system unsuitable for transporting blood specimens collected for evaluation of transfusion reactions.

An enzyme linked immunosorbent assay (ELISA) for detecting IgG sensitized erythrocytes.

This paper describes an Enzyme Linked Immunosorbent Assay (ELISA) for detecting IgG sensitized erythrocytes utilizing a commercially available anti-human IgG conjugated with alkaline phosphatase. Erythrocyte hemolysis in the assay was minimized by dissolving the p-nitrophenyl phosphate substrate in a carbonate-bicarbonate buffer. Nonspecific absorption of the enzyme conjugate to erythrocytes and glassware was reduced by adding 1% bovine serum albumin to wash solutions. Assay sensitivity was increased with greater concentrations of enzyme conjugate and erythrocytes in the incubation stage. The sensitivity of the described ELISA procedure is approximately equal to that of the standard antiglobulin test. Some possible future applications of ELISA in the blood bank are discussed.

Generation of cytotoxic T lymphocytes in vitro. VII. Suppressive effect of irradiated MLC cells on CTL response.

Irradiated cells obtained from MLC at the peak of the CTL response caused profound suppression of generation of CTL when added in small numbers at the initiation of primary MLC prepared with normal spleen cells. The inhibitory activity of the MLC cells was not affected by irradiation (1000 rads) but was abolished by treatment with anti-theta serum and complement. The suppression was immunologically specific. The response of A (H-2a) spleen cells toward C3H (H-2k) alloantigens was suppressed by irradiated MLC cells obtained from MLC prepared with A spleen cells and irradiated C3H-stimulating cells, whereas the response of A spleen cells toward DBA/2 (H-2d) alloantigens was affected relatively little. However, if irradiated C3H X DBA/2 F1 hybrid spleen cells were used to stimulate A spleen cells in MLC, addition of irradiated MLC cells having cytotoxic activity toward C3H antigens abolished the response to both C3H and DBA/2 antigens. The response to DBA/2 antigens was much less affected when a mixture of irradiated C3H and DBA/2 spleen cells was used as stimulating cells. Thus, the presence of MLC cells having cytotoxic activity toward one alloantigen abolished the response to another non-cross reacting antigen only when both antigens were present on the same F1 hybrid-stimulating cells. This suppression of generation of CTL by irradiated MLC cells apparently involves inactivation of alloantigen-bearing stimulating cells as a result of residual cytotoxic activity of the irradiated MLC cells. This mechanism may be active during the decline in CTL activity noted in the normal immune response in vivo and in vitro.