A critical assessment of the National Institutes of Health Consensus Development Program against the eras which shaped it

This research study offers a critical assessment of NIH's Consensus Development Program (CDP), focusing upon its historical and valuative bases and its institutionalization in response to social and political forces. The analysis encompasses systems-level, as well as interpersonal factors in the adoption of consensus as the mechanism for resolving scientific controversies in clinical practice application. Further, the evolution of the CDP is also considered from an ecological perspective as a reasoned adaptation by NIH to pressures from its supporters and clients for translating biomedical research into medical practice. The assessment examines federal science policy and institutional designs for the inclusion of the public interest and democratic deliberation.^ The study relies on three distinct approaches to social research. Conventional historical methods were utilized in the interpretation of social and political influences across eras on the evolution of the National Institutes of Health and its response to demands for accountability and relevance through its Consensus Development Program. An embedded single-case study was utilized for an empirical examination of the CDP mechanism through five exemplar conferences. Lastly, a sociohistorical approach was taken to the CDP in order to consider its responsiveness to the values of the eras which created and shaped it. An exploration of organizational behavior with considerations for institutional reform as a response to continuing political and social pressure, it is a study of organizational birth, growth, and response to demands from its environment. The study has explanatory import in its attempt to account for the creation, timing, and form of the CDP, relative to political, institutional, and cultural pressures, and predictive import thorough its historical view which provides a basis for informed speculation on the playing out of tensions between extramural and intermural scientists and the current demands for health care reform. ^

Errors in the administration of medication in inpatient hospitals: A systematic review of the research literature on commercial computerized physician order entry systems

Errors in the administration of medication represent a significant loss of medical resources and pose life altering or life threatening risks to patients. This paper considered the question, what impact do Computerized Physician Order Entry (CPOE) systems have on medication errors in the hospital inpatient environment? Previous reviews have examined evidence of the impact of CPOE on medication errors, but have come to ambiguous conclusions as to the impact of CPOE and decision support systems (DSS). Forty-three papers were identified. Thirty-one demonstrated a significant reduction in prescribing error rates for all or some drug types; decreases in minor errors were most often reported. Several studies reported increases in the rate of duplicate orders and failures to remove contraindicated drugs, often attributed to inappropriate design or to an inability to operate the system properly. The evidence on the effectiveness of CPOE to reduce errors in medication administration is compelling though it is limited by modest study sample sizes and designs. ^

Understanding and Characterizing Shared Decision-Making and Behavioral Intent in Medical Uncertainty

Applying Theoretical Constructs to Address Medical Uncertainty Situations involving medical reasoning usually include some level of medical uncertainty. Despite the identification of shared decision-making (SDM) as an effective technique, it has been observed that the likelihood of physicians and patients engaging in shared decision making is lower in those situations where it is most needed; specifically in circumstances of medical uncertainty. Having identified shared decision making as an effective, yet often a neglected approach to resolving a lack of information exchange in situations involving medical uncertainty, the next step is to determine the way(s) in which SDM can be integrated and the supplemental processes that may facilitate its integration. SDM involves unique types of communication and relationships between patients and physicians. Therefore, it is necessary to further understand and incorporate human behavioral elements - in particular, behavioral intent - in order to successfully identify and realize the potential benefits of SDM. This paper discusses the background and potential interaction between the theories of shared decision-making, medical uncertainty, and behavioral intent. Identifying Shared Decision-Making Elements in Medical Encounters Dealing with Uncertainty A recent summary of the state of medical knowledge in the U.S. reported that nearly half (47%) of all treatments were of unknown effectiveness, and an additional 7% involved an uncertain tradeoff between benefits and harms. Shared decision-making (SDM) was identified as an effective technique for managing uncertainty when two or more parties were involved. In order to understand which of the elements of SDM are used most frequently and effectively, it is necessary to identify these key elements, and understand how these elements related to each other and the SDM process. The elements identified through the course of the present research were selected from basic principles of the SDM model and the “Data, Information, Knowledge, Wisdom” (DIKW) Hierarchy. The goal of this ethnographic research was to identify which common elements of shared decision-making patients are most often observed applying in the medical encounter. The results of the present study facilitated the understanding of which elements patients were more likely to exhibit during a primary care medical encounter, as well as determining variables of interest leading to more successful shared decision-making practices between patients and their physicians. Understanding Behavioral Intent to Participate in Shared Decision-Making in Medically Uncertain Situations Objective: This article describes the process undertaken to identify and validate behavioral and normative beliefs and behavioral intent of men between the ages of 45-70 with regard to participating in shared decision-making in medically uncertain situations. This article also discusses the preliminary results of the aforementioned processes and explores potential future uses of this information which may facilitate greater understanding, efficiency and effectiveness of doctor-patient consultations.Design: Qualitative Study using deductive content analysisSetting: Individual semi-structure patient interviews were conducted until data saturation was reached. Researchers read the transcripts and developed a list of codes.Subjects: 25 subjects drawn from the Philadelphia community.Measurements: Qualitative indicators were developed to measure respondents’ experiences and beliefs related to behavioral intent to participate in shared decision-making during medical uncertainty. Subjects were also asked to complete the Krantz Health Opinion Survey as a method of triangulation.Results: Several factors were repeatedly described by respondents as being essential to participate in shared decision-making in medical uncertainty. These factors included past experience with medical uncertainty, an individual’s personality, and the relationship between the patient and his physician.Conclusions: The findings of this study led to the development of a category framework that helped understand an individual’s needs and motivational factors in their intent to participate in shared decision-making. The three main categories include 1) an individual’s representation of medically uncertainty, 2) how the individual copes with medical uncertainty, and 3) the individual’s behavioral intent to seek information and participate in shared decision-making during times of medically uncertain situations.

Structure and biosynthesis of a pyruvate -dependent enzyme---phosphatidylserine decarboxylase from {\it Escherichia coli\/}

Phosphatidylserine decarboxylase of E. coli, a cytoplasmic membrane protein, catalyzes the formation of phosphatidylethanolamine, the principal phospholipid of the organism. The activity of the enzyme is dependent on a covalently bound pyruvate (Satre and Kennedy (1978) J. Biol. Chem. 253, 479-483). This study shows that the enzyme consists of two nonidentical subunits, $\alpha$ (Mr = 7,332) and $\beta$ (Mr = 28,579), with the pyruvate prosthetic group in amide linkage to the amino-terminus of the $\alpha$ subunit. Partial protein sequence and DNA sequence analysis reveal that the two subunits are derived from a proenzyme ($\pi$ subunit, Mr = 35,893) through a post-translational event. During the conversion of the proenzyme to the $\alpha$ and $\beta$ subunits, the peptide bond between Gly253-Ser254 is cleaved, and Ser254 is converted to the pyruvate prosthetic group at the amino-terminus of the $\alpha$ subunit (Li and Dowhan (1988) J. Biol. Chem. 263, 11516-11522).^ The proenzyme cannot be detected in cells carrying either single or multiple copies of the gene (psd), but can be observed in a T7 RNA polymerase/promoter and transcription-translation system. The cleavage of the wild-type proenzyme occurs rapidly with a half-time on the order of 2 min. Changing of the Ser254 to cysteine (S254C) or threonine (S254T) slows the cleavage rate dramatically and results in mutants with a half-time for processing of around 2-4 h. Change of the Ser254 to alanine (S254A) blocks the cleavage of the proenzyme. The reduced processing rate with the mutations of the proenzyme is consistent with less of the functional enzyme being made. Mutants S254C and S254T produce $\sim$15% and $\sim$1%, respectively, of the activity of the wild-type allele, but can still complement a temperature-sensitive mutant of the psd locus. Neither detectable activity nor complementation is observed by mutant S254A. These results are consistent with the hydroxyl-group of the Ser254 playing a critical role in the cleavage of the peptide bond Gly253-Ser254 of the pro-phosphatidylserine decarboxylase, and support the mechanism proposed by Snell and co-workers (Recsei and Snell (1984) Annu. Rev. Biochem. 53, 357-387) for the formation of the prosthetic group of pyruvate-dependent decarboxylases. ^

Molecular analysis of a neurovirulent murine leukemia virus, {\it ts\/}1

ts1 is a neurovirulent spontaneous temperature-sensitive mutant of Moloney murine leukemia virus TB (MoMuLV-TB). MoMuLV-TB causes T-cell lymphoma or lymphoid leukemia in mice after a long latency period whereas ts1 causes a progressive hindlimb paralytic disease after a much shorter latency period. In previous studies, it had been shown that the temperature-sensitive defect resided in the $env$ gene. At the restrictive temperature, the envelope precursor polyprotein, gPr80$\sp{env}$, is inefficiently processed intracellularly into a heterodimer consisting of two cleavage products, gp70 and Prp15E. This inefficient processing is correlated with neurovirulence. In this study, the nucleotide sequences of the env genes for both ts1 and MoMuLV-TB were determined, and the encoded amino acid sequences were deduced from the DNA sequences. There were four unique amino acid substitutions in the gPr80$\sp{env}$ of ts1. In order to determine which unique amino acid was responsible for the phenotypic characteristics of ts1, a set of hybrid genomes was constructed by exchanging restriction fragments between ts1 and MoMuLV-TB. NIH 3T3 cells were transfected with the hybrid genomes to obtain infectious hybrid viruses. Assays of the hybrid viruses showed that a Val-25$\to$Ile substitution in gPr80$\sp{env}$ was responsible for the temperature sensitivity, inefficient processing, and neurovirulence of ts1. In further studies, the Ile-25 in gPr80$\sp{env}$ was substituted with Thr, Ala, Leu, Gly, and Glu by site-directed mutagenesis to generate a new set of mutant viruses, i.e., ts1-T, -A, -L, -G, and -E, respectively. The rank order of the mutants for temperature sensitivity was: ts1-E $>$ ts1-G $>$ ts1-L $>$ ts1-A $>$ ts1 $>$ ts1-T. The degree of temperature sensitivity of each of the mutants also correlated with the degree of inefficient processing of gPr80$\sp{env}$. The mutant viruses were assayed for neurovirulence. ts1-T caused whole body tremor, ts1-A caused hindlimb paralysis, ts1-L caused paraparesis, but ts1-G and -E were not neurovirulent. These results show that inefficient processing of gPr80$\sp{env}$ is correlated with neurovirulence, but if processing of gPr80$\sp{env}$ is too inefficient there is no neurovirulence. Furthermore, the disease profile of each of the neurovirulent viruses depends on the degree of inefficient processing of gPr80$\sp{env}$. ^

The p53 tumor suppressor pathway in culture and {\it in vivo\/}

p53 functions as a tumor suppressor through its ability to initiate either growth arrest or apoptosis in cells which have sustained DNA damage. p53 elicits these cellular phenotypes through its biochemical function as a transcriptional activator. By inducing the expression of a battery of target genes, p53 is able to prevent the propagation of cells with damaged DNA. However, the genes transcriptionally induced by p53 which have been identified to date do not fully explain p53 function. p53 has been demonstrated to activate genes involved in cell cycle inhibition, apoptosis and cell proliferation. The reasons for simultaneous activation of p53 targets with disparate, opposing functions are not clear, but may be due to the use of transformed cell lines in previous experiments. In the studies presented in this thesis, the pathway of p53 tumor suppression has been studied in detail in two systems chosen for their relevance to the natural cell environment. One utilizes a normal, unaltered cultured cell system; the other the whole mouse. In order to better understand the role of the known p53 targets in effecting p53 function in normal cells, early rat embryo fibroblasts were irradiated with ultraviolet light to induce DNA damage. It was discovered that p53 protein levels increased in response to irradiation. The known targets of p53, namely, $p21\sp{WAF1/CIP1},\ mdm2,\ cyclin\ G,$ and bax, were shown for the first time to have a differential temporal induction. The growth suppressor $p21\sp{WAF1/CIP1}$ was induced first, followed by cyclin G then mdm2, which is involved in proliferation through its inactivation of p53, and finally, the apoptosis promoter, bax. These findings indicated that p53 activates its target genes in a manner to allow maximum effectiveness of target function. The rat embryo fibroblasts were shown to undergo apoptosis 24 h after irradiation. Additionally, investigation of these cells for cell cycle alterations demonstrated a brief arrest in G1. In the second study, thymocytes from mice with wild type p53 were shown to undergo apoptosis and activate p53 target genes upon ionizing radiation treatment, while thymocytes from mice deficient in p53 could not. The p53 target genes mdm2 and fas were tested in vivo for their ability to mediate p53-regulated apoptosis, and were found dispensible for that cellular function. Therefore, the p53 targets identified to date do not fully explain the ability of p53 to function as a tumor suppressor. Potentially, functional redundancy between the known targets would account for the data seen in these experiments. Additionally, identification of additional target genes should add further understanding of the p53 pathway of tumor suppression. ^

Cyclin D1 mediates epithelial proliferation and links {\it ras\/} activation to the cell cycle

The studies presented in this thesis focus on two aspects of the involvement of cyclin D1 in epithelial proliferation. Since cyclin D1 has been identified as a target for genetic alterations and deregulation in a variety of human cancers, we studied cyclin D1 expression in two experimental models of epithelial carcinogenesis. These studies provided evidence that cyclin D1 was a potential target of the activating mutation of the Ha-ras gene characteristic of the experimental protocol. In addition, evidence from two independent in vitro models suggested that cyclin D1 was indeed part of the primary cellular response to activated ras, and at least partly responsible for the increase in proliferation observed in ras-transformed cells.^ Cyclin D1 has also been described as a key regulator of the passage through the G1 phase of the cell cycle. Cyclin D1 is induced in response to mitogens in a variety of cell lines, and cells engineered to overexpress cyclin D1 show accelerated G1 transit. In order to study the involvement of cyclin D1 in epithelial cell growth and differentiation, we generated transgenic mice that constitutively overexpress cyclin D1 in stratified epithelia. These mice developed thymic hyperplasia and skin hyperproliferation, providing in vivo evidence of the potential of cyclin D1 to regulate growth of epithelial cells. ^

Neocortical hyperexcitability defect in a mutant mouse model of spike-wave epilepsy, {\it stargazer}

Single-locus mutations in mice can express epileptic phenotypes and provide critical insights into the naturally occurring defects that alter excitability and mediate synchronization in the central nervous system (CNS). One such recessive mutation (on chromosome (Chr) 15), stargazer(stg/stg) expresses frequent bilateral 6-7 cycles per second (c/sec) spike-wave seizures associated with behavioral arrest, and provides a valuable opportunity to examine the inherited lesion associated with spike-wave synchronization.^ The existence of distinct and heterogeneous defects mediating spike-wave discharge (SWD) generation has been demonstrated by the presence of multiple genetic loci expressing generalized spike-wave activity and the differential effects of pharmacological agents on SWDs in different spike-wave epilepsy models. Attempts at understanding the different basic mechanisms underlying spike-wave synchronization have focused on $\gamma$-aminobutyric acid (GABA) receptor-, low threshold T-type Ca$\sp{2+}$ channel-, and N-methyl-D-aspartate receptor (NMDA-R)-mediated transmission. It is believed that defects in these modes of transmission can mediate the conversion of normal oscillations in a trisynaptic circuit, which includes the neocortex, reticular nucleus and thalamus, into spike-wave activity. However, the underlying lesions involved in spike-wave synchronization have not been clearly identified.^ The purpose of this research project was to locate and characterize a distinct neuronal hyperexcitability defect favoring spike-wave synchronization in the stargazer brain. One experimental approach for anatomically locating areas of synchronization and hyperexcitability involved an attempt to map patterns of hypersynchronous activity with antibodies to activity-induced proteins.^ A second approach to characterizing the neuronal defect involved examining the neuronal responses in the mutant following application of pharmacological agents with well known sites of action.^ In order to test the hypothesis that an NMDA receptor mediated hyperexcitability defect exists in stargazer neocortex, extracellular field recordings were used to examine the effects of CPP and MK-801 on coronal neocortical brain slices of stargazer and wild type perfused with 0 Mg$\sp{2+}$ artificial cerebral spinal fluid (aCSF).^ To study how NMDA receptor antagonists might promote increased excitability in stargazer neocortex, two basic hypotheses were tested: (1) NMDA receptor antagonists directly activate deep layer principal pyramidal cells in the neocortex of stargazer, presumably by opening NMDA receptor channels altered by the stg mutation; and (2) NMDA receptor antagonists disinhibit the neocortical network by blocking recurrent excitatory synaptic inputs onto inhibitory interneurons in the deep layers of stargazer neocortex.^ In order to test whether CPP might disinhibit the 0 Mg$\sp{2+}$ bursting network in the mutant by acting on inhibitory interneurons, the inhibitory inputs were pharmacologically removed by application of GABA receptor antagonists to the cortical network, and the effects of CPP under 0 Mg$\sp{2+}$aCSF perfusion in layer V of stg/stg were then compared with those found in +/+ neocortex using in vitro extracellular field recordings. (Abstract shortened by UMI.) ^