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1.  Rapid Assessment of Clinical Information Systems in the Healthcare Setting: An Efficient Method for Time-Pressed Evaluation 
Summary
Objective
Recent legislation in the United States provides strong incentives for implementation of electronic health records (EHRs). The ensuing transformation in U.S. health care, will increase demand for new methods to evaluate clinical informatics interventions. Timeline constraints and a rapidly changing environment will make traditional evaluation techniques burdensome. This paper describes an anthropological approach that provides a fast and flexible way to evaluate clinical information systems.
Methods
Adapting mixed-method evaluation approaches from anthropology, we describe a rapid assessment process (RAP) for assessing clinical informatics interventions in health care that we developed and used during seven site visits to diverse community hospitals and primary care settings in the United States..
Setting
Our multi-disciplinary team used RAP to evaluate factors that either encouraged people to use clinical decision support (CDS) systems, or interfered with use of these systems in settings ranging from large urban hospitals to single-practitioner, private family practices in small towns.
Results
Critical elements of the method include: 1) developing a fieldwork guide; 2) carefully selecting observation sites and participants; 3) thoroughly preparing for site visits; 4) partnering with local collaborators; 5) collecting robust data by using multiple researchers and methods; and 6) analyzing and reporting data in a structured manner helpful to the oraganizations being evluated.
Conclusions
RAP, iteratively developed over the course of visits to seven clinical sites across the U.S., has succeeded in allowing a multidisciplinary team of informatics researchers to plan, gather and analyze data, and report results in a maximally efficient manner.
doi:10.3414/ME10-01-0042
PMCID: PMC3746487  PMID: 21170469
Ethnography; Qualitative Methods; Clinical Informatics; Healthcare Evaluation Mechanisms; Computerized Medical Records Systems
2.  The early development of neutron diffraction: science in the wings of the Manhattan Project 
Early neutron diffraction experiments performed in 1944 using the first nuclear reactors are described.
Although neutron diffraction was first observed using radioactive decay sources shortly after the discovery of the neutron, it was only with the availability of higher intensity neutron beams from the first nuclear reactors, constructed as part of the Manhattan Project, that systematic investigation of Bragg scattering became possible. Remarkably, at a time when the war effort was singularly focused on the development of the atomic bomb, groups working at Oak Ridge and Chicago carried out key measurements and recognized the future utility of neutron diffraction quite independent of its contributions to the measurement of nuclear cross sections. Ernest O. Wollan, Lyle B. Borst and Walter H. Zinn were all able to observe neutron diffraction in 1944 using the X-10 graphite reactor and the CP-3 heavy water reactor. Subsequent work by Wollan and Clifford G. Shull, who joined Wollan’s group at Oak Ridge in 1946, laid the foundations for widespread application of neutron diffraction as an important research tool.
doi:10.1107/S0108767312036021
PMCID: PMC3526866  PMID: 23250059
neutron diffraction; Manhattan Project
3.  The nucleotide sequence of Saccharomyces cerevisiae chromosome V 
Nature  1997;387(6632 Suppl):78-81.
Here we report the sequence of 569,202 base pairs of Saccharomyces cerevisiae chromosome V. Analysis of the sequence revealed a centromere, two telomeres and 271 open reading frames (ORFs) plus 13 tRNAs and four small nuclear RNAs. There are two Ty1 transposable elements, each of which contains an ORF (included in the count of 271). Of the ORFs, 78 (29%) are new, 81 (30%) have potential homologues in the public databases, and 112 (41%) are previously characterized yeast genes.
PMCID: PMC3057095  PMID: 9169868
4.  Modeling hot flushes and quality of life in breast cancer survivors 
Objectives
To evaluate the relationships among measures of hot flushes, perceived hot flush interference, sleep disturbance, and measures of quality of life while controlling for potential covariates (patient and treatment variables).
Methods
Breast cancer survivors (n = 395) due to receive aromatase inhibitor therapy provided demographic information, physiological hot flush data via sternal skin conductance monitoring, hot flush frequency via written diary and electronic event marker, hot flush severity and bother via written diary, and questionnaire data via the Hot Flash Related Daily Interference Scale, Pittsburgh Sleep Quality Index, the EuroQOL, Hospital Anxiety and Depression Scale and the Center for Epidemiologic Studies Depression Scale.
Results
Confirmatory factor analysis supported a two-factor model for hot flush symptoms (frequency and severity). Although there was strong convergence among self-reported hot flush measures, there was a high degree of unexplained variance associated with physiological measures. This suggests that self-report and physiological measures do not overlap substantially. The structural model showed that greater hot flush frequency and severity were directly related to greater perceived interference with daily life activities. Greater perceived interference, in turn, directly predicted greater sleep disruption, which predicted lower perceived health state and more symptoms of anxiety and depression.
Conclusions
Findings suggest hot flush interference may be the most appropriate single measure to include in clinical trials of vasomotor symptom therapies. Measuring and ameliorating patients' perceptions of hot flush interference with life activities and subjective sleep quality may be the most direct routes to improving quality of life.
doi:10.3109/13697131003717070
PMCID: PMC3022093  PMID: 20450413
Hot Flushes; Menopause; Breast Cancer; Quality of Life; Structural Model
5.  Insulin-Degrading Enzyme Binds to the Nonglycosylated Precursor of Varicella-Zoster Virus gE Protein Found in the Endoplasmic Reticulum ▿  
Journal of Virology  2009;84(2):847-855.
Insulin degradation enzyme (IDE) is a 110-kDa zinc metalloprotease found in the cytosol of all cells. IDE degrades insulin and a variety of small proteins including amyloid-β. Recently, IDE has been proposed as the receptor for varicella-zoster virus (VZV) attachment. During our reassessment, some of the original studies were repeated and expanded in scope. We first confirmed that IDE antibody reduced VZV spread. For additional controls, we repeated the same experiments with herpes simplex virus (HSV)-infected cells as well as uninfected cells. There was a visible reduction in HSV spread but less than seen in the VZV system. Of greater importance, IDE antibody also inhibited the growth of uninfected cells. Second, we repeated the coprecipitation assays. We confirmed that antibodies to VZV gE (open reading frame 68) coprecipitated IDE and that anti-IDE antibody coprecipitated gE. However, the detected gE protein was not the mature 98-kDa form; rather, it was a precursor 73-kDa gE form found in the endoplasmic reticulum. Additional control experiments included VZV-infected cell cultures treated with tunicamycin to block gE glycosylation in the endoplasmic reticulum; again, the anti-IDE antibody coprecipitated a 73-kDa gE product. Finally, Orbitrap mass spectrometry analysis of a chromatographically purified gE sample revealed four cellular proteins associated with the unfolded protein response: BiP (HSPA5), HSPA8, HSPD1, and PPIA (peptidyl-propyl cis-trans isomerase). We conclude that IDE protease binds to the 73-kDa gE precursor and that this event occurs in the cytosol but not as a receptor/ligand interaction.
doi:10.1128/JVI.01801-09
PMCID: PMC2798375  PMID: 19864391
6.  Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people 
Quality & Safety in Health Care  2009;18(5):341-346.
Introduction:
Care home residents are at particular risk from medication errors, and our objective was to determine the prevalence and potential harm of prescribing, monitoring, dispensing and administration errors in UK care homes, and to identify their causes.
Methods:
A prospective study of a random sample of residents within a purposive sample of homes in three areas. Errors were identified by patient interview, note review, observation of practice and examination of dispensed items. Causes were understood by observation and from theoretically framed interviews with home staff, doctors and pharmacists. Potential harm from errors was assessed by expert judgement.
Results:
The 256 residents recruited in 55 homes were taking a mean of 8.0 medicines. One hundred and seventy-eight (69.5%) of residents had one or more errors. The mean number per resident was 1.9 errors. The mean potential harm from prescribing, monitoring, administration and dispensing errors was 2.6, 3.7, 2.1 and 2.0 (0 = no harm, 10 = death), respectively. Contributing factors from the 89 interviews included doctors who were not accessible, did not know the residents and lacked information in homes when prescribing; home staff’s high workload, lack of medicines training and drug round interruptions; lack of team work among home, practice and pharmacy; inefficient ordering systems; inaccurate medicine records and prevalence of verbal communication; and difficult to fill (and check) medication administration systems.
Conclusions:
That two thirds of residents were exposed to one or more medication errors is of concern. The will to improve exists, but there is a lack of overall responsibility. Action is required from all concerned.
doi:10.1136/qshc.2009.034231
PMCID: PMC2762085  PMID: 19812095
7.  What's so special about medications: a pharmacist's observations from the POE study. 
Observations from a multi-site observational study of physician order entry (POE) confirm that implementing POE is problematic, and suggest that implementing medication order entry is particularly difficult. A pharmacist participating in the study group sought to answer the question: What makes medications different? Analysis of themes specific to medication POE in this study's large data set was undertaken using a grounded theory approach. Emerging themes in the data are explored and include: (1) order complexity and the consequences of error; (2) impacts on professional roles; (3) prescribing needs in different settings; and (4) technology impact on medication administration. Awareness of potential roadblocks and lessons learned from previous implementation attempts should help organizations considering medication POE to optimize their own strategies.
PMCID: PMC2243687  PMID: 11825161
8.  A diffusion of innovations model of physician order entry. 
OBJECTIVE: To interpret the results of a cross-site study of physician order entry (POE) in hospitals using a diffusion of innovations theory framework. METHODS: Qualitative study using observation, focus groups, and interviews. Data were analyzed by an interdisciplinary team of researchers using a grounded approach to identify themes. Themes were then interpreted using classical Diffusion of Innovations (DOI) theory as described by Rogers [1]. RESULTS: Four high level themes were identified: organizational issues; clinical and professional issues; technology implementation issues; and issues related to the organization of information and knowledge. Further analysis using the DOI framework indicated that POE is an especially complex information technology innovation when one considers communication, time, and social system issues in addition to attributes of the innovation itself. CONCLUSION: Implementation strategies for POE should be designed to account for its complex nature. The ideal would be a system that is both customizable and integrated with other parts of the information system, is implemented with maximum involvement of users and high levels of support, and is surrounded by an atmosphere of trust and collaboration.
PMCID: PMC2243456  PMID: 11825150
9.  Insulin-like growth factor-1 content and pattern of expression correlates with histopathologic grade in diffusely infiltrating astrocytomas. 
Neuro-Oncology  1999;1(2):109-119.
Studies of experimental tumorigenesis have strongly implicated signaling of the insulin-like growth factor 1 (IGF-1) as a key component in astrocytic neoplasia; however, its role in the growth of low-grade and malignant human tumors is not well understood. Correlative analyses of IGF-1, p53, and Ki-67 (MIB-1) immunohistochemistry and IGF-1 receptor (IGF-1R) mRNA expression were performed to examine the cellular pattern of IGF-1 signaling in 39 cases of astrocytoma (World Health Organization grades II-IV). Tumor cells expressing IGF-1 and IGF-1R were present in all tumor grades. The proportion of tumor cells that expressed IGF-1 correlated with both histopathologic grade and Ki-67 labeling indices, while expression of IGF-1R mRNA correlated with Ki-67 indices. In cases where stereotactic tissue sampling could be identified with a specific tumor area by neuroimaging features, the numbers of IGF-1 immunoreactive cells correlated with the tumor zones of highest cellularity and Ki-67 labeling. In glioblastomas, the localization of IGF-1 immunoreactivity was notable for several features: frequent accentuation in the perivascular tumor cells surrounding microvascular hyperplasia; increased levels in reactive astrocytes at the margins of tumor infiltration; and selective expression in microvascular cells exhibiting endothelial/pericytic hyperplasia. IGF-1R expression was particularly prominent in tumor cells adjacent to both microvascular hyperplasia and palisading necrosis. These data suggest that IGF-1 signaling occurs early in astroglial tumorigenesis in the setting of cell proliferation. The distinctive correlative patterns of IGF-1 and IGF-1R expression in glioblastomas also suggest that IGF-1 signaling has an association with the development of malignant phenotypes related to aberrant angiogenesis and invasive tumor interactions with reactive brain.
PMCID: PMC1920755  PMID: 11550306
10.  Biodegradation of dimethylsilanediol in soils. 
Applied and Environmental Microbiology  1996;62(12):4352-4360.
The biodegradation potential of [14C]dimethylsilanediol, the monomer unit of polydimethylsiloxane, in soils was investigated. Dimethylsilanediol was found to be biodegraded in all of the tested soils, as monitored by the production of 14CO2. When 2-propanol was added to the soil as a carbon source in addition to [14C]dimethylsilanediol, the production of 14CO2 increased. A method for the selection of primary substrates that support cometabolic degradation of a target compound was developed. By this method, the activity observed in the soils was successfully transferred to liquid culture. A fungus, Fusarium oxysporum Schlechtendahl, and a bacterium, an Arthrobacter species, were isolated from two different soils, and both microorganisms were able to cometabolize [14C]dimethylsilanediol to 14CO2 in liquid culture. In addition, the Arthrobacter sp. that was isolated grew on dimethylsulfone, and we believe that this is the first reported instance of a microorganism using dimethylsulfone as its primary carbon source. Previous evidence has shown that polydimethylsiloxane is hydrolyzed in soil to the monomer, dimethylsilanediol. Now, biodegradation of dimethylsilanediol in soil has been demonstrated.
PMCID: PMC168263  PMID: 8953708
12.  Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. 
Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.
PMCID: PMC442471  PMID: 3335642
13.  Selective and differential medium for detecting Clostridium botulinum. 
A selective and differential growth medium was developed for detection of Clostridium botulinum types A, B, and F. The medium consisted of peptone-glucose-yeast extract agar supplemented with cycloserine, 250 micrograms/ml; sulfamethoxazole, 76 micrograms/ml; and trimethoprim, 4 micrograms/ml as selective inhibitors and various types and levels of botulinal antibodies for type differentiation in the immunodiffusion reaction. Growth of proteolytic types of C. botulinum were not affected by the incorporation of the selective agents, but some nonproteolytic types were suppressed. Cross-reactions between types A and B were visually distinguishable, whereas cross-reactions between type F and Clostridium sporogenes did not occur at the optimum antibody titer. Optimum antibody titer varied with toxin type. The proposed selective differential medium should be valuable in isolating and typing of proteolytic C. botulinum types A, B, and F from samples containing mixed microbial populations.
PMCID: PMC291803  PMID: 2867740
14.  Arylamidase Activity of Salmonella Species 
Applied Microbiology  1975;29(6):726-728.
Arylamidase activity in cell extracts of sonically cell treated suspensions of 23 Salmonella strains, including 12 strains of S. typhimurium, was investigated. All cultures hydrolyzed five of nine different neutral and basic substrates. Activity against aspartyl-, cystyl- histidinyl-, and isoleucyl-β-naphylamide was negligible. Alanyl-β-naphthylamide was the preferred substrate for the Salmonella species; however, specific activities ranged widely. Of several gram-negative organisms surveyed, all except Proteus vulgaris hydrolyzed alanyl-β-naphthylamide at the fastest rate. The most preferred substrate for the Proteus culture was glycyl-β-naphthylamide. No relationship could be shown between virulence and arylamidase activity for the Salmonella strains.
PMCID: PMC187070  PMID: 808165
16.  Technique for Preparing High-Quality Microphotographs by Fluorescence Microscopy 
Applied Microbiology  1974;28(6):1063-1065.
Simple techniques resulting in high-quality microphotographs by fluorescence microscopy are described for the preparation of Salmonella cultures and slides.
Images
PMCID: PMC186882  PMID: 4451364
17.  Isolation of Salmonellae from Pork Carcasses 
Applied Microbiology  1973;25(5):731-734.
Four hundred and twenty pork carcasses from four abattoirs were examined for the presence of salmonellae by use of swabbing-enrichment techniques and contact plate methods. Carcasses from only one abattoir were found to be contaminated by swabbing-enrichment (23.3%) and contact plate (17.9%) methods. The area of the skin side of the ham, near the anal opening, was determined to be the area to examine for isolating salmonellae from pork carcasses with the greatest frequency. The most frequently isolated species of salmonellae in this study were Salmonella derby, S. anatum, S. typhimurium, and S. indiana.
PMCID: PMC380903  PMID: 4577175
18.  Effect of lactation stage and concurrent pregnancy on milk composition in the bottlenose dolphin 
Although many toothed whales (Cetacea: Odontoceti) lactate for 2–3 years or more, it is not known whether milk composition is affected by lactation stage in any odontocete species. We collected 64 pooled milk samples spanning 1–30 months postpartum from three captive bottlenose dolphins Tursiops truncatus. Milks were assayed for water, fat, crude protein (TN × 6.38) and sugar; gross energy was calculated. Ovulation and pregnancy were determined via monitoring of milk progesterone. Based on analysis of changes in milk composition for each individual dolphin, there were significant increases (P<0.05) in fat (in all three dolphins) and crude protein (in two of three), and a decrease (P<0.05) in water (in two of three) over the course of lactation, but the sugar content did not change. In all three animals, the energy content was positively correlated with month of lactation, but the percentage of energy provided by crude protein declined slightly but significantly (P<0.05). At mid-lactation (7–12 months postpartum, n=17), milk averaged 73.0±1.0% water, 12.8±1.0% fat, 8.9±0.5% crude protein, 1.0±0.1% sugar, 1.76±0.09 kcal g−1 (=7.25 kJ g−1) and 30.3±1.3% protein:energy per cent. This protein:energy per cent was surprisingly high compared with other cetaceans and in relation to the growth rates of calves. Milk progesterone indicated that dolphins ovulated and conceived between 413 and 673 days postpartum, following an increase in milk energy density. The significance of these observed compositional changes to calf nutrition will depend on the amounts of milk produced at different stages of lactation, and how milk composition and yield are influenced by sampling procedure, maternal diet and maternal condition, none of which are known.
doi:10.1111/j.1469-7998.2007.00309.x
PMCID: PMC3227479  PMID: 22140298
bottlenose dolphin; Tursiops; milk composition; nutrition; lactation; Cetacea
19.  Incidence of Salmonellae in Meat and Meat Products 
Applied Microbiology  1969;17(6):899-902.
Standard enrichment, plating, and biochemical techniques were used to assess the incidence of Salmonella species on beef and pork carcasses and processed meat products. The incidence of Salmonella in pork carcasses was 56% and in beef carcasses, 74%. These figures are about the same as previously reported for pork but much higher than previously reported for beef carcasses; however, they represent only three to five abattoirs in Georgia and do not necessarily represent contamination levels throughout the country. Examination of carcasses by area did not indicate greater incidence of Salmonella in any one area. Two areas suggested for representative sampling are the cervical and anal areas of the carcass. Of the sausage samples examined, 38% of the fresh pork sausage, 9% of the smoked pork sausage, and 1 sample (souse) of 16 samples of miscellaneous sausage products were contaminated. Examination of subsamples indicated that Salmonella, when present in sausage products, could be found in any section of the entire sample.
PMCID: PMC377835  PMID: 5797942

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