Characterization of 4-hydroxyphenylpyruvate dioxygenases, inhibition by herbicides and engineering for herbicide tolerance in crops.

4-Hydroxyphenylpyruvate dioxgenase (HPPD) enzymes from rat and from several plants contained only about a single inhibitor-binding active site per dimer which matched the content of iron in the purified Arabidopsis thaliana and Avena sativa enzymes. The dimeric HPPDs were about 10 fold more catalytically active than the tetrameric P. fluorescens enzyme with kcat/KmHPP values ranging from 0.8 to 2.5 s-1 µM-1. Most were also highly sensitive to herbicides with, for example, Ki values for mesotrione ranging from 25 to 100 pM. Curiously HPPDs from cool climate grasses were much less herbicide-sensitive. When likewise expressed in Nicotinia tabacum, Avena sativa HPPD, Ki value of 11 nM for mesotrione, conferred far greater tolerance to mesotrione (CallistoTM) than did any of the more sensitive HPPDs. Targeted mutagenesis of the Avena HPPD led to the discovery of 4 mutations imparting improved inherent tolerance, defined as the ratio of Ki to KmHPP, by about 16 fold without any loss of catalytic activity. The Nicotinia line with the highest expression of this quadruple mutant exhibited substantial resistance even up to a 3 kg/ha post-emergence application of mesotrione. The maximum observed expression level of heterologous plant HPPDs in tobacco was ca. 0.35% of the total soluble protein whereas the endogenous tobacco HPPD constituted only ca. 0.00075%. At such high expression even HPPDs with impaired catalytic activity could be effective. A quintuple mutant Avena sativa HPPD conferred substantial tolerance across a broad range of HPPD herbicide chemistries despite being only ca. 5 % as catalytically active as the wild type enzyme. Testing various wild type and mutant HPPDs in tobacco revealed that tolerance to field rates of herbicide generally requires about two order of magnitude increases in both inherent herbicide tolerance and expression relative to endogenous levels. This double hurdle may explain why target-site based resistance to HPPD-inhibiting herbicides has been slow to evolve in weeds.

A comparison of the accuracy of clinical decisions based on full-text articles and on journal abstracts alone: a study among residents in a tertiary care hospital.

BACKGROUND: Many clinicians depend solely on journal abstracts to guide clinical decisions. OBJECTIVES: This study aims to determine if there are differences in the accuracy of responses to simulated cases between resident physicians provided with an abstract only and those with full-text articles. It also attempts to describe their information-seeking behaviour. METHODS: Seventy-seven resident physicians from four specialty departments of a tertiary care hospital completed a paper-based questionnaire with clinical simulation cases, then randomly assigned to two intervention groups-access to abstracts-only and access to both abstracts and full-text. While having access to medical literature, they completed an online version of the same questionnaire. FINDINGS: The average improvement across departments was not significantly different between the abstracts-only group and the full-text group (p=0.44), but when accounting for an interaction between intervention and department, the effect was significant (p=0.049) with improvement greater with full-text in the surgery department. Overall, the accuracy of responses was greater after the provision of either abstracts-only or full-text (p<0.0001). Although some residents indicated that 'accumulated knowledge' was sufficient to respond to the patient management questions, in most instances (83% of cases) they still sought medical literature. CONCLUSIONS: Our findings support studies that doctors will use evidence when convenient and current evidence improved clinical decisions. The accuracy of decisions improved after the provision of evidence. Clinical decisions guided by full-text articles were more accurate than those guided by abstracts alone, but the results seem to be driven by a significant difference in one department.

Lower short- and long-term mortality associated with overweight and obesity in a large cohort study of adult intensive care unit patients.

INTRODUCTION: Two thirds of United States adults are overweight or obese, which puts them at higher risk of developing chronic diseases and of death compared with normal-weight individuals. However, recent studies have found that overweight and obesity by themselves may be protective in some contexts, such as hospitalization in an intensive care unit (ICU). Our objective was to determine the relation between body mass index (BMI) and mortality at 30 days and 1 year after ICU admission. METHODS: We performed a cohort analysis of 16,812 adult patients from MIMIC-II, a large database of ICU patients at a tertiary care hospital in Boston, Massachusetts. The data were originally collected during the course of clinical care, and we subsequently extracted our dataset independent of the study outcome. RESULTS: Compared with normal-weight patients, obese patients had 26% and 43% lower mortality risk at 30 days and 1 year after ICU admission, respectively (odds ratio (OR), 0.74; 95% confidence interval (CI), 0.64 to 0.86) and 0.57 (95% CI, 0.49 to 0.67)); overweight patients had nearly 20% and 30% lower mortality risk (OR, 0.81; 95% CI, 0.70 to 0.93) and OR, 0.68 (95% CI, 0.59 to 0.79)). Severely obese patients (BMI ≥ 40 kg/m2) did not have a significant survival advantage at 30 days (OR, 0.94; 95% CI, 0.74 to 1.20), but did have 30% lower mortality risk at 1 year (OR, 0.70 (95% CI, 0.54 to 0.90)). No significant difference in admission acuity or ICU and hospital length of stay was found across BMI categories. CONCLUSION: Our study supports the hypothesis that patients who are overweight or obese have improved survival both 30 days and 1 year after ICU admission.

Use of Electronic Health Record Data to Evaluate the Impact of Race on 30-Day Mortality in Patients Admitted to the Intensive Care Unit.

INTRODUCTION: The current body of literature examining the impact of race upon outcomes for patients admitted to the intensive care unit (ICU) is limited. The primary objective of our study was to explore this question using a large cohort drawn from an electronic health record (EHR)-based data source. METHODS: We conducted a retrospective cohort study using Multiparameter Intelligent Monitoring in Intensive Care (MIMIC-II), an EHR-derived database encompassing ICU admissions to an academic medical center in Boston, Massachusetts, between 2001 and 2008. Adults admitted to a medical or surgical ICU were assessed for the primary outcome of 30-day mortality and secondary outcomes of in-hospital mortality and hospital length-of-stay. Multivariate logistic regression was used to determine the association between race and the primary outcome. RESULTS: The study cohort consisted of 14,684 adult ICU patients-10,562 White, 1311 Black, 363 Asian, 868 "Other," and 1580 without known race. Thirty-day mortality rates experienced by Black and Asian individuals were significantly lower than mortality among those identified as White, with odds ratios of 0.62 (95 % CI 0.50-0.77) and 0.64 (95 % CI 0.44-0.93), respectively. Patients without known race experienced the highest crude mortality overall (27.4 %) and twice the adjusted odds of mortality compared with the White group. CONCLUSIONS: In a large, racially diverse cohort of general ICU patients, White patients experienced significantly higher mortality than non-White patients. Our results are consistent with findings from other studies that indicate that the non-White race does not appear to negatively impact short-term survival following ICU admission.

Combining structured and unstructured data to identify a cohort of ICU patients who received dialysis.

OBJECTIVE: To develop a generalizable method for identifying patient cohorts from electronic health record (EHR) data-in this case, patients having dialysis-that uses simple information retrieval (IR) tools. METHODS: We used the coded data and clinical notes from the 24,506 adult patients in the Multiparameter Intelligent Monitoring in Intensive Care database to identify patients who had dialysis. We used SQL queries to search the procedure, diagnosis, and coded nursing observations tables based on ICD-9 and local codes. We used a domain-specific search engine to find clinical notes containing terms related to dialysis. We manually validated the available records for a 10% random sample of patients who potentially had dialysis and a random sample of 200 patients who were not identified as having dialysis based on any of the sources. RESULTS: We identified 1844 patients that potentially had dialysis: 1481 from the three coded sources and 1624 from the clinical notes. Precision for identifying dialysis patients based on available data was estimated to be 78.4% (95% CI 71.9% to 84.2%) and recall was 100% (95% CI 86% to 100%). CONCLUSIONS: Combining structured EHR data with information from clinical notes using simple queries increases the utility of both types of data for cohort identification. Patients identified by more than one source are more likely to meet the inclusion criteria; however, including patients found in any of the sources increases recall. This method is attractive because it is available to researchers with access to EHR data and off-the-shelf IR tools.

High vitamin B12 levels are not associated with increased mortality risk for ICU patients after adjusting for liver function: a cohort study.

BACKGROUND AND AIMS: Recent research has suggested that high vitamin B12 levels may be associated with increased mortality after ICU admission. However, it is known that impaired liver function may lead to elevated B12 since B12 is metabolized through the liver, and therefore high B12 levels may serve as a proxy for poor liver function. The aim of this study is to assess the impact that liver function and liver disease have on the relationship between high vitamin B12 levels and mortality in the ICU. METHODS: We performed an observational cohort study using ICU data that were collected from patients admitted to four ICU types (medical, surgical, cardiac care and cardiac surgery recovery) in one large urban hospital from 2001 to 2008. We analyzed the medical records of 1,684 adult patients (age ≥ 18 years) who had vitamin B12 and liver function measurements up to 14 days prior to ICU admission or within 24 hours after admission. RESULTS: While we found an association between high B12 and mortality when we did not control for any potential confounders, after we adjusted for liver function and liver disease, no significant association existed between B12 and mortality using multivariable logistic regression (30-day mortality: OR=1.18, 95% CI 0.81 to 1.72, p=0.3890; 90-day mortality: OR=1.20, 95% CI 0.84 to 1.71, p=0.3077). CONCLUSIONS: Elevated B12 levels are not a significant predictor of mortality after ICU admission when liver function is controlled for, and may instead be a proxy for poor liver function.

The pattern of name tokens in narrative clinical text and a comparison of five systems for redacting them.

OBJECTIVE: To understand the factors that influence success in scrubbing personal names from narrative text. MATERIALS AND METHODS: We developed a scrubber, the NLM Name Scrubber (NLM-NS), to redact personal names from narrative clinical reports, hand tagged words in a set of gold standard narrative reports as personal names or not, and measured the scrubbing success of NLM-NS and that of four other scrubbing/name recognition tools (MIST, MITdeid, LingPipe, and ANNIE/GATE) against the gold standard reports. We ran three comparisons which used increasingly larger name lists. RESULTS: The test reports contained more than 1 million words, of which 2388 were patient and 20,160 were provider name tokens. NLM-NS failed to scrub only 2 of the 2388 instances of patient name tokens. Its sensitivity was 0.999 on both patient and provider name tokens and missed fewer instances of patient name tokens in all comparisons with other scrubbers. MIST produced the best all token specificity and F-measure for name instances in our most relevant study (study 2), with values of 0.997 and 0.938, respectively. In that same comparison, NLM-NS was second best, with values of 0.986 and 0.748, respectively, and MITdeid was a close third, with values of 0.985 and 0.796 respectively. With the addition of the Clinical Center name list to their native name lists, Ling Pipe, MITdeid, MIST, and ANNIE/GATE all improved substantially. MITdeid and Ling Pipe gained the most--reaching patient name sensitivity of 0.995 (F-measure=0.705) and 0.989 (F-measure=0.386), respectively. DISCUSSION: The privacy risk due to two name tokens missed by NLM-NS was statistically negligible, since neither individual could be distinguished among more than 150,000 people listed in the US Social Security Registry. CONCLUSIONS: The nature and size of name lists have substantial influences on scrubbing success. The use of very large name lists with frequency statistics accounts for much of NLM-NS scrubbing success.