Chris Gennings

Ineffective triggering predicts increased duration of mechanical ventilation.

Objectives: To determine whether high rates of ineffective triggering within the first 24 hrs of mechanical ventilation (MV) are associated with longer MV duration and shorter ventilator‐free survival (VFS). Design: Prospective cohort study. Setting: Medical intensive care unit (ICU) at an academic medical center. Patients: Sixty patients requiring invasive MV. Interventions: None. Measurements: Patients had pressure‐time and flow‐time waveforms recorded for 10 mins within the first 24 hrs of MV initiation. Ineffective triggering index (ITI) was calculated by dividing the number of ineffectively triggered breaths by the total number of breaths (triggered and ineffectively triggered). A priori, patients were classified into ITI >=10% or ITI <10%. Patient demographics, MV reason, codiagnosis of chronic obstructive pulmonary disease (COPD), sedation levels, and ventilator parameters were recorded. Measurements and Main Results: Sixteen of 60 patients had ITI >=10%. The two groups had similar characteristics, including COPD frequency and ventilation parameters, except that patients with ITI >=10% were more likely to have pressured triggered breaths (56% vs. 16%, p = .003) and had a higher intrinsic respiratory rate (22 breaths/min vs. 18, p = .03), but the set ventilator rate was the same in both groups (9 breaths/min vs. 9, p = .78). Multivariable analyses adjusting for pressure triggering also demonstrated that ITI >=10% was an independent predictor of longer MV duration (10 days vs. 4, p = .0004) and shorter VFS (14 days vs. 21, p = .03). Patients with ITI >=10% had a longer ICU length of stay (8 days vs. 4, p = .01) and hospital length of stay (21 days vs. 8, p = .03). Mortality was the same in the two groups, but patients with ITI >=10% were less likely to be discharged home (44% vs. 73%, p = .04). Conclusions: Ineffective triggering is a common problem early in the course of MV and is associated with increased morbidity, including longer MV duration, shorter VFS, longer length of stay, and lower likelihood of home discharge.

Randomized trial comparing daily interruption of sedation and nursing-implemented sedation algorithm in medical intensive care unit patients

IntroductionDaily interruption of sedation (DIS) and sedation algorithms (SAs) have been shown to decrease mechanical ventilation (MV) duration. We conducted a randomized study comparing these strategies.MethodsMechanically ventilated adults 18 years old or older in the medical intensive care unit (ICU) were randomly assigned to DIS or SA. Exclusion criteria were severe neurocognitive dysfunction, administration of neuromuscular blockers, and tracheostomy. Study endpoints were total MV duration and 28-day ventilator-free survival.ResultsThe study was terminated prematurely after 74 patients were enrolled (DIS 36 and SA 38). The two groups had similar age, gender, racial distribution, Acute Physiology and Chronic Health Evaluation II score, and reason for MV. The Data Safety Monitoring Board convened after DIS patients were found to have higher hospital mortality; however, no causal connection between DIS and increased mortality was identified. Interim analysis demonstrated a significant difference in primary endpoint, and study termination was recommended. The DIS group had longer total duration of MV (median 6.7 versus 3.9 days; P = 0.0003), slower improvement of Sequential Organ Failure Assessment over time (0.70 versus 0.23 units per day; P = 0.025), longer ICU length of stay (15 versus 8 days; P < 0.0001), and longer hospital length of stay (23 versus 12 days; P = 0.01).ConclusionIn our cohort of patients, the use of SA was associated with reduced duration of MV and lengths of stay compared with DIS. Based on these results, DIS may not be appropriate in all mechanically ventilated patients.Trial registrationClinicalTrials.gov NCT00205517.

A Statistical Approach to the Construction and Analysis of Isobolograms

Current statistical procedures used in the construction of isobolograms do not use recent advances in mathematical statistics. The variability in the experimental data is either ignored or incompletely accounted for in the analyses. The decision procedures currently used to characterize the type of interaction between two agents do not permit the determination of the level of statistical significance associated with a given conclusion. Furthermore, the often formidable sample size is not exploited in the current isobologram methodology. Statistical techniques exist that may be used to construct isobolograms and decision procedures with a reliable level of significance. An isobologram is a contour of constant response of the underlying dose-response surface. Consequently, response surface methods (RSM) are useful in the estimation and analysis of isobolograms. The interaction between ethanol and chloral hydrate in female ICR mice was evaluated using the RSM approach by fitting the logistic model to quantal data. The loss of righting reflex was quantitated in mice 30 min after coadministration of the two drugs, injected IP on a body weight basis (mg/kg). The study consisted of 39 groups with 6 animals per group. Analysis of our data supports the conclusion of synergy between the drugs as reported by others; however, our results were obtained with a significantly smaller number of animals. These studies also demonstrate that response surface modeling can be used for determining additivity, synergism, and antagonism at a given preselected level of significance.

Protocols for the assurance of microarray data quality and process control

Microarrays represent a powerful technology that provides the ability to simultaneously measure the expression of thousands of genes. However, it is a multi-step process with numerous potential sources of variation that can compromise data analysis and interpretation if left uncontrolled, necessitating the development of quality control protocols to ensure assay consistency and high-quality data. In response to emerging standards, such as the minimum information about a microarray experiment standard, tools are required to ascertain the quality and reproducibility of results within and across studies. To this end, an intralaboratory quality control protocol for two color, spotted microarrays was developed using cDNA microarrays from in vivo and in vitro dose-response and time-course studies. The protocol combines: (i) diagnostic plots monitoring the degree of feature saturation, global feature and background intensities, and feature misalignments with (ii) plots monitoring the intensity distributions within arrays with (iii) a support vector machine (SVM) model. The protocol is applicable to any laboratory with sufficient datasets to establish historical high- and low-quality data.

The vitamin D3 analog, ILX-23-7553, enhances the response to Adriamycin and irradiation in MCF-7 breast tumor cells

Abstract. Ionizing radiation and the anthracycline antibiotic, Adriamycin, generally fail to promote a primary apoptotic response in experimental breast tumor cell lines. Similarly, the primary response of breast tumor cells to vitamin D3 (1,25(OH)2D3) and vitamin D3 analogs such as EB 1089 is growth inhibition. Previous studies have demonstrated that pretreatment of MCF-7 breast tumor cells with vitamin D3 or EB 1089 can increase sensitivity to both Adriamycin and irradiation. Purpose: The capacity of the vitamin D3 analog, ILX 23-7553, to enhance the antiproliferative and cytotoxic effects of Adriamycin or irradiation and to promote apoptosis in MCF-7 breast tumor cells was assessed in the present study. Results: Pretreatment of MCF-7 cells with ILX 23-7553 followed by Adriamycin or irradiation decreased viable cell numbers by 97% and 93%, respectively. Cell numbers were reduced by 56%, 74% and 75% by ILX 23-7553, Adriamycin and irradiation alone. Pretreatment with ILX 23-7553 also shifted the dose response curve for clonogenic survival, increasing sensitivity to Adriamycin 2.5-fold and sensitivity to radiation fourfold. In addition, ILX 23-7553 pretreatment conferred sensitivity to Adriamycin- or irradiation-induced DNA fragmentation and resulted in morphological changes indicative of apoptotic cell death in MCF-7 cells. Statistical analysis demonstrated that ILX 23-7553 interacts additively and not synergistically with both Adriamycin and irradiation. Conclusions: ILX 23-7553 enhances the effects of Adriamycin and irradiation in MCF-7 breast tumor cells by decreasing viable cell numbers, reducing clonogenic survival and inducing apoptotic cell death. Current studies are focused on elucidating the mechanisms underlying the induction of apoptosis as well as understanding the nature of the interactions between ILX 23-7553 and Adriamycin or irradiation.

Empirical Bayes Gene Screening Tool for Time-Course or Dose-Response Microarray Data

Abstract An efficient method to reduce the dimensionality of microarray gene expression data from thousands or tens of thousands of cDNA clones down to a subset of the most differentially expressed cDNA clones is essential in order to simplify the massive amount of data generated from microarray experiments. An extension to the methods of Efron et al. [Efron, B., Tibshirani, R., Storey, J., Tusher, V. (2001). Empirical Bayes analysis of a microarray experiment. J. Am. Statist. Assoc. 96:1151–1160] is applied to a differential time-course experiment to determine a subset of cDNAs that have the largest probability of being differentially expressed with respect to treatment conditions across a set of unequally spaced time points. The proposed extension, which is advocated to be a screening tool, allows for inference across a continuous variable in addition to incorporating a more complex experimental design and allowing for multiple design replications. With the current data the focus is on a time-course experiment; however, the proposed methods can easily be implemented on a dose–response experiment, or any other microarray experiment that contains a continuous variable of interest. The proposed empirical Bayes gene-screening tool is compared with the Efron et al. (2001) method in addition to an adjusted model-based t-value using a time-course data set where the toxicological effect of a specific mixture of chemicals is being studied.

Impact of HbA1c Measurement on Hospital Readmission Rates: Analysis of 70,000 Clinical Database Patient Records

Management of hyperglycemia in hospitalized patients has a significant bearing on outcome, in terms of both morbidity and mortality. However, there are few national assessments of diabetes care during hospitalization which could serve as a baseline for change. This analysis of a large clinical database (74 million unique encounters corresponding to 17 million unique patients) was undertaken to provide such an assessment and to find future directions which might lead to improvements in patient safety. Almost 70,000 inpatient diabetes encounters were identified with sufficient detail for analysis. Multivariable logistic regression was used to fit the relationship between the measurement of HbA1c and early readmission while controlling for covariates such as demographics, severity and type of the disease, and type of admission. Results show that the measurement of HbA1c was performed infrequently (18.4%) in the inpatient setting. The statistical model suggests that the relationship between the probability of readmission and the HbA1c measurement depends on the primary diagnosis. The data suggest further that the greater attention to diabetes reflected in HbA1c determination may improve patient outcomes and lower cost of inpatient care.

Statistical analysis of interactive cytotoxicity in human epidermal keratinocytes following exposure to a mixture of four metals

Exposure to mixtures of chemicals is an important and relevant environmental issue. Of particular interest is the detection and characterization of departure of biological effects from additivity. Methodology based on the assumption of additivity is used in fitting single-chemicaldata. Interactionsare determined and characterized by making comparisons between the observed and predicted responses at mixtures along a fixed ratio ray of the component substances. Two simultaneous tests are developed for testing for any departure from additivity. Multiple comparisons procedures are used to compare observed responses to that predicted under additivity. A simultaneous confidence band on the predicted responses along the mixture ray is also developed. The methods are illustrated with cytotoxicity data that arise when human epidermal keratinocytes are exposed to a mixture of arsenic, chromium, cadmium, and lead. Synergistic, antagonistic, and additive cytotoxicities were observed at different dose levels of the four-metal mixture.

Efficacy of a combination of acetylcholinesterase reactivators, HI-6 and obidoxime, against tabun and soman poisoning of mice

The bispyridinium oxime HI-6, 1-((((4-amino-carbonyl) pyridinio)methoxy) methyl)-2-(hydroxyimino)-methyl) pyridinium dichloride monohydrate, combined with atropine is an effective treatment for soman (pinacolyl methylphosphonofluoridate) poisoning but is relatively ineffective against tabun (ethyl N-dimethyl phosphoroamidocyanidate) poisoning in mice. This contrasts with those results obtained using the bispyridinium oxime obidoxime [1,1′-(oxy bis(methylene)) bis(4-(hydroxyimino)-methyl) pyridinium dibromide]. The purpose of this study was to investigate the efficacy of the combination of HI-6 and obidoxime plus atropine against poisoning by tabun and soman in mice. The combination of ineffective single doses of obidoxime (5 or 10 mg/kg) and HI-6 (25 or 50 mg/kg) improved the treatment of tabun poisoning over either oxime alone. Combinations employing higher concentrations of obidoxime (25 or 50 mg/kg) and HI-6 (100 or 200 mg/kg) resulted in significant toxicity in the absence of organophosphate poisoning. Against soman poisoning the addition of obidoxime to HI-6 did not attenuate the efficacy of HI-6. The half-life of elimination and peak serum concentrations of HI-6 and obidoxime were not altered following administration of the combined injection. Reactivation of tabun-inhibited acetylcholinesterase was found consistently in the diaphragm but not in the brain. Using response surface methods it was possible to estimate the optimal therapy against soman and tabun poisoning (74.5 mg/kg HI-6+31.9 mg obidoxime against 1052 μg/kg challenge of tabun and 129 mg/kg HI-6 +0 mg/kg obidoxime against 390 μg/kg challenge of soman). It is proposed that reactivation of tabun inhibited acetylcholinesterase at the diaphragm may be responsible for the increased efficacy of the combination of HI-6 and obidoxime against tabun poisoning in mice.

Interpreting plots of a multidimensional dose−response surface in a parallel coordinate system

The dose-response surface for a combination of drugs is a multidimensional figure. Consequently, it is not possible to view such a surface using orthogonal axes when the number of dimensions exceeds 3. Parallel axes have been used to represent hyperdimensional figures. This paper reports on the use of parallel coordinate axes to plot the dose-response surface and its contours of constant response (isobols) for a combination of drugs. It is shown that patterns formed by intersecting line segments in the parallel system can aid in the interpretation of the fitted dose-response surface. More generally, analytic results are developed that permit the ready visualization and characterization of interaction effects of a polynomial model.