Transition Networks in a Cohort of Patients with Congestive Heart Failure: A Novel Application of Informatics Methods to Inform Care Coordination.

BACKGROUND: Unnecessary hospital readmissions are one source of escalating costs that may be reduced through improved care coordination, but how best to design and evaluate coordination programs is poorly understood. Measuring patient flow between service visits could support decisions for coordinating care, particularly for conditions such as congestive heart failure (CHF) which have high morbidity, costs, and hospital readmission rates. OBJECTIVES: To determine the feasibility of using network analysis to explore patterns of service delivery for patients with CHF in the context of readmissions. METHODS: A retrospective cohort study used de-identified records for patients ≥18 years with an ICD-9 diagnosis code 428.0-428.9, and service visits between July 2011 and June 2012. Patients were stratified by admission outcome. Traditional and novel network analysis techniques were applied to characterize care patterns. RESULTS: Patients transitioned between services in different order and frequency depending on admission status. Patient-to-service CoUsage networks were diffuse suggesting unstructured flow of patients with no obvious coordination hubs. In service-to-service Transition networks a specialty heart failure service was on the care path to the most other services for never admitted patients, evidence of how specialist care may prevent hospital admissions for some patients. For patients admitted once, transitions expanded for a clinic-based internal medicine service which clinical experts identified as a Patient Centered Medical Home implemented in the first month for which we obtained data. CONCLUSIONS: We detected valid patterns consistent with a targeted care initiative, which experts could understand and explain, suggesting the method has utility for understanding coordination. The analysis revealed strong but complex patterns that could not be demonstrated using traditional linear methods alone. Network analysis supports measurement of real world health care service delivery, shows how transitions vary between services based on outcome, and with further development has potential to inform coordination strategies.

An age difference of two billion years between a metal-rich and a metal-poor globular cluster.

Globular clusters trace the formation history of the spheroidal components of our Galaxy and other galaxies, which represent the bulk of star formation over the history of the Universe. The clusters exhibit a range of metallicities (abundances of elements heavier than helium), with metal-poor clusters dominating the stellar halo of the Galaxy, and higher-metallicity clusters found within the inner Galaxy, associated with the stellar bulge, or the thick disk. Age differences between these clusters can indicate the sequence in which the components of the Galaxy formed, and in particular which clusters were formed outside the Galaxy and were later engulfed along with their original host galaxies, and which were formed within it. Here we report an absolute age of 9.9 ± 0.7 billion years (at 95 per cent confidence) for the metal-rich globular cluster 47 Tucanae, determined by modelling the properties of the cluster's white-dwarf cooling sequence. This is about two billion years younger than has been inferred for the metal-poor cluster NGC 6397 from the same models, and provides quantitative evidence that metal-rich clusters like 47 Tucanae formed later than metal-poor halo clusters like NGC 6397.

Neutrino and axion bounds from the globular cluster M5 (NGC 5904).

The red-giant branch (RGB) in globular clusters is extended to larger brightness if the degenerate helium core loses too much energy in "dark channels." Based on a large set of archival observations, we provide high-precision photometry for the Galactic globular cluster M5 (NGC 5904), allowing for a detailed comparison between the observed tip of the RGB with predictions based on contemporary stellar evolution theory. In particular, we derive 95% confidence limits of g(ae)<4.3×10(-13) on the axion-electron coupling and µ(ν)<4.5×10(-12)µ(B) (Bohr magneton µ(B)=e/2m(e)) on a neutrino dipole moment, based on a detailed analysis of statistical and systematic uncertainties. The cluster distance is the single largest source of uncertainty and can be improved in the future.

Clinical trial: single- and multiple-dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects.

BACKGROUND: The pharmacokinetics of polyethylene glycol 3350 (PEG-3350) have not been fully described because of lack of a sufficiently sensitive analytical method. AIM: To describe the pharmacokinetics of PEG-3350 in humans. METHODS: A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG-3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 microg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. RESULTS: Peak PEG-3350 plasma concentrations occurred at 2-4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4-6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG-3350. Mean faecal excretion of the administered dose was 93% in young subjects. CONCLUSIONS: For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG-3350 in humans. These studies confirmed that orally administered PEG-3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.

Automatic segmentation in three-dimensional analysis of fibrovascular pigmentepithelial detachment using high-definition optical coherence tomography.

BACKGROUND/AIMS: A limited number of scans compromise conventional optical coherence tomography (OCT) to track chorioretinal disease in its full extension. Failures in edge-detection algorithms falsify the results of retinal mapping even further. High-definition-OCT (HD-OCT) is based on raster scanning and was used to visualise the localisation and volume of intra- and sub-pigment-epithelial (RPE) changes in fibrovascular pigment epithelial detachments (fPED). Two different scanning patterns were evaluated. METHODS: 22 eyes with fPED were imaged using a frequency-domain, high-speed prototype of the Cirrus HD-OCT. The axial resolution was 6 mum, and the scanning speed was 25 kA scans/s. Two different scanning patterns covering an area of 6 x 6 mm in the macular retina were compared. Three-dimensional topographic reconstructions and volume calculations were performed using MATLAB-based automatic segmentation software. RESULTS: Detailed information about layer-specific distribution of fluid accumulation and volumetric measurements can be obtained for retinal- and sub-RPE volumes. Both raster scans show a high correlation (p<0.01; R2>0.89) of measured values, that is PED volume/area, retinal volume and mean retinal thickness. Quality control of the automatic segmentation revealed reasonable results in over 90% of the examinations. CONCLUSION: Automatic segmentation allows for detailed quantitative and topographic analysis of the RPE and the overlying retina. In fPED, the 128 x 512 scanning-pattern shows mild advantages when compared with the 256 x 256 scan. Together with the ability for automatic segmentation, HD-OCT clearly improves the clinical monitoring of chorioretinal disease by adding relevant new parameters. HD-OCT is likely capable of enhancing the understanding of pathophysiology and benefits of treatment for current anti-CNV strategies in future.

Absorption, tissue distribution, metabolism and elimination of taurine given orally to rats.

Three biodisposition studies with taurine were performed in male and female adult rats at dosages of 30 and 300 mg/kg. A single oral dose of (14)C-taurine was rapidly absorbed, distributed to tissues and excreted unchanged in urine. Elimination of radioactivity from intracellular pools was slow. Pre-treatment of animals for 14 days with unlabelled taurine did not significantly affect the fate of (14)C-taurine. At the higher dose there was more extensive excretion combined with a lower percentage of the dose in the carcass, indicating the possibility of saturation of the tubular reabsorption mechanism for taurine. Daily administration of unlabelled taurine for 14 days did not result in an increase in total taurine in the brain. The data indicate that exogenous taurine rapidly equilibrates with endogenous body pools and that any excess is rapidly eliminated by the kidneys.

Independent component analysis of pulse oximetry signals.

This paper describes the application of Independent Component Analysis (ICA) to signals from a pulse oximeter, an instrument that measures arterial blood oxygen content. ICA uses estimates of the second- and higher-order joint statistics of the input signals to separate the signal and interference. For time-derivative pulse oximetry signals, the skew of the arterial pulse component is generally much greater than that of the interference, and this can be used to aid the separation. This paper shows an example of ICA used on pulse oximetry signals and then presents simulations to demonstrate that, for pulse oximetry signals, ICA based on third-order statistics of the derivative is indeed superior to fourth-order ICA.

Perceived information needs and communication difficulties of inpatient physicians and nurses.

In order to understand the differing perceptions of information needs and communication patterns of healthcare professionals as they relate to medical errors, we conducted a survey and 5 focus group sessions of inpatient physicians and nurses. Although nurses and physicians stated differing information needs, both groups expressed significant problems with obtaining patient, domain and institution-specific information in a timely manner. Identification of appropriate providers and establishing contact with those people was perceived as the most pressing communication need. All focus group participants felt that communication difficulties were common and could give examples in which such difficulties led to adverse events. Our studies suggest that information needs and communication difficulties are common and can lead to medical errors or near misses. Many of these problems may be amenable to information technology solutions.

Development of an ontology to model medical errors, information needs, and the clinical communication space.

Medical errors are common, costly and often preventable. Work in understanding the proximal causes of medical errors demonstrates that systems failures predispose to adverse clinical events. Most of these systems failures are due to lack of appropriate information at the appropriate time during the course of clinical care. Problems with clinical communication are common proximal causes of medical errors. We have begun a project designed to measure the impact of wireless computing on medical errors. We report here on our efforts to develop an ontology representing the intersection of medical errors, information needs and the communication space. We will use this ontology to support the collection, storage and interpretation of project data. The ontology's formal representation of the concepts in this novel domain will help guide the rational deployment of our informatics interventions. A real-life scenario is evaluated using the ontology in order to demonstrate its utility.

Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters.

It is well established that human serum paraoxonase (PON1) catalyzes the hydrolysis of organophosphate insecticides and nerve agents, as well as that of a number of aromatic carboxylic acid esters. Our laboratory has recently found a new class of PON1 substrates that includes at least 30 lactones and cyclic carbonate esters. The lactone substrates vary in their ring size from 4 to 7 atoms. Substituents on the ring carbons may enhance or reduce the rate of lactone hydrolysis. An appreciable degree of stereospecificity exists with some activities differing up to 9-fold between enantiomers (i.e., S-alpha-hydroxy-gamma-butyrolactone is hydrolyzed 5 to 9 times faster than the R form). Thiolactones are hydrolyzed less efficiently, and some lactams are potent inhibitors. Four lactone-containing drugs-spironolactone, mevastatin, simvastatin, and lovastatin-have been identified as substrates for PON1. All lactone substrates are hydrolyzed by both the Q and R isozymes of human serum PON1. However, some lactone substrates are hydrolyzed faster by the Q than R isozyme, whereas others show a reverse preference. Moreover, these new substrates include homogentisic acid lactone, mevalonic acid lactone, homocysteine thiolactone, and gamma-hydroxybutyric acid lactone-all lactone forms of endogenous compounds. It is reasonable to expect that further investigations may uncover PON1 lactone substrates that are, themselves, endogenous compounds. In this article we characterize the basic enzymatic properties of PON1's newly identified hydrolytic activities with lactone and cyclic carbonate ester substrates and compare these properties with those of representative arylesters and organophosphates.

Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation.

The paraoxonase gene family contains at least three members: PON1, PON2, and PON3. The physiological roles of the corresponding gene products are still uncertain. Until recently, only the serum paraoxonase/arylesterase (PON1) had been purified and characterized. Here we report the purification, cloning, and characterization of rabbit serum PON3. PON3 is a 40-kDa protein associated with the high density lipoprotein fraction of serum. In contrast to PON1, PON3 has very limited arylesterase and no paraoxonase activities but rapidly hydrolyzes lactones such as statin prodrugs (e.g. lovastatin). These differences facilitated the complete separation of PON3 from PON1 during purification. PON3 hydrolyzes aromatic lactones and 5- or 6-member ring lactones with aliphatic substituents but not simple lactones or those with polar substituents. We cloned PON3 from total rabbit liver RNA and expressed it in mammalian 293T/17 cells. The recombinant PON3 has the same apparent molecular mass and substrate specificity as the enzyme purified from serum. Rabbit serum PON3 is more efficient than rabbit PON1 in protecting low density lipoprotein from copper-induced oxidation. This is the first report that identifies a second PON enzyme in mammalian serum and the first to describe an enzymatic activity for PON3.

Sensitization of 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin cytotoxicity by 5-bromo-2'-deoxyuridine in human glioma.

5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma cells. At a fixed concentration of BrdUrd and BCNU, the greatest cell loss was observed in exponentially growing cells. As cells approached plateau growth, cytotoxicity was reduced as indicated by greater cell viability. Under varying growth conditions the percentage of thymine replacement by bromouracil in DNA, as determined by gas chromatography/mass spectrometry analysis, declined as cultures approached maximum density. These data indicate BrdUrd must be incorporated into DNA for the enhanced effect to be observed. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysis (at 95% CL), a relationship between the level of bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional alkylating agents exert cytotoxicity by forming cross-links between cDNA strands, increased cross-link formation was not observed in BrdUrd substituted DNA as determined by alkaline elution. The data suggest that DNA damage induced by halogenated pyrimidines may not involve interstrand cross-links and that these agents may be useful in the treatment of glioma in combination with alkylating agents.

A distance to the galaxy NGC4258 from observations of Cepheid variable stars.

Cepheid variable stars pulsate in a way that is correlated with their intrinsic luminosity, making them useful as 'standard candles' for determining distances to galaxies; the potential systematic uncertainties in the resulting distances have been estimated to be only 8-10%. They have played a crucial role in establishing the extragalactic distance scale and hence the value of the Hubble constant. Here we report observations of Cepheids in the nearby galaxy NGC4258; the distance calculated from the Cepheids is 8.1 +/- 0.4 Mpc, where the uncertainty does not include possible systematic errors. There is an independently determined geometric distance to this galaxy of 7.2 +/- 0.5 Mpc, based on the observed proper motions of water masers orbiting the central black hole; the distances differ by 1.3sigma. If the maser-based distance is adopted and the Cepheid distance scale revised accordingly, the derived value of the Hubble constant would increase by 12 +/- 9%, while the expansion age of the Universe would decrease by the same amount.

Preferential cytotoxicity of cells transduced with cytosine deaminase compared to bystander cells after treatment with 5-flucytosine.

In vitro experiments from our laboratory and others have suggested that herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) gene therapy depends on gap junctional intercellular communication (GJIC) to produce a strong bystander effect. Furthermore, we have shown that cells transduced with HSV-TK can be protected from GCV-mediated toxicity by GJIC with bystander cells. We wished to determine whether GJIC affected either the bystander or protective effect of the cytosine deaminase (CD)/5-flucytosine (5-FC) gene therapy approach, in which CD converts 5-FC to 5-fluorouracil (5-FU). To test this, we designed a coculture system using communication-competent WB rat hepatocytes and a noncommunicating subclone (aB1), which were transduced with CD and with antibiotic resistance genes so that we could independently determine the survival of the CD-containing or bystander cells. We found that, compared to the HSV-TK/GCV strategy, bystander killing resulting from treatment with CD/5-FC does not depend on GJIC. However, our most striking finding was that both communication-competent and -incompetent CD-transduced cells were preferentially killed, by a factor of up to 500, compared to bystander cells. The lesser dependence of the CD/5-FC system on GJIC, combined with the finding that most cancer cells lack the capacity for GJIC, suggest that the CD/5-FC system may be superior to the HSV-TK/GCV approach for gene therapy. However, the premature death of the CD-transduced 5-FU "factory" suggests that other strategies may be necessary to produce a sufficient quantity of 5-FU for a duration long enough to produce permanent tumor regression.

Regional pharmacokinetics of 5-fluorouracil in dogs: role of the liver, gastrointestinal tract, and lungs.

The purpose of this study was to determine the presence and extent of pulmonary elimination for 5-fluorouracil (FUra). A secondary aim was to characterize the relative importance of the liver, gastrointestinal tract, splanchnic region, and lungs toward the overall elimination of FUra. A total of 10 mixed-breed male and female dogs were used in these acute studies in which FUra was administered through a cephalic vein. Six dogs were studied at sequentially escalated dose rates of 0.125, 0.250, 0.500, 0.750, and 1.00 micromol/min/kg (8-fold range); four dogs were studied at sequentially escalated dose rates of 0.0625, 0.250, 0.750, 1.50, and 2.00 micromol/min/kg (32-fold range). Each infusion lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, and pulmonary artery), perfusion rates were measured (hepatic artery, portal vein, and cardiac output), and pharmacokinetic parameters were directly assessed. Pulmonary elimination of FUra was conclusively demonstrated. Although only 17% of the drug was extracted by the lungs at the lowest dose rate, pulmonary clearance (16.0 ml/min/kg) was on the order of splanchnic clearance (13.5 ml/min/kg), or larger. As the dose rate increased, pulmonary clearance was more easily saturated than splanchnic clearance. Thus, it appears that at increasing dose rates, the splanchnic region becomes a more significant pathway, whereas the lungs have a reduced role in the overall elimination of FUra.

Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics.

BACKGROUND: This study evaluated the dose-related ethanol-like subjective effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine hydrochloride in recently detoxified alcoholics. METHODS: Twenty male inpatients meeting DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 10 to 27 days prior to the study completed 3 test days that involved the intravenous infusion of ketamine hydrochloride (0.1 mg/kg or 0.5 mg/kg) or saline solution under randomized double-blind conditions. Ethanol-like subjective effects were assessed using the Sensation Scale; the Biphasic Alcohol Effects Scale; visual analog scales to measure "high" and degree of similarity to ethanol, cocaine, and marijuana; a scale assessing the number of standard alcohol drinks producing similar subjective effects; and visual analog scales measuring ethanol craving. RESULTS: Ketamine produced dose-related ethanol-like effects on each scale measuring its similarity to ethanol. Its effects were more similar to the sedative or descending limb effects of ethanol than to the stimulant or ascending limb effects. Ketamine effects also were more like ethanol than marijuana or cocaine. Ethanol-like effects were more prominent at the higher ketamine dose, a dose rated as similar to greater levels of ethanol intoxication. However, ketamine did not increase craving for ethanol. CONCLUSION: The production of ethanol-like subjective effects by ketamine supports the potential clinical importance of NMDA receptor antagonism among the mechanisms underlying the subjective effects of ethanol in humans.

Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

A new route, jet injection for anesthetic induction in children--III. Ketamine pharmacokinetic studies.

The jet injector route for ketamine was used on 30 children 1-6 years of age undergoing various surgical procedures. A randomly selected dose of 2.5, 3.5, or 6.0 mg/kg of ketamine was given to induce anesthesia. Peak plasma ketamine levels did not follow a simple arithmetic increment related to dose. Dosage based on mg/m2 body surface area or mg/kg body weight provided similar blood levels of ketamine. The beta-phase t1/2 of ketamine in these children was shorter than that found in adults. Considerable individual variability was observed in both the plasma levels to a given dose of jet-injected ketamine and in the beta-phase t1/2. The ketamine beta-t1/2s were not dose related.

Lesion contrast enhancement in medical ultrasound imaging.

Methods for improving the contrast-to-noise ratio (CNR) of low-contrast lesions in medical ultrasound imaging are described. Differences in the frequency spectra and amplitude distributions of the lesion and its surroundings can be used to increase the CNR of the lesion relative to the background. Automated graylevel mapping is used in combination with a contrast-weighted form of frequency-diversity speckle reduction. In clinical studies, the techniques have yielded mean CNR improvements of 3.2 dB above ordinary frequency-diversity imaging and 5.6 dB over sharper conventional images, with no post-processing graylevel mapping.