Drug use and phylogenetic clustering of hepatitis C virus infection among people who use drugs in Vancouver, Canada: A latent class analysis approach.

This study estimated latent classes (ie, unobserved subgroups in a population) of people who use drugs in Vancouver, Canada, and examined how these classes relate to phylogenetic clustering of hepatitis C virus (HCV) infection. HCV antibody-positive people who use drugs from two cohorts in Vancouver, Canada (1996-2012), with a Core-E2 sequence were included. Time-stamped phylogenetic trees were inferred, and phylogenetic clustering was determined by time to most common recent ancestor. Latent classes were estimated, and the association with the phylogenetic clustering outcome was assessed using an inclusive classify/analyse approach. Among 699 HCV RNA-positive participants (26% female, 24% HIV+), recent drug use included injecting cocaine (80%), injecting heroin (70%), injecting cocaine/heroin (ie, speedball, 38%) and crack cocaine smoking (28%). Latent class analysis identified four distinct subgroups of drug use typologies: (i) cocaine injecting, (ii) opioid and cocaine injecting, (iii) crack cocaine smoking and (iv) heroin injecting and currently receiving opioid substitution therapy. After adjusting for age and HIV infection, compared to the group defined by heroin injecting and currently receiving opioid substitution therapy, the odds of phylogenetic cluster membership was greater in the cocaine injecting group (adjusted OR [aOR]: 3.06; 95% CI: 1.73, 5.42) and lower in the crack cocaine smoking group (aOR: 0.06; 95% CI: 0.01, 0.48). Combining latent class and phylogenetic clustering analyses provides novel insights into the complex dynamics of HCV transmission. Incorporating differing risk profiles associated with drug use may provide opportunities to further optimize and target HCV treatment and prevention strategies.

Identification of risk factors associated with acute kidney injury in patients admitted to acute medical units.

In 2009, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report identified significant deficiencies in the management of acute kidney injury (AKI) in hospitals in the UK. Many errors arose from failure to recognise patients with AKI and those at risk of developing AKI. Currently, there is no universally accepted risk factor assessment for identifying such patients on admission to acute medical units (AMUs). A multicentre prospective observational study was performed in the AMUs of 10 hospitals in England and Scotland to define the risk factors associated with AKI and to assess quality of care. Data were collected on consecutive acute medical admissions over two separate 24-h periods. Acute kidney injury was present in 55/316 (17.7%) patients, with sepsis, hypovolaemia, chronic kidney disease (CKD) and diabetes mellitus identified as the major risk factors. Deficiencies in patient care were identified, reinforcing the continuing need to improve the management of AKI.

Initial results of the high resolution edge Thomson scattering upgrade at DIII-D.

Validation of models of pedestal structure is an important part of predicting pedestal height and performance in future tokamaks. The Thomson scattering diagnostic at DIII-D has been upgraded in support of validating these models. Spatial and temporal resolution, as well as signal to noise ratio, have all been specifically enhanced in the pedestal region. This region is now diagnosed by 20 view-chords with a spacing of 6 mm and a scattering length of just under 5 mm sampled at a nominal rate of 250 Hz. When mapped to the outboard midplane, this corresponds to ~3 mm spacing. These measurements are being used to test critical gradient models, in which pedestal gradients increase in time until a threshold is reached. This paper will describe the specifications of the upgrade and present initial results of the system.

Vascular access type and risk of mortality in a national prospective cohort of haemodialysis patients.

BACKGROUND: Central venous catheters (CVC) are a potential source of bacteraemia and have been associated with increased mortality in haemodialysis patients. We aimed to investigate the relationships between haemodialysis vascular access, taking into account changes in vascular access type during patients' lives, and cause specific mortality risk in a national cohort of dialysis patients. METHODS: Prospective cohort study including all patients receiving haemodialysis in Scotland at annual cross sectional surveys in 2009, 2010 and 2011. Data were collected through the Scottish Renal Registry and by a structured review of case records following death. Cox proportional hazards regression and multivariable logistic regression were used to model survival and risk of death from septicaemia respectively. RESULTS: Of a cohort of 2666 patients, 873 (32%) died during follow-up. After case-mix adjustment, patients using only tunnelled CVC during follow-up had a higher risk of all cause mortality across all strata of prior renal replacement therapy exposure [adjusted hazard ratio (HR): 1.83-2.08]. Case-mix adjusted risks of cardiovascular death (adjusted HR: 2.20-2.95) and infection-related death (adjusted HR: 3.10-3.63) were also higher in this group. Patients using tunnelled CVCs during follow-up and prior to death had 6.9-fold higher odds of death from septicaemia compared with those using only arteriovenous fistulae or grafts. CONCLUSION: Compared with an arteriovenous fistula or graft, sustained use of tunnelled CVCs for vascular access is associated with higher risks of all-cause, cardiovascular and infection-related mortality.

Thomson scattering diagnostic upgrade on DIII-D.

The DIII-D Thomson scattering system has been upgraded. A new data acquisition hardware was installed, adding the capacity for additional spatial channels and longer acquisition times for temperature and density measurements. Detector modules were replaced with faster transimpedance circuitry, increasing the signal-to-noise ratio by a factor of 2. This allows for future expansion to the edge system. A second phase upgrade scheduled for 2010-2011 includes the installation of four 1 J/pulse Nd:YAG lasers at 50 Hz repetition rate. This paper presents the first completed phase of the upgrade and performance comparison between the original system and the upgraded system. The plan for the second phase is also presented.

Resonant pedestal pressure reduction induced by a thermal transport enhancement due to stochastic magnetic boundary layers in high temperature plasmas.

Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p(e) in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q95 resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p(e) reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q95 resonant character of type-I edge localized mode suppression by RMPs.

Countering imbalanced datasets to improve adverse drug event predictive models in labor and delivery.

BACKGROUND: The IOM report, Preventing Medication Errors, emphasizes the overall lack of knowledge of the incidence of adverse drug events (ADE). Operating rooms, emergency departments and intensive care units are known to have a higher incidence of ADE. Labor and delivery (L&D) is an emergency care unit that could have an increased risk of ADE, where reported rates remain low and under-reporting is suspected. Risk factor identification with electronic pattern recognition techniques could improve ADE detection rates. OBJECTIVE: The objective of the present study is to apply Synthetic Minority Over Sampling Technique (SMOTE) as an enhanced sampling method in a sparse dataset to generate prediction models to identify ADE in women admitted for labor and delivery based on patient risk factors and comorbidities. RESULTS: By creating synthetic cases with the SMOTE algorithm and using a 10-fold cross-validation technique, we demonstrated improved performance of the Naïve Bayes and the decision tree algorithms. The true positive rate (TPR) of 0.32 in the raw dataset increased to 0.67 in the 800% over-sampled dataset. CONCLUSION: Enhanced performance from classification algorithms can be attained with the use of synthetic minority class oversampling techniques in sparse clinical datasets. Predictive models created in this manner can be used to develop evidence based ADE monitoring systems.

Dust measurements in tokamaks (invited).

Dust production and accumulation present potential safety and operational issues for the ITER. Dust diagnostics can be divided into two groups: diagnostics of dust on surfaces and diagnostics of dust in plasma. Diagnostics from both groups are employed in contemporary tokamaks; new diagnostics suitable for ITER are also being developed and tested. Dust accumulation in ITER is likely to occur in hidden areas, e.g., between tiles and under divertor baffles. A novel electrostatic dust detector for monitoring dust in these regions has been developed and tested at PPPL. In the DIII-D tokamak dust diagnostics include Mie scattering from Nd:YAG lasers, visible imaging, and spectroscopy. Laser scattering is able to resolve particles between 0.16 and 1.6 microm in diameter; using these data the total dust content in the edge plasmas and trends in the dust production rates within this size range have been established. Individual dust particles are observed by visible imaging using fast framing cameras, detecting dust particles of a few microns in diameter and larger. Dust velocities and trajectories can be determined in two-dimension with a single camera or three-dimension using multiple cameras, but determination of particle size is challenging. In order to calibrate diagnostics and benchmark dust dynamics modeling, precharacterized carbon dust has been injected into the lower divertor of DIII-D. Injected dust is seen by cameras, and spectroscopic diagnostics observe an increase in carbon line (CI, CII, C(2) dimer) and thermal continuum emissions from the injected dust. The latter observation can be used in the design of novel dust survey diagnostics.

UMLS-based automatic image indexing.

To date, most accurate image retrieval techniques rely on textual descriptions of images. Our goal is to automatically generate indexing terms for an image extracted from a biomedical article by identifying Unified Medical Language System (UMLS) concepts in image caption and its discussion in the text. In a pilot evaluation of the suggested image indexing method by five physicians, a third of the automatically identified index terms were found suitable for indexing.

Sex- and strain-dependent effects of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) in the mouse.

We have previously demonstrated that 50mg/kg of epigallocatechin gallate (EGCG) is hepatotoxic to female Swiss Webster mice, while lower doses of EGCG and epicatechin gallate (ECG) modulate various cytochrome P450 (CYP) isoforms. Therefore, this study was designed to further investigate the role of strain and sex in catechin-mediated enzyme modulation and hepatotoxicity in mice. Male and female BALB/c and male Swiss Webster mice were treated with either ECG or EGCG (25 and 50 mg/kg, ip) for 7 days. The results demonstrated that EGCG (50 mg/kg) produced severe hepatic necrosis, elevated ALT activities and a 20% mortality rate in male Swiss Webster mice and mild hepatotoxicity in male BALB/c mice. In female BALB/c mice the mortality rate was 20%, which correlated with extensive hepatic necrosis. Of the two catechins, only ECG significantly inhibited CYP isoforms. Specifically, prostatic aromatase activity decreased by 31+/-2%, while CYP1A catalytic activity and polypeptide levels were decreased 29+/-6% and 25+/-4%, respectively. However, CYP2E1 and CYP3A activity remained unchanged following ECG administration. Additionally, EGCG did not alter aromatase, CYP1A, CYP3A or CYP2E1 in male Swiss Webster mice. In conclusion, EGCG (50 mg/kg) elicits mortality in both male and female Swiss Webster mice, as well as female BALB/c mice. ECG significantly inhibits both aromatase and CYP1A in male Swiss Webster mice. Therefore, sex-specific modulation of CYP isoforms occurs following administration of EGCG and ECG in Swiss Webster mice.

Tamoxifen and epigallocatechin gallate are synergistically cytotoxic to MDA-MB-231 human breast cancer cells.

High concentrations of specific catechins [epigallocatechin gallate (EGCG), epigallocatechin (EGC) and epicatechin gallate (ECG)] inhibit the proliferation of many different cancer cell lines. The aim of this work was to determine if low concentrations of catechins with and without 4-hydroxytamoxifen (4-OHT) co-treatment would cause significant cytotoxicity in estrogen receptor-positive (ERalpha+) and -negative (ERalpha-) human breast cancer cells. Therefore, MCF-7, T47D, MDA-MB-231 and HS578T cells were incubated with EGCG, EGC or ECG (5-25 microM) individually and in combination with 4-OHT for 7 days. Cell number was determined by the sulforhodamine B cell proliferation assay. As single agents, none of the catechins were cytotoxic to T47D cells, while only EGCG (20 microM) elicited cytotoxicity in MCF-7 cells. Additionally, no benefit was gained by combination treatment with 4-OHT. ERalpha- human breast cancer cells were more susceptible as all three catechins were significantly cytotoxic to HS578T cells at concentrations of 10 microM. In this cell line, combination with 4-OHT did not increase cytotoxicity. However, the most striking results were produced in MDA-MB-231 cells. In this cell line, EGCG (25 microM) produced a greater cytotoxic effect than 4-OHT (1 microM) and the combination of the two resulted in synergistic cytotoxicity. In conclusion, low concentrations of catechins are cytotoxic to ERalpha- human breast cancer cells, and the combination of EGCG and 4-OHT elicits synergistic cytotoxicity in MDA-MB-231 cells.

Short term treatment with St. John's wort, hypericin or hyperforin fails to induce CYP450 isoforms in the Swiss Webster mouse.

This investigation was designed to determine whether St. John's wort (SJW)(435 mg/kg/d), a readily available antidepressant, or its purported active constituents hypericin (1 mg/kg/d) and hyperforin (10 mg/kg/d) were able to induce various hepatic cytochrome P450 (CYP450) isoforms. SJW, hypericin and hyperforin were administered to male Swiss Webster mice for four consecutive days and hepatic microsomes were prepared on day 5. None of the three treatments resulted in a statistical change in total hepatic CYP450 (SJW treated 0.95 +/- 0.09 nmol/mg vs control 1.09 +/- 0.14 nmol/mg). Furthermore, the catalytic activities of CYP1A2. CYP2E1 and CYP3A were unchanged from control following all three treatments as determined by ethoxyresorufin O-deethylation, p-nitrophenol hydroxylation and erythromycin N-demethylation respectively. Additionally, western immunoblotting demonstrated that there was no significant change in the polypeptide levels of any of the three isoforms. These results indicate that four days of treatment with moderate to high doses of SJW, hyperforin or hypericin fails to induce these CYP450 isoforms in the male Swiss Webster mouse.

St. John's wort extract induces CYP3A and CYP2E1 in the Swiss Webster mouse.

This investigation was designed to determine the ability of St. John's wort (SJW), a readily available antidepressant, to induce various hepatic drug metabolizing enzymes. SJW (140 or 280 mg/kg/day) was administered to male Swiss Webster mice for 1, 2, or 3 weeks. Enzymatic activity was analyzed in hepatic microsomes for all of the following drug metabolizing enzymes: CYP3A, CYP1A, CYP2E1, and UDP-glucuronosyltransferase (UDPGT). The catalytic activity of CYP1A was unchanged from control following any dose or duration of SJW, while both CYP3A and CYP2E1 catalytic activities were increased 2-fold by both SJW concentrations but only following 3 weeks of administration. Results from Western immunoblotting studies supported the changes in catalytic activity, as protein levels for CYP2E1 and CYP3A were increased (2.5-fold and 6-fold, respectively) following 3 weeks of SJW administration. Additionally, the catalytic activity of the conjugation enzyme UDPGT was unchanged from control following all SJW treatments. These results indicate that in the mouse moderate doses of SJW cause an increase in the catalytic activity and polypeptide levels of CYP2E1 and CYP3A but only following 21 days of administration, while the catalytic activity of CYP1A and UDPGT activity remain unaffected.

Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: mechanistic studies.

This study was designed to elucidate the mechanism of retinol's potentiation of acetaminophen-induced hepatotoxicity. To accomplish this, the major bioactivation and detoxification pathways for acetaminophen were investigated following retinol (75 mg/kg/day, 4 days), acetaminophen (400 mg/kg), and retinol + acetaminophen treatment. Hepatic microsomes were used to determine the catalytic activity and polypeptide levels of cytochrome P450 enzymes involved in the murine metabolism of acetaminophen. Results showed that the catalytic activity and polypeptide levels of CYP1A2, CYP2E1, and CYP3A were unchanged in the treatment groups compared to vehicle and untreated controls. In combination, retinol + acetaminophen caused a significantly greater depletion of GSH compared to corn oil + acetaminophen (0.36 +/- 0.11 vs 0.89 +/- 0.19 micromol/g, respectively, p < 0.05). This greater GSH depletion correlated with a higher degree of hepatic injury in the retinol + acetaminophen-treated animals but is probably not the cause of the potentiated injury since the results showed that retinol treatment itself did not alter hepatic glutathione (3.34 +/- 0.43 vs 3.44 +/- 0.46 micromol/g for retinol vs vehicle, respectively). However, hepatic UDPGA stores were decreased in the retinol-treated group compared to untreated and corn oil controls (54.6 +/- 10.6 vs 200.6 +/- 17.6 nmol/g for retinol and untreated control, respectively, p < 0.001). This demonstrates that there is significantly less hepatic UDPGA available for conjugation following retinol administration. The results suggest that decreased hepatic UDPGA is likely the cause of retinol's potentiation of acetaminophen-induced hepatic injury.

The role of hyaluronan in the pulmonary alveolus.

The duplex nature of the lining of the pulmonary alveolus has long been appreciated. It appears that surfactant is present at the interface with air where it prevents the collapse of the alveolus by lowering surface tension and that the surfactant rests on an aqueous subphase. This subphase has enough structure to form a smooth, continuous surface over the projections of the epithelial cells and because of its hydrophilic nature it attracts the polar heads of surfactant phospholipids. The chemical composition of the subphase has not been addressed. Type II cells in the wall of the alveolus are specialized to produce surfactant and they also secrete hyaluronan (hyaluronic acid) into the subphase. In solution, molecules of hyaluronan appear to be flexible coils which self-aggregate. The resulting solutions are quite viscous and exhibit non-Newtonian behavior. Hyaluronan binds to cell surface receptors and to proteins in the extracellular matrix. The networks formed with self-aggregated hyaluronan with or without proteins create gels whose properties depend largely upon the molecular weight of the hyaluronan and its concentration. Hyaluronan is also known to interact with phospholipids and has hydrophobic regions which could bind to the hydrophobic surfactant proteins B and C. The working hypothesis presented herein states that hyaluronan interacts with itself and with proteins in the subphase to form a hydrophilic gel. At the epithelial cell layer the components are concentrated due to tethered HA molecules and the gel smooths over cell projections. At the air interface the components are so dilute that a layer which is essentially water is present. The surfactant phospholipids spread on the water. Direct interactions of HA and surfactant phospholipids may also occur and contribute to the stability of the surfactant layer.

The effect of retinol on hepatic and renal drug-metabolising enzymes.

Retinol pretreatment (75 mg/kg/day, 4 days) potentiated paracetamol-induced hepatotoxicity in BALB/c mice (alanine aminotransferase (ALT) activity; 2510+/-602 vs 1155+/-282 IU/l; retinol+paracetamol vs corn oil+paracetamol, respectively, P<0.05); however, this potentiation did not occur in the kidney, indicating an organ-specific response. Retinol treatment alone was not toxic in either organ, as indicated by ALT activity, blood urea nitrogen and creatinine. The potentiation effect could be mediated by retinol's induction of CYP450 isoforms relevant to paracetamol metabolism or through depletion of glutathione. Therefore, these parameters were investigated in both organs. Following retinol treatment, renal CYP2E1 and hepatic CYP1A2 and CYP2E1 catalytic activities and polypeptide levels were unchanged. However, retinol significantly decreased both the catalytic activity (0.23+/-0.03 vs 0.53+/-0.06 nmol/mg/min; retinol vs untreated, respectively, P<0.05) and polypeptide levels (58+/-0.6% of control) of hepatic CYP3A. Inhibition of renal CYP3A did not occur as catalytic activity and polypeptide levels were unchanged from control. Following retinol treatment, total reduced glutathione levels, in both organs, were not significantly different from control. Therefore, the potentiation of paracetamol-induced hepatotoxicity is independent of CYP450 and glutathione.

The feasibility of remote-controlled assistance as a search tool for patient education.

Patients often desire more information about their conditions than they receive during a physician office visit. To address the patient's information needs, a touchscreen information kiosk was implemented. Results from the first prototype identified interface, security, and technical issues. Misspelling of search terms was identified as the most observable cause of search failure. An experimental remote control assistance feature was added in the second prototype. The feature allowed a medical librarian to provide real-time remote help during searches by taking control of the patient's computer. Remote assistance improved patient satisfaction, increased ease of use, and raised document retrieval rate (86.7% vs. 56.7%). Both patients and librarians found the application useful. Reasons included its convenience and flexibility, opportunity for direct patient contact, ability to teach through direct demonstration, and complementing the librarian's role as an information gateway. The project demonstrated the feasibility of applying remote control technology to patient education.

Role of cytochrome P4502E1 in retinol's attenuation of carbon tetrachloride-induced hepatotoxicity in the Swiss Webster mouse.

In the mouse, retinol administration attenuates carbon tetrachloride (CCl4)-induced hepatic injury. We have investigated the role of cytochrome P4502E1 (CYP2E1) in this interaction. Male Swiss Webster mice were administered retinol (75 mg/kg/d) or vehicle for 3 days prior to CCl4 (30 microl/kg, ip). Hepatotoxicity produced by CCl4 was assessed by plasma alanine aminotransferase (ALT) activity and light microscopy (ALT activity of 1391+/-430 vs. 274+/-92 IU/L for vehicle + CCl4 and retinol + CCl4 treatments respectively, p < 0.05). Retinol's attenuation of liver injury was maintained when CCl4 was administered 48 h after the conclusion of the retinol pretreatment. Aniline hydroxylation activity, an indicator of CYP2E1 catalytic activity, determined on day 4 was 33.8% of untreated control in vehicle + CCl4 treatments while the retinol + CCl4 treatment group was 94.2% of untreated control. Additionally, CYP2E1 immunoreactive protein was 78% lower in vehicle + CCl4 vs. retinol + CCl4 treatment groups. Attenuation of potentiated hepatotoxicity was also observed when CYP2E1 was induced by acetone (ALT activity of 3119+/-1066 vs. 247+/-77 IU/L for vehicle and retinol treatments respectively, p < 0.05). In the mouse, retinol itself does not alter constitutive or inducible CYP2E1 expression. However, in combination with CCl4 retinol does reduce the amount of CCl4 bioactivated to its toxic metabolite. We conclude that retinol attenuates CCl4-induced hepatotoxicity by causing a decrease in CCl4 bioactivation but does not cause a decrease in CYP2E1 expression.

Medical student database development: a model for record management in a multi-departmental setting.

Student records flow through medical school offices at a rapid rate. Much of this data is often tracked on paper, spread across multiple departments. The Medical Student Informatics Group at the University of Utah School of Medicine identified offices and organizations documenting student information. We assessed departmental needs, identified records, and researched database software available within the private sector and academic community. Although a host of database applications exist, few publications discuss database models for storage and retrieval of student records. We developed and deployed an Internet based application to meet current requirements, and allow for future expandability. During a test period, users were polled regarding utility, security, stability, ease of use, data accuracy, and potential project expansion. Feedback demonstrated widespread approval, and considerable interest in additional feature development. This experience suggests that many medical schools would benefit from centralized database management of student records.

Image acquisition context: procedure description attributes for clinically relevant indexing and selective retrieval of biomedical images.

OBJECTIVE: To support clinically relevant indexing of biomedical images and image-related information based on the attributes of image acquisition procedures and the judgments (observations) expressed by observers in the process of image interpretation. DESIGN: The authors introduce the notion of "image acquisition context," the set of attributes that describe image acquisition procedures, and present a standards-based strategy for utilizing the attributes of image acquisition context as indexing and retrieval keys for digital image libraries. METHODS: The authors' indexing strategy is based on an interdependent message/terminology architecture that combines the Digital Imaging and Communication in Medicine (DICOM) standard, the SNOMED (Systematized Nomenclature of Human and Veterinary Medicine) vocabulary, and the SNOMED DICOM microglossary. The SNOMED DICOM microglossary provides context-dependent mapping of terminology to DICOM data elements. RESULTS: The capability of embedding standard coded descriptors in DICOM image headers and image-interpretation reports improves the potential for selective retrieval of image-related information. This favorably affects information management in digital libraries.