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.

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.

Heparin facilitates the extraction of tissue fibronectin.

Extraction of fibronectin from two human tissues, lung parenchyma and placental villi, was facilitated by the incorporation of heparin into extraction media. The effect of heparin was additive to the effect of urea which is known to extract fibronectin. These experiments provide further evidence that fibronectin and glycosaminoglycans are associated in connective tissues and the use of heparin forms the basis for a simple method for extraction and quantitation of tissue fibronectin.

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.

Cold-insoluble globulin (fibronectin) in connective tissues of adult human lung and in trophoblast basement membrane.

Cold-insoluble globulin (CIG), which is immunochemically indistinguishable from the fibroblast surface protein known as large external transformation-sensitive glycoprotein and fibronectin, was detected immunologically in connective tissue fractions from adult human lung. The fractions tested were (a) intact parenchyma, (b) acidic structural glycoproteins (ASG) extracted from lung parenchyma with 0.3 M acetic acid, and (c) isolated alveolar basement membrane (ABM). For comparison with ABM, preparations of human glomerular basement membrane and human trophoblast basement membrane (TBM) were tested. CIG was not detected in glomerular basement membrane but was present in large amounts in TBM. The CIG antigen could be solubilized from the parenchyma and from ABM by collagenase digestion which indicates that CIG occurs in lung connective tissue in association with collagen. Fibrinogen antigenic determinants were present in the ASG fraction, but the question of whether CIG and fibrin(ogen) are associated in lung connective tissue requires further study. When CIG was quantified by electroimmunoassay, intact lung parenchyma contained approximately equal to 0.4% CIG, ASG contained 3-4.5% CIG, ABM contained 0.1-0.9% CIG and TBM contained 1.5%-7.2% Cg. the evidence suggests that CIG is a chemical constituent of lung connective tissue matrix where it may influence the function of alveoli.

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.

Left ventricular mass increases during cardiac allograft vascular rejection.

OBJECTIVES: This study evaluated whether left ventricular mass increases during cellular or vascular (humoral) cardiac allograft rejection. BACKGROUND: An increase in left ventricular mass during cellular cardiac allograft rejection has been described by other investigators, although controversy has existed over the validity of these findings. Left ventricular mass changes have not been evaluated in the setting of vascular (humoral) cardiac allograft rejection. METHODS: To determine the effect of allograft rejection on left ventricular mass, we retrospectively reviewed endomyocardial biopsy results and corresponding echocardiograms in 41 cardiac transplant recipients undergoing treatment for allograft rejection. Left ventricular mass was assessed by two-dimensional echocardiography using the method of Schiller. Maintenance immunosuppression included cyclosporine in all patients. RESULTS: Although significant changes in left ventricular wall thickness, mass and dimensions were not observed in patients experiencing moderate or severe cellular allograft rejection (International Society for Heart and Lung Transplantation grades III and IV, n = 27), marked changes were noted in patients with vascular (humoral) rejection (n = 14). Patients with vascular rejection demonstrated an echocardiographic mean (+/- SEM) increase in left ventricular wall mass (from 109 +/- 17 to 151 +/- 17 g), and left ventricular wall thickness (from 1.3 +/- 0.1 to 1.6 +/- 0.1 cm) during the rejection episode. Additionally, vascular rejection was associated with a trend toward an increase in left ventricular systolic dimension (from 2.6 +/- 0.1 to 3.0 +/- 0.2 cm) and a decrease in left ventricular fractional shortening and increased incidence of hemodynamic compromise with rejection (50% for vascular vs. 11% for cellular rejection). CONCLUSIONS: Left ventricular mass increases during episodes of vascular (humoral) rejection, but there is no significant change in left ventricular mass during cellular cardiac allograft rejection.

Comparison of observer and videodensitometric measurements of simulated coronary artery stenoses.

To test the applicability of an automated vessel measurement technique to coronary arteriography, a videodensitometric method with caliper measurements on digital subtraction images of a moving coronary artery phantom was compared. Percent diameter stenosis was determined by both methods, revealing a twofold improvement in reproducibility with the videodensitometric method, with percent stenosis being determined within +/- 10% for two different iodine concentrations injected during continuous flow into the simulated coronary arteries. Absolute diameters were also measured by the videodensitometric method, showing a high degree of correlation between measured and true diameter for vessels between 0.5-3.0 mm.

Presence of fibronectin in basement membranes and acidic structural glycoproteins from human placenta and lung.

Cold-insoluble globulin was detected in both trophoblast and alveolar basement membrane preparations, whereas it was not detected in GBM preparations. Acidic structural glycoproteins from both placental villi and lung parenchyma, which were extracted with 0.3 M acetic acid and recovered by adjusting the pH to 4.7, also contained CIg. Fractions of TBM, solubilized by either dilute alkali (0.01 N NaOH), by reduction and alkylation of the disulfide bonds, or by 0.3 M acetic acid extraction, all contained the antigen and possessed properties similar to those of ASG. The ASG fractions also reacted with antifibrinogen, but proof that the two types of determinants occur on a given molecular species is lacking at present. Purified collagenase solubilized CIg from ABM, from lung parenchyma, and from the stroma of placental villi, and this finding is strong evidence for an association of CIg with collagen in these connective tissues.

An event model of medical information representation.

OBJECTIVE: Develop a model for structured and encoded representation of medical information that supports human review, decision support applications, ad hoc queries, statistical analysis, and natural-language processing. DESIGN: A medical information representation model was developed from manual and semiautomated analysis of patient data. The key assumption of the model is that medical information can be represented as a series of linked events. The event representation has two main components. The first component is a frame or template definition that specifies the attributes of the event. The second component is a structured vocabulary, the terms of which are taken as the values of the slots in the event template structure. Individual event instances are linked by specific named relationships. RESULTS: The proposed model was used to represent a chest-radiograph report. CONCLUSIONS: The event model of medical information representation provides a mechanism for formal definition of the logical structure of medical data and allows explicit time-oriented and associative relationships between event instances.

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.

Hyaluronan affects extravascular water in lungs of unanesthetized rabbits.

We have determined whether changes in lung hyaluronan content affect extravascular water in lungs of unanesthetized rabbits. Three groups of experiments were performed. In group 1 (n = 12), no infusions were given; in group 2, nine pairs of rabbits received either intravenous hyaluronidase (750 U.kg-1.min-1) or an equivalent volume of saline; in group 3, nine pairs of rabbits received either hyaluronidase or saline, followed by intravenous saline infusion amounting to 24% of body weight. At the end of each experiment, one lung was analyzed for extravascular lung water by the wet-dry method. Except for group 3, in all animals the other lung was analyzed for hyaluronan content by a method that involved hydrolyzing lung hyaluronan with fungal hyaluronidase to release reducing N-acetyl glucosamine groups, which were quantified. In group 1, lung hyaluronan, which varied from 50 to 159 micrograms/g dry wt (mean 106 +/- 35 micrograms/g dry wt), significantly correlated with variation in extravascular lung water (mean 4.2 +/- 0.3 g/g dry wt). In group 2 rabbits given hyaluronidase, lung hyaluronan was 40% lower and extravascular lung water was 14.6% lower than in paired controls (P less than 0.01). In group 3, volume expansion did not affect lung water, except after hyaluronidase when lung water was 47% higher than paired controls. We conclude that in the lung the content of hyaluronan is one of the determinants of extravascular water content.

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.

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.

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.

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.

Evaluation of a semantic data model for chest radiology: application of a new methodology.

An essential step toward the effective processing of the medical language is the development of representational models that formalize the language semantics. These models, also known as semantic data models, help to unlock the meaning of descriptive expressions, making them accessible to computer systems. The present study tries to determine the quality of a semantic data model created to encode chest radiology findings. The evaluation methodology relied on the ability of physicians to extract information from textual and encoded representations of chest X-ray reports, whilst answering questions associated with each report. The evaluation demonstrated that the encoded reports seemed to have the same information content of the original textual reports. The methodology generated useful data regarding the quality of the data model, demonstrating that certain segments were creating ambiguous representations and that some details were not being represented.

Evaluation of the agar gel immunodiffusion test for diagnosis of subclinical paratuberculosis in cattle.

Concurrent bacteriologic culture of feces and agar gel immunodiffusion (AGID) testing was performed on all cows and bred heifers over 14 months old in 10 dairy herds during a 32-month period to determine the effectiveness of the AGID test for the detection of subclinical paratuberculosis. Herds were sampled 5 times and, when possible, culled animals were tested again at slaughter. During 5 herd-wide samplings, Mycobacterium paratuberculosis was isolated from 139 fecal specimens obtained from 109 cattle. Results of the AGID test were simultaneously positive 40 of 139 times (28.8%). Thirty-six of the 109 cattle (33.0%) determined to be infected had a positive AGID test result at some point during the 5 herd-wide samplings. When results of tests performed at time of slaughter were included, 117 cattle were identified as infected by culture methods; 55 of these (47.0%) were AGID test-positive at some point during the study. The upper limit of the maximal false-positive rate for the AGID test was 2.1%. On the basis of colony counts from cultures, subclinically infected cows shedding higher numbers of M paratuberculosis in their feces were more likely to have positive AGID test results (P less than 0.0001). In known infected cattle, neither the culture nor AGID test results were consistently positive on repeated testing. Of 48 official calfhood paratuberculosis vaccinates tested as adults, 3 had positive AGID test results and in 1 of these, M paratuberculosis was also isolated from the feces, indicating that the rate of false-positive AGID test results in calfhood vaccinates is low.

Evaluation of an inpatient decentralized pharmacy team program in an HMO setting.

Decentralized drug distribution and clinical pharmacy services were implemented on two nursing units, orthopedics and oncology, of a health maintenance organization-owned hospital. The use of targeted high-cost drugs was assessed before and during the decentralized pharmacy services intervention on the experimental units and on a comparison unit. Other assessments included a survey of nurses from the experimental units and surveillance of telephone encounters between the central pharmacy and the experimental units. In the experimental units, there were significant changes in cefazolin therapy for prophylaxis, aminoglycoside therapy, and metoclopramide use from baseline to the intervention periods. Cefazolin use for prophylaxis essentially remained the same in the comparison unit. Telephone encounters decreased substantially from the before- to the during-program period. An increase in the proportion of inappropriately drawn aminoglycoside blood levels was also noted in the during-program period. Decentralized pharmacy services appeared to reduce the cost of targeted drugs and improve communications with the nursing units.