Incarceration and drug use patterns among a cohort of injection drug users

Aims   Drug law enforcement remains the dominant response to drug-related harm. However, the impact of incarceration on deterring drug use remains under-evaluated. We sought to explore the relationship between incarceration and patterns of drug use among people who inject drugs (IDU).
Design   Using generalized estimating equations (GEE), we examined the prevalence and correlates of injection cessation among participants in the Vancouver Injection Drug User Study followed over 9 years. In subanalyses, we used McNemar's tests and linear growth curve analyses to assess changes in drug use patterns before and after a period of incarceration among participants reporting incarceration and those not incarcerated.
Findings   Among 1603 IDU, 842 (53%) reported injection cessation for at least 6 months at some point during follow-up. In multivariate GEE analyses, recent incarceration was associated negatively with injection cessation [adjusted odds ratio (AOR) = 0.43, 95% confidence interval (CI) 0.37–0.50], whereas the use of methadone was associated positively with cessation (AOR = 1.38, 95% CI 1.22–1.56). In subanalyses assessing longitudinal patterns of drug use among incarcerated individuals and those not incarcerated over the study period, linear growth curve analyses indicated that there were no statistically significant differences in patterns of drug use between the two groups (all P  > 0.05).
Conclusions   These observational data suggest that incarceration does not reduce drug use among IDU. Incarceration may inhibit access to mechanisms that promote injection cessation among IDU. In contrast, results indicate that methadone use is associated positively with injection cessation, independent of previous frequency of drug use.     

Biological study of the Angiogenesis Inhibitor N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin

The α-glucosidase inhibitors N-methyl-1-deoxynojirimycin (MDNJ) and castanospermine have been shown to inhibit angiogenesis. A hybrid of 1-deoxynojirimycin (DNJ) and an aryl-1,2,3-triazole, which inhibits both an α-glucosidase and methionine aminopeptidase-2 (MetAP2), displayed properties associated with inhibition of angiogenesis (Bioorg. Med. Chem., 16, 2008 , 6333–7). The biological evaluation of a structural analogue N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin is described herein. Although this alkyne derivative did not inhibit MetAP2, it inhibited a bacterial α-glucosidase, altered bovine aortic endothelial cell (BAEC) surface oligosaccharide expression and inhibited BAEC proliferation by inducing G1 phase cell cycle arrest. Experiments showed G1 arrest was attributable to the α-glucosidase inhibitor inducing an increase in p27^Kip1 expression and high phosphorylation of ERK1/2 without a reduction in cyclin D1. The DNJ derivative (0.1 mm ) prevented capillary tube formation from bovine aortic endothelial cells, whereas DNJ or other analogues were unable to inhibit tube formation at the same concentration. Stress fiber assembly in bovine aortic endothelial cells was abolished, and BAEC migration was inhibited indicating the inhibition of tube formation by this derivative is partially a result of a reduction in cell motility. The agent also caused a reduction in secretion of MMP-2 from bovine aortic endothelial cells. Therefore, the new α-glucosidase inhibitor has a different mechanism by which it inhibits angiogenesis in vitro when compared with deoxynojirimycin, the deoxynojirimycin -triazole hybrid, N-methyl-1-deoxynojirimycin and castanospermine.     

Comparison of Meropenem MICs and Susceptibilities for Carbapenemase-Producing Klebsiella pneumoniae Isolates by Various Testing Methods

We describe the levels of agreement between broth microdilution, Etest, Vitek 2, Sensititre, and MicroScan methods to accurately define the meropenem MIC and categorical interpretation of susceptibility against carbapenemase-producing Klebsiella pneumoniae (KPC). A total of 46 clinical K. pneumoniae isolates with KPC genotypes, all modified Hodge test and bla_KPC positive, collected from two hospitals in NY were included. Results obtained by each method were compared with those from broth microdilution (the reference method), and agreement was assessed based on MICs and Clinical Laboratory Standards Institute (CLSI) interpretative criteria using 2010 susceptibility breakpoints. Based on broth microdilution, 0%, 2.2%, and 97.8% of the KPC isolates were classified as susceptible, intermediate, and resistant to meropenem, respectively. Results from MicroScan demonstrated the most agreement with those from broth microdilution, with 95.6% agreement based on the MIC and 2.2% classified as minor errors, and no major or very major errors. Etest demonstrated 82.6% agreement with broth microdilution MICs, a very major error rate of 2.2%, and a minor error rate of 2.2%. Vitek 2 MIC agreement was 30.4%, with a 23.9% very major error rate and a 39.1% minor error rate. Sensititre demonstrated MIC agreement for 26.1% of isolates, with a 3% very major error rate and a 26.1% minor error rate. Application of FDA breakpoints had little effect on minor error rates but increased very major error rates to 58.7% for Vitek 2 and Sensititre. Meropenem MIC results and categorical interpretations for carbapenemase-producing K. pneumoniae differ by methodology. Confirmation of testing results is encouraged when an accurate MIC is required for antibiotic dosing optimization.Carbapenems are considered first-line therapy for infection with multidrug-resistant Enterobacteriaceae (14). However, the increasing emergence of serine-based carbapenemase-producing Klebsiella pneumoniae (KPC) worldwide is of growing concern. This problem is particularly worrisome due to the fact that this K. pneumoniae is one of the leading causes of hospital-acquired infections in severely ill patients, and few antibiotics retain microbiological activity against isolates that produce bla_KPC (15). Additionally, studies have demonstrated increased mortality rates in patients infected with carbapenem-resistant Enterobacteriaceae compared with those infected with susceptible strains (1, 12, 13).Detection of KPC based strictly on susceptibility testing is challenging due mostly to the heterogeneous expression of β-lactam resistance (15). Many automated systems report KPC as susceptible to meropenem, and while some isolates truly are, the MICs for most KPC are above the Food and Drug Administration (FDA) susceptibility breakpoint (4 μg/ml) (11). To address testing and reporting issues, the Clinical Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing changed the susceptibility breakpoint for meropenem, imipenem, and doripenem to ≤1 μg/ml against Enterobacteriaceae in January 2010 (8). At the time of writing, the FDA breakpoint remained at ≤4 μg/ml for meropenem.Given the lack of options for antibiotics that retain susceptibility against pathogens that produce KPC, selection of a dosing regimen that could potentially treat infections caused by these organisms depends on the ability to accurately determine the antibiotic MIC. With respect to KPC, the accurate determination of the meropenem MIC may permit the application of pharmacodynamic principles to dosing regimen optimization by administering higher doses and using prolonged or continuous infusions, as has been accomplished against other resilient bacteria (3, 10, 14).Herein, we describe the levels of agreement between commonly used testing methods (broth microdilution [BMD], Etest, Vitek 2, Sensititre, and MicroScan) in their abilities to accurately determine the meropenem MIC and further classify categorical susceptibilities of carbapenemase-producing K. pneumoniae isolates based on the 2010 CLSI breakpoints compared with FDA breakpoints.     

Microscopic change in macroscopically normal equine cartilage from osteoarthritic joints

The objective of this study was to assess whether macroscopically normal articular cartilage taken from joints containing focal osteoarthritic lesions is histologically similar to articular cartilage taken from macroscopically normal joints. Metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints were obtained from 10 horses following euthanasia. Gross articular cartilage damage was scored and the cartilage assigned to one of two groups: (1) macroscopically normal cartilage from normal joints (control) and (2) macroscopically normal cartilage from diseased joints in which there were focal osteoarthritic lesions. Chondrocytes expressing specific cytokines and cytokine receptors were identified by immunohistochemistry. The total number of chondrocytes, and percentage of chondrocytes positive for these cytokines and receptors, was recorded in the superficial, middle, and deep cartilage zones. There was a significant increase in the expression of interleukin-1beta in the superficial and middle zones and interleukin-18 receptor in the superficial zone in Group 2 compared with Group 1 control samples. A significant positive correlation also was found between the grade of osteoarthritis and the percentage of chondrocytes positive for interleukin-1beta in the superficial and middle zones, and for interleukin-18 and interleukin-18R in the superficial zone. There was a significant increase in histology score for glycosaminoglycan loss in Group 2 compared with that in Group 1. In joints with focal osteoarthritis lesions, all the articular cartilage, even if macroscopically apparently normal, may have microscopic changes associated with osteoarthritis.     

Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators

Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto)thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (alpha1beta1gammadelta, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7) expressed in mammalian cells or Xenopus oocytes. At alpha2beta4, alpha4beta2, alpha4beta4, and alpha7, but not alpha1beta1gammadelta, alpha3beta2, or alpha3beta4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA(A), and N-methyl-d-aspartate receptors or voltage-gated Na(+) and Ca(2+) channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at alpha4beta2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [(3)H]epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.     

Activities of ceftobiprole, a novel broad-spectrum cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis

Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 microg/ml and 8.0 microg/ml for 321 clinical isolates of Haemophilus influenzae and between < or =0.004 microg/ml and 1.0 microg/ml for 49 clinical isolates of Moraxella catarrhalis. Ceftobiprole MIC(50) and MIC(90) values for H. influenzae were 0.06 microg/ml and 0.25 microg/ml for beta-lactamase-positive strains (n = 262), 0.03 microg/ml and 0.25 microg/ml for beta-lactamase-negative strains (n = 40), and 0.5 microg/ml and 2.0 microg/ml for beta-lactamase-negative ampicillin-resistant strains (n = 19), respectively. Ceftobiprole MIC(50) and MIC(90) values for beta-lactamase-positive M. catarrhalis strains (n = 40) were 0.12 microg/ml and 0.5 microg/ml, respectively, whereas the ceftobiprole MIC range for beta-lactamase-negative M. catarrhalis strains (n = 9) was < or =0.004 to 0.03 microg/ml. Ceftriaxone MICs usually were generally at least twofold lower than those of ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against H. influenzae, with MIC(90) values of azithromycin and telithromycin of 2 microg/ml and 4 microg/ml, respectively. Except for selected quinolone-nonsusceptible H. influenzae strains, moxifloxacin proved highly active, with MIC(90) values of 0.12 microg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2x MIC by 24 h against all 10 H. influenzae strains surveyed. Only modest increases in MICs were found for H. influenzae or M. catarrhalis clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low.     

Recalibration of risk prediction models in a large multicenter cohort of admissions to adult, general critical care units in the United Kingdom

OBJECTIVE: To assess the performance of published risk prediction models in common use in adult critical care in the United Kingdom and to recalibrate these models in a large representative database of critical care admissions. DESIGN: Prospective cohort study. SETTING: A total of 163 adult general critical care units in England, Wales, and Northern Ireland, during the period of December 1995 to August 2003. PATIENTS: A total of 231,930 admissions, of which 141,106 met inclusion criteria and had sufficient data recorded for all risk prediction models. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The published versions of the Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE II UK, APACHE III, Simplified Acute Physiology Score (SAPS) II, and Mortality Probability Models (MPM) II were evaluated for discrimination and calibration by means of a combination of appropriate statistical measures recommended by an expert steering committee. All models showed good discrimination (the c index varied from 0.803 to 0.832) but imperfect calibration. Recalibration of the models, which was performed by both the Cox method and re-estimating coefficients, led to improved discrimination and calibration, although all models still showed significant departures from perfect calibration. CONCLUSIONS: Risk prediction models developed in another country require validation and recalibration before being used to provide risk-adjusted outcomes within a new country setting. Periodic reassessment is beneficial to ensure calibration is maintained.     

Computers in medicine. Virtual rehabilitation: dream or reality?

Coronary heart disease is the number one cause of death for men and women in the United States and internationally. Identification of persons at risk for cardiovascular disease and reduction of cardiovascular risk factors are key factors in managing this tremendous societal burden. The internet holds great promise in helping to identify and manage persons at high risk of a cardiac or vascular event. The Internet has the capability to assess risk and provide support for cardiovascular risk reduction for large numbers of persons in a cost effective and time efficient manner. The purpose of this report is to describe important advances in the use of the Internet in identifying persons at risk for a cardiovascular event and in the Internet's ability to provide interventions designed to reduce this risk.