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We continue our work on endpoints and startpoints in T0-quasimetric spaces. In particular we specialize some of our earlier results to the case of two-valued T0-quasimetrics, that is, essentially, to partial orders. For instance, we observe that in a complete lattice the startpoints (resp., endpoints) in our sense are exactly the completely join-irreducible (resp., completely meet-irreducible) elements. We also discuss for a partially ordered set the connection between its Dedekind-MacNeille completion and the q-hyperconvex hull of its natural T0-quasimetric space.

Objective: Abnormal function of high-density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL-associated proteins over 2 years of follow-up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial., Methods: The antioxidant capacity of HDL, paraoxonase 1 (PON-1) activity, and levels of HDL-associated haptoglobin (Hp), HDL-associated apolipoprotein A-I (Apo A-I), and myeloperoxidase (MPO) were measured in 550 TEAR participants at 4 time points (time 0 [pretreatment] and at 24, 48, and 102 weeks of treatment). Repeated-measures analysis using mixed-effects linear models with an autoregressive covariate structure was performed to model the within-subject covariance over time., Results: Mixed-effects models, which were controlled for traditional CV risk factors, treatment regimen, prednisone use, and statin use, demonstrated significant associations between RA disease activity, measured using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate, or C-reactive protein level, and the profile of HDL function over time. Specifically, decreases in RA disease activity over time were associated with increases in PON-1 activity and levels of HDL-associated Apo A-I, and decreases in the HDL inflammatory index and levels of MPO and HDL-associated Hp., Conclusion: Reduced disease activity in patients with early RA treated with MTX monotherapy, MTX + ETN combination therapy, or MTX + SSZ + HCQ triple therapy in the TEAR trial was associated with improvements in the HDL function profile. Additional studies are warranted to evaluate abnormal HDL function as a potential mechanism and therapeutic target for CV risk in patients with RA., (© 2016, American College of Rheumatology.)

Objective: To evaluate long-term changes in cholesterol levels in patients with early rheumatoid arthritis (RA) who were randomized to begin treatment with methotrexate (MTX) monotherapy, MTX plus etanercept, or triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial., Methods: Levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed in 416 patients participating in the TEAR trial, during 102 weeks of followup. Associations of cholesterol changes with disease activity and drug treatment were evaluated using repeated-measures analysis with mixed-effect linear models to model within-subject covariance over time., Results: Mixed-effect models controlling for traditional cardiovascular (CV) risk factors, TEAR treatment, and baseline prednisone and statin use demonstrated significant inverse associations of RA disease activity with changes in cholesterol over time. Decreases in the 28-joint Disease Activity Score, the C-reactive protein level, or the erythrocyte sedimentation rate were associated with increases in levels of HDL cholesterol, LDL cholesterol, and total cholesterol in all treatment groups (P < 0.001-0.035). Triple therapy was strongly associated with higher levels of HDL cholesterol, lower levels of LDL cholesterol, and higher ratios of total cholesterol:HDL cholesterol (P < 0.001 for all) compared to MTX monotherapy or MTX plus etanercept therapy over the 2-year followup., Conclusion: Decreases in RA disease activity over long-term followup were associated with increases in cholesterol levels in patients with early RA treated with either biologic or nonbiologic therapies. The use of triple therapy during 2 years of followup was associated with higher HDL cholesterol levels, lower LDL cholesterol levels, and lower total cholesterol:HDL cholesterol ratios compared to those observed in patients who received MTX monotherapy or MTX plus etanercept combination therapy. Additional studies are needed to assess the effects of these cholesterol changes on CV events in patients with RA., (© 2016, American College of Rheumatology.)

Background: Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infections in intubated and mechanically ventilated patients. Endotracheal tubes (ETTs) appear to be an independent risk factor for VAP. Silver-coated ETTs slowly release silver cations. It is these silver ions that appear to have a strong antimicrobial effect. Because of this antimicrobial effect of silver, silver-coated ETTs could be an effective intervention to prevent VAP in people who require mechanical ventilation for 24 hours or longer., Objectives: Our primary objective was to investigate whether silver-coated ETTs are effective in reducing the risk of VAP and hospital mortality in comparison with standard non-coated ETTs in people who require mechanical ventilation for 24 hours or longer. Our secondary objective was to ascertain whether silver-coated ETTs are effective in reducing the following clinical outcomes: device-related adverse events, duration of intubation, length of hospital and intensive care unit (ICU) stay, costs, and time to VAP onset., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014 Issue 10, MEDLINE, EMBASE, EBSCO CINAHL, and reference lists of trials. We contacted corresponding authors for additional information and unpublished studies. We did not impose any restrictions on the basis of date of publication or language. The date of the last search was October 2014., Selection Criteria: We included all randomized controlled trials (RCTs) and quasi-randomized trials that evaluated the effects of silver-coated ETTs or a combination of silver with any antimicrobial-coated ETTs with standard non-coated ETTs or with other antimicrobial-coated ETTs in critically ill people who required mechanical ventilation for 24 hours or longer. We also included studies that evaluated the cost-effectiveness of silver-coated ETTs or a combination of silver with any antimicrobial-coated ETTs., Data Collection and Analysis: Two review authors (GT, HV) independently extracted the data and summarized study details from all included studies using the specially designed data extraction form. We used standard methodological procedures expected by The Cochrane Collaboration. We performed meta-analysis for outcomes when possible., Main Results: We found three eligible randomized controlled trials, with a total of 2081 participants. One of the three included studies did not mention the amount of participants and presented no outcome data. The 'Risk of bias' assessment indicated that there was a high risk of detection bias owing to lack of blinding of outcomes assessors, but we assessed all other domains to be at low risk of bias. Trial design and conduct were generally adequate, with the most common areas of weakness in blinding. The majority of participants were included in centres across North America. The mean age of participants ranged from 61 to 64 years, and the mean duration of intubation was between 3.2 and 7.7 days. One trial comparing silver-coated ETTs versus non-coated ETTs showed a statistically significant decrease in VAP in favour of the silver-coated ETT (1 RCT, 1509 participants; 4.8% versus 7.5%, risk ratio (RR) 0.64, 95% confidence interval (CI) 0.43 to 0.96; number needed to treat for an additional beneficial outcome (NNTB) = 37; low-quality evidence). The risk of VAP within 10 days of intubation was significantly lower with the silver-coated ETTs compared with non-coated ETTs (1 RCT, 1509 participants; 3.5% versus 6.7%, RR 0.51, 95% CI 0.31 to 0.82; NNTB = 32; low-quality evidence). Silver-coated ETT was associated with delayed time to VAP occurrence compared with non-coated ETT (1 RCT, 1509 participants; hazard ratio 0.55, 95% CI 0.37 to 0.84). The confidence intervals for the results of the following outcomes did not exclude potentially important differences with either treatment. There were no statistically significant differences between groups in hospital mortality (1 RCT, 1509 participants; 30.4% versus 26.6%, RR 1.09, 95% CI 0.93 to 1.29; low-quality evidence); device-related adverse events (2 RCTs, 2081 participants; RR 0.65, 95% CI 0.37 to 1.16; low-quality evidence); duration of intubation; and length of hospital and ICU stay. We found no clinical studies evaluating the cost-effectiveness of silver-coated ETTs., Authors' Conclusions: This review provides limited evidence that silver-coated ETT reduces the risk of VAP, especially during the first 10 days of mechanical ventilation.

Protein splicing in trans results in the ligation of two protein or peptide segments linked to appropriate intein fragments. We have characterized the trans-splicing reaction mediated by a naturally expressed, approximately 100-residue N-terminal fragment of the Mycobacterium tuberculosis intein and a synthetic peptide containing the 38 C-terminal intein residues, and found that the splicing reaction was very versatile and robust. The efficiency of splicing was nearly independent of temperature between 4 and 37 degrees C and pH between 6.0 and 7.5, with only a slight decline at pH values as high as 8.5. In addition, there was considerable flexibility in the choice of the C-terminal intein fragment, no significant difference in protein ligation efficiency being observed between reactions utilizing the N-terminal fragment and either the naturally expressed 107-residue C-terminal portion of the intein, much smaller synthetic peptides, or the 107-residue C-terminal intein fragment modified by fusion of a maltose binding protein domain to its N-terminus. The ability to use different types of the C-terminal intein fragments and a broad range of reaction conditions make protein splicing in trans a versatile tool for protein ligation., (Copyright 2000 John Wiley & Sons, Inc.)

The enantiomers of the anorectic drug amfepramone [rac-diethylpropion, rac-2-(diethylamino)-1-phenyl-1-propanone; rac-DEP] were separated in the preparative scale by crystallization. With enantiopure di-O-benzoyltartaric acid as salt-forming chiral selector, diastereoisomeric salts of DEP enantiomers with a final purity of more than 97.5% were obtained. Analytical liquid chromatographic and electrophoretic methods for the control of the enantiomeric purity and the stoichiometry of the salts were developed. The enantioseparation of rac-DEP by capillary electrophoresis (CE) using hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as chiral discriminator and phosphate buffer (pH 3.3) as run buffer led to good separations. HPLC methods were developed using polysaccharide chiral stationary phases (CSP). The separation of the two enantiomers and the two main degradation products (1-phenyl-1,2-propanedione and propiophenone), known from solid and liquid pharmaceutical preparations, was attained in one run on the silica-based CSP cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD). The conditions which might affect the enantioselectivity and the quality of the enantiomeric separation were investigated for Chiralcel OD and the related CSP amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD). Both CSPs showed very similar chromatographic properties. The separation factors could be influenced significantly by varying the polar organic modifier added to the mobile phase., (Copyright 1999 Wiley-Liss, Inc.)

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their "Guidelines on interchangeability of multisource pharmaceutical products." This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.