Canadian cost analysis comparing maintenance therapy with bortezomib versus lenalidomide for patients with multiple myeloma post autologous stem cell transplant.

BACKGROUND: Multiple myeloma (MM) is a cancer caused by malignant plasma cells that accumulate mostly in the bone marrow. In Canada, the most common maintenance therapy options after autologous stem cell transplant (ASCT) are bortezomib and lenalidomide. OBJECTIVE: To determine the incremental cost between bortezomib and lenalidomide maintenance therapies for patients with MM post ASCT. METHODS: Analyses were conducted to compare the annual costs of bortezomib and lenalidomide maintenance treatments for patients with MM post ASCT in Canada. The base case analysis included the acquisition costs of the drugs and administration costs. Additional analyses were conducted which considered the cost of experiencing adverse events (AEs) and the cost of treating second primary malignancies (SPMs). RESULTS: In the Canadian healthcare system, the total annual per patient cost was $33,967 for bortezomib maintenance therapy versus $131,765 for lenalidomide maintenance therapy. One-way sensitivity analyses demonstrated that both AEs and SPMs had little impact on the incremental cost, and that differences between the two maintenance therapies were mainly due to the acquisition costs of the drugs. CONCLUSIONS: Bortezomib is significantly less costly than lenalidomide, and is an economically reasonable maintenance treatment option for patients with MM post ASCT.

Clinician reported ease of use for a novel fibrin sealant patch for hemostasis: results from four randomized controlled trials.

BACKGROUND: In addition to rapid and sustained efficacy, ease of use is also an important characteristic of topical hemostats. OBJECTIVES: To evaluate clinician-reported ease of use for the Evarrest fibrin sealant patch across various surgical bleeding situations. METHODS: An ease of use questionnaire (EUQ) was validated and administered in four randomized studies comparing the fibrin sealant patch to standard of care (SoC) in soft tissue and hepatic surgical bleeding. Three of these randomized studies have been previously published and all have been registered (NCT00658723; NCT00977925; NCT01166243; NCT01993888). The EUQ is a 19 item instrument evaluating clinician's preferences on five subscales: product ease of use, satisfaction with product properties and efficiency, confidence in product efficacy, global confidence, and global satisfaction. A pair-wise meta-analysis using a random effects model was conducted on EUQ scores for trials that reported data for both treatment arms. Individual scores are presented for each trial. RESULTS: The fibrin sealant patch demonstrated numerically greater scores than SoC in all EUQ subscales. The meta-analysis demonstrated that fibrin sealant patch scores improved for all subscales compared with SoC: satisfaction with product properties (mean difference [MD] = 0.38, 95% CI: 0.04 to 0.73; P = 0.03), confidence in efficacy (MD = 1.10, 95% CI: 0.47 to 1.74; P = 0.0007), global confidence (MD = 0.57, 95% CI: 0.05 to 1.10, P = 0.03), global satisfaction (MD = 0.79, 95% CI: 0.32 to 1.26, P = 0.001), and ease of use (MD = 0.33, 95% CI: -0.29 to 0.94; P = 0.23). Fibrin sealant patch single arm trial results aligned with these findings. CONCLUSIONS: Physicians consistently reported high EUQ scores for the fibrin sealant patch across surgical bleeding populations. An important limitation of this study was that the composition of SoC varied across studies and EUQ data were only available for the SoC in two of four trials. Future studies should evaluate ease of use for other hemostats and across other surgical subspecialties, as data are currently limited.

A meta-analysis of the efficacy and safety of unboosted atazanavir compared with ritonavir-boosted protease inhibitor maintenance therapy in HIV-infected adults with established virological suppression after induction.

OBJECTIVES: Treatment simplification involving induction with a ritonavir (RTV)-boosted protease inhibitor (PI) replaced by a nonboosted PI (i.e. atazanavir) has been shown to be a viable option for long-term antiretroviral therapy. To evaluate the clinical evidence for this approach, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating efficacy and safety in patients with established virological suppression. METHODS: Several databases were searched without limits on time or language. Searches of conferences were also conducted. RCTs were included if they compared a PI/RTV regimen to unboosted atazanavir, after induction with PI/RTV. The meta-analysis was conducted using a random effects model for the proportion achieving virological suppression (i.e. HIV RNA < 50 and <400 HIV-1 RNA copies/mL), CD4 cell counts, lipid levels and liver function tests. Dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs). RESULTS: Five studies (n = 1249) met the inclusion criteria. The meta-analysis demonstrated no statistically significant difference in efficacy (i.e. HIV RNA < 50 copies/mL) between PI/RTV and unboosted atazanavir [RR = 1.04; 95% confidence interval (CI) 0.99 to 1.10], with no heterogeneity. Findings were similar in a subanalysis of studies where atazanavir/RTV was the only PI/RTV used during induction. Additional efficacy results support these findings. A significant reduction in total cholesterol (P < 0.00001), triglycerides (P = 0.0002), low-density lipoprotein (LDL) cholesterol (P = 0.009) and hyperbilirubinaemia (P = 0.02) was observed with unboosted atazanavir vs. PI/RTV. CONCLUSIONS: The meta-analysis demonstrated that switching patients with virological suppression from an RTV-boosted PI to unboosted atazanavir leads to improvements in safety (i.e. blood parameter abnormalities) without sacrificing virological efficacy.

Adapted Finnish Migraine-Specific Questionnaire for family studies (FMSQ(FS)): a validation study in two languages.

BACKGROUND AND PURPOSE: The hypothesis of a genetic component in the etiology of migraine is getting a foothold. However, to explore genetic associations, precision in clinical phenotypization is crucial. For this reason, migraine-specific questionnaires, well discriminating between primary headaches, are required when large numbers of individuals need to be assessed. METHODS: We adapted and translated in two languages, German and Italian, the Finnish Migraine-Specific Questionnaire for use in family studies. RESULTS AND CONCLUSIONS: This adaptation proved to be reliable when differentiating from primary headaches, and to be in very good agreement with the standard for comparison. However, discriminating between migraine with and without aura still relays on a specialist evaluation. This article describes the validation of this questionnaire.

Validation of a questionnaire for assessing physical work load.

OBJECTIVES: Reliable, valid, and compatible methods are required for exploring the complex interactive effects of psychosocial and physical stressors on complaints and disorders. An instrument for assessing physical work load that integrates information from a biomechanical model of lumbar load is presented and validated. METHODS: Four hundred and fifty-five people working in nursing homes for elderly people in Germany filled out the developed questionnaire 3 times within 1 year. Test-retest reliability was calculated, and validity was checked several times. Relationships with other, theoretically related and unrelated variables were examined. RESULTS: The test-retest reliability of the questionnaire measures was about 0.65. The convergent and discriminant validity was satisfactory, and the questionnaire was able to separate professional subgroups with different physical work loads. The Spearman rank-order correlations between physical load and musculoskeletal complaints were about 0.30. CONCLUSIONS: The method developed in this study is a reliable and valid instrument for assessing physical work load. The integration of statistical methods from psychological testing and theory in the development of methods exploring the effects of physical work load is advocated.

Crystallization and X-ray diffraction data of a tRNASec acceptor-stem helix.

tRNASec is a UGA suppressor tRNA which co-translationally inserts selenocysteine into proteins. Its eight-base-pair tRNASec acceptor stem, which contains key recognition elements, was synthesized using solid-phase phosphoramidite RNA chemistry. High-resolution X-ray diffraction data were collected using synchrotron radiation under cryogenic cooling conditions. The crystals diffract to a maximal resolution of 1.8 A. X-ray diffraction data were processed to 2.4 A. tRNASec microhelix crystallizes in space group R32, with cell constants a = 47.02, b = 47.02, c = 373.03 A, alpha = beta = 90, gamma = 120 degrees. The crystals contain three RNA molecules per asymmetric unit.

Complications in laparoscopic surgery.

Over the last few years, laparoscopic surgery has gained widespread acceptance in surgical practice. The indications range has expanded extraordinarily in that time. Some of the practiced procedures are already considered the gold standard, while others are still on the way there. The fascinating technique and results notwithstanding, a number of risks, mistakes, and complications are possible in both the initial and the advanced states. We present our experience from 2118 laparoscopic operations performed between February 1991 to March 1995, focusing on the intraoperative complications (Tables 1, 2).

Laparoscopic surgery. Mistakes and risks when the method is introduced.

Laparoscopic cholecystectomy and appendectomy are widely accepted in clinical practice. In the initial stage, when the method is introduced, there are a number of mistakes, risks, and complications possible. The surgeons, the staff, the instruments, the anesthetist, and, last but not least, the patient, are among the possible contributing causes. We try to analyze the reasons and conditions leading to possible complications. Complications we have experienced are reported. In our conclusions we try to show how it is possible to avoid severe problems.

Formation of thrombin-antithrombin III complex using polyamide and hemophan dialyzers.

The recently developed ELISA for the thrombin-antithrombin III complex (TAT) is a sensitive, specific, and simplified means of detecting intravascular coagulation. For further evaluation of the thrombogenicity of a polyamide (P) and a Hemophan (H) hollow-fibre dialyzer a cross-over study was done in ten stable patients on maintenance hemodialysis. At the same doses of heparin (mean bolus of 30 U/kg bw and maintenance doses of 86 U/kg bw), thrombin time and partial thromboplastin time were significantly lower using H. At the end of dialysis TAT was significantly higher in H (mean +/- SEM before HD 3.57 +/- .56, at 240 min 14.9 +/- 6.5 ng/ml, p less than 0.05, Wilcoxon-test) than in P (before HD 4.36 +/- .98, at 240 min 8.95 +/- 3.0 ng/ml, p less than 0.05 H 240 vs. P 240, Wilcoxon-test). Visible clotting was more pronounced in the H filter. Among other favourable features of blood compatibility the polyamide/polyvinylpyrrolidone copolymer with a hydrophilic/hydrophobic microdomain structure has less thrombogenicity. The modified cellulosic membrane H has advantages in complement activation and leukocyte depression, but thrombogenicity seems less favourable since the incorporated diethyl-amino-ethyl groups with their positive charge bind and inactivate negatively charged heparin.

[Investigations on the utilization of D-gluconate and D-glucono-delta-lactone in the metabolism of the normal and alloxan diabetic rat (author's transl)]. / Untersuchungen über die Verwertung von D-Gluconat und D-Glucono-delta-lacton im Stoffwechsel der normalen und alloxandiabetischen Ratte.

Radioactivity was measured in the blood of normal and alloxan diabetic rats, after the oral administration of [U-14C]gluconate and [U-14C]glucono-delta-lactone, respectively. Radioactivity was also measured in the intestinal contents and feces 5 h after ingestion of the radioactive materials, It was concluded that the lactone is better absorbed from the intestine than the gluconate anion. According to this enhanced membrane permeation and the higher concentration reached in blood, the space of distribution of the lactone is larger than that of gluconate (50 and 41% of body weight, respectively); a higher retention in tissues and a greater loss in urine was also observed after administration of the lactone. Incorporation into liver glycogen is also higher from the lactone than from gluconate after oral administration, particularly in diabetic animals. The initial deficit in the oxidation of gluconate compared to that of the lactone, caused by a lag period of 7 and 4 h, respectively, is completely compensated during the following 8-9 h. The oxidative turnover of gluconolactone and of gluconate is significantly enhanced in diabetic animals. The better utilization in diabetic metabolism is in part explainable by a rise of glycolytic intermediates in the liver, which are decreased in starvation and diabetes. The limiting step of gluconate metabolism is the initial phosphorylation. Possibilities are discufor the dietetic use of gluconic acid in the form of an apolar derivative (lactone, ester).

Thiamine pyrophosphokinase activity in liver, heart and brain crude extracts of control and thiamine deficient rats.

The activity of thiamine pyrophosphokinase has been measured in liver, heart muscle and brain of normal and thiamine deficient rats. The activity measurement has been performed by use of thiamine-35S as substrate and separation of the reaction products by high voltage electrophoresis. KM has been determined as 7.1.10(-6) mol/l. The activity of thiamine pyrophosphokinase is reduced in liver and heart muscle of thiamine deficient rats significantly, whereas no decrease of the enzyme activity has been found in the brain. The content of thiamine pyrophosphate has been measured in the liver of normal and thiamine deficient rats. Injection of thiamine to deficient rats normalized the content of thiamine pyrophosphate in the liver within 6 hours. Our data suggest that thiamine pyrophosphokinase is an adaptive enzyme, the activity of which depends on the thiamine content of the cells.

Uronic acid dehydrogenase from Pseudomonas syringae. Purification and properties.

1. Uronic acid dehydrogenase was purified to homogeneity. After a 338-fold purification a yield of 16% was achieved with a specific activity of 81 mumol NADH formed min-1 mg protein-1. 2. The purity of the enzyme was controlled by disc electrophoresis, sodium dodecylsulfate electrophoresis and ultracentrifugation. 3. A molecular weight of 60 000 was determined by gel chromatography and by ultracentrifugation. 4. The native enzyme is composed of two subunits, their molecular weight being 30 000 as estimated by sodium dodecylsulfate electrophoresis. The subunits as such are inactive. 5. The absorption spectrum with a maximum at 278 nm shows no evidence for a prosthetic group. 6. For catalytic activity no SH groups and no metals seem to be necessary. 7. The Michaelis constants determined with the pure enzyme are for glucuronic acid Km = 0.37 mM, galacturonic acid Km = 54 muM and NAD+ (with glucuronic acid) Km = 80 muM. 8. A weak reverse reaction could be observed with glucaric acid lactones at acidic pH. 9. NADH is competitive with NAD+. The inhibitor constant is Ki = 60 muM. 10. The NAD+ binding site seems to be of lower specificity than the uronic acid binding site.