Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

Role of physical exercise in low back pain rehabilitation: a randomized controlled trial of a three-month exercise program in patients who have completed multidisciplinary rehabilitation.

STUDY DESIGN: Randomized controlled trial with 1-year follow-up. OBJECTIVE: To analyze the effects of an exercise program or routine follow-up on patients with chronic low back pain who have completed functional multidisciplinary rehabilitation. The short- and long-term outcome in terms of symptoms and physical and social functioning was compared. SUMMARY OF BACKGROUND DATA: Systematic reviews have shown that functional multidisciplinary rehabilitation improves physical function and reduces pain in patients with chronic low back pain. However, long-term maintenance of these improvements is inconsistent and the role of exercise in achieving this goal is unclear. METHODS: One hundred five chronic patients with low back pain who had completed a 3-week functional multidisciplinary rehabilitation program were randomized to either a 3-month exercise program (n = 56) or routine follow-up (n = 49). The exercise program consisted of 24 training sessions during 12 weeks. Patients underwent evaluations of trunk muscle endurance, cardiovascular endurance, lumbar spine mobility (flexion and extension range-of-motion, fingertip-to-floor distance), pain and perceived functional ability at the beginning and the end of functional multidisciplinary rehabilitation, at the end of the exercise program (3 months) and at 1-year follow-up. Disability was also assessed at the same time points except at the beginning of functional multidisciplinary rehabilitation. RESULTS: At the end of the functional multidisciplinary rehabilitation, both groups improved significantly in all physical parameters except flexion and extension range-of-motion. At the 3 month and 1 year follow-up, both groups maintained improvements in all parameters except for cardiovascular endurance. Only the exercise program group improved in disability score and trunk muscle endurance. No differences between groups were found. CONCLUSION: A favorable long-term outcome was observed after functional multidisciplinary rehabilitation in both patient groups. Patients who participated in an exercise program obtained some additional benefits. The relevance of these benefits to overall health status need to be further investigated.

Superantigen-induced immune stimulation amplifies mouse mammary tumor virus infection and allows virus transmission.

Endogenous and infectious mouse mammary tumor viruses (MMTVs) encode in their 3' long terminal repeat a protein that exerts superantigen activity; that is, it is able to interact with T cells via the variable domain of the T cell receptor (TCR) beta chain. We show here that transmission of an infectious MMTV is prevented when superantigen-reactive cells are absent through either clonal deletion due to the expression of an endogenous MTV with identical superantigen specificity or exclusion due to expression of a transgenic TCR beta chain that does not interact with the viral superantigen. A strict requirement for superantigen-reactive T cells is also seen for a local immune response following MMTV infection. This immune response locally amplifies the number of MMTV-infected B cells, most likely owing to their clonal expansion. Collectively, our data indicate that a superantigen-induced immune response is critical for the MMTV life cycle.

High-intensity intermittent training in hypoxia: a double-blinded, placebo-controlled field study in youth football players.

High-intensity intermittent training in hypoxia: A double-blinded, placebo-controlled field study in youth football players. J Strength Cond Res 29(1): 226-237, 2015-This study examined the effects of 5 weeks (∼60 minutes per training, 2 d·wk) of run-based high-intensity repeated-sprint ability (RSA) and explosive strength/agility/sprint training in either normobaric hypoxia repeated sprints in hypoxia (RSH; inspired oxygen fraction [FIO2] = 14.3%) or repeated sprints in normoxia (RSN; FIO2 = 21.0%) on physical performance in 16 highly trained, under-18 male footballers. For both RSH (n = 8) and RSN (n = 8) groups, lower-limb explosive power, sprinting (10-40 m) times, maximal aerobic speed, repeated-sprint (10 × 30 m, 30-s rest) and repeated-agility (RA) (6 × 20 m, 30-s rest) abilities were evaluated in normoxia before and after supervised training. Lower-limb explosive power (+6.5 ± 1.9% vs. +5.0 ± 7.6% for RSH and RSN, respectively; both p < 0.001) and performance during maximal sprinting increased (from -6.6 ± 2.2% vs. -4.3 ± 2.6% at 10 m to -1.7 ± 1.7% vs. -1.3 ± 2.3% at 40 m for RSH and RSN, respectively; p values ranging from <0.05 to <0.01) to a similar extent in RSH and RSN. Both groups improved best (-3.0 ± 1.7% vs. -2.3 ± 1.8%; both p ≤ 0.05) and mean (-3.2 ± 1.7%, p < 0.01 vs. -1.9 ± 2.6%, p ≤ 0.05 for RSH and RSN, respectively) repeated-sprint times, whereas sprint decrement did not change. Significant interactions effects (p ≤ 0.05) between condition and time were found for RA ability-related parameters with very likely greater gains (p ≤ 0.05) for RSH than RSN (initial sprint: 4.4 ± 1.9% vs. 2.0 ± 1.7% and cumulated times: 4.3 ± 0.6% vs. 2.4 ± 1.7%). Maximal aerobic speed remained unchanged throughout the protocol. In youth highly trained football players, the addition of 10 repeated-sprint training sessions performed in hypoxia vs. normoxia to their regular football practice over a 5-week in-season period was more efficient at enhancing RA ability (including direction changes), whereas it had no additional effect on improvements in lower-limb explosive power, maximal sprinting, and RSA performance.

Risque thrombotique sous procréation médicalement assistée [Thrombotic risk in assisted reproductive technology].

Use of assisted reproductive technology (ART) is increasing in many developed countries. Arterial and venous thromboembolic complications are reported during ART with an incidence of 0.1%. The development of these events has been mainly ascribed to the presence of ovarian hyperstimulation syndrome (OHSS). Precise mechanisms by which OHSS and exogenous hormonal stimulation used in ART induce thromboembolic events remain unclear. However, vascular endothelial growth factor secreted during OHSS, high estradiol concentrations, and blood hyperviscosity play a major role in inducing a prothrombotic state. Therefore, before planning an ART, individual thromboembolic risk should be assessed and thromboprophylaxis offered to high risk patients. Prophylaxis should be initiated in women who develop moderate-to-severe OHSS.

Bilateral olfactory sensory input enhances chemotaxis behavior.

Neural comparisons of bilateral sensory inputs are essential for visual depth perception and accurate localization of sounds in space. All animals, from single-cell prokaryotes to humans, orient themselves in response to environmental chemical stimuli, but the contribution of spatial integration of neural activity in olfaction remains unclear. We investigated this problem in Drosophila melanogaster larvae. Using high-resolution behavioral analysis, we studied the chemotaxis behavior of larvae with a single functional olfactory neuron on either the left or right side of the head, allowing us to examine unilateral or bilateral olfactory input. We developed new spectroscopic methods to create stable odorant gradients in which odor concentrations were experimentally measured. In these controlled environments, we observed that a single functional neuron provided sufficient information to permit larval chemotaxis. We found additional evidence that the overall accuracy of navigation is enhanced by the increase in the signal-to-noise ratio conferred by bilateral sensory input.

Anaerobically controlled expression system derived from the arcDABC operon of Pseudomonas aeruginosa: application to lipase production.

The anaerobically inducible arcDABC operon encodes the enzymes of the arginine deiminase pathway in Pseudomonas aeruginosa. Upon induction, the arcAB mRNAs and proteins reach high intracellular levels, because of a strong anaerobically controlled promoter and mRNA processing in arcD, leading to stable downstream transcripts. We explored the usefulness of this system for the construction of expression vectors. The lacZ gene of Escherichia coli was expressed to the highest levels when fused close to the arc promoter. Insertion of lacZ further downstream into arcA or arcB did not stabilize the intrinsically unstable lacZ mRNA. On the contrary, lacZ mRNA appeared to be a vulnerable endonuclease target destabilizing arcAB mRNAs in the 5'-to-3' direction in P. aeruginosa. The native arc promoter was modified for optional expression in the -10 sequence and in the -40 region, which is a binding site for the anaerobic regulator ANR. In P. aeruginosa grown either anaerobically or with oxygen limitation in unshaken cultures, this promoter was stronger than the induced tac promoter. The P. aeruginosa lipAH genes, which encode extracellular lipase and lipase foldase, respectively, were fused directly to the modified arc promoter in an IncQ vector plasmid. Semianaerobic static cultures of P. aeruginosa PAO1 carrying this recombinant plasmid overproduced extracellular lipase 30-fold during stationary phase compared with the production by strain PAO1 without the plasmid. Severe oxygen limitation, in contrast, resulted in poor lipase productivity despite effective induction of the ANR-dependent promoter, suggesting that secretion of active lipase is blocked by the absence of oxygen. In conclusion, the modified arc promoter is useful for driving the expression of cloned genes in P. aeruginosa during oxygen-limited growth and stationary phase.

Efficacy of brief motivational intervention in reducing binge drinking in young men: A randomized controlled trial.

Background: Brief motivational intervention (BMI) is one of the few effective strategies targeting alcohol consumption, but has not been tested in young men in the community. We evaluated the efficacy of BMI in reducing alcohol use and related problems among binge drinkers and in maintaining low-risk drinking among non-bingers. Methods: A random sample of a census of men included during army conscription (which is mandatory for 20-year-old males in Switzerland) was randomized to receive a single face-to-face BMI session (N = 199) or no intervention (N = 219). A six-month follow-up rate was obtained for 88.7% of the subjects. Results: Among binge drinkers, there was 20% less drinking in the BMI group versus the control group (incidence rate ratio = 0.80, confidence interval 0.66-0.98, p = 0.03): the BMI group showed a weekly reduction of 1.5 drinks compared to an increase of 0.8 drinks weekly in the control group. Among subjects who experienced one or more alcohol-related consequences over the last 12 months, there was 19% less drinking in the BMI group compared to the control group (incidence rate ratio = 0.81; confidence interval 0.67-0.97, p = 0.04). Among non-bingers, BMI did not contribute to the maintenance of low-risk drinking. Conclusion: BMI reduced the alcohol use of binge drinkers, particularly among those who experienced certain alcohol-related adverse consequences. No preventive effect of BMI was observed among non-bingers. BMI is a plausible secondary preventive option for young binge drinkers. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.

HIV-1 superinfection with a triple-class drug-resistant strain in a patient successfully controlled with antiretroviral treatment.

We report a case of HIV-1 superinfection (HSI) with a clade B, triple-class resistant virus in a patient successfully controlling viremia with continuous combination antiretroviral therapy started 8 years earlier during primary HIV infection. The course of HIV infection prior to HSI was monitored in both the source partner and recipient (8 and 11 years, respectively) and 4 years following HSI. This case report demonstrates re-infection with HIV-1 despite effective combination antiretroviral therapy.

Cefuroxime prophylaxis is effective in noninstrumented spine surgery: a double-blind, placebo-controlled study.

STUDY DESIGN: Double-blind, placebo-controlled randomized clinical trial. OBJECTIVE: To assess the efficacy of 1 preoperative 1.5 g dose of cefuroxime in preventing surgical site infection after surgery for herniated disc. SUMMARY OF BACKGROUND DATA: Antibiotic prophylaxis was only tested in nonconclusive trials in this setting. METHODS: The study was conducted in 2 university hospitals in Switzerland. Patients were assessed for occurrence of surgical site infection (defined by the criteria of the Centers for Diseases Control and Prevention), other infections, or adverse events up to 6 months after surgery. Outcome measures were compared in a univariate, per-protocol analysis. RESULTS: Baseline characteristics were similar in patients allocated to cefuroxime (n = 613) or placebo (n = 624). Eight (1.3%) patients in the cefuroxime group and 18 patients (2.8%) in the placebo group developed a surgical site infection (P = 0.073). A diagnosis of spondylodiscitis or epidural abscess was made in 9 patients in the placebo group, but none in the cefuroxime group (P < 0.01), which corresponded to a number necessary to treat of 69 patients to prevent one of these infections. There were no significant adverse events attributed to either cefuroxime or placebo. CONCLUSION: A single, preoperative dose of cefuroxime significantly reduces the risk of organ-space infection, most notably spondylodiscitis, after surgery for herniated disc.

Case management for frequent users of the emergency department: study protocol of a randomised controlled trial.

BACKGROUND: We devised a randomised controlled trial to evaluate the effectiveness and efficiency of an intervention based on case management care for frequent emergency department users. The aim of the intervention is to reduce such patients' emergency department use, to improve their quality of life, and to reduce costs consequent on frequent use. The intervention consists of a combination of comprehensive case management care and standard emergency care. It uses a clinical case management model that is patient-identified, patient-directed, and developed to provide high intensity services. It provides a continuum of hospital- and community-based patient services, which include clinical assessment, outreach referral, and coordination and communication with other service providers. METHODS/DESIGN: We aim to recruit, during the first year of the study, 250 patients who visit the emergency department of the University Hospital of Lausanne, Switzerland. Eligible patients will have visited the emergency department 5 or more times during the previous 12 months. Randomisation of the participants to the intervention or control groups will be computer generated and concealed. The statistician and each patient will be blinded to the patient's allocation. Participants in the intervention group (N = 125), additionally to standard emergency care, will receive case management from a team, 1 (ambulatory care) to 3 (hospitalization) times during their stay and after 1, 3, and 5 months, at their residence, in the hospital or in the ambulatory care setting. In between the consultations provided, the patients will have the opportunity to contact, at any moment, the case management team. Participants in the control group (N = 125) will receive standard emergency care only. Data will be collected at baseline and 2, 5.5, 9, and 12 months later, including: number of emergency department visits, quality of life (EuroQOL and WHOQOL), health services use, and relevant costs. Data on feelings of discrimination and patient's satisfaction will also be collected at the baseline and 12 months later. DISCUSSION: Our study will help to clarify knowledge gaps regarding the positive outcomes (emergency department visits, quality of life, efficiency, and cost-utility) of an intervention based on case management care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01934322.

Cross validation of experts versus registration methods for target localization in deep brain stimulation.

In the last five years, Deep Brain Stimulation (DBS) has become the most popular and effective surgical technique for the treatent of Parkinson's disease (PD). The Subthalamic Nucleus (STN) is the usual target involved when applying DBS. Unfortunately, the STN is in general not visible in common medical imaging modalities. Therefore, atlas-based segmentation is commonly considered to locate it in the images. In this paper, we propose a scheme that allows both, to perform a comparison between different registration algorithms and to evaluate their ability to locate the STN automatically. Using this scheme we can evaluate the expert variability against the error of the algorithms and we demonstrate that automatic STN location is possible and as accurate as the methods currently used.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. Experimental approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg·kg−1) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. Key results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone Cmax was correlated with SPT assessment (ρS= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. Conclusions and implications: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.