Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels

Background: The imatinib trough plasma concentration (C(min)) correlates with clinical response in cancer patients. Therapeutic drug monitoring (TDM) of plasma C(min) is therefore suggested. In practice, however, blood sampling for TDM is often not performed at trough. The corresponding measurement is thus only remotely informative about C(min) exposure. Objectives: The objectives of this study were to improve the interpretation of randomly measured concentrations by using a Bayesian approach for the prediction of C(min), incorporating correlation between pharmacokinetic parameters, and to compare the predictive performance of this method with alternative approaches, by comparing predictions with actual measured trough levels, and with predictions obtained by a reference method, respectively. Methods: A Bayesian maximum a posteriori (MAP) estimation method accounting for correlation (MAP-ρ) between pharmacokinetic parameters was developed on the basis of a population pharmacokinetic model, which was validated on external data. Thirty-one paired random and trough levels, observed in gastrointestinal stromal tumour patients, were then used for the evaluation of the Bayesian MAP-ρ method: individual C(min) predictions, derived from single random observations, were compared with actual measured trough levels for assessment of predictive performance (accuracy and precision). The method was also compared with alternative approaches: classical Bayesian MAP estimation assuming uncorrelated pharmacokinetic parameters, linear extrapolation along the typical elimination constant of imatinib, and non-linear mixed-effects modelling (NONMEM) first-order conditional estimation (FOCE) with interaction. Predictions of all methods were finally compared with 'best-possible' predictions obtained by a reference method (NONMEM FOCE, using both random and trough observations for individual C(min) prediction). Results: The developed Bayesian MAP-ρ method accounting for correlation between pharmacokinetic parameters allowed non-biased prediction of imatinib C(min) with a precision of ±30.7%. This predictive performance was similar for the alternative methods that were applied. The range of relative prediction errors was, however, smallest for the Bayesian MAP-ρ method and largest for the linear extrapolation method. When compared with the reference method, predictive performance was comparable for all methods. The time interval between random and trough sampling did not influence the precision of Bayesian MAP-ρ predictions. Conclusion: Clinical interpretation of randomly measured imatinib plasma concentrations can be assisted by Bayesian TDM. Classical Bayesian MAP estimation can be applied even without consideration of the correlation between pharmacokinetic parameters. Individual C(min) predictions are expected to vary less through Bayesian TDM than linear extrapolation. Bayesian TDM could be developed in the future for other targeted anticancer drugs and for the prediction of other pharmacokinetic parameters that have been correlated with clinical outcomes.

Wake Up, Shake Up Breakfast Club

The Wake Up, Shake Up club was first set up in February 2013. The aim of the club is to support working parents and offer an affordable alternative to local childcare options. It is also an opportunity to re-enforce school healthy eating guidelines and explore different food options with children.The club is run by staff members of Holywell Childcare. 33 children attend each morning. There is a charge of €1 per child per day to cover staff costs. A selection of cereals is served each morning along with toast, fruit and fruit juice. Children can take part in different activities after breakfast, such as crafts, games, and even yoga ! Part of theBreakfast Clubs Pilot Programme Initiative Type Breakfast Clubs Location Dublin Target Groups Children ( 4-12 years) Start 18th Feb 2013

Local anaesthetic medication for the treatment of asthma

It is presumed that drugs able to prevent bronchial spasm and/or inflammation may have therapeutic potential to control asthma symptoms. The local anaesthetic lidocaine has recently received increased attention as an alternative form of treatment for asthmatic patients. This paper reviews the major findings on the topic and summarizes the putative mechanisms underlying the airway effects of local anaesthetic agents. We think that lidocaine extends the spectrum of options in asthma therapy, probably by counteracting both spasmogenic and inflammatory stimuli in the bronchial airways. The possibility of development of new anti-asthma compounds based on the synthesis of lidocaine derivatives is also on the horizon.

Policy Options for New Student Contributions in Higher Education - Report to the Minister

The Government’s Framework for Sustainable Economic Renewal- Building Ireland’s Smart Economy, launched by the Taoiseach in late 2008, establishes Ireland’s ambition to become internationally renowned as an Innovation Island. At the core of achieving this ambition will be our capacity for producing highly skilled graduates and fostering a climate of creative thinking and advanced research and development. This relies on the quality of undergraduate provision right across the sciences, arts and humanities in our third level institutions. The development of a new national strategy for higher education is now underway. The strategy will aim to identify a vision and objectives for the development of the sector over the next twenty years. Leading higher education systems internationally are characterised by wide revenue sources that, in many cases, include a form of direct student contribution through a tuition fee or student loans system. If Ireland’s higher education system is to develop and meet future demands in an environment of increasingly tight public resources, then it is appropriate that the sector’s level of dependence on Exchequer funding should come under review.

Artificial muscle to wash blood out of fibrillating atrium: an alternative to lifelong anticoagulation.

The Atripump is a motorless, volume displacement pump based on artificial muscle technology that could reproduce the pump function of normal atrium. It could help prevent blood clots due to blood stagnation and eventually avoid anticoagulation therapy in atrial fibrillation (AF). An animal study has been designed to assess mechanical effects of this pump on fibrillating atrium. The Atripump is a dome shaped silicone coated nitinol actuator. A pacemaker like control unit drives the actuator. In five adult sheep, the right atrium (RA) was exposed and dome sutured onto the epicardium. Atrial fibrillation was induced using rapid epicardial pacing (600 beats/min). Ejection fraction of the RA was obtained with intracardiac ultrasound in baseline, AF and Atripump assisted AF conditions. The dome's contraction rate was 60/min with power supply of 12V, 400 mA for 200 ms and ran for 2 hours in total. Mean temperature on the RA was 39+/-1.5 degrees C. Right atrium ejection fraction was 31% in baseline conditions, 5% and 20% in AF and assisted AF, respectively. In two animals a thrombus appeared in the right appendix and washed out once the pump was turned on. The Atripump washes blood out the RA acting as an anticoagulant device. Possible clinical implications in patients with chronic AF are prevention of embolism of cardiac origin and avoidance of hemorrhagic complication due to chronic anticoagulation.

Evaluation of rapid alternative methods for drug susceptibility testing in clinical isolates of Mycobacterium tuberculosis

A study was carried out to compare the performance of a commercial method (MGIT) and four inexpensive drug susceptibility methods: nitrate reductase assay (NRA), microscopic observation drug susceptibility (MODS) assay, MTT test, and broth microdilution method (BMM). A total of 64 clinical isolates of Mycobacterium tuberculosis were studied. The Lowenstein-Jensen proportion method (PM) was used as gold standard. MGIT, NRA, MODS, and MTT results were available on an average of less than 10 days, whereas BMM results could be reported in about 20 days. Most of the evaluated tests showed excellent performance for isoniazid and rifampicin, with sensitivity and specificity values > 90%. With most of the assays, sensitivity for ethambutol was low (62-87%) whereas for streptomycin, sensitivity values ranged from 84 to 100%; NRA-discrepancies were associated with cultures with a low proportion of EMB-resistant organisms while most discrepancies with quantitative tests (MMT and BMM) were seen with isolates whose minimal inhibitory concentrations fell close the cutoff. MGIT is reliable but still expensive. NRA is the most inexpensive and easiest method to perform without changing the organization of the routine PM laboratory performance. While MODS, MTT, and BMM, have the disadvantage from the point of view of biosafety, they offer the possibility of detecting partial resistant strains. This study shows a very good level of agreement of the four low-cost methods compared to the PM for rapid detection of isoniazid, rifampicin and streptomycin resistance (Kappa values > 0.8); more standardization is needed for ethambutol.

RT-PCR diagnosis of patients with acute nonlymphocytic leukemia and inv(16)(p13q22) and identification of new alternative splicing in CBFB-MYH11 transcripts.

As acute nonlymphocytic leukemia (ANLL) with inv(16) (p13q22) or t(16;16)(p13;q22) has been shown to result from the fusion of transcription factor subunit core binding factor (CBFB) to a myosin heavy chain (MYH11), we sought to design methods to detect this rearrangement using reverse transcriptase-polymerase chain reaction (RT-PCR). In all of 27 inv(16)(p13q22) and four t(16;16)(p13;q22) cases tested, a chimeric CBFB-MYH11 transcript coding for an in-frame fusion protein was detected. In a more extensive RT-PCR analysis with different primer pairs, we detected a second new chimeric CBFB-MYH11 transcript in 10 of 11 patients tested. The CBFB-MYH11 reading frame of the second transcript was maintained in one patient but not in the others. We show that the different CBFB-MYH11 transcripts in one patient arise from alternative splicing. Translation of the transcript in which the CBFB-MYH11 reading frame is not maintained leads to a slightly truncated CBFB protein.

Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival.

Patients with glioblastoma (GBM) have variable clinical courses, but the factors that underlie this heterogeneity are not understood. To determine whether the presence of the telomerase-independent alternative lengthening of telomeres (ALTs) mechanism is a significant prognostic factor for survival, we performed a retrospective analysis of 573 GBM patients. The presence of ALT was identified in paraffin sections using a combination of immunofluorescence for promyelocytic leukemia body and telomere fluorescence in situ hybridization. Alternative lengthening of telomere was present in 15% of the GBM patients. Patients with ALT had longer survival that was independent of age, surgery, and other treatments. Mutations in isocitrate dehydrogenase (IDH1mut) 1 frequently accompanied ALT, and in the presence of both molecular events, there was significantly longer overall survival. These data suggest that most ALT+ tumors may be less aggressive proneural GBMs, and the better prognosis may relate to the set of genetic changes associated with this tumor subtype. Despite improved overall survival of patients treated with the addition of chemotherapy to radiotherapy and surgery, ALT and chemotherapy independently provided a survival advantage, but these factors were not found to be additive. These results suggest a critical need for developing new therapies to target these specific GBM subtypes.

Multiple adenosine 3',5'-cyclic [corrected] monophosphate response element DNA-binding proteins generated by gene diversification and alternative exon splicing.

The protein sequence deduced from the open reading frame of a human placental cDNA encoding a cAMP-responsive enhancer (CRE)-binding protein (CREB-327) has structural features characteristic of several other transcriptional transactivator proteins including jun, fos, C/EBP, myc, and CRE-BP1. Results of Southwestern analysis of nuclear extracts from several different cell lines show that there are multiple CRE-binding proteins, which vary in size in cell lines derived from different tissues and animal species. To examine the molecular diversity of CREB-327 and related proteins at the nucleic acid level, we used labeled cDNAs from human placenta that encode two different CRE-binding proteins (CREB-327 and CRE-BP1) to probe Northern and Southern blots. Both probes hybridized to multiple fragments on Southern blots of genomic DNA from various species. Alternatively, when a human placental c-jun probe was hybridized to the same blot, a single fragment was detected in most cases, consistent with the intronless nature of the human c-jun gene. The CREB-327 probe hybridized to multiple mRNAs, derived from human placenta, ranging in size from 2-9 kilobases. In contrast, the CRE-BP1 probe identified a single 4-kilobase mRNA. Sequence analyses of several overlapping human genomic cosmid clones containing CREB-327 sequences in conjunction with polymerase chain reaction indicates that the CREB-327/341 cDNAs are composed of at least eight or nine exons, and analyses of human placental cDNAs provide direct evidence for at least one alternatively spliced exon. Analyses of mouse/hamster-human hybridoma DNAs by Southern blotting and polymerase chain reaction localizes the CREB-327/341 gene to human chromosome 2. The results indicate that there is a dichotomy of CREB-like proteins, those that are related by overall structure and DNA-binding specificity as well as those that are related by close similarities of primary sequences.

Insuffisance rénale severe sur maladie des emboles de cholestérol: controverses thérapeutiques revisitées [Severe renal insufficiency secondary to renal cholesterol emboli: therapeutical options revisited]

Disseminated cholesterol crystal embolism is observed in elderly men with severe atherosclerosis. This syndrome may be triggered by arterial catheterizations, major vascular surgery, thrombolytic and/or anticoagulation treatment. Cutaneous signs, subacute renal insufficiency, a marked inflammatory syndrome and eosinophilia are common. Immunologic testing is normal except for hypocomplementaemia. The diagnosis may be confirmed by biopsy (skin, gastrointestinal or renal), and/or by a fundoscopic examination. The treatment consists in withdrawing all form of anticoagulation, proscribing vascular surgery and arterial catheterization, prescribing aspirin and statins, and controlling arterial blood pressure. Corticosteroids may be given in refractory cases. The prognosis of cholesterol crystal embolism is poor but may be improved by statins.

Options for clinical trials of pre and post-natal treatments for congenital toxoplasmosis

Clinical trials comparing different drug regimens and strategies for the treatment of congenital toxoplasmosis and its clinical manifestations in the liveborn child in different clinical settings should aim at formally evaluating the net benefit of existing treatments and at developing new therapeutic options. Currently, there is no ideal drug for congenital toxoplasmosis; future research should focus on the screening of new active drugs and on their pre-clinical and early clinical development, with a focus on pharmacokinetic/dynamic studies and teratogenicity. For the prenatal treatment of congenital toxoplasmosis, a trial comparing spiramycine to pyrimethamine-sulphadiazine and placebo would allow a formal estimation of the effect of both drugs in infected pregnant women. In newborn children, the net benefit of pyrimethamine-sulphadiazine should also be formally assessed. These trials will be implemented in settings where prenatal screening for Toxoplasma gondii is currently implemented. Trials should be carefully designed to allow for translation to other settings and modelling tools like cost-effectiveness analysis should be used to provide clinicians and founders with the best available evidence to establish recommendations.

Schooling in the Network Society : Internet in Primary and Secondary Education. Research report (synthesis document)

Aquest projecte té la intenció d'identificar i analitzar els efectes de la introducció d'Internet a les escoles catalanes (educació primària i secundària). L'objectiu és posar de manifest la manera com s'utilitza la xarxa en aquest àmbit i en quina mesura contribueix a l'aparició, en els centres educatius, d'una nova cultura adaptada a les necessitats de la societat xarxa. Amb aquest propòsit, aquest projecte desplega les seves línies d'anàlisi per a fer atenció al procés d'incorporació d'Internet, principalment, en tres direccions: la pràctica pedagògica, les formes d'organització i gestió dels centres educatius i la seva vinculació amb la comunitat i el territori. Aquesta investigació ha estat desenvolupada pel grup de recerca ENS (Education and Network Society). Amb una perspectiva comparativa, el treball d'aquest grup vol contribuir, sobre la base de dades empíriques, a interpretar la transformació de l'àmbit educatiu no universitari en els paràmetres que estableix, avui dia, la nostra societat.

Appropriate end-points for right results in the age of antiangiogenic agents: Future options for phase II trials in patients with recurrent glioblastoma.

The progression-free survival rate at 6months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.