Two doses of daclizumab are sufficient for prolonged interleukin-2Ralpha chain blockade.

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Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Cytochrome P-450 2D6 and 2C19 polymorphisms and consumption of care in psychiatric practice

Background: Cytochrome P-450 2D6 (CYP2D6) and 2C19 (CYP2C19) are known to contain functional polymorphisms that can alter the metabolic rate of many antidepressants (AD) and antipsychotics (AP). Individuals with no metabolic activity and with increased activity may be at risk for an unsatisfactory drug response. Objectives: Aim of this study was to assess the influence of CYP2D6 and CYP2C19 phenotypes on the consumption of care in psychiatric patients. Methods: The study was conducted in a psychiatric hospital in the Netherlands, including all admissions from July 2001 until July 2010, of patients genotyped for (at least) the CYP2D6 ∗3 ∗4 and gene multiplication and CYP2C19 ∗2. Patients were classified as poor metabolizers (PM), ultrarapid metabolizers (UM), intermediate metabolizers (IM) and extensive metabolizers (EM). To study the consumption of care, several outcome measures were calculated for PM and UM and compared to EM. Results: 7377 admissions were analyzed, belonging to 3859 unique patients. The total duration of hospital stays with AP and/or AD treatment was longer for CYP2D6 UM than for CYP2D6 EM (66 versus 48 days,

Space-based ultra-long wavelength radio observatory (low cost) - SURO-LC

SURO-LC is the radio astronomer's equivalent of the first high resolution X-ray space telescopes. It opens up a largely unexplored spectral band, previously hidden from Earth, to make new discoveries in the nearby and distant universe. The proposed mission offers the first omnidirectional low frequency radio survey at high sensitivity and high resolution.\ud SURO-LC all-sky or rapid monitoring (for rapid solar and galactic events) operation is in the largely un-explored frequency domain between 0.1 and 70 MHz, of which the 0.1 - 30 MHz range is mostly inaccessible from earth because of ionospheric blocking and man-made radio frequency interference (RFI).\ud SURO-LC deploys a formation of nine spacecraft in a low relative-drift Lissajous orbit at SEL2, 1.5 million km from earth in a radio clean environment. Eight spherically distributed Cubesat daughters, equipped with 3 orthogonal dipole antennas, form a distributed interferometric radio telescope. An offset mothership provides data acquisition, digital signal processing, and ground communication

We mind your step: understanding and preventing drop-out in the transfer from paediatric to adult tertiary endocrine healthcare

Introduction: Transition from paediatric to adult endocrinology can be challenging for adolescents, their families and healthcare professionals. Previous studies have shown that up to 25% of young adults with endocrine disorders are lost to follow-up after moving out of paediatric care. This poses a health risk for young adults, which can lead to serious and expensive medical acute and long-term complications. Methods: In order to understand and prevent dropout, we studied electronic medical records of patients with endocrine disorders. These patients were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our hospital in 2013–2014 and should have made the transfer to adult care at the time of the study. Results: Of 387 adolescents, 131 had an indication for adult follow-up within our university hospital. Thirty-three (25%) were lost to follow-up. In 24 of them (73%), the invitation for the adult OPC had never been sent. We describe the failures in logistic processes that eventually led to dropout in these patients. Conclusion: We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Of all dropouts, 73% could be attributed to the failure of logistic steps. In order to prevent these dropouts, we provide practical recommendations for patients and paediatric and adult endocrinologists