Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia:a non-inferiority, multicentre, randomised trial

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin. Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 109 cells per L before major surgery or less than 50 × 109 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 109 cells per L before major surgery or 45 × 109 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of –10%. This trial is registered with ClinicalTrials.gov, NCT01621204. Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49–55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; pnon-inferiority=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI –2·1%; pnon-inferiority=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred. Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles. Funding: GlaxoSmithKline and Novartis

Moderators, Mediators, and Other Predictors of Risperidone Response in Children with Autistic Disorder and Irritability

Objective/Background: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritabilityin autistic disorder. This paper explores moderators and mediators of this effect. Method: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. Results: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: Those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. Conclusion: The benefit–risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems non-specifically predict better outcome. Mineral interactions with risperidone deserve further study

Regulation of the Na,K-ATPase Gamma-Subunit FXYD2 by Runx1 and Ret Signaling in Normal and Injured Non-Peptidergic Nociceptive Sensory Neurons

Dorsal root ganglia (DRGs) contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury

An Error Analysis of Feedback Correlation Beamforming for the IS-95 Reverse Link

We investigate the application of an existing beamforming weight estimation method to the IS-95 reverse link and propose an extension to the algorithm which yields dramatically improved accuracy. An error analysis presents the statistical parameters of the various estimators. This includes an eigenvector perturbation analysis and the derivation of the Cram'er-Rao lower bound for this situation. Sample results are used to demonstrate the close agreement between observed and predicted values, thereby justifying the use of the analytical derivations to reduce simulation complexity in cell capacity evaluation studies. Technical Subject Area: Smart Antennas & Interference Cancellation 3 This research has been supported by the Canadian Institute for Telecommunications Research under the NCE program of the Government of Canada. y Denotes designated presenter z Denotes contact author A.M. Earnshaw -- An Error Analysis of Feedback Correlation Beamforming 1 1 Introduction Digital beamfor..

The Performance of Camera Translation Direction Estimators from Optical Flow: Analysis, Comparison, and Theoretical Limits

A noniterative method using optical flow to recover the translation direction of a moving camera has been previously proposed in [4]. We present a detailed explanation of the bias in this algorithm and compare methods for eliminating this bias, as well as presenting a comprehensive error analysis. This analysis includes a necessary modification to the Cram'erRao lower bound (CRLB). We propose a simple iterative modification to the algorithm which produces unbiased translation direction estimates that approach the CRLB. Numerical results are used to compare the various techniques on synthetic and real image sequences. Index Terms -- translation direction estimation, linear constraints, optical flow, error analysis, performance comparison 3 This research has been partially supported by grants from the Information Technology Research Centre of Ontario and the Natural Sciences and Engineering Research Council of Canada. This work was presented in part at the 1995 IEEE International Confe..

A Combined Soft-Decision Deinterleaver/Decoder for the IS95 Reverse Link

The reverse link encoding steps of the IS95 cellular CDMA standard consist of convolutional encoding, block interleaving, and orthogonal Walsh function encoding. Deinterleaving individual symbol metrics obtained from the Walsh function matched filters followed by conventional Viterbi decoding produces suboptimal results, as unwanted inter-symbol Walsh function correlation is introduced. We propose a combined deinterleaver/decoder with improved performance over existing decoders with little added overhead and no extra decoding delay. Applied to the IS95 reverse link, the proposed decoder has about 1.0 dB gain over soft decision decoding with interleaved symbol metrics at a bit error rate of 10

A Chip-Level IS95-Compliant Cellular CDMA Simulator: Design, Implementation, and Analysis

Cell capacity in a CDMA communication system can be increased through the use of base station antenna arrays and digital beamforming. We have therefore developed a comprehensive chip-level simulator of the reverse link component of an IS95-compliant cellular system. This level of detail is necessary to validate our simplifying models for imperfect beamforming and imperfect power control. This paper explains in detail the implementation of the entire reverse link simulation process. The various techniques available for power control and beamforming are then described, together with methods for estimating maximum cell capacity. An error analysis which was used to validate the accuracy of the simulator is included. Finally, sample simulation results are presented, our ongoing research is discussed, and some concluding remarks are made

A Perturbation Analysis and Performance Bound for the Estimation of 3-D Camera Translation Direction

The estimation of the 3-D displacement of a moving camera relative to a scene is critical for applications in robotics as well as object-based video compression. By estimating the relative motion within a scene, object positions can be accurately predicted for the future, thereby reducing the amount of information which must be coded. This problem has an inherently nonlinear nature and can therefore be computationally expensive. However, several related linear methods which use optical flow to recover the translation direction of a moving camera have been previously presented. These algorithms all depend on solving a constrained least-squares minimization problem. In this paper, we investigate the effects of noise perturbations on eigenvector and eigenvalue estimates for least-squares solutions, including a necessary modification to the Cram'er-Rao lower bound (CRLB) which specifies the minimum possible covariance matrix for constrained estimators. We propose a computationally simple nonlinear algorithm which produces near-optimal translation direction estimates (in the sense that the mean vector is unbiased and the covariance matrix approaches the CRLB). Sample numerical results are used to compare the various techniques and illustrate the agreement between predicted and observed values. Finally, some remaining problems meriting further investigation are discussed

Investigating the Effects of Imperfect Digital Beamforming on Cell Capacity in a Cellular CDMA Communication System

Cell capacity in a CDMA communication system can be increased through the use of base station antenna arrays and digital beamforming. It is necessary to estimate suitable beamforming weights from the received signal data which contains interference and noise. This imperfect beamforming produces corrupted weight values which affect the performance of the system. Due to the data coding methods used in IS95, it is necessary to utilize an enhanced beamforming weight estimation technique which we present here. This permits significantly more accurate estimates of the beamforming coefficients to be made. A simplified method for cell capacity estimation based on the power control information is also included. Sample simulation results indicate that approximately a 50% increase in capacity is obtained when beamforming with two antenna elements is used instead of one element. Results obtained from the proposed imperfect beamforming and the power control capacity estimation technique agree with those obtained for the situation where perfect beamforming weights are used