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Summary Background For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. Methods TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Findings Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10 −16 ) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. Funding National Heart, Lung, and Blood Institute, National Institutes of Health.

The purpose of this study was to define the hematologic response to total splenectomy (TS) or partial splenectomy (PS) in children with hereditary spherocytosis (HS) or sickle cell disease (SCD).The Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium registry collected hematologic outcomes of children with CHA undergoing TS or PS to 1 year after surgery. Using random effects mixed modeling, we evaluated the association of operative type with change in hemoglobin, reticulocyte counts, and bilirubin. We also compared laparoscopic to open splenectomy.The analysis included 130 children, with 62.3% (n=81) undergoing TS. For children with HS, all hematologic measures improved after TS, including a 4.1g/dl increase in hemoglobin. Hematologic parameters also improved after PS, although the response was less robust (hemoglobin increase 2.4 g/dl, p0.001). For children with SCD, there was no change in hemoglobin. Laparoscopy was not associated with differences in hematologic outcomes compared to open. TS and laparoscopy were associated with shorter length of stay.Children with HS have an excellent hematologic response after TS or PS, although the hematologic response is more robust following TS. Children with SCD have smaller changes in their hematologic parameters. These data offer guidance to families and clinicians considering TS or PS.

This article addresses the conflict between an ever-expanding right of publicity and the federally guaranteed rights provided by copyright law. This conflict is highlighted in the Wendt v. Host International case in which the actors George Wendt and John Ratzenberger from Cheers used the right of publicity to prevent the show's creators from licensing the use of the Norm and Cliff characters in the decor of a chain of airport bars. Even though the licensing of the characters was explicitly allowed under copyright law, the Ninth Circuit held that the right of publicity prevented the creators from doing so. Similarly, performers have successfully used the right of publicity to prevent the making of sound-alike recordings even though the Copyright Act explicitly permits such recordings. The vast majority of courts have not preempted the right of publicity even when it conflicts with clearly established copyright law. This is true, in part, because most courts have relied almost exclusively on the preemption clause of the Copyright Act which is ambiguous and difficult to apply. Neither courts nor scholars have looked much beyond the Copyright Act's explicit preemption clause when considering preemption of publicity rights. This article proposes a new approach to analyzing copyright preemption - one which incorporates the broader principles of the Supremacy Clause to determine when copyright law should preempt the right of publicity. The article then presents a practical test for determining when the right of publicity stands as an obstacle to copyright law and should therefore be preempted.

This article proposes a new test for determining what is a true threat - speech not protected by the First Amendment. Despite the importance of the true threats exception to the First Amendment, this is an underexplored area of constitutional law. Even though the Supreme Court has made clear that true threats are punishable, it has not clearly defined what speech constitutes a true threat. To make this determination circuit courts have adopted inconsistent and inadequate tests including a reasonable listener test. The Supreme Court has never granted certiorari to resolve the issue. The law surrounding threats has gained recent attention in two cases involving alleged threats conveyed over the internet: the Nuremberg Files case and the Jake Baker case. A Ninth Circuit decision (currently being considered for en banc review) recently reversed the district court decision in the Nuremberg Files case and its analysis highlights the circuit court confusion on what constitutes a true threat. This article discusses the failings of the current circuit tests, as well as the inadequacy of the alternatives suggested by scholars. This article proposes a new test which adds both an intent prong and an actor prong to the generally accepted reasonable listener test. An extensive test suite of cases demonstrates the efficacy of the proposed test. This article resolves the current confusion and presents a true threats test which provides greater protection for speakers while preserving the rights of potential victims.