Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.

Sustainability of Intravenous Alteplase Administration via Telephone-Based Consult: Data from a US Health System.

OBJECTIVES: Telephone-based consults using remote imaging review and standardization of evaluation but without visualizing the patient are an alternative to video-telestroke consults but are less well-studied. We aim to demonstrate the safety and efficacy of telephone-based acute consults in which IV tPA was administered over nearly a decade within one health system. MATERIALS AND METHODS: Clinical characteristics and outcomes were compared between a community hospital (spoke; uses telephone-based consults) and the academic comprehensive stroke center (hub; uses oversight of on-site neurology trainees) from 2008-2017. In both institutions acute therapy decisions are made by the same stroke neurologists. RESULTS: 2518 acute ischemic stroke consults were evaluated at hub and 2049 at spoke. Of these, 191 patients received IV tPA at hub and 184 at spoke. Patients at hub were younger (median (IQR): 61 (51-74) vs 69 (56-81) years, p = 0.0021) but admission National Institutes of Health Stroke Scale (NIHSS) was similar. There were no differences between door-to-needle times (69 (56-101) vs 69 (51-92) minutes, p = 0.13), last known well-to-tPA times (157 (113-202) vs 144 (110-175) minutes, p = 0.053), and rates of overall intracranial hemorrhage (ICH) after tPA (n = 23 (13.5%) vs 31 (17.0%), p = 0.35). In multivariable analyses, hospital was not an independent predictor of ICH after tPA. CONCLUSIONS: In a large dataset over nearly a decade, assessment for IV tPA administration using telephone assessment along with imaging review and emergency department standardization resulted in similar safety and outcomes as in the presence of on-site stroke/neurology expertise. Future studies are needed to confirm these findings.

Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project.

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Post-Stroke Depression in Patients with Large Spontaneous Intracerebral Hemorrhage.

OBJECTIVES: To determine factors associated with post-stroke depression (PSD) and relationship between PSD and functional outcomes in spontaneous intracerebral hemorrhage (ICH) using prospective data from a large clinical trial. MATERIALS AND METHODS: MISTIE III, a randomized, multicenter, placebo-controlled trial, was conducted to determine if minimally invasive surgery with thrombolysis improves outcome compared to standard medical care. Our primary outcome was post-stroke depression at 180 days. Secondary outcomes were change in blinded assessment of modified Rankin Scale (mRS) from 30 to 180 days, and from 180 to 365 days. Logistic regression models were used to assess the relationship between PSD and outcomes. RESULTS: Among 379 survivors at day 180, 308 completed Center for Epidemiologic Studies Depression Scale, of which 111 (36%) were depressed. In the multivariable analysis, female sex (Adjusted Odds Ratio [AOR], 95% Confidence Interval [CI]: 1.93 [1.07-3.48]), Hispanic ethnicity (3.05 [1.19-7.85]), intraventricular hemorrhage (1.88 [1.02-3.45]), right-sided lesions (3.00 [1.43-6.29]), impaired mini mental state examination at day 30 (2.50 [1.13-5.54]), and not being at home at day 30 (3.17 [1.05-9.57]) were significantly associated with higher odds of PSD. Patients with PSD were significantly more likely to have unchanged or worsening mRS from day 30 to 180 (42.3% vs. 25.9%; p=0.004), but not from day 180 to 365. CONCLUSIONS: We report high burden of PSD in patients with large volume ICH. Impaired cognition and not living at home may be more important than physical limitations in predicting PSD. Increased screening of high-risk post-stroke patients for depression, especially females and Hispanics may be warranted.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

The number of microspheres in Y90 radioembolization directly affects normal tissue radiation exposure.

PURPOSE: In Y90 radioembolization, the number of microspheres infused varies by more than a factor of 20 over the shelf-life of the glass radioembolization device. We investigated the effect of the number of Y90 microspheres on normal liver tissue. METHOD: Healthy pigs received lobar radioembolization with glass Y90 microspheres at 4, 8, 12, and 16 days post-calibration, representing a > 20× range in the number of microspheres deposited per milliliter in tissue. Animals were survived for 1-month post-treatment and the livers were explanted and scanned on a micro CT system to fully characterize the microscopic distribution of individual microspheres. A complete 3D microdosimetric evaluation of each liver was performed with a spatially correlated analysis of histopathologic effect. RESULTS: Through whole-lobe microscopic identification of each microsphere, a consistent number of microspheres per sphere cluster was found at 4, 8, and 12 days postcalibration, despite an 8-fold increase in total microspheres infused from days 4 to 12. The additional microspheres instead resulted in more clusters formed and, therefore, a more homogeneous microscopic absorbed dose. The increased absorbed-dose homogeneity resulted in a greater volume fraction of the liver receiving a potentially toxic absorbed dose based on radiobiologic models. Histopathologic findings in the animals support a possible increase in normal liver toxicity in later treatments with more spheres (i.e., ≥ day 12) compared to early treatments with less spheres (i.e., ≤ day 8). CONCLUSION: The microdosimetric evidence presented supports a recommendation of caution when treating large volumes (e.g., right lobe) using glass 90Y microspheres at more than 8 days post-calibration, i.e., after "2nd week" Monday. The favorable normal tissue microscopic distribution and associated low toxicity of first week therapies may encourage opportunities for dose escalation with glass microspheres and could also be considered for patients with decreased hepatic reserve.

Relationship of White Matter Lesions with Intracerebral Hemorrhage Expansion and Functional Outcome: MISTIE II and CLEAR III.

BACKGROUND/OBJECTIVE: Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials. METHODS: In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint. RESULTS: Of 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors. CONCLUSIONS: Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.

Influence of Intracerebral Hemorrhage Location on Outcomes in Patients With Severe Intraventricular Hemorrhage.

Background and Purpose- We investigated the prognostic significance of spontaneous intracerebral hemorrhage location in presence of severe intraventricular hemorrhage. Methods- We analyzed diagnostic computed tomography scans from 467/500 (excluding primary intraventricular hemorrhage) subjects from the CLEAR (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) III trial. We measured intracerebral hemorrhage engagement with specific anatomic regions, and estimated association of each region with blinded assessment of dichotomized poor stroke outcomes: mortality, modified Rankin Scale score of 4 to 6, National Institutes of Health Stroke Scale score of >4, stroke impact scale score of <60, Barthel Index <86, and EuroQol visual analogue scale score of <50 and <70 at days 30 and 180, respectively, using logistic regression models. Results- Frequency of anatomic region involvement consisted of thalamus (332 lesions, 71.1% of subjects), caudate (219, 46.9%), posterior limb internal capsule (188, 40.3%), globus pallidus/putamen (127, 27.2%), anterior limb internal capsule (108, 23.1%), and lobar (29, 6.2%). Thalamic location was independently associated with mortality (days 30 and 180) and with poor outcomes on most stroke scales at day 180 on adjusted analysis. Posterior limb internal capsule and globus pallidus/putamen involvement was associated with increased odds of worse disability at days 30 and 180. Anterior limb internal capsule and caudate locations were associated with decreased mortality on days 30 and 180. Anterior limb internal capsule lesions were associated with decreased long-term morbidity. Conclusions- Acute intracerebral hemorrhage lesion topography provides important insights into anatomic correlates of mortality and functional outcomes even in severe intraventricular hemorrhage causing obstructive hydrocephalus. Models accounting for intracerebral hemorrhage location in addition to volumes may improve outcome prediction and permit stratification of benefit from aggressive acute interventions. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00784134.

Bariatric Embolization of Arteries for the Treatment of Obesity (BEAT Obesity) Trial: Results at 1 Year.

Background Bariatric embolization is a new endovascular procedure to treat patients with obesity. However, the safety and efficacy of bariatric embolization are unknown. Purpose To evaluate the safety and efficacy of bariatric embolization in severely obese adults at up to 12 months after the procedure. Materials and Methods For this prospective study (NCT0216512 on ClinicalTrials.gov ), 20 participants (16 women) aged 27-68 years (mean ± standard deviation, 44 years ± 11) with mean body mass index of 45 ± 4.1 were enrolled at two institutions from June 2014 to February 2018. Transarterial embolization of the gastric fundus was performed using 300- to 500-µm embolic microspheres. Primary end points were 30-day adverse events and weight loss at up to 12 months. Secondary end points at up to 12 months included technical feasibility, health-related quality of life (Short Form-36 Health Survey ([SF-36]), impact of weight on quality of life (IWQOL-Lite), and hunger or appetite using a visual assessment scale. Analysis of outcomes was performed by using one-sample t tests and other exploratory statistics. Results Bariatric embolization was performed successfully for all participants with no major adverse events. Eight participants had a total of 11 minor adverse events. Mean excess weight loss was 8.2% (95% confidence interval [CI]: 6.3%, 10%; P < .001) at 1 month, 11.5% (95% CI: 8.7%, 14%; P < .001) at 3 months, 12.8% (95% CI: 8.3%, 17%; P < .001) at 6 months, and 11.5% (95% CI: 6.8%, 16%; P < .001) at 12 months. From baseline to 12 months, mean SF-36 scores increased (mental component summary, from 46 ± 11 to 50 ± 10, P = .44; physical component summary, from 46 ± 8.0 to 50 ± 9.3, P = .15) and mean IWQOL-Lite scores increased from 57 ± 18 to 77 ± 18 (P < .001). Hunger or appetite decreased for 4 weeks after embolization and increased thereafter, without reaching pre-embolization levels. Conclusion Bariatric embolization is well tolerated in severely obese adults, inducing appetite suppression and weight loss for up to 12 months. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.

Association between second hand smoke (SHS) exposure and caregiver stress in children with poorly controlled asthma.

Objective: Urban children with asthma experience high rates of second hand smoke (SHS) exposure. The objective was to examine whether SHS exposure is associated with symptom frequency in children with poorly controlled asthma. Methods: Children were enrolled in a RCT to test the efficacy of an environmental control behavioral intervention versus an attention control group and followed over 12 months. SHS exposure assessed using salivary cotinine measurement. Frequency of child asthma symptoms, healthcare utilization, household smoking and caregiver daily life stress were obtained via caregiver report. Time of enrollment was recorded to assess seasonal factors. Symptom days and nights were the primary outcomes. Multivariable models and odds ratios examined factors that best predicted increased frequency of daytime/nighttime symptoms. Results: Children (n = 222) with a mean age of 6.3 (SD 2.7) years, were primarily male (65%), African American (94%), Medicaid insured (94%), and had poorly controlled asthma (54%). The final multivariable model indicated symptoms in the fall (OR 2.78; 95% CI 1.16, 6.52) and increased caregiver daily life stress (OR 1.13, 95% CI 1.02, 1.25) were significantly associated with increased symptom days when controlling for cotinine level, intervention status, child age and home and car smoking restrictions. Conclusions: There was no impact of SHS exposure on increased symptom frequency. High caregiver daily life stress and symptoms in fall season may place children with asthma at risk for increased day/nighttime symptoms. Close monitoring of symptoms and medication use during the fall season and intervening on caregiver life stress may decrease asthma morbidity in children with poorly controlled asthma.

Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease.

BACKGROUND: Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. METHODS: In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. RESULTS: In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. CONCLUSION: This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke.

Quantitative susceptibility mapping as a monitoring biomarker in cerebral cavernous malformations with recent hemorrhage.

BACKGROUND: Quantitative Susceptibility Mapping (QSM) MRI allows accurate assessment of iron content in cerebral cavernous malformations (CCM), and a threshold increase by 6% in QSM has been shown to reflect new symptomatic hemorrhage (SH) in previously stable lesions. PURPOSE/HYPOTHESIS: It is unclear how lesional QSM evolves in CCMs after recent SH, and whether this could serve as a monitoring biomarker in clinical trials aimed at preventing rebleeding in these lesions. STUDY TYPE: This is a prospective observational cohort study. POPULATION: 16 CCM patients who experienced a SH within the past year, whose lesion was not resected or irradiated. FIELD STRENGTH/SEQUENCE: The data acquisition was performed using QSM sequence implemented on a 3T MRI system ASSESSMENT: The lesional QSM assessments at baseline and yearly during 22 patient-years of follow-up were performed by a trained research staff including imaging scientists. STATISTICAL TESTS: Biomarker changes were assessed in relation to clinical events. Clinical trial modeling was performed using two-tailed tests of time-averaged difference (assuming within-patient correlation of 0.8, power = 0.9 and alpha = 0.1) to detect 20%, 30% or 50% effects of intervention on clinical and biomarkers event rates during two years of follow-up. RESULTS: The change in mean lesional QSM of index hemorrhagic lesions was +7.93% per patient-year in the whole cohort. There were 5 cases (31%) of recurrent SH or lesional growth, and twice as many instances (62%) with a threshold (6%) increase in QSM. There were no instances of SH hemorrhage or lesional growth without an associated threshold increase in QSM during the same epoch. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1133-1138.

Predicting the Emergence of Sexual Violence in Adolescence.

This study aims to report the epidemiology of sexual violence (SV) perpetration for both female and male youth across a broad age spectrum. Additionally, the etiology of SV perpetration is examined by identifying prior exposures that predict a first SV perpetration. Six waves of data were collected nationally online, between 2006 and 2012, from 1586 youth between 10 and 21 years of age. Five types of SV were assessed: sexual harassment, sexual assault, coercive sex, attempted rape, and rape. To identify how prior exposures may predict the emergence of SV in adolescence, parsimonious lagged multivariable logistic regression models estimated the odds of first perpetrating each of the five types of SV within the context of other variables (e.g., rape attitudes). Average age at first perpetration was between 15 and 16 years of age, depending on SV type. Several characteristics were more commonly reported by perpetrators than non-perpetrators (e.g., alcohol use, other types of SV perpetration and victimization). After adjusting for potentially influential characteristics, prior exposure to parental spousal abuse and current exposure to violent pornography were each strongly associated with the emergence of SV perpetration-attempted rape being the exception for violent pornography. Current aggressive behavior was also significantly implicated in all types of first SV perpetration except rape. Previous victimization of sexual harassment and current victimization of psychological abuse in relationships were additionally predictive of one's first SV perpetration, albeit in various patterns. In this national longitudinal study of different types of SV perpetration among adolescent men and women, findings suggest several malleable factors that need to be targeted, especially scripts of inter-personal violence that are being modeled by abusive parents in youths' homes and also reinforced by violent pornography. The predictive value of victimization for a subsequent first SV perpetration highlights the inter-relatedness of different types of violence involvement. Universal and holistic prevention programming that targets aggressive behaviors and violent scripts in inter-personal relationships is needed well before the age of 15 years.

ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.

Group sequential designs with prospectively planned rules for subpopulation enrichment.

We propose a class of randomized trial designs aimed at gaining the advantages of wider generalizability and faster recruitment while mitigating the risks of including a population for which there is greater a priori uncertainty. We focus on testing null hypotheses for the overall population and a predefined subpopulation. Our designs have preplanned rules for modifying enrollment criteria based on data accrued at interim analyses. For example, enrollment can be restricted if the participants from a predefined subpopulation are not benefiting from the new treatment. Our designs have the following features: the multiple testing procedure fully leverages the correlation among statistics for different populations; the asymptotic familywise Type I error rate is strongly controlled; for outcomes that are binary or normally distributed, the decision rule and multiple testing procedure are functions of the data only through minimal sufficient statistics. Our designs incorporate standard group sequential boundaries for each population of interest; this may be helpful in communicating the designs, because many clinical investigators are familiar with such boundaries, which can be summarized succinctly in a single table or graph. We demonstrate these designs through simulations of a Phase III trial of a new treatment for stroke. User-friendly, free software implementing these designs is described. Copyright © 2016 John Wiley & Sons, Ltd.

Preventive Care Delivery to Young Children With Sickle Cell Disease.

Preventive services can reduce the morbidity of sickle cell disease (SCD) in children but are delivered unreliably. We conducted a retrospective cohort study of children aged 2 to 5 years with SCD, evaluating each child for 14 months and expecting that he/she should receive ≥75% of days covered by antibiotic prophylaxis, ≥1 influenza immunization, and ≥1 transcranial Doppler ultrasound (TCD). We used logistic regression to quantify the relationship between ambulatory generalist and hematologist visits and preventive services delivery. Of 266 children meeting the inclusion criteria, 30% consistently filled prophylactic antibiotic prescriptions. Having ≥2 generalist, non-well child care visits or ≥2 hematologist visits was associated with more reliable antibiotic prophylaxis. Forty-one percent of children received ≥1 influenza immunizations. Children with ≥2 hematologist visits were most likely to be immunized (62% vs. 35% among children without a hematologist visit). Only 25% of children received ≥1 TCD. Children most likely to receive a TCD (42%) were those with ≥2 hematologist visits. One in 20 children received all 3 preventive services. Preventive services delivery to young children with SCD was inconsistent but associated with multiple visits to ambulatory providers. Better connecting children with SCD to hematologists and strengthening preventive care delivery by generalists are both essential.

Risk Factors for Venous Thromboembolism in Pediatric Trauma Patients and Validation of a Novel Scoring System: The Risk of Clots in Kids With Trauma Score.

OBJECTIVES: Identify risk factors for venous thromboembolism and develop venous thromboembolism risk assessment models for pediatric trauma patients. DESIGN: Single institution and national registry retrospective cohort studies. SETTING: John Hopkins level 1 adult and pediatric trauma center and National Trauma Data Bank. PATIENTS: Patients 21 years and younger hospitalized following traumatic injuries at John Hopkins (1987-2011). Patients 21 years and younger in the National Trauma Data Bank (2008-2010 and 2011-2012). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics of Johns Hopkins patients with and without venous thromboembolism were compared, and multivariable logistic regression analysis was used to identify independent venous thromboembolism risk factors. Weighted risk assessment scoring systems were developed based on these and previously identified factors from National Trauma Data Bank patients (2008-2010); the scoring systems were validated in this cohort from Johns Hopkins and a cohort from the National Trauma Data Bank (2011-2012). Forty-nine of 17,366 pediatric trauma patients (0.28%) were diagnosed with venous thromboembolism after admission to our trauma center. After adjusting for potential confounders, venous thromboembolism was independently associated with older age, surgery, blood transfusion, higher Injury Severity Score, and lower Glasgow Coma Scale score. These and additional factors were identified in 402,329 pediatric patients from the National Trauma Data Bank from 2008 to 2010; independent risk factors from the logistic regression analysis of this National Trauma Data Bank cohort were selected and incorporated into weighted risk assessment scoring systems. Two models were developed and were cross-validated in two separate pediatric trauma cohorts: 1) 282,535 patients in the National Trauma Data Bank from 2011 to 2012 and 2) 17,366 patients from Johns Hopkins. The receiver operating curve using these models in the validation cohorts had area under the curves that ranged 90-94%. CONCLUSIONS: Venous thromboembolism is infrequent after trauma in pediatric patients. We developed weighted scoring systems to stratify pediatric trauma patients at risk for venous thromboembolism. These systems may have potential to guide risk-appropriate venous thromboembolism prophylaxis in children after trauma.