Blood Pressure Management After Endovascular Therapy for Acute Ischemic Stroke: The BEST-II Randomized Clinical Trial.

Importance: The effects of moderate systolic blood pressure (SBP) lowering after successful recanalization with endovascular therapy for acute ischemic stroke are uncertain. Objective: To determine the futility of lower SBP targets after endovascular therapy (<140 mm Hg or 160 mm Hg) compared with a higher target (≤180 mm Hg). Design, Setting, and Participants: Randomized, open-label, blinded end point, phase 2, futility clinical trial that enrolled 120 patients with acute ischemic stroke who had undergone successful endovascular therapy at 3 US comprehensive stroke centers from January 2020 to March 2022 (final follow-up, June 2022). Intervention: After undergoing endovascular therapy, participants were randomized to 1 of 3 SBP targets: 40 to less than 140 mm Hg, 40 to less than 160 mm Hg, and 40 to 180 mm Hg or less (guideline recommended) group, initiated within 60 minutes of recanalization and maintained for 24 hours. Main Outcomes and Measures: Prespecified multiple primary outcomes for the primary futility analysis were follow-up infarct volume measured at 36 (±12) hours and utility-weighted modified Rankin Scale (mRS) score (range, 0 [worst] to 1 [best]) at 90 (±14) days. Linear regression models were used to test the harm-futility boundaries of a 10-mL increase (slope of 0.5) in the follow-up infarct volume or a 0.10 decrease (slope of -0.005) in the utility-weighted mRS score with each 20-mm Hg SBP target reduction after endovascular therapy (1-sided α = .05). Additional prespecified futility criterion was a less than 25% predicted probability of success for a future 2-group, superiority trial comparing SBP targets of the low- and mid-thresholds with the high-threshold (maximum sample size, 1500 with respect to the utility-weighted mRS score outcome). Results: Among 120 patients randomized (mean [SD] age, 69.6 [14.5] years; 69 females [58%]), 113 (94.2%) completed the trial. The mean follow-up infarct volume was 32.4 mL (95% CI, 18.0 to 46.7 mL) for the less than 140-mm Hg group, 50.7 mL (95% CI, 33.7 to 67.7 mL), for the less than 160-mm Hg group, and 46.4 mL (95% CI, 24.5 to 68.2 mL) for the 180-mm Hg or less group. The mean utility-weighted mRS score was 0.51 (95% CI, 0.38 to 0.63) for the less than 140-mm Hg group, 0.47 (95% CI, 0.35 to 0.60) for the less than 160-mm Hg group, and 0.58 (95% CI, 0.46 to 0.71) for the high-target group. The slope of the follow-up infarct volume for each mm Hg decrease in the SBP target, adjusted for the baseline Alberta Stroke Program Early CT score, was -0.29 (95% CI, -0.81 to ∞; futility P = .99). The slope of the utility-weighted mRS score for each mm Hg decrease in the SBP target after endovascular therapy, adjusted for baseline utility-weighted mRS score, was -0.0019 (95% CI, -∞ to 0.0017; futility P = .93). Comparing the high-target SBP group with the lower-target groups, the predicted probability of success for a future trial was 25% for the less than 140-mm Hg group and 14% for the 160-mm Hg group. Conclusions and Relevance: Among patients with acute ischemic stroke, lower SBP targets less than either 140 mm Hg or 160 mm Hg after successful endovascular therapy did not meet prespecified criteria for futility compared with an SBP target of 180 mm Hg or less. However, the findings suggested a low probability of benefit from lower SBP targets after endovascular therapy if tested in a future larger trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04116112.

Four-Dimensional flow Magnetic Resonance Imaging for Assessment of Pediatric Coarctation of the Aorta.

BACKGROUND: Coarctation of the aorta (CoA) typically requires repair, but re-interventions and vascular complications occur, particularly with associated defects like bicuspid aortic valve (BAV). Magnetic resonance imaging (MRI) may identify anatomic and hemodynamic factors contributing to clinical complications. PURPOSE: To investigate 4D flow MRI characteristics in pediatric CoA to determine parameters for long-term clinical surveillance. STUDY TYPE: Retrospective. POPULATION: CoA (n = 21), CoA with BAV (n = 24), BAV alone (n = 29), and healthy control (n = 25). FIELD STRENGTH/SEQUENCE: A 1.5 T, 3D CE IR FLASH MRA, 4D flow MRI using 3D time resolved PC-MRI with velocity encoding. ASSESSMENT: Thoracic aorta diameters were measured from 3D CE-MRA. Peak systolic velocities and wall shear stress were calculated and flow patterns were visualized throughout the thoracic aorta using 4D flow. Repair characteristics, re-interventions, and need for anti-hypertensive medications were recorded. STATISTICS: Descriptive statistics, ANOVA with post hoc t-testing and Bonferroni correction, Kruskal-Wallis H, intraclass correlation coefficient, Fleiss' kappa. RESULTS: Patients with CoA with or without repair had smaller transverse arch diameters compared to BAV alone and control cohorts (P < 0.05), higher peak systolic flow velocities and wall shear stress compared to controls in the transverse arch and descending aorta (P < 0.05), and flow derangements in the descending aorta. The most common CoA repairs were extended end-to-end anastomosis (n = 22/45, 48.9%, age at repair 1 ± 2 years, seven re-interventions) and stent/interposition graft placement (n = 10/45, 22.2%, age at repair 12 ± 3 years, one re-intervention). Anti-hypertensive medications were prescribed to 33.3% (n = 15/45) of CoA and 34.4% of BAV alone patients (n = 10/29). DATA CONCLUSIONS: Despite repair, CoA alters hemodynamics and flow patterns in the transverse arch and descending aorta. These findings may contribute to vascular remodeling and secondary complications. 4D flow MRI may be valuable in risk stratification, treatment selection and postintervention assessment. Long-term, prospective studies are warranted to correlate patient and MRI factors with clinical outcomes. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Eccentric Enlargement of the Aortic Sinuses in Pediatric and Adult Patients with Bicuspid Aortic Valves: A Cardiac MRI Study.

Aortic root size and cusp fusion pattern have been related to disease outcomes in bicuspid aortic valve (BAV). This study seeks to characterize symmetry of the aortic sinuses in adult and pediatric BAV patients and its relationship to valvulopathy and root aortopathy. Aortic sinus-to-commissure (S-C) lengths were measured on cardiac MRI of adult and pediatric BAV patients with right-and-left coronary (RL) or right-and-non-coronary (RN) leaflet fusion and tricuspid aortic valve (TAV) controls. Coefficient of variance (CoV) of S-C lengths was calculated to quantify sinus asymmetry, or eccentricity. BAV cohort included 149 adults (48 ± 15 years) and 51 children (15 ± 5 years). TAV cohort included 40 adults (60 ± 13 years) and 20 children (15 ± 5 years). In adult and pediatric BAV patients, the non-fused aortic sinus was larger than either fused sinus. In RL fusion, the non-coronary S-C distance was larger than right or left S-C distances in adults (n = 121, p < 0.001) and larger than the right S-C distance in children (n = 41, p = 0.013). Sinus eccentricity (CoV) in BAV patients was higher than in TAV patients (p < 0.001) and did not correlate with age (p = 0.12). CoV trended higher in RL adults with aortic regurgitation (AR) compared to those without AR (p = 0.081), but was lower in RN adults with AR than without AR (p = 0.006). CoV did not correlate to root Z scores (p = 0.06-0.55) or ascending aortic (AAo) Z scores in adults (p = 0.45-0.55) but correlated negatively to AAo Z score in children (p = 0.005-0.03). Most adult and pediatric BAV patients with RL and RN leaflet fusion demonstrate eccentric dominance of the non-fused aortic sinus irrespective of age. The degree of eccentricity varies with valve dysfunction and BAV phenotype but does not relate to the degree of aortic root dilatation, nor does eccentricity correlate with ascending aorta dilatation in adults.

MR angiography and 2-D phase-contrast imaging for evaluation of meso-rex bypass function.

BACKGROUND: The meso-Rex bypass restores blood flow to the liver in patients with extrahepatic portal vein thrombosis. Stenosis occurs in some cases, causing the reappearance of portal hypertension. Complications such as thrombocytopenia present on a spectrum and there are currently no guidelines regarding a threshold for endovascular intervention. While Doppler ultrasound (US) is common for routine evaluation, magnetic resonance (MR) angiography with two-dimensional phase-contrast MRI (2-D PC-MRI) may improve the assessment of meso-Rex bypass function. OBJECTIVES: To determine the feasibility and utility of MR angiography with 2-D PC-MRI in evaluating children with meso-Rex bypass and to correlate meso-Rex bypass blood flow to markers of portal hypertension. MATERIALS AND METHODS: MR angiography and 2-D PC-MRI in meso-Rex bypass patients were retrospectively analyzed. Minimum bypass diameter was measured on MR angiography and used to calculate cross-sectional area. Meso-Rex bypass blood flow was measured using 2-D PC-MRI and divided by ascending aortic flow to quantify bypass flow relative to systemic circulation. Platelet and white blood cell counts were recorded. Correlation was performed between minimum bypass area, blood flow and clinical data. RESULTS: Twenty-five children (median age: 9.5 years) with meso-Rex bypass underwent MR angiography and 2-D PC-MRI. The majority of patients were referred to imaging given clinical concern for complications. Eighteen of the 25 patients demonstrated >50% narrowing of the bypass cross-sectional area. The mean platelet count in 19 patients was 127 K/µL. There was a significant correlation between minimum cross-sectional bypass area and bypass flow (rho=0.469, P=0.018) and between bypass flow and platelet counts (r=0.525, P=0.021). CONCLUSION: Two-dimensional PC-MRI can quantify meso-Rex bypass blood flow relative to total systemic flow. In a cohort of 25 children, bypass flow correlated to minimum bypass area and platelet count. Two-dimensional PC-MRI may be valuable alongside MR angiography to assess bypass integrity.

Comprehensive MR Analysis of Cardiac Function, Aortic Hemodynamics and Left Ventricular Strain in Pediatric Cohort with Isolated Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) disease demonstrates a range of clinical presentations and complications. We aim to use cardiac MRI (CMR) to evaluate left ventricular (LV) parameters, myocardial strain and aortic hemodynamics in pediatric BAV patients with and without aortic stenosis (AS) or regurgitation (AR) compared to tricuspid aortic valve (TAV) controls. We identified 58 pediatric BAV patients without additional cardiovascular pathology and 25 healthy TAV controls (15.3 ± 2.2 years) who underwent CMR with 4D flow. BAV cohort included subgroups with no valvulopathy (n = 13, 14.3 ± 4.7 years), isolated AS (n = 19, 14.5 ± 4.0 years), mixed valve disease (AS + AR) (n = 13, 17.1 ± 3.2 years), and prior valvotomy/valvuloplasty (n = 13, 13.9 ± 3.2 years). CMR data included LV volumetric and mass indices, myocardial strain and aortic hemodynamics. BAV patients with no valvulopathy or isolated AS had similar LV parameters to controls excepting cardiac output (p < 0.05). AS + AR and post-surgical patients had abnormal LV volumetric and mass indices (p < 0.01). Post-surgical patients had decreased global longitudinal strain (p = 0.02); other subgroups had comparable strain to controls. Patients with valvulopathy demonstrated elevated velocity and wall shear stress (WSS) in the ascending aorta (AAo) and arch (p < 0.01), while those without valve dysfunction had only elevated AAo velocity (p = 0.03). Across the cohort, elevated AAo velocity and WSS correlated to higher LV mass (p < 0.01), and abnormal hemodynamics correlated to decreased strain rates (p < 0.045). Pediatric BAV patients demonstrate abnormalities in LV parameters as a function of valvular dysfunction, most significantly in children with AS + AR or prior valvotomy/valvuloplasty. Correlations between aortic hemodynamics, LV mass and strain suggest valvular dysfunction could drive LV remodeling. Multiparametric CMR assessment in pediatric BAV may help stratify risk for cardiac remodeling and dysfunction.

Neisseria meningitidis factor H-binding protein bound to monoclonal antibody JAR5: implications for antibody synergy.

Factor H-binding protein (fHbp) is an important antigen of Neisseria meningitidis that is capable of eliciting a robust protective immune response in humans. Previous studies on the interactions of fHbp with antibodies revealed that some anti-fHbp monoclonal antibodies that are unable to trigger complement-mediated bacterial killing in vitro are highly co-operative and become bactericidal if used in combination. Several factors have been shown to influence such co-operativity, including IgG subclass and antigen density. To investigate the structural basis of the anti-fHbp antibody synergy, we determined the crystal structure of the complex between fHbp and the Fab (fragment antigen-binding) fragment of JAR5, a specific anti-fHbp murine monoclonal antibody known to be highly co-operative with other monoclonal antibodies. We show that JAR5 is highly synergic with monoclonal antibody (mAb) 12C1, whose structure in complex with fHbp has been previously solved. Structural analyses of the epitopes recognized by JAR5 and 12C1, and computational modeling of full-length IgG mAbs of JAR5 and 12C1 bound to the same fHbp molecule, provide insights into the spatial orientation of Fc (fragment crystallizable) regions and into the possible implications for the susceptibility of meningococci to complement-mediated killing.

Sleep and Limb Movement Characteristics of Children With Atopic Dermatitis Coincidentally Undergoing Clinical Polysomnography.

STUDY OBJECTIVES: Atopic dermatitis (AD) is a prevalent, chronic, itchy skin condition. Children undergoing polysomnography (PSG) may coincidentally have AD. Many children with AD have sleep disturbances. Our study aimed to characterize limb movements in children with AD and their effect on sleep. METHODS: A retrospective chart review was conducted for children who underwent comprehensive attended PSG and had AD. PSG sleep parameters were compared to published normative data. A subset of patients with markedly elevated total limb movements was further compared to a matched group of patients with a diagnosis of periodic limb movement disorder (PLMD) and no history of AD. RESULTS: There were 34 children with AD 6.36 ± 3.21 years (mean ± standard deviation), 50% female and with mild to moderate AD. There was increased wake after sleep onset (WASO = 46.0 ± 37.8 minutes), sleep onset latency (46.5 ± 53.0 minutes) and total limb movement index (13.9 ± 7.5 events/h) compared to normative values. Although our cohort was mostly mild AD, 7 of the 34 children with AD (20%) had a total limb movement index during sleep > 15 events/h. Increased total limb movements in PLMD versus patients with AD was most notable during stage N2 sleep (38 ± 17 versus 22 ± 7, P = .01, respectively). CONCLUSIONS: We found altered PSG parameters in children with AD, suggesting that clinicians should consider the diagnosis when affected children undergo PSG. Although our AD cohort was mild, we still determined a need to consider AD when diagnosing PLMD given the presence of elevated total limb movements in children with AD. CITATION: Treister AD, Stefek H, Grimaldi D, Rupani N, Zee P, Yob J, Sheldon S, Fishbein AB. Sleep and limb movement characteristics of children with atopic dermatitis coincidentally undergoing clinical polysomnography. J Clin Sleep Med. 2019;15(8):1107-1113.

Heterogeneity in rhesus macaque complement factor H binding to meningococcal factor H binding protein (FHbp) informs selection of primates to assess immunogenicity of FHbp-based vaccines.

Neisseria meningitidis causes disease only in humans. An important mechanism underlying this host specificity is the ability of the organism to resist complement by recruiting the complement downregulator factor H (FH) to the bacterial surface. In previous studies, binding of FH to one of the major meningococcal FH ligands, factor H binding protein (FHbp), was reported to be specific for human FH. Here we report that sera from 23 of 73 rhesus macaques (32%) tested had high FH binding to FHbp. Similar to human FH, binding of macaque FH to the meningococcal cell surface inhibited the complement alternative pathway by decreasing deposition of C3b. FH contains 20 domains (or short consensus repeats), with domains 6 and 7 being responsible for binding of human FH to FHbp. DNA sequence analyses of FH domains 6 and 7 from macaques with high or low FH binding showed a polymorphism at residue 352 in domain 6, with Tyr being associated with high binding and His with low binding. A recombinant macaque FH 6,7/Fc fragment with Tyr352 showed higher binding to FHbp than the corresponding fragment with His352. In previous studies in human FH transgenic mice, binding of FH to FHbp vaccines decreased protective antibody responses, and mutant FHbp vaccines with decreased FH binding elicited serum antibodies with greater protective activity. Thus, macaques with high FH binding to FHbp represent an attractive nonhuman primate model to investigate further the effects of FH binding on the immunogenicity of FHbp vaccines.