Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial.

BACKGROUND: Carvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure. METHODS: PREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete. FINDINGS: Between July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths. INTERPRETATION: Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. FUNDING: National Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.

Echocardiographic image collection and evaluation in infants with CHD: lessons learned from the imaging core lab for the Residual Lesion Score study.

Many factors affect patient outcome after congenital heart surgery, including the complexity of the heart disease, pre-operative status, patient specific factors (prematurity, nutritional status and/or presence of comorbid conditions or genetic syndromes), and post-operative residual lesions. The Residual Lesion Score is a novel tool for assessing whether specific residual cardiac lesions after surgery have a measurable impact on outcome. The goal is to understand which residual lesions can be tolerated and which should be addressed prior to leaving the operating room. The Residual Lesion Score study is a large multicentre prospective study designed to evaluate the association of Residual Lesion Score to outcomes in infants undergoing surgery for CHD. This Pediatric Heart Network and National Heart, Lung, and Blood Institute-funded study prospectively enrolled 1,149 infants undergoing 5 different congenital cardiac surgical repairs at 17 surgical centres. Given the contribution of echocardiographic measurements in assigning the Residual Lesion Score, the Residual Lesion Score study made use of a centralised core lab in addition to site review of all data. The data collection plan was designed with the added goal of collecting image quality information in a way that would permit us to improve our understanding of the reproducibility, variability, and feasibility of the echocardiographic measurements being made. There were significant challenges along the way, including the coordination, de-identification, storage, and interpretation of very large quantities of imaging data. This necessitated the development of new infrastructure and technology, as well as use of novel statistical methods. The study was successfully completed, but the size and complexity of the population being studied and the data being extracted required more technologic and human resources than expected which impacted the length and cost of conducting the study. This paper outlines the process of designing and executing this complex protocol, some of the barriers to implementation and lessons to be considered in the design of future studies.

Unravelling the Mystery of COVID-19 Pathogenesis: Spike Protein and Cu Can Synergize to Trigger ROS Production.

The COVID-19 pandemic has had a devastating impact on global health, highlighting the need to understand how the SARS-CoV-2 virus damages the lungs in order to develop effective treatments. Recent research has shown that patients with COVID-19 experience severe oxidative damage to various biomolecules. We propose that the overproduction of reactive oxygen species (ROS) in SARS-CoV-2 infection involves an interaction between copper ions and the virus's spike protein. We tested two peptide fragments, Ac-ELDKYFKNH-NH2 (L1) and Ac-WSHPQFEK-NH2 (L2), derived from the spike protein of the Wuhan strain and the ß variant, respectively, and found that they bind Cu(II) ions and form a three-nitrogen complexes at lung pH. Our research demonstrates that these complexes trigger the overproduction of ROS, which can break both DNA strands and transform DNA into its linear form. Using A549 cells, we demonstrated that ROS overproduction occurs in the mitochondria, not in the cytoplasm. Our findings highlight the importance of the interaction between copper ions and the virus's spike protein in the development of lung damage and may aid in the development of therapeutic procedures.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. METHODS: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. RESULTS: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. CONCLUSIONS: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Outcomes of Repair of Congenital Aortic Valve Lesions Using Autologous Pericardium vs Porcine Intestinal Submucosa.

BACKGROUND: Outcomes following congenital aortic valve (AoV) repair are plagued by progressive dysfunction of currently available leaflet substitute materials. OBJECTIVES: We compared the long-term outcomes of congenital AoV repair using porcine intestinal submucosa vs autologous pericardium (AP). METHODS: This was a single-center retrospective review of all patients who underwent congenital AoV repair with either porcine intestinal submucosa or AP from October 2009 to March 2013. The primary outcome was postdischarge (late) unplanned AoV reintervention. Secondary outcomes included number of late AoV reinterventions and a composite of at least moderate aortic regurgitation or stenosis at latest follow-up or before the first reintervention. Associations between leaflet repair material and outcomes were assessed using multivariable regression models, adjusting for prespecified patient-related and operative variables. RESULTS: Of 26 porcine intestinal submucosa and 49 AP patients who met entry criteria, the median age was 11.0 years (IQR: 4.7-16.6 years). At a median follow-up of 8.5 years (IQR: 4.4-9.6 years), 17 (65.4%) porcine intestinal submucosa and 22 (44.9%) AP patients underwent at least 1 AoV reintervention. On multivariable analysis, porcine intestinal submucosa use was significantly associated with unplanned AoV reintervention (HR: 4.6; 95% CI: 2.2-9.8; P < 0.001), number of postdischarge AoV reinterventions (incidence rate ratio: 1.7; 95% CI: 1.0-2.9; P = 0.037), and at least moderate aortic regurgitation or stenosis at latest follow-up or before the first reintervention (OR: 5.0; 95% CI: 1.2-21.0; P = 0.027). CONCLUSIONS: Aortic valvuloplasty with porcine intestinal submucosa is associated with earlier time to reintervention compared with autologous pericardium. The search for the ideal AoV leaflet repair material continues.

Osseointegration Foundation Charity Overdenture Program Study.

This investigation has been stimulated by the Osseointegration Foundation, working in conjunction with the Zest Anchors implant company. There are three basic valuable activities that emerge from a professional foundation, which were reflected in this case study. They include disseminating information to practitioners, to persuade young clinicians to become research investigators, and to reach out to patients in need of treatment who cannot afford it without a charitable opportunity.

Gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography compared with diagnostic computed tomography in relapsed prostate cancer.

The aim of this study was to evaluate if prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has a higher detection rate compared to standard contrast CT imaging for patients with a rising prostate-specific antigen (PSA) following definitive treatment (i.e., curative radical prostatectomy, radiotherapy, and brachytherapy) for prostate cancer in a private hospital setting. A retrospective single-site clinical audit was conducted on 150 PSMA PET/CT scans done for patients with a rising PSA after definitive treatment for prostate cancer. All studies were performed using I and T Ga-68 PSMA produced on a Scintomics radiopharmaceutical unit (Munich). All scans were performed on a GE 710 PET/CT scanner. All studies were compared to standard CT and other imaging. Of the 150 patients who had a 68Gallium (Ga)-PSMA PET/CT for a rise in their PSA levels, 102/150 (68%) of patients had PSMA-avid scans compared to the conventional imaging group which had an overall detection rate of 42% (63/150). The rates of detection were 100%, 90%, 92%, 67%, and 25% at PSA levels of >10 µg/L, 5-10 µg/L, >1.5 µg/L, 0.5-1.5 µg/L, and <0.5 µg/L, respectively. PSMA PET/CT also solely picked up 39/102 (38%) of prostate cancer relapses compared to the conventional imaging group. In our study of 150 patients with biochemical recurrence of prostate cancer, 68Ga-PSMA PET/CT demonstrated a superior detection rate (P < 0.05) compared to conventional imaging, including patients with low PSA levels (<0.5 µg/L).

Normal Values for Left Ventricular Strain and Synchrony in Children Based on Speckle Tracking Echocardiography.

Strain and synchrony are associated with clinical outcomes in children with heart diseases. Robust normative data for these values, measured by 2-dimensional speckle tracking echocardiography (2DSTE), are limited. Therefore, we aimed to derive normal ranges and z-scores of 2DSTE strain and synchrony parameters in children. Subjects were <21 years old with structurally and functionally normal hearts. High frame-rate 2-dimensional echocardiographic images were retrospectively analyzed to measure longitudinal (LS) and circumferential (CS) strain and synchrony; views used were apical 4, 2, and 3-chamber (AP 4, 2, 3) and mid-papillary short-axis (SAX-M). Synchrony measures included standard deviation of time to peak strain, maximal wall delay, and cross-correlation mean segmental delay; these were calculated without and with heart rate (HR) correction (divided by √RR). Z-score equations were created for AP4 and SAX-M strain components. n = 312 subjects (40% female) were included (age 3 days to 20.5 years). Mean strain values (%) were: AP4 -24.4 ± 3.2, AP2 -24.2 ± 3.3, AP3 -24.6 ± 3.4, SAX-M -25.8 ± 3.4. Significant differences between ages were present for all strain components (AP4 p < 0.001; AP2 p = 0.003; AP3 p = 0.014; SAX-M p = 0.01). LS components decreased with increasing age and body surface area (p < 0.001 for all); CS did not. Longitudinal, but not circumferential, synchrony parameters decreased with age; however, these were nonsignificant after HR correction. In conclusion, normal pediatric 2DSTE strain and synchrony parameters and z-scores are reported to provide a foundation for incorporation into clinical practice. LS decline with age whereas CS does not. Age-related decreases in LS synchrony were mostly nonsignificant when corrected for HR.

Impact of surgical pulmonary valve replacement on ventricular strain and synchrony in patients with repaired tetralogy of Fallot: a cardiovascular magnetic resonance feature tracking study.

BACKGROUND: In patients with repaired tetralogy of Fallot (TOF), a better understanding of the impact of surgical pulmonary valve replacement (PVR) on ventricular mechanics may lead to improved indications and outcomes. Therefore, we used cardiovascular magnetic resonance (CMR) feature tracking analysis to quantify ventricular strain and synchrony in repaired TOF patients before and after PVR. METHODS: Thirty-six repaired TOF patients (median age 22.4 years) prospectively underwent CMR a mean of 4.5 ± 3.8 months before PVR surgery and 7.3 ± 2.1 months after PVR surgery. Feature tracking analysis on cine steady-state free precession images was used to measure right ventricular (RV) and left ventricular (LV) circumferential strain from short-axis views at basal, mid-ventricular, and apical levels; and longitudinal strain from 4-chamber views. Intraventricular synchrony was quantified using the maximum difference in time-to-peak strain, the standard deviation of the time-to-peak, and cross correlation delay (CCD) metrics; interventricular synchrony was assessed using the CCD metric. RESULTS: Following PVR, RV end-diastolic volume, end-systolic volume, and ejection fraction declined, and LV end-diastolic volume and end-systolic volume both increased with no significant change in the LV ejection fraction. LV global basal and apical circumferential strains, and basal synchrony improved. RV global circumferential and longitudinal strains were unchanged, and there was a varied impact on synchrony across the locations. Interventricular synchrony worsened at the midventricular level but was unchanged at the base and apex, and on 4-chamber views. CONCLUSIONS: Surgical PVR in repaired TOF patients led to improved LV global strain and no change in RV global strain. LV and RV synchrony parameters improved or were unchanged, and interventricular synchrony worsened at the midventricular level.

Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome.

The Pediatric Heart Network randomized trial of atenolol versus losartan in the Marfan syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. In this report we present treatment effects on aortic stiffness and determine whether baseline aortic stiffness predicts aortic-root growth and clinical outcomes. Echocardiograms at 0, 6, 12, 24, and 36 months from 608 subjects (6 months to 25 years) who met original Ghent criteria and had a maximum aortic-root z-score (ARz) >3 were centrally reviewed. Stiffness index (SI) and elastic modulus (EM) were calculated for aortic root and ascending aorta. Data were analyzed using multivariable mixed effects modeling and Cox regression. Heart rate-corrected aortic-root SI over 3 years decreased with atenolol but did not change with losartan (-0.298 ± 0.139 vs 0.141 ± 0.139/year, p = 0.01). In the entire cohort, above-median aortic-root SI (>9.1) and EM (>618 mm Hg) predicted a smaller annual decrease in ARz (p ≤0.001). Upper-quartile aortic-root EM (>914 mm Hg) predicted the composite outcome of aortic-root surgery, dissection, or death (hazard ratio 2.17, 95% confidence interval 1.02 to 4.63, p = 0.04). Crude 3-year event rates were 10.4% versus 3.2% for higher versus lower EM groups. In conclusion, atenolol was associated with a decrease in aortic-root SI, whereas losartan was not. Higher baseline aortic-root SI and EM were associated with a smaller decrease in ARz and increased risk for clinical outcomes. These data suggest that noninvasive aortic stiffness measures may identify patients at higher risk of progressive aortic enlargement and adverse clinical outcomes, potentially allowing for closer monitoring and more aggressive therapy.

Management of pseudophakic cystoid macular edema.

Pseudophakic cystoid macular edema (PCME) is a common complication following cataract surgery. Acute PCME may resolve spontaneously, but some patients will develop chronic macular edema that affects vision and is difficult to treat. This disease was described more than 50 years ago, and there are multiple options for clinical management. We discuss mechanisms, clinical efficacy, and adverse effects of these treatment modalities. Topical non-steroidal anti-inflammatory agents and corticosteroids are widely used and, when combined, may have a synergistic effect. Intravitreal corticosteroids and anti-vascular endothelial growth factor (anti-VEGF) agents have shown promise when topical medications either fail or have had limited effects. Randomized clinical studies evaluating anti-VEGF agents are needed to fully evaluate benefits and risks. When PCME is either refractory to medical therapy or is associated with significant vitreous involvement, pars plana vitrectomy has been shown to improve outcomes, though it is associated with additional risks.

Ventricular strain in fetuses with aortic stenosis and evolving hypoplastic left heart syndrome before and after prenatal aortic valvuloplasty.

OBJECTIVE: The impact of prenatal intervention on fetal cardiac function has not been well defined. We assessed standard ventricular function parameters and strain in fetuses with evolving hypoplastic left heart syndrome (HLHS) treated with fetal aortic valvuloplasty (fAVP). METHODS: Fetuses with valvar aortic stenosis that underwent fAVP were studied. Echocardiographic images prior to intervention (Pre), within 1 week after fAVP (Post), and at the last prenatal follow-up examination (FU) were analyzed. Left ventricular (LV) circumferential (LVCS) and longitudinal strain (LVLS), right ventricular (RV) longitudinal strain (RVLS), and LV end-diastolic dimension Z-scores (LVIDD-Z) were documented and compared according to postnatal outcome. RESULTS: Among 57 fetuses studied, the postnatal outcome was biventricular in 23 and univentricular in 34. Prior to fAVP, strain was <4 in most cases, regardless of outcome. Biventricular fetuses had higher LVCS and LVLS segmental strain than univentricular fetuses. Among fetuses with a biventricular outcome, LVCS and LVLS increased as LVIDD-Z decreased in late gestation, whereas LVCS and LVLS remained <4 in univentricular fetuses, although the LVIDD-Z decreased to <0 in all cases. Septal RVLS increased after fAVP in the biventricular but not the univentricular outcome group. CONCLUSION: In utero aortic valve dilation appears to have a beneficial effect on both LV and RV function in some fetuses with evolving HLHS.

Impact of transcatheter pulmonary valve replacement on biventricular strain and synchrony assessed by cardiac magnetic resonance feature tracking.

BACKGROUND: Transcatheter pulmonary valve (TPV) replacement is an emerging therapy intended to restore pulmonary valve function in patients with right ventricular outflow tract conduit dysfunction; the impact of this technique on ventricular strain and synchrony is not known. METHODS AND RESULTS: Cardiac magnetic resonance and ECG data acquired at 1 center as part of the US Melody TPV trial were analyzed. Biventricular strain and mechanical synchrony measurements were made based on short-axis and 4-chamber steady-state free precession images using feature tracking software. Post- versus pre-TPV replacement findings were compared for all patients (n=31) and subgroups with predominant pulmonary regurgitation (n=13) or stenosis (n=18). Most patients had tetralogy of Fallot (18/31). After TPV replacement, left ventricular (LV) circumferential strain increased for the whole cohort (P<0.001) and both subgroups (pulmonary regurgitation P=0.01; pulmonary stenosis P=0.02). LV longitudinal strain increased for the whole cohort (P=0.02) and pulmonary regurgitation subgroup (P=0.05); circumferential right ventricular strain increased for the pulmonary stenosis group only (P=0.05). LV longitudinal synchrony improved significantly in the pulmonary regurgitation group (maximum wall delay P=0.03; cross-correlation delay P=0.01). Electric measures of synchrony did not improve. CONCLUSIONS: In patients with right ventricular outflow tract conduit dysfunction, TPV replacement is associated with improved global LV strain, as well as improved right ventricular strain and LV synchrony in subgroups. Given the associations between strain and synchrony and clinical outcomes, these findings support potential long-term benefits of TPV replacement.

Echocardiographic methods, quality review, and measurement accuracy in a randomized multicenter clinical trial of Marfan syndrome.

BACKGROUND: The Pediatric Heart Network is conducting a large international randomized trial to compare aortic root growth and other cardiovascular outcomes in 608 subjects with Marfan syndrome randomized to receive atenolol or losartan for 3 years. The authors report here the echocardiographic methods and baseline echocardiographic characteristics of the randomized subjects, describe the interobserver agreement of aortic measurements, and identify factors influencing agreement. METHODS: Individuals aged 6 months to 25 years who met the original Ghent criteria and had body surface area-adjusted maximum aortic root diameter (ROOTmax) Z scores > 3 were eligible for inclusion. The primary outcome measure for the trial is the change over time in ROOTmaxZ score. A detailed echocardiographic protocol was established and implemented across 22 centers, with an extensive training and quality review process. RESULTS: Interobserver agreement for the aortic measurements was excellent, with intraclass correlation coefficients ranging from 0.921 to 0.989. Lower interobserver percentage error in ROOTmax measurements was independently associated (model R(2) = 0.15) with better image quality (P = .002) and later study reading date (P < .001). Echocardiographic characteristics of the randomized subjects did not differ by treatment arm. Subjects with ROOTmaxZ scores ≥ 4.5 (36%) were more likely to have mitral valve prolapse and dilation of the main pulmonary artery and left ventricle, but there were no differences in aortic regurgitation, aortic stiffness indices, mitral regurgitation, or left ventricular function compared with subjects with ROOTmaxZ scores < 4.5. CONCLUSIONS: The echocardiographic methodology, training, and quality review process resulted in a robust evaluation of aortic root dimensions, with excellent reproducibility.

Comparison of cardiac MRI tissue tracking and myocardial tagging for assessment of regional ventricular strain.

This study sought to compare regional measures of ventricular strain by tissue tracking (TT) to those derived from myocardial tagging (MT) within cardiac MR (CMR), in normal subjects and patients with hypertrophic cardiomyopathy. CMR images from 13 normal subjects and 11 subjects with hypertrophic cardiomyopathy were retrospectively analyzed. For each subject, equivalent mid-papillary level short-axis cine steady-state free precession and MT slices from the same examination were evaluated. The time to peak circumferential strain and magnitude of the peak strain were calculated for 6 matched left ventricular segments. Data from 24 slices (n = 144 segments) were compared. The mean difference between techniques in magnitude of peak strain and time to peak strain was 1 ± 9% and 1 ± 58 ms, respectively. The mean difference in the standard deviation of time to peak strain within a slice was 0 ± 19 ms (mean cardiac cycle duration 1,013 ± 204 ms). Bland-Altman analysis showed closer agreement in time to peak strain than peak strain magnitude. Measurements of segmental time to peak strain by TT and MT were in close agreement; agreement for the magnitude of peak segmental strain was more modest. The TT approach does not add to CMR examination time and may be a useful tool for the assessment of ventricular synchrony.

Ranibizumab in patients with dense cataract and proliferative diabetic retinopathy with rubeosis.

BACKGROUND: To evaluate the safety of ranibizumab as a surgical adjunct during cataract surgery in patients with proliferative diabetic retinopathy (PDR) with rubeosis, and to evaluate the efficacy and adverse effects of ranibizumab in treating PDR with rubeosis. MATERIALS AND METHODS: Three intravitreal injections of 0.5 mg ranibizumab were administered on day-1, months-1 and -2 with cataract surgery 6-16 days after first injection. Retreatments with ranibizumab injections and pan-retinal photocoagulation (PRP) were given if recurrence or persistence of PDR was noted between months-3 and -11. Safety observation visits occurred at months-12, -18 and -24. Primary end points were incidence and severity of adverse events (AEs) that were related to both cataract surgery and treatment of PDR with rubeosis through month -12. RESULTS: Of six patients screened, four (mean age 61.3 years) were enrolled. No AEs were noted with either cataract surgery or treatment of PDR. Neovascularization of iris (NVI) promptly regressed by 4 days after first ranibizumab injection, prior to cataract surgery in three of four patients (one had significantly regressed NVI by post-injection day-3 visit); NVI was not noted in any patient at 2 weeks after first ranibizumab injection. Recurrence of rubeosis or NVA after 3 monthly injections was not observed in any. At month-12, PDR was not present when assessed clinically and by fluorescein angiogram (FA). Only one patient developed neovascularization of disc and neovascularization elsewhere and required retreatments at months-5 and -9. CONCLUSIONS: Multiple intravitreal injections of ranibizumab may be a safe, effective treatment adjunct for PDR and diabetes-related rubeosis.

Circumferential and longitudinal ventricular strain in the normal human fetus.

BACKGROUND: Echocardiography with speckle tracking is a novel, angle-independent technique for assessing global and regional cardiac function. Normal data on longitudinal strain have been reported for human fetuses. The aim of this study was to define circumferential left ventricular (LV) strain in a normal fetal population. METHODS: Singleton fetuses between 17 and 42 weeks in gestational age with no adverse maternal health issues or fetal abnormalities were studied. Regional and averaged cardiac strain were measured using syngo Velocity Vector Imaging software. RESULTS: Data from 81 fetuses were analyzed (mean gestational age, 29.2 ± 5.7 weeks). Overall, average midventricular circumferential strain was 18.7 ± 3.3%, LV longitudinal strain was 15.2 ± 2.7%, and right ventricular longitudinal strain was 16.0 ± 3.3%, with no correlation with gestational age. CONCLUSION: This is the first study to report normal fetal LV circumferential strain. These data may be useful as a reference for assessing fetal cardiac function. The retrospective study design and relatively low frame rates used in this study were important limitations.

Impaired cardiac reserve and severely diminished skeletal muscle O2 utilization mediate exercise intolerance in Barth syndrome.

Barth syndrome (BTHS) is a mitochondrial myopathy characterized by reports of exercise intolerance. We sought to determine if 1) BTHS leads to abnormalities of skeletal muscle O(2) extraction/utilization and 2) exercise intolerance in BTHS is related to impaired O(2) extraction/utilization, impaired cardiac function, or both. Participants with BTHS (age: 17 ± 5 yr, n = 15) and control participants (age: 13 ± 4 yr, n = 9) underwent graded exercise testing on a cycle ergometer with continuous ECG and metabolic measurements. Echocardiography was performed at rest and at peak exercise. Near-infrared spectroscopy of the vastus lateralis muscle was continuously recorded for measurements of skeletal muscle O(2) extraction. Adjusting for age, peak O(2) consumption (16.5 ± 4.0 vs. 39.5 ± 12.3 ml·kg(-1)·min(-1), P < 0.001) and peak work rate (58 ± 19 vs. 166 ± 60 W, P < 0.001) were significantly lower in BTHS than control participants. The percent increase from rest to peak exercise in ejection fraction (BTHS: 3 ± 10 vs. control: 19 ± 4%, P < 0.01) was blunted in BTHS compared with control participants. The muscle tissue O(2) saturation change from rest to peak exercise was paradoxically opposite (BTHS: 8 ± 16 vs. control: -5 ± 9, P < 0.01), and the deoxyhemoglobin change was blunted (BTHS: 0 ± 12 vs. control: 10 ± 8, P < 0.09) in BTHS compared with control participants, indicating impaired skeletal muscle extraction in BTHS. In conclusion, severe exercise intolerance in BTHS is due to both cardiac and skeletal muscle impairments that are consistent with cardiac and skeletal mitochondrial myopathy. These findings provide further insight to the pathophysiology of BTHS.

Comparison of echocardiographic and cardiac magnetic resonance imaging measurements of functional single ventricular volumes, mass, and ejection fraction (from the Pediatric Heart Network Fontan Cross-Sectional Study).

Assessment of the size and function of a functional single ventricle (FSV) is a key element in the management of patients after the Fontan procedure. Measurement variability of ventricular mass, volume, and ejection fraction (EF) among observers by echocardiography and cardiac magnetic resonance imaging (CMR) and their reproducibility among readers in these patients have not been described. From the 546 patients enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study (mean age 11.9 +/- 3.4 years), 100 echocardiograms and 50 CMR studies were assessed for measurement reproducibility; 124 subjects with paired studies were selected for comparison between modalities. Interobserver agreement for qualitative grading of ventricular function by echocardiography was modest for left ventricular (LV) morphology (kappa = 0.42) and weak for right ventricular (RV) morphology (kappa = 0.12). For quantitative assessment, high intraclass correlation coefficients were found for echocardiographic interobserver agreement (LV 0.87 to 0.92, RV 0.82 to 0.85) of systolic and diastolic volumes, respectively. In contrast, intraclass correlation coefficients for LV and RV mass were moderate (LV 0.78, RV 0.72). The corresponding intraclass correlation coefficients by CMR were high (LV 0.96, RV 0.85). Volumes by echocardiography averaged 70% of CMR values. Interobserver reproducibility for the EF was similar for the 2 modalities. Although the absolute mean difference between modalities for the EF was small (<2%), 95% limits of agreement were wide. In conclusion, agreement between observers of qualitative FSV function by echocardiography is modest. Measurements of FSV volume by 2-dimensional echocardiography underestimate CMR measurements, but their reproducibility is high. Echocardiographic and CMR measurements of FSV EF demonstrate similar interobserver reproducibility, whereas measurements of FSV mass and LV diastolic volume are more reproducible by CMR.

Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells.

PURPOSE: Nearly all eye drops contain preservatives to decrease contamination. Nonpreservatives such as disodium-ethylene diamine tetra-acetate (EDTA) and phosphate-buffered saline are also regularly added as buffering agents. These components can add to the toxicity of eye drops and cause ocular surface disease. To evaluate the potential toxicity of these common components and their comparative effects on the ocular surface, a tissue culture model utilizing immortalized corneal and conjunctival epithelial cells was utilized. METHODS: Immortalized human conjunctival and corneal epithelial cells were grown. At confluency, medium was replaced with 100 microL of varying concentrations of preservatives: benzalkonium chloride (BAK), methyl paraben (MP), sodium perborate (SP), chlorobutanol (Cbl), and stabilized thimerosal (Thi); varying concentrations of buffer: EDTA; media (viable control); and formalin (dead control). After 1 h, solutions were replaced with 150 microL of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazonium bromide). After 4 h, solutions decanted, 100 microL of acid isopropanol added, and the optical density determined at 572 nm to evaluate cell viability. RESULTS: Conjunctival and corneal cell toxicity was seen with all preservatives. Depending upon concentration, BAK exhibited from 56% to 89% toxicity. In comparison, Cbl exhibited from 50% to 86%, MP from 30% to 76%, SP from 23% to 59%, and Thi from 70% to 95%. EDTA with minimal toxicity (from 6% to 59%) was indistinguishable from SP. CONCLUSIONS: Generally, the order of decreasing toxicity at the most commonly used concentrations: Thi (0.0025%) > BAK (0.025%) > Cbl (0.25%) > MP (0.01%) > SP (0.0025%) approximately EDTA (0.01%). Even at low concentration, these agents will cause some degree of ocular tissue damage.