Evaluation of ocular motility deviation changes in exotropic patients after cycloplegic eye drops versus prism adaptation test.

PURPOSE: To evaluate changes in ocular motility deviation with cycloplegic eye drop examination compared to the prism adaptation test in patients with strabismus. METHODS: The medical charts were reviewed of all patients who underwent primary strabismus surgery in our center from December 2013 to July 2015. Data collected included demographics, medical history, and findings on pre-operative ophthalmic/orthoptic examination. Ocular motility deviation was measured before instillation of cycloplegic eye drops, immediately after maximal dilation (end point), and 10 and 20 min later. Prism adaptation test readings were taken at baseline, immediately after prism removal (end point), and 10 and 20 min later. RESULTS: A total of 43 patients had complete pre- and post-operative evaluations. Our analysis focused only on the exotropic patients (n = 33). On cycloplegics, there was no significant difference in ocular motility deviation between baseline and end point for distance and near (p = 0.584, p = 0.468, respectively). On prism adaptation test, comparison of ocular motility deviation between baseline and end point was statistically significant for distance and near (p = 0.002, p = 0.001, respectively). Changes remained significant 10 min after the end point for near (p = 0.011). Comparison at the end points between the tests revealed statistical significance for distance and near, favoring the prism adaptation test (p = 0.001 and p < 0.001, respectively). This significance was maintained even after 10 min for near (p = 0.036). CONCLUSION: The prism adaptation test is preferred over cycloplegic eye drops for the evaluation of maximal reserve of distance/near motility before surgical correction of exotropia.

Management of severe persistent fetal vasculature: case series and review of the literature.

PURPOSE: Persistent fetal vasculature (PFV) is a unique ocular disorder usually presenting early in life. The unregressed embryonal hyaloid vasculature poses a risk of severe ocular complications leading to decreased visual acuity. Surgery is the mainstay of therapy in complicated cases. We describe the clinical presentation and surgical treatment of PFV managed at our center from 2012 to 2015. METHODS: The study is a case series comprised eight patients who were diagnosed with complicated severe PFV. All were managed with a tailored surgical approach. The clinical characteristics, medical and surgical treatment, and follow-up findings of each case are described. RESULTS: There were six males and two females. Surgical intervention involved anterior or posterior vitrectomy, lens extraction, and intraocular lens implantation. Hyaloid stalk removal with release of ciliary traction was variably utilized in selected cases. Endodiathermy controlled intraocular bleeding, and intraocular scissors proved helpful in anterior PFV for disinserting the ciliary process from an abnormally thickened posterior lens capsule. Visual outcomes differed in each case, depending on multiple clinical factors. CONCLUSION: Severe complex PFV presents a therapeutic challenge. A tailored surgical approach with meticulous postoperative management is essential for visual rehabilitation.

Horizontal Deviations in Congenital Brown Syndrome.

PURPOSE: To report the incidence of horizontal deviations requiring surgical correction in patients with congenital Brown syndrome. METHODS: In a retrospective study, the medical records of all children who underwent a surgical correction of congenital Brown syndrome at Schneider Children's Medical Center of Israel from 1998 to 2016 were reviewed, analyzing the presence of preoperative primary position horizontal misalignment. RESULTS: Overall, 19 eyes (8 right and 11 left eyes) of 16 patients (7 males, 9 females; mean age: 4.2 ± 2.6 years) were included in this study. Fourteen patients (88%) had surgery for correction of a compensatory head position, including 8 patients (50%) with a head tilt and 6 patients (38%) with a chin-up position, and 2 patients had surgery for primary position hypotropia. All of them underwent a weakening procedure of the superior oblique tendon, by either Z-tenectomy (81%, n = 13) or suture elongation of the superior oblique tendon (19%, n = 3). Fifty-six percent of patients (n = 9) had primary position horizontal deviation before surgery, including 50% (n = 8) exodeviations, ranging from exophoria of 4 prism diopters (PD) to exotropia of 30 PD, and one esotropia of 14 PD. Fifty percent of patients (n = 8) had surgery to correct the horizontal deviation by a recession of either one (31%, n = 5) or two (19%, n = 3) muscles. Mean preoperative horizontal deviation (9.3 ± 3.4 PD) decreased significantly following surgery (1.7 ± 1 PD, P = .001) (paired t test). CONCLUSIONS: Significant horizontal misalignment is often present in patients with congenital Brown syndrome and its correction should be considered at the time of surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(2):113-116.].

Analysing the ocular biometry of new-born infants.

PURPOSE: To model and analyse the ocular biometry of new-born infants. METHODS: This work is based on previously published data of a cohort of 66 new-born infants aged 0-3 days. After exclusion of seven myopic subjects, the available retinoscopy, keratometry and ultrasound biometry data were analysed, along with calculated parameters such as lens power and whole eye power. RESULTS: Male infants have significantly flatter corneas that female infants (Mann-Whitney U test, p < 0.001), which was associated with a difference in gestational age between genders (multiple linear regression; p = 0.043). No other gender-based differences were seen. Corneal curvature (Pearson, r = 0.575; p < 0.001), lens power (r = -0.681; p < 0.001), and anterior chamber depth (r = 0.654; p < 0.001) were all correlated to axial length, but not refraction (r = -0.114; p = 0.42). Most ocular parameters were associated with gestational age (linear regression analysis; p < 0.05), rather than birth length, birth weight, fertilization method or parental myopia (all p > 0.05), suggesting scaled eye growth during the last weeks before birth. Multivariate Gaussian analysis demonstrated that a statistical eye model can be defined that generates synthetic data that is significantly equal to the original data (non-parametric Mann-Whitney test for equality; all p < 0.05), with similar variability (non-parametric Levene test; all p > 0.05). CONCLUSION: The eye undergoes a scaled growth until birth, at which time male and female infants have similar values. The models presented may serve as an early biometry reference.

Difficulty in Distinguishing Posterior Reversible Encephalopathy Syndrome, Hypoxic-Ischemic Insult, and Acute Toxic Leukoencephalopathy in Children.

AIM: This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic-ischemic insult (HII), and acute toxic leukoencephalopathy (ATL). METHODS: The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014. RESULTS: All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved. CONCLUSIONS: Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted.

Ultrasonographic demonstration of the superior ophthalmic vein in the orbit of premature infants with and without retinopathy of prematurity.

Retinopathy of prematurity (ROP), which develops due to abnormal retinal vascularization in premature babies, can lead to irreversible vision loss. B-scan ocular ultrasonography is a noninvasive examination which makes it possible to image the eye and orbit. Our purpose was to echographically assess the orbit of premature babies with and without retinopathy of prematurity (ROP), with a focus on the superior ophthalmic vein (SOV) which is normally not detected by orbital ultrasound. A prospective study design was used after approved by the local institutional review board. ROP was diagnosed by routine ophthalmoscopic exam. Orbital ultrasound was performed by a single experienced ophthalmologist and ultra-sonographer who was masked to the routine ROP screening results. The results of the ophthalmoscopic exam were compared to the orbital ultrasound findings. The study group was divided into those diagnosed with ROP and those not diagnosed with ROP and were found to be comparable by age and weight at the time of the US examination. The SOV was dilated in 21 of 22 eyes (95.4%) with ROP and in only 5 of 32 eyes (15.6%) without ROP. The present study suggests an association between ROP and dilatation of the SOV.

Medical And Surgical Management Of Orbital Cellulitis In Children.

OBJECTIVE: The purpose of this study was to identify features of orbital cellulitis that predict response to conservative treatment without surgical intervention and factors associated with a decision for surgery. PATIENTS AND METHODS: The medical files of patients diagnosed with orbital cellulitis at a tertiary medical center in central Israel between 1995 and 2010 were reviewed for clinical data, diagnosis, complications, and type of treatment. Comparison was made between patients treated with antibiotics and patients treated with antibiotics and surgery. RESULTS: Fifty-one patients (35 male) with a mean age of 6.1 years were identified. Main clinical signs included fever (mean 38.5°C), proptosis (82.3%), extraocular motility restriction (74.5%), and ocular pain (41.1%). Forty-one patients were successfully treated with antibiotics and 10 required endoscopic sinus surgery. On between-group comparison, the surgery group had severe eye pain (p = 0.009), severe proptosis (P = 0.02), longer intravenous antibiotic treatment (13.2 vs. 9.2 days, p = 0.04), and several imaging findings. Additional factors associated with surgical intervention included older children, subperiorbital abscess, larger dimension of the abscess (mean 15 mm), involvement of frontal sinuses and findings of intraorbital air bubbles. There was no visual deterioration in either group and no late sequelae. CONCLUSION: Factors associated with surgery included age older than 9 years, severe ocular pain, severe proptosis, and subperiorbital large abscess. These may be used for early identification of patients at risk of failure of only medical management.

Retinal NFL thinning on OCT correlates with visual field loss in pediatric craniopharyngioma.

OBJECTIVE: To investigate the use of peripapillary optical coherence tomography for monitoring optic neuropathy in pediatric craniopharyngioma. DESIGN: Retrospective, consecutive-cohort, single-centre chart analysis. PARTICIPANTS: Twenty children with craniopharyngioma treated at a pediatric medical centre from 1999 to 2011. METHODS: The medical files were reviewed for demographics and optic nerve function. Findings for visual acuity and visual fields were analyzed against repeated optical coherence tomography (OCT) measurements of peripapillary nerve fibre layer thickness (using either time-domain Stratus OCT or spectral-domain Cirrus OCT). RESULTS: Average age at diagnosis was 6.5 ± 3.88 years. The most common presenting symptom was headache; only 1 child complained of visual loss. Mean best corrected visual acuity (logMAR) was 0.036 ± 0.06 in the 17 healthy eyes and 1.05 ± 1.45 in the 23 eyes with optic neuropathy. Positive signs included relative afferent pupillary defect (8/20), visual acuity loss (7/20), temporal visual field loss (bilateral 4/15, unilateral 4/15), papilledema (3/20), and unilateral/bilateral optic disc pallor (14/20). RNFL thickness was significantly lower in eyes with optic neuropathy than in healthy eyes (65 ± 22 µm vs 86.2 ± 29 µm; p = 0.000) and correlated with visual acuity (r = -0.43 to -0.17, p = 0.0001) and presence or absence of a visual field defect (mean difference, 26.1 ± 5.8 µm, p = 0.003). Ten children showed no change in RNFL thickness over time (mean 18 ± 14.2 months). CONCLUSIONS: A thinner RNFL on ocular coherence tomography is correlated with poorer visual acuity and visual field loss. Ocular coherence tomography may serve as an objective method to quantify axonal loss caused by craniopharyngioma. Further investigation is needed to determine its use for evaluating progressive axonal loss over time.

Lipemia retinalis: case report and review of the literature.

We report the case of a 12-week-old boy presenting with increased cholesterol and triglyceride levels. Examination revealed lipemia retinalis. Genetic evaluation demonstrated lipoprotein lipase deficiency. The patient was treated with dietary restrictions, which resulted in rapid clinical improvement.

Time to normalization of intracranial pressure secondary to intraventricular hemorrhage and the need for retinopathy of prematurity treatment in infants diagnosed with both conditions.

PURPOSE: To determine whether time to normalization of increased intracranial pressure (ICP) caused by intraventricular hemorrhage (IVH) is associated with retinopathy of prematurity (ROP) treatment in premature infants diagnosed with both conditions. METHODS: The medical records of all premature infants born at ≤ 35 weeks' gestation and/or birth weight of ≤ 1500 g diagnosed with both any stage of ROP and any grade of IVH, with or without secondary increased ICP (defined as ≥ 20 cm H(2)O) were retrospectively reviewed. Adjusting for birth weight and gestational age, we compared time to normalization of increased ICP in infants treated for increased ICP only with that of infants treated for both increased ICP and ROP. RESULTS: A total of 21 infants were included. ICP levels normalized at a significantly older postnatal age in infants treated for both increased ICP and ROP (100 days) than in those treated for elevated ICP alone (45 days), after we adjusted for the results for birth weight and gestational age (P = 0.049). CONCLUSIONS: Earlier control of increased ICP secondary to IVH may reduce the need for ROP treatment in premature babies initially diagnosed with both conditions.

Long-term follow-up for ophthalmologic sequelae in children treated with corticosteroids for infantile spasms.

The aim of the study was to determine if early steroid treatment of infantile spasms is associated with ocular complications years after its termination. Twenty-five patients with infantile spasms who underwent prolonged treatment with intramuscular synthetic adrenocorticotropic hormone (ACTH) and oral prednisone were evaluated for ocular complications 2 to 33 years after treatment cessation. Patients were followed by an ophthalmic examination that included anterior and posterior segments and measurement of intraocular pressure. Intraocular pressure was normal bilaterally in all patients. Findings on anterior segment examination were unremarkable. On posterior segment examination, 3 patients had an increased cup/disc ratio with normal intraocular pressure. In 2 patients, the increased ratio was considered an anatomical variant. Posterior segment findings in 2 patients were attributed to their background disease. In conclusion, early treatment with high-dose synthetic adrenocorticotropic hormone and oral prednisone for infantile spasm is apparently not associated with a risk of occular complications on long-term follow-up.

Preoperative Visual Loss is the Main Cause of Irreversible Poor Vision in Children with a Brain Tumor.

The purpose of this study was to characterize the severe postoperative irreversible visual loss induced by optic neuropathy in some children with a brain tumor. The computerized database (2003-2008) of a neuro-ophthalmology service of a major pediatric tertiary center was reviewed for all children with severe irreversible visual loss (counting fingers or less) due to brain-tumor-related optic neuropathy at their last follow-up examination. Data on age, gender, etiology, initial symptoms, and signs, visual acuity before and after surgery and at last examination, neuroimaging findings, and treatment were collected. Of 240 children, 198 were operated. Of those, 10 (5%, 5 boys and 5 girls) met the study criteria. Data for the initial visual examination were available for eight children: one had binocular blindness (uncertain light perception, counting fingers); three had monocular blindness already at diagnosis (no light perception, counting fingers, no fixation); three had 6/60 vision in the worse eye; and one had good vision bilaterally (6/10). Four children had direct optic nerve compression, four papilledema, and three gliomas. Four children (40%; with craniopharyngioma, pineal germinoma, or posterior fossa tumor) exhibited a rapid deterioration in vision after tumor depression (one direct optic nerve compression and three increased intracranial pressure); two had monocular visual loss postoperatively; vision remained stable in four (after ≥5 follow-up visits), but did not improve. This study shows that tumor-related optic neuropathy may be associated with marked visual loss inspite of successful tumor resection; in 40% of children, the deterioration occurs perioperatively. Direct compression is the main cause of visual loss, while papilledema usually resolved without visual sequelae. However, autoregulatory changes may be responsible for rapid visual loss following decompression for chronic papilledema. Clinicians need reminding about the problem of postoperative visual loss and we speculate on how it can be avoided.

Intravitreal bevacizumab as supplemental treatment or monotherapy for severe retinopathy of prematurity.

PURPOSE: To investigate the benefit of intravitreal bevacizumab as supplemental or primary treatment for retinopathy of prematurity. METHODS: The files of nine consecutive infants treated with intravitreal bevacizumab for bilateral severe posterior retinopathy of prematurity were reviewed. RESULTS: Gestational age was 24 weeks to 27 weeks, and birth weight was 660 g to 1,131 g. Indications for treatment were retinopathy of prematurity progression from Stage 3 to 4A or 2 to 3 with extraretinal neovascularization despite laser treatment; active neovascular Stage 4A disease after laser and cryo-treatment; anterior segment neovascularization and bleeding after laser treatment; and aggressive posterior disease with tunica vasculosa lentis and vitreous haze, which prevented laser treatment. One patient (two eyes) underwent lens-sparing vitrectomy after bevacizumab treatment; one eye acquired macular fold. One patient underwent bilateral scleral buckle. Bevacizumab treatment was associated with subsidence of the active vascular component in all eyes. Anatomical results were favorable in 17 eyes. There were no local or systemic complications. CONCLUSION: Intravitreal bevacizumab may serve as a supplemental therapeutic agent for severe laser-refractory retinopathy of prematurity or as monotherapy when media opacities preclude diode laser photocoagulation or the patient is too sick for lengthy laser treatment.

Suppression of the oculocephalic reflex (doll's eyes phenomenon) in normal full-term babies.

PURPOSE: To determine the precise age of suppression of the oculocephalic reflex in infants and its relationship to specific clinical characteristics. METHODS: The oculocephalic reflex was prospectively tested in 325 healthy full-term babies aged 1 to 32 weeks attending an orthopedic outpatient clinic. Two ophthalmologists raised the baby's head 30 degrees above horizontal and rapidly rotated it in the horizontal and vertical planes while watching the conjugate eye movement. Suppression of the reflex, by observer agreement, was analyzed in relation to gestational age, postpartum age, postconceptional age, birth weight, and current weight. The data were fitted to a logistic regression model to determine the probability of suppression of the reflex according to the clinical variables. RESULTS: The oculocephalic reflex was suppressed in 75% of babies by the age of 11.5 weeks and in more than 95% of babies aged 20 weeks. Although postpartum age had a greater influence than gestational age, both were significantly correlated with suppression of the reflex (p = 0.01 and p = 0.04, respectively; two-sided t-test). Postpartum age was the best single variable explaining absence of the reflex. On logistic regression with cross-validation, the model including postpartum age and current weight yielded the best results; both these factors were highly correlated with suppression of the reflex (r = 0.74). CONCLUSIONS: The oculocephalic reflex is suppressed in the vast majority of normal infants by age 11.5 weeks. The disappearance of the reflex occurs gradually and longitudinally and is part of the normal maturation of the visual system.

Effect of repeated applanation tonometry on the accuracy of intraocular pressure measurements.

PURPOSE: To evaluate the stability of successive applanation tonometry measurements in glaucomatous eyes. METHODS: A prospective, comparative, randomized, and evaluator-masked study was conducted in a tertiary medical center. Sixty-seven patients with glaucoma attending our glaucoma clinic underwent four successive intraocular pressure (IOP) measurements with Goldmann-type applanation tonometry. Findings were compared with 70 patients scheduled for cataract surgery, similar in age and sex. The results were statistically analyzed with repeated measures analysis. RESULTS: In the glaucoma group, the difference between the first and second IOP measurements was statistically significant (15.94 mmHg vs 14.9 mmHg, p < 0.0001), as was the decrease in IOP from the first measurement to each of the other successive measurements. No significant change in IOP was noted in the control group (mean, 13.7 mmHg). CONCLUSIONS: Patients with glaucoma show a decrease in IOP on repeated applanation tonometry measurements. By contrast, in individuals without glaucoma, no significant decrease in IOP on repeated applanation tonometry measurements was found.

Sub-Tenon's ropivacaine block for pain relief after primary strabismus surgery.

PURPOSE: Pain is the main cause of patient distress/dissatisfaction after strabismus surgery. The aim of the study was to evaluate the effect of sub-Tenon's block with ropivacaine at the end of strabismus surgery on post-operative pain. METHODS: A prospective trial was conducted in 79 patients (age 1.0-65 years) scheduled for outpatient primary strabismus surgery with fixed sutures under general anesthesia (GA) at a major tertiary hospital. Half the patients were randomly allocated to receive sub-Tenon's block with ropivacaine 0.2% at conclusion of the operation. Primary outcome measures were visual analog scale (VAS) scores at arrival to the post-anesthesia care unit (PACU), at discharge 3 hr later, 12-16 hr post-operatively, and 24 hr post-operatively. Supplemental analgesia requirements and patient satisfaction were recorded as well. Data were presented as median (range). Mann-Whitney test, Pearson chi(2)-test or Fisher's exact test was used for statistical analysis; p

Long-term ophthalmological follow-up of children with Parinaud syndrome.

BACKGROUND AND OBJECTIVE: To assess the long-term ophthalmological outcome of Parinaud syndrome. PATIENTS AND METHODS: The files of 6 children with tumor-related Parinaud syndrome diagnosed and observed from 2000 to 2007 were reviewed. All had papilledema indicating increased intracranial pressure. RESULTS: Mean presentation-to-diagnosis delay was 3.6 weeks. Treatment consisted of surgical shunting and complete or partial resection with adjuvant chemotherapy (n = 4) and radiation (n = 3). Visual acuity remained stable or improved in 8 of 9 eyes with 20/30 visual acuity at diagnosis; improved bilaterally in 1 patient from 20/100 to 20/25; and deteriorated bilaterally in 1 patient from 20/30 and 20/200 to counting fingers and hand motions, respectively. The most improvement was achieved within 4 months. Findings at follow-up (mean: 4.2 years) included up gaze limitation (minimal in 2 patients), abnormal convergence, convergence retraction nystagmus, and light-near dissociation. One child had bilateral optic atrophy. CONCLUSION: Children with tumor-related Parinaud syndrome tend to have subtle but measurable residual ophthalmological findings years after diagnosis and treatment.

Ocular complications in children and adolescents following renal transplantation.

Ocular complications after renal transplantation are common in adults. Nevertheless, data regarding these complications in children are insufficient. The purpose of the present study was to assess ocular morbidity in pediatric renal graft recipients. A retrospective observational study of 71 patients aged 11.2 +/- 5.5 yr was conducted. Mean duration of follow-up was 5.6 +/- 3.5 yr. A total of 16 ocular complications were found in 12 (17%) of the patients. Three patients suffered from more than one complication. Cataract was the most common finding (six patients, 8.4%) followed by swollen disk and hypertensive retinopathy in four patients (5.7%) each and increased intra-ocular pressure in two patients (3%). Mean time interval between transplantation and occurrence of first abnormal ocular finding was 37 +/- 34.5 months. The follow-up time was significantly longer in patients with ophthalmological problems than in those without complications (7.8 yr vs. 5.2 yr, p < 0.02). No statistically significant association was found between the occurrence of ocular complications and the age of the patients at transplantation, donor source, duration of dialysis prior to transplantation, previous corticosteroid therapy or presence of acute rejection episodes. The results of the study point to the importance of regular concurrent ophthalmological follow-up in pediatric renal graft recipients to reduce/prevent ocular morbidity.

Effect of intravitreal bevacizumab (avastin) on the growing rabbit eye.

PURPOSE: To study the effect of intravitreal bevacizumab (Avastin) on the structure and growth of the young rabbit eye. MATERIALS AND METHODS: Twelve 6-week-old rabbits underwent intravitreal injection of bevacizumab (1.25 mg/0.05 ml) in one eye and no injection in the other (study group). Six additional rabbits served as controls. Slit lamp examination, fundus evaluation, and measurements of corneal power, central corneal thickness, corneal astigmatism, and axial length were performed before treatment and 1, 2, and 3 months after. At 3 months, the rabbits were sacrificed for histological study. RESULTS: Within the study group, there were no significant differences in clinical parameters between the bevacizumab-treated and fellow eyes at any timepoint or overall. The estimated confidence intervals extended to about one standard deviation of their respective values. Comparison of the injected eyes in the study group with the uninjected eyes in the control group yielded similar findings. There were no between-group differences in ocular growth and no abnormalities of the anterior and posterior segments or the retina and retinal vasculature. CONCLUSIONS: Intravitreal bevacizumab apparently has no adverse effect on the growth and development of the young rabbit eye, in a biologically or statistically significant way.

Z-tenotomy of the superior oblique tendon and horizontal rectus muscle surgery for A-pattern horizontal strabismus.

PURPOSE: Few studies have investigated combined surgeries for horizontal deviation and A pattern caused by superior oblique overaction (SOOA). This study presents our experience with combined surgery and examines the effect of the type of strabismus and prior surgery on outcome. METHODS: The medical records of patients who underwent combined surgery for horizontal deviation occurring with A-pattern misalignment from 2000 through 2004 were reviewed. The procedure consisted of horizontal extraocular muscle recession or resection with superior oblique Z-tenotomy. The criteria for surgical success were horizontal deviation at primary gaze of