Identifying the most proximal multi-level factors associated with meeting each of the 24-h movement behavior recommendations in a sample of autistic adults.

BACKGROUND: Autistic adults have poorer 24-h movement behaviors, including lower levels of physical activity, more time spent being sedentary, and shorter sleep duration than neurotypical adults. Social ecological frameworks posit that 24-h movement behaviors are determined by multi-level domains; however, not known is which multi-level factors are most important to meeting each of the 24-h movement behavior guidelines among autistic adults. OBJECTIVE: This study examined the relative importance of a range of multi-level determinants on meeting guidelines for the 24-h movement behaviors of aerobic physical activity, sedentary behavior, and sleep. METHODS: We administered at cross-sectional electronic survey to a national self-selecting, convenience sample of autistic adults and caregivers of autistic adults residing in the USA. We used machine learning to examine the relative variable importance (VIMP) of 55 multi-level variables with meeting recommendations for physical activity, sedentary behavior, and sleep duration. VIMPs >0 indicate predictive variables/domains. RESULTS: A greater number of group activities attended in the last 3-months, and greater independence in completing activities of daily living were most important to meeting aerobic physical activity guidelines. Group activity participation and marital status were important to meeting sedentary behavior guidelines while having a fewer number of comorbidities was most important to achieving adequate sleep. CONCLUSIONS: These data support hypotheses about the role of family and social level interventions targeting movement behaviors in autistic adults.

Resolution of Pseudophakic Cystoid Macular Edema: 2 mg Intravitreal Triamcinolone Acetonide versus 40 mg Posterior Sub-Tenon Triamcinolone Acetonide.

PURPOSE: To compare 2 mg intravitreal triamcinolone (IVT) versus 40 mg posterior sub-Tenon triamcinolone acetonide (STT) for the treatment of eyes with pseudophakic cystoid macular edema. METHODS: A retrospective, single-center review of eyes receiving 2 mg IVT between 3/1/2012-3/1/2017 and 40 mg STT between 1/1/2015-3/1/2017. Visual acuity (VA) and central macular thickness (CMT) were recorded at baseline, 1-, 3-, and 6-month follow-up visits. RESULTS: Forty-five eyes were included in the IVT group and 50 eyes in the STT group. Change in VA from baseline to 1, 3, and 6 months was not significantly different between IVT and STT (6 months: 2.3 lines vs. 2.4 lines, p = .10). The IVT group achieved significantly better CMT improvement from baseline compared to STT at 1 month (255 µm vs. 187 µm; p = .03), but this difference was not present at month 3 (214 µm vs. 212 µm; p = .79) or month 6 (176 µm vs. 207 µm; p = .29). During the 6-month follow-up period, approximately 7% of eyes in the IVT group and 12% of eyes in the STT group developed ocular hypertension (p = .43), and all cases were successfully managed with topical anti-ocular hypertensive therapy or observation. CONCLUSIONS: 2 mg IVT and 40 mg STT both achieved significant improvement in vision and CMT with no significant difference between interventions at 3- and 6-month follow-up.

EN FACE VERSUS 12-LINE RADIAL OPTICAL COHERENCE TOMOGRAPHY SCAN PATTERNS FOR DETECTION OF MACULAR FLUID IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To compare fluid detection of autosegmented en face to 12-line radial spectral domain optical coherence tomography scan patterns in neovascular age-related macular degeneration. METHODS: Retrospective observational case series. Sixty-seven patients (94 eyes) with neovascular age-related macular degeneration underwent autosegmented en face optical coherence tomography (with associated 304-line raster scan) and 12-line radial scan patterns. Sensitivity and specificity of fluid detection for en face scan and 12-line radial scans were determined by combining radial and 304-line raster scans as a gold standard. RESULTS: Two hundred and fifty-eight en face and 12-line radial spectral domain optical coherence tomography scans were interpreted. Seventy-five scans (58.1%) had fluid, whereas 54 scans (41.9%) did not. En face scan pattern fluid detection sensitivity and specificity was 89.3% and 61.1%, respectively. Twelve-line radial scan pattern fluid detection sensitivity and specificity was 97.3% and 100%, respectively. The difference in fluid detection between scan patterns was statistically significant (P = 0.01). Decreased central macular thickness was associated with false-positive (P = 0.035) and false-negative (P = 0.01) fluid detection on en face scans. CONCLUSION: En face optical coherence tomography alone is not as sensitive or specific as the 12-line radial scan pattern in detecting fluid in neovascular age-related macular degeneration. En face scans should be corroborated with other optical coherence tomography protocols to guide clinical decision making.

Outcomes of Eyes Lost to Follow-up with Proliferative Diabetic Retinopathy That Received Panretinal Photocoagulation versus Intravitreal Anti-Vascular Endothelial Growth Factor.

PURPOSE: To compare anatomic and functional outcomes in eyes with proliferative diabetic retinopathy (PDR) that were lost to follow-up (LTFU) for more than 6 months after treatment with either intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) agents or panretinal photocoagulation (PRP). DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-nine patients who were LTFU immediately after treatment for more than 6 months between September 2013 and September 2016. METHODS: Patients with eyes receiving either intravitreal anti-VEGF treatment or PRP with the next follow-up visit occurring more than 6 months after treatment were identified. Visual acuity (VA) and anatomic outcomes at the visit before being LTFU, the return visit, the 6-month visit after return, the 12-month visit after return, and the final visit were gathered and compared between the 2 treatment groups. MAIN OUTCOMES MEASURES: Visual acuity and anatomic outcomes. RESULTS: Seventy-six eyes of 59 patients were included in the study, of which 30 received IVI with anti-VEGF and 46 received PRP. In the anti-VEGF group, mean VA worsened significantly when comparing the visit before being LTFU (0.43±0.38 logarithm of the minimum angle of resolution [logMAR]) with the return visit (0.97±0.80 logMAR; P = 0.001) as well as with the final visit (0.92±0.94 logMAR; P = 0.01). In the PRP group, mean VA worsened significantly when comparing the visit before being LTFU (0.42±0.34 logMAR) with the return visit (0.62±0.64 logMAR; P = 0.03). However, no significant difference was observed at the final visit (0.46±0.47 logMAR; P = 0.38). There was a significantly greater number of eyes with tractional retinal detachment in the IVI group compared with the PRP group at the final visit (10 vs. 1, respectively; P = 0.005). There was a significantly greater incidence of neovascularization of the iris in the IVI arm compared with the PRP arm at the final visit (4 vs. 0, respectively; P = 0.02). CONCLUSIONS: Eyes with PDR that received only intravitreal anti-VEGF demonstrated worse anatomic and functional outcomes after being LTFU compared with eyes that received PRP. Given the potential sequelae of being LTFU, the choice of treatment for PDR must be considered carefully.

ENDOPHTHALMITIS AFTER PARS PLANA VITRECTOMY: Efficacy of Intraoperative Subconjunctival Antibiotics.

PURPOSE: To examine rates of acute infectious endophthalmitis after pars plana vitrectomy (PPV) in eyes that received intraoperative subconjunctival antibiotics versus eyes that did not. METHODS: A retrospective, nonrandomized, comparative case series of 18,886 consecutive cases of transconjunctival 23-, 25-, and 27-gauge PPV over a 5-year period was performed. The impact of prophylactic intraoperative subconjunctival antibiotics on the development of acute infectious postoperative endophthalmitis was examined. RESULTS: Of 18,886 cases of PPV, 14,068 (74.5%) received intraoperative subconjunctival antibiotics, whereas 4,818 (25.5%) did not. Sixteen cases (0.085%, 1/1,176) of post-PPV endophthalmitis were identified. The incidence of endophthalmitis in eyes that received subconjunctival antibiotics was 0.078% (11/14,068 cases, 1/1,282), whereas the incidence in those that did not receive subconjunctival antibiotics was 0.10% (5/4,818 cases, 1/1,000). No statistically significant difference was identified in the incidence of endophthalmitis between those that received subconjunctival antibiotics and those that did not (P = 0.598). Microbial culture was performed in 11 cases with 6 culture-positive cases (5/8 cases that received subconjunctival antibiotics and 1/3 cases that did not). CONCLUSION: Prophylactic subconjunctival antibiotics were not associated with a significantly reduced rate of post-PPV endophthalmitis. With consideration of emerging multidrug-resistant bacteria, routine prophylactic subconjunctival antibiotics may not be justified.

Topiramate-induced macular neurosensory retinal detachment.

PURPOSE: To present a previously unreported retinal side-effect from topiramate use in two cases. OBSERVATIONS: Macular neurosensory retinal detachments were seen in two patients shortly after beginning oral topiramate. The macular detachments resolved shortly after discontinuing this medication. CONCLUSIONS AND IMPORTANCE: As these two cases represent the first reports of topiramate-induced macular neurosensory retinal detachment, clinicians should be aware of this potential ocular side effect when administering this medication.

Ophthalmic Complications Associated with Direct Oral Anticoagulant Medications.

OBJECTIVE: To describe the clinical features and management of six patients with ocular complications associated with direct oral anticoagulants (DOACs). METHODS: The medical records of all adult patients known to be taking a DOAC and with an unusual bleeding event at a large tertiary referral center over a one-year period were reviewed. Patients with less than one-month follow-up were excluded. Data collection included relevant clinic notes, operative reports, surgical videos, and clinical images (fundus photography, optical coherence tomography, B-scan ultrasonography, and fluorescein angiography). RESULTS: Six eyes in six patients were identified with an unusual bleeding event associated with DOAC use. One patient was taking apixaban, two patients were taking dabigatran, and three patients were taking rivaroxaban. Two patients had large submacular hemorrhage (including one with vitreous hemorrhage breakthrough), three patients had vitreous hemorrhage, and one patient had recurrent hyphema. Presenting visual acuity ranged from 20/40 to light perception. Three individuals required therapeutic and/or diagnostic pars plana vitrectomy for vitreous hemorrhage. Final visual acuity ranged from 20/25 to count finger vision. The associated DOAC was permanently discontinued in two of the six cases. Follow-up was one to four months from onset of identified DOAC-related complication. CONCLUSIONS: DOAC use may be associated with ocular bleeding. Ophthalmologists should be aware of potential hemorrhagic complications and obtain consultation with primary providers regarding DOAC cessation guidelines.

Alternating Bi-Weekly Intravitreal Ranibizumab and Bevacizumab for Refractory Neovascular Age-Related Macular Degeneration with Pigment Epithelial Detachment.

OBJECTIVE: To describe visual and anatomical outcomes following bi-weekly intravitreal ranibizumab/bevacizumab injections in eyes with refractory neovascular age-related macular degeneration (AMD) and pigment epithelial detachment (PED). DESIGN: Retrospective, consecutive, interventional case series. PARTICIPANTS: Eighteen patients diagnosed with neovascular AMD that were refractory to anti-VEGF therapy and received alternating biweekly ranibizumab/bevacizumab injections were included. METHODS: Patients with neovascular AMD and PED that were refractory to at least 11 monthly ranibizumab or bevacizumab injections were included in this study at a large, single retina practice. Following inclusion, patients received four bi-weekly alternating ranibizumab/bevacizumab intravitreal injections. After completing a course of four bi-weekly injections, patients were treated with variable regimens of intravitreal anti-vascular endothelial growth factor (VEGF) therapy. The primary outcomes of the study included change in visual acuity (VA) and central foveal thickness (CFT) at eight weeks follow-up. RESULTS: Study eyes had previously received a mean of 22 intravitreal anti-VEGF injections. At enrollment, mean VA was 20/95 and mean CFT was 455 µm. After four bi-weekly anti-VEGF injections, mean VA improved to 20/65 (p < 0.001), and mean CFT decreased to 387 µm (p = 0.029). In patients with PED, there was a mean 27.9% reduction in height (p = 0.046) at eight weeks' follow-up. CONCLUSIONS: Four injections of bi-weekly alternating ranibizumab/bevacizumab improved visual acuity and reduced macular thickness in a number of patients with refractory neovascular AMD and PED.

Quantification of Diabetic Macular Ischemia Using Optical Coherence Tomography Angiography and Its Relationship with Visual Acuity.

PURPOSE: To quantify foveal avascular zone (FAZ) area and macular vascular density objectively using optical coherence tomography angiography (OCTA) and to examine correlations with visual acuity in eyes with diabetic retinopathy (DR) in the absence of diabetic macular edema. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-four eyes from 55 patients with DR and 34 control eyes from 27 age-matched healthy participants. METHODS: All eyes underwent OCTA (RTVue-XR Avanti; Optovue, Inc, Fremont, CA). Integrated automated algorithms were used to quantify FAZ area and macular vascular density. MAIN OUTCOME MEASURES: FAZ area, vessel area density (VAD), vessel length density (VLD), and visual acuity. RESULTS: In each study eye, DR was classified as mild nonproliferative DR (NPDR; n = 32 [38%]), moderate-to-severe NPDR (n = 31 [37%]), or proliferative DR (n = 21 [25%]). Mean FAZ area was greater in diabetic eyes compared with control eyes both in the superficial (0.427 mm2 vs. 0.275 mm2; P < 0.001) and deep (0.616 mm2 vs. 0.372 mm2; P < 0.001) vascular networks. Mean VAD was lower in diabetic eyes compared with control eyes in both the superficial (49.44% vs. 55.09%; P < 0.001) and deep (56.65% vs. 61.32%; P < 0.001) networks. Mean VLD was also lower in diabetic eyes compared with control eyes in both the superficial (17.68 mm-1 vs. 21.55 mm-1; P < 0.001) and deep (21.19 mm-1 vs. 24.38 mm-1; P < 0.001) networks. In all eyes, there was a statistically significant negative correlation between the logarithm of the minimum angle of resolution (logMAR) visual acuity and the vascular density in both the superficial (VAD, ρ = -0.52; VLD, ρ = -0.54; P < 0.001) and deep (VAD, ρ = -0.50; VLD, ρ = -0.50; P < 0.001) networks. A positive correlation was found between logMAR visual acuity and FAZ area in both the superficial (ρ = 0.29; P < 0.01) and deep (ρ = 0.48; P < 0.001) networks. CONCLUSIONS: Automated quantitative algorithms allow for objective assessment of retinal vascular changes in eyes with DR that are correlated to visual acuity. These methods may prove useful in monitoring disease progression and identifying parameters that affect visual function.

25-GAUGE TROCAR CANNULA FOR ACUTE ENDOPHTHALMITIS-RELATED IN-OFFICE VITREOUS TAP AND INJECTION: Patient Comfort and Physician Ease of Use.

PURPOSE: To assess comfort and procedural facility using a 25-gauge trocar cannula as a port to diagnose and treat acute endophthalmitis compared with a standard vitreous tap and injection technique. METHODS: Eighteen consecutive patients with acute endophthalmitis were randomized into two treatment arms: 1) Standard vitreous tap and injection technique, and 2) A technique where a valved 25-gauge trocar cannula is inserted through the pars plana as done in sutureless vitrectomy surgery and subsequent vitreous sampling and injections are performed through the port. A standardized anesthetic protocol was used and subjects were masked to the technique performed. Primary outcomes measured were patient comfort using a Wong-Baker pain scale and standardized physician ease-of-use scoring scale. Secondary outcomes included vitreous sampling success rate and volume of vitreous sample. RESULTS: No significant differences were found when comparing patient comfort (P = 0.340), physician ease-of-use scores (P = 0.796), vitreous sample volume (P = 0.149), successful vitreous taps (P = 0.620), and microbiologic yield (P = 1.000) between treatment arms. There were no adverse events. CONCLUSION: The 25-gauge trocar technique provides a safe, well-tolerated, and equally effective alternative to the standard vitreous tap and injection technique for delivery of intravitreal antibiotics, and procuring of vitreous sample, requiring a single sharp penetration.

Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema.

PURPOSE: To evaluate the short-term functional and anatomic outcomes of patients with persistent diabetic macular edema (DME) who were converted from bevacizumab and/or ranibizumab to aflibercept. DESIGN: Retrospective, interventional, noncomparative, consecutive case series. METHODS: Only eyes treated with at least 4 consecutive injections of ranibizumab/bevacizumab spaced 4-6 weeks apart prior to conversion and with at least 2 aflibercept injections afterward were considered for inclusion. Pertinent patient demographic, examination, and treatment data were extracted from clinical charts and tabulated for analysis. RESULTS: Fifty eyes of 37 patients were included. Eyes received a mean of 13.7 bevacizumab/ranibizumab injections prior to conversion, followed by 4.1 aflibercept injections over 4.6 months of subsequent follow-up. The mean logMAR visual acuity at the pre-switch visit was 0.60 ± 0.43 (Snellen equivalent, 20/80). This improved to 0.55 ± 0.48 (Snellen equivalent, 20/70) by the second visit after conversion, corresponding to a mean logMAR change of -0.05 ± 0.22 (P = .12). The average central macular thickness from the pre-switch spectral-domain optical coherence tomography scan was 459.2 ± 139.2 µm. This significantly improved to 348.7 ± 107.8 µm by the second visit following conversion, reflecting a mean decrease of 112 ± 141 µm (P < .0001). The mean intraocular pressure (IOP) recorded at the pre-switch visit was 15.1 ± 3.3 mm Hg. At the second follow-up after converting to aflibercept, the IOP averaged 14.9 ± 3.2 mm Hg, with a mean decrease of 0.2 ± 3.0 mm Hg (P = .63). CONCLUSIONS: Conversion to aflibercept for persistent DME resulted in significant anatomic improvements. While trends towards improved visual acuity and reduction in IOP were observed, these were not statistically significant.

Effect of Serial Intrasilicone Oil Bevacizumab Injections in Eyes With Recurrent Proliferative Vitreoretinopathy Retinal Detachment.

PURPOSE: To investigate the effect of serial intrasilicone oil bevacizumab injections (1.25 mg/0.05 mL) on visual acuity (VA) and anatomic outcomes in eyes undergoing proliferative vitreoretinopathy (PVR)-related retinal detachment (RD) repair. DESIGN: Prospective, nonrandomized, historical-control pilot study. METHODS: setting: Tertiary care center. STUDY POPULATION: Nondiabetic eyes undergoing pars plana vitrectomy (PPV) and silicone oil tamponade with or without scleral buckling procedure (SBP) for recurrent RD due to PVR. INTERVENTION: Intrasilicone oil injection of 1.25 mg bevacizumab was performed intraoperatively and at postoperative months 1, 2, and 3. OUTCOMES: Retinal reattachment rate, final VA, and rate of epiretinal membrane (ERM) formation at month 6. RESULTS: Twenty eyes of 20 patients were enrolled and compared to a historical control group composed of 35 age- and sex-matched controls. In the study group, logMAR VA improved from mean 1.78 ± 0.43 (Snellen 20/1205) to 1.43 ± 0.70 (Snellen 20/538, P = .04), retinal reattachment was achieved in 14 of 20 eyes (70%), and ERM formation was observed in 7 of 20 eyes (35%) at 6 months. In the control group, logMAR VA improved from mean 1.50 ± 0.74 (Snellen 20/632) to 1.43 ± 0.58 (Snellen 20/538, P = .64), retinal reattachment was achieved in 25 of 35 eyes (71%), and ERM formation was observed in 7 of 35 eyes (20%) at 6 months. No significant difference in final VA (P = .96), retinal reattachment rate (P = .75), or ERM formation (P = .33) was observed between groups. No intrasilicone oil injection-related adverse events occurred. CONCLUSIONS: Serial intrasilicone oil injections of bevacizumab did not improve retinal reattachment rate, improve final VA, or reduce ERM formation in patients undergoing PVR-related RD surgery.

Radial versus raster spectral-domain optical coherence tomography scan patterns for detection of macular fluid in neovascular age-related macular degeneration.

BACKGROUND/AIMS: To compare the 12-line radial to the 25-line raster spectral-domain optical coherence tomography (SD-OCT) acquisition patterns at detecting intraretinal or subretinal fluid in eyes with neovascular age-related macular degeneration (AMD). METHODS: Retrospective cross-sectional analysis of 200 eyes with neovascular AMD. Sequential 12-line radial and 25-line raster scans were evaluated for the presence of intraretinal/subretinal fluid. RESULTS: A total of 394 SD-OCT scans were interpreted (1.97 scans per eye). The 12-line radial detected intraretinal/subretinal fluid in all but 7 of 394 scans (1.7%; 95% CI 0.7% to 3.6%), resulting in a sensitivity of 98.3%. The 25-line raster detected intraretinal/subretinal fluid in all but 10 of 394 scans (2.5%; 95% CI 1.2% to 4.6%), resulting in a sensitivity of 97.5%. This small difference in fluid detection between the two acquisition patterns for neovascular AMD was not found to be statistically significant (p=0.6276). CONCLUSIONS: The 12-line radial scan is statistically comparable with the 25-line raster scan in detecting the presence of intraretinal/subretinal fluid in neovascular AMD. The 12-line radial SD-OCT pattern alone may be adequate to guide day-to-day clinical decisions in a more time-efficient manner.

Optical Coherence Tomography Angiography and En Face Optical Coherence Tomography Features of Paracentral Acute Middle Maculopathy.

PURPOSE: To characterize the optical coherence tomography (OCT) angiography, en face OCT, and microperimetry features of paracentral acute middle maculopathy in both the acute phase and after resolution, and to propose a classification of distinct subtypes of this entity. DESIGN: Retrospective observational case series. METHODS: Clinical histories, high-resolution digital color imaging, spectral-domain OCT images, fluorescein angiography, OCT angiography images, and en face OCT images of 16 patients with paracentral acute middle maculopathy were evaluated. Microperimetry was available in 6 patients. RESULTS: The most common referring diagnoses were isolated branch retinal arterial occlusion (5/16), combined central retinal vein and cilioretinal artery occlusion (4/16), and isolated central retinal vein occlusion (4/16). All patients demonstrated hyperreflective plaque-like lesions at the level of the inner nuclear layer on spectral-domain OCT, with no fluorescein angiographic correlate. OCT angiography demonstrated variable areas of capillary dropout within the superficial and deep retinal capillary plexi in these areas. En face OCT highlighted confluent areas of middle retina hyperreflectivity corresponding to these lesions. Three distinct en face OCT patterns were observed: arteriolar, fern-like, and globular. Microperimetry demonstrated relative scotomas mapping to the area of middle retinal hyperreflectivity seen on en face OCT. CONCLUSIONS: Paracentral acute middle maculopathy may be best evaluated with the use of en face OCT imaging, which corresponds to subjective and objective visual field defects. En face OCT appearance may be used to classify paracentral acute maculopathy into distinct subtypes.

Inpatient Ophthalmology Consultation for Fungemia: Prevalence of Ocular Involvement and Necessity of Funduscopic Screening.

PURPOSE: To determine the generalizability of recent data assessing the necessity of ophthalmic consultation for fungemic patients, we examined the prevalence, microbial profile, and treatment of fungal chorioretinitis and endophthalmitis among patients with positive fungal cultures referred for ophthalmologic consultation at a tertiary care medical center. DESIGN: Retrospective cross-sectional study. METHODS: All inpatient ophthalmology consultations from Wills Eye Hospital at Thomas Jefferson University between January 1, 2006 and December 31, 2012 were retrospectively reviewed and cross-referenced to a microbiologic database of positive fungal blood cultures. This included 227 adult consecutive inpatients with positive fungal blood cultures (n = 215) or suspected fungemia (n = 12). Clinical data were extracted from records held by the microbiology laboratory and inpatient records. Patients were deemed to have ocular fungal involvement if dilated fundus examination demonstrated evidence of chorioretinitis or endophthalmitis. RESULTS: Two hundred and twenty-seven consultations were requested to evaluate patients for ocular manifestations of fungemia. Eleven patients (4.8%, 95% CI 2.4%-8.5%) were diagnosed with fungal chorioretinitis or endophthalmitis. Of these 11 patients, 5 had visual symptoms, 2 were asymptomatic, and 4 were unable to communicate. A total of 5 patients (2.2%) received intravitreal injections following funduscopic screening. An additional 11 patients (4.8%) had nonspecific fundus lesions considered to be inconsistent with ocular fungal involvement. The most common fungal species identified were Candida albicans (n = 85), Candida glabrata (n = 63), and Candida parapsilosis (n = 44). CONCLUSIONS: The current study found a low rate of disseminated ocular involvement in patients with positive fungal cultures referred for ophthalmologic consultation. However, 2 patients with ocular fungal involvement denied visual symptoms and over half of affected patients were asymptomatic or unable to communicate. As the presence and severity of ocular involvement in fungemic patients may dictate the mode and duration of antifungal treatment, funduscopic screenings may still have an important role.