Progression Over 5 Years of Prelaminar Hyperreflective Lines to Optic Disc Drusen in the Copenhagen Child Cohort 2000 Eye Study

Background: The purpose of the study was to examine 5-year changes in eyes with optic disc drusen at baseline on optical coherence tomography (OCT) scans and the relation of incident drusen to hyperreflective prelaminar lines. Methods: The study included children who presented at baseline, when participants were aged 11-12 years, and again 5 years later. Grading for optic disc drusen was made in all. Grading for prelaminar lines was made in all children at follow-up and in eyes with optic disc drusen at baseline. Analyses included associations with scleral canal diameter at baseline in all children with optic disc drusen and a nested control group of 115 children without optic disc drusen. Data are reported as the number of children having at least one drusen or at least one hyperreflective line per person. Results: The analysis included 724 children who attended both rounds of the study. Of these, 11 (1.5%) had optic disc drusen at baseline. Five additional children had developed optic disc drusen at follow-up, whereas optic disc drusen had disappeared in none, so that 16 (2.2%) children had optic disc drusen in one or both eyes at follow-up. Children with optic disc drusen at the 5-year follow-up had had a mean scleral canal diameter of 1,364 µm (interquartile range [IQR] 81 µm), compared with 1,457 µm (IQR 197) µm in 115 nested controls without optic disc drusen (P < 0.001). Optic disc drusen at follow-up were associated with more hypermetropic refraction. All children who had optic disc drusen at follow-up also had prelaminar hyperreflective lines. In addition, such lines were found at follow-up in 24 of the remaining 708 children without optic disc drusen (P < 0.001). Prelaminar hyperreflective lines with or without optic disc drusen were associated with a narrower scleral canal (diameter 1,364 µm, IQR 119 µm) compared with absence of prelaminar lines (1,486 µm, IQR 206 µm; P < 0.0001). Conclusion: This study provides the first evidence from a prospective study that small optic discs and prelaminar hyperreflective lines on OCT are risk factors for the development of optic disc drusen. The association between prelaminar hyperreflective lines, hypermetropia, and a narrow scleral canal supports that a crowded disc is an essential predisposing factor for the development of optic disc drusen.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Progression Over 5 Years of Prelaminar Hyperreflective Lines to Optic Disc Drusen in the Copenhagen Child Cohort 2000 Eye Study Lasse Malmqvist, MD, PhD, Xiao Q. Li, MD, PhD, Mathias H. Hansen, MD, Alexander K. Thomsen, MB, Anne M. Skovgaard, MD, DMSc, Else M. Olsen, MD, PhD, Michael Larsen, MD, DMSc, Inger C. Munch, MD, PhD, Steffen Hamann, MD, PhD Background: The purpose of the study was to examine 5-year changes in eyes with optic disc drusen at baseline on optical coherence tomography (OCT) scans and the relation of incident drusen to hyperreflective prelaminar lines. Methods: The study included children who presented at baseline, when participants were aged 11-12 years, and again 5 years later. Grading for optic disc drusen was made in all. Grading for prelaminar lines was made in all children at follow-up and in eyes with optic disc drusen at baseline. Analyses included associations with scleral canal diameter at baseline in all children with optic disc drusen and a nested control group of 115 children without optic disc drusen. Data are reported as the number of children having at least one drusen or at least one hyperreflective line per person. Results: The analysis included 724 children who attended both rounds of the study. Of these, 11 (1.5%) had optic disc drusen at baseline. Five additional children had developed optic disc drusen at follow-up, whereas optic disc drusen had disappeared in none, so that 16 (2.2%) children had optic disc drusen in one or both eyes at follow-up. Children with optic disc drusen at the 5-year follow-up had had a mean scleral canal diameter of 1,364 mm (interquartile range [IQR] 81 mm), compared with 1,457 mm (IQR 197) mm in 115 nested controls without optic disc drusen (P , 0.001). Optic disc drusen at follow-up were associated with more hypermetropic refraction. All children who had optic disc drusen at follow-up also had prelaminar hyperreflective Department of Ophthalmology (LM, XQL, MHH, AKT, ML, SH), Rigshospitalet, Glostrup, Denmark; Faculty of Health and Medical Sciences (ML, ICM, SH), University of Copenhagen, Copenhagen, Denmark; Department of Public Health (AMS, EMO), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; National Institute of Public Health (AMS); and Centre for Clinical Research and Prevention (EMO, ICM), Capital Region, Denmark. Supported by the Jørgen Bagenkop Nielsens Myopi-Fond, Øjenforeningen, and Synoptik-Fonden. The authors report no conflicts of interest. Address correspondence to Lasse Malmqvist, MD, PhD, Department of Ophthalmology, Rigshospitalet, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark, E-mail: [e-mail] Malmqvist et al: J Neuro-Ophthalmol 2020; 40: 315-321 lines. In addition, such lines were found at follow-up in 24 of the remaining 708 children without optic disc drusen (P , 0.001). Prelaminar hyperreflective lines with or without optic disc drusen were associated with a narrower scleral canal (diameter 1,364 mm, IQR 119 mm) compared with absence of prelaminar lines (1,486 mm, IQR 206 mm; P , 0.0001). Conclusion: This study provides the first evidence from a prospective study that small optic discs and prelaminar hyperreflective lines on OCT are risk factors for the development of optic disc drusen. The association between prelaminar hyperreflective lines, hypermetropia, and a narrow scleral canal supports that a crowded disc is an essential predisposing factor for the development of optic disc drusen. Journal of Neuro-Ophthalmology 2020;40:315-321 doi: 10.1097/WNO.0000000000000911 © 2020 by North American Neuro-Ophthalmology Society O ptic disc drusen are seen in increasing size and number with increasing age (1). They are associated with visual field defects in rough proportion to how much space they take up within the optic nerve head (2). Optical coherence tomography (OCT) shows not only the threedimensional contour and position of optic disc drusen and the size of the scleral canal but also the prelaminar hyperreflective lines that are believed by some to be early optic disc drusen or precursors thereof (2-9). Prelaminar hyperreflective lines have just recently been described in relation to optic disc drusen. However, a prevalence of the lines in normal subjects several times higher than histopathologic verified optic disc drusen in the general population suggests that the lines are not specific as early optic disc drusen (9,10). This could lead to an overestimation of optic disc drusen on B-scan ultrasound as the possible hyperechogenic lines might mimic drusen. 315 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology Using OCT, narrow scleral canals have been shown to be associated with optic disc drusen (11-15), and this was confirmed by baseline data from the Copenhagen Child Cohort 2000 (CCC 2000) Study where optic disc drusen in children aged 11-12 years were indeed associated with narrow scleral canals (15). By contrast, some studies of adults with optic disc drusen have found larger scleral canals than in adults without optic disc drusen (14,16). This has led to the proposal that the anatomical opening in the Bruch membrane, which is the narrowest part of the scleral canal, may enlarge with age and with the expansion of optic disc drusen (16). The purpose of this study was to validate a narrow scleral canal as a risk factor for the development of optic disc drusen and to examine the relation of incident drusen to hyperreflective prelaminar lines in a 5-year prospective OCT study of optic nerve head morphology in a cohort of healthy children. METHODS Study Population This was a prospective cohort study of children enrolled in the Copenhagen Child Cohort 2000 Eye Study (15). The participants were examined at the age of 11-12 years and again at the age of 16-17 years. Before each examination, informed consent was obtained from the children's parents or legal guardians. The study was approved by the medical ethics committee of the Capital Region of Denmark. All procedures adhered to the tenets of the Declaration of Helsinki. Data Acquisition Participants were interviewed and examined according to the same procedure at both visits. A full ophthalmic and general medical history was obtained, after which bestcorrected visual acuity was determined using ETDRS charts (4-m original series, Precision-Vision, La Salle, IL). An interferometric device (IOL-MASTER, version 3.01.0294; Carl Zeiss Meditec, La Jolla, CA) was used to measure ocular axial length. Spherical equivalent refraction was calculated as the algebraic sum of the value of the sphere and half the cylinder. Enhanced depth imaging spectral-domain OCT (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany) was performed in a high resolution mode with averaging of 25 B-scans for each of the following configurations and in a fundustracked follow-up mode at the second examination: A 20-degree 6-line radial scan, a 12-degree peripapillary circumferential scan, and a 30-degree fovea-centered 7-line horizontal scan block (15). Image Analysis A single grader (A.K.T.) assessed all 20-degree 6-line radial OCT scans from both eyes of all re-examined children 316 (1,448 eyes in 724 subjects) using proprietary software (Heidelberg Eye Explorer, version 1.6.1.0; Heidelberg Engineering) and the Optic Disc Drusen Studies Consortium guidelines to identify hyporeflective round or ovoid elements with a full or partial hyperreflective margin within the optic nerve head (4). Suspicion of optic disc drusen was raised in 23 children by the primary grader of the follow-up scans (A.K.T.), after which the scans from these children were evaluated independently by 2 supervising graders (L.M. and S.H.) who had graded the scans made at age 11-12 years. Agreement in 22 of 23 children yielded a kappa value of 0.795. The matter was settled by reevaluation and consensus on the final verdict of optic disc drusen being absent in the discrepant case. The occurrence of prelaminar hyperreflective lines was assessed by a single grader (A.K.T.). Prelaminar hyperreflective lines on OCT were defined according to the following criteria: 1) Anatomic location in the prelaminar portion of the optic nerve head. 2) Lines of horizontal hyperreflectivity longer than 50 mm. 3) Lines of hyperreflectivity should not be "broken" by shadowing from overlaying layers. All eyes where optic disc drusen had been identified at 11-12 years were reviewed and graded for change, including appearance, disappearance, expansion, and shrinkage of optic disc drusen. In 3 children, the follow-up OCT scans were not optimally aligned to the baseline scans, which left 21 eyes in 13 children with optic disc drusen at follow-up for a formal comparison of optic nerve head anatomy between baseline and follow-up. Measurements of mean scleral canal diameter were performed at age 11-12 years and again at age 16-17 years in all children with optic disc drusen and in a random control subject group, approximately 10 times larger, who had also been used in a nested case-control analysis in the 11-12 year study report (15). Only the control subjects who attended both visits were included in the longitudinal analysis. This control group consisted of randomly selected children without optic disc drusen. The scleral canal has previously been defined as the area in which the optic nerve runs, with the posterior border of the lamina cribrosa defined as the outer aspects of the canal and the Bruch membrane opening defined as the inner aspect of the canal (16). The diameter of the opening of the Bruch membrane at the optic disc was used as a surrogate measure of the diameter of the scleral canal as this part represents the narrowest part of the canal. The mean scleral canal diameter was calculated as the mean of the Bruch membrane opening diameter on 6 radial disccentered OCT scans (15). The scleral canal cross-sectional area was calculated as that of a circle with a diameter equal to the mean Bruch membrane opening diameter. Statistics SAS statistical software (SAS 9.4; SAS Institute, Cary, NC) was used for statistical analyses. Means and SDs were calculated for normal distributions, whereas medians and Malmqvist et al: J Neuro-Ophthalmol 2020; 40: 315-321 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology interquartile ranges (IQRs) were calculated for continuous variables with skewed distributions. Only right eyes were used for analyses in children without optic disc drusen. In children with bilateral optic disc drusen, the eye with the largest grader-estimated volume of optic disc drusen was used. In children with unilateral optic disc drusen, only the affected eye was used. The Student t-test or the Wilcoxon signed-rank test (skewed distribution) was used to compare the group of children with optic disc drusen with the group of children without optic disc drusen. Chi-square/ Fisher exact tests were used for categorical data. In the analysis of scleral canal diameter characteristics, cases of optic disc drusen were compared with controls in a nested case-control study. Histograms and the Kolmogorov-Smirnov test were used to ensure assumptions of normal distribution and homogeneity of variance. The assumptions of linearity, variance homogeneity, and normality of the distribution of residuals underlying the linear regression model were assessed by review of relevant plots. The paired t test was used when comparing data between the initial and follow-up examination. The level of statistical significance for comparisons was set at P , 0.05. RESULTS A total of 724 children with and without optic disc drusen participated in both the baseline and the 5-year follow-up visit of the Copenhagen Child Cohort 2000 Eye Study. The mean interval between examinations was 5.0 years (±0.46 years). All 724 re-examined children were included in the analyses presented in this report. Optic disc drusen were found in 27 eyes in 16 children (2.2%) (Table 1) whose median scleral canal diameter was 1,364 mm (IQR 81 mm) compared with 1,457 mm (IQR 197 mm) in the nested controls (P , 0.001, Table 1). The 16 children with optic disc drusen showed no significant difference in scleral canal diameter from the initial to the follow-up examination, whereas a median decrease from 1,528 mm (IQR 185 mm) to 1,457 mm (IQR 196) was found in children without optic disc drusen (P , 0.001). Prelaminar hyperreflective lines were found in all 16 children with optic disc drusen and in 3.4% of children without optic disc drusen (P , 0.001, Table 1). The median scleral canal diameter was 1,364 mm (IQR 119 mm) in subjects with prelaminar hyperreflective lines, compared with 1,486 mm (IQR 206 mm) in subjects without prelaminar hyperreflective lines (P , 0.001). In the group of children with optic disc drusen, a refractive shift in the hypermetropic direction was found, from 0.01 D (SD 0.49 D) at baseline to 0.09 D (SD 0.33 D) at follow-up. By contrast, the group of children without optic disc drusen showed a shift in the myopic direction, from 20.09 D (SD 0.93 D) at baseline to 20.27 D (SD 1.18 D) at follow-up, resulting in a significant difference in change between the 2 groups (P , 0.001). There were no significant differences between children with and without optic disc drusen in age, gender, axial length, or visual acuity (Table 1). A qualitative comparison of optic nerve head anatomy between baseline and follow-up found that among 21 eyes with optic disc drusen at follow-up, 5 eyes had no optic disc drusen at baseline and that in these eyes the optic disc drusen had developed at locations where prelaminar hyperreflective lines had been present at baseline (Fig. 1). The size of optic disc drusen seen at both visits had increased in 11 of 16 eyes (Fig. 1). In 7 eyes with optic disc drusen at baseline, new optic disc drusen had developed in areas without prelaminar hyperreflective lines. In 8 eyes with optic disc drusen at baseline, new optic disc drusen had developed in areas with prelaminar hyperreflective lines. Full or partial regression of optic disc drusen present at baseline was not seen in any case. An increase in the number of prelaminar hyperreflective lines was found in 15 of 21 eyes with optic disc drusen (Fig. 2). TABLE 1. Study population characteristics of 16-17 years old children with and without optic disc drusen Number (%) Boys/girls in % Age (IQR), yrs Visual acuity, EDTRS letters Refractive error, D Axial length (IQR), mm Scleral canal diameter (IQR), mm Occurrence of hyperreflective lines in % Optic Disc Drusen No Drusen 16 (2.2%) 44/56 16.6 (0.3) 91.8 ± 3.8 0.09 ± 0.33 23.1 (1.3) 1,364 (81) 100 708 (97.8%) 45/55 16.6 (0.3) 90.9 ± 4.6 20.27 ± 1.18 23.4 (1.1) - 3.4 Nested Controls Without Drusen 115 (16%) 42/58 16.6 (0.3) 90.9 ± 4.8 20.17 ± 0.9 23.5 (1.1) 1,457 (197) P* 1.0† 0.90‡ 0.35§ ,0.001§ 0.24‡ ,0.001‡ ,0.001† EDTRS, Early Treatment Diabetic Retinopathy Study; IQR, interquartile range; RNFL, retinal nerve fiber layer. *P-values represent comparisons between children with optic disc drusen and all children without drusen, except for scleral canal diameter where the comparison was between children with optic disc drusen and a random subsample of 115 children without drusen included in both baseline and follow-up examination. † 2 x test. ‡ Wilcoxon rank-sum test. § Students t-test. Data are presented as mean ± SD or as proportions. In variables with skewed distribution, median and interquartile range are presented. Malmqvist et al: J Neuro-Ophthalmol 2020; 40: 315-321 317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 1. Optical coherence tomography scans of optic nerve heads from 3 participants in the CCC2000 Study. A1, B1, C1. Baseline scans made at the age of 12 years. A2, B2, C2. Five-year follow-up scans tracked to the same locations as the baseline scans. A1 and A2. An optic nerve head with deep prelaminar hyperreflective lines (dotted arrows) but no optic disc drusen at baseline and additional hyperreflective lines plus a hyporeflective core (arrow) at follow-up. B1 and B2. A deep optic disc drusen (arrow) at baseline that was seen at follow-up to have expanded and to have become associated with nerve fiber herniation (vertical arrow) into the outer retina. C1 and C2. A posterior or deep optic disc drusen (arrow) at baseline that was found at follow-up to have expanded. Prelaminar lines and nerve fiber herniation were more visible and possibly more pronounced at follow-up. Four of 21 eyes showed an increase in the size of peripapillary hyperreflective ovoid mass-like structures (PHOMS) (Fig. 2), which are believed to represent herniations of optic nerve fibers often seen in crowded optic nerve heads of various etiologies (17). There were no cases of optic disc drusen migration without a change in drusen size. DISCUSSION This 5-year prospective study of optic disc characteristics related to optic disc drusen assessed the Bruch membrane 318 opening diameter, drusen location, size and number, and prelaminar hyperreflective lines. The diameter of the opening in the Bruch membrane is a commonly used measure of the scleral canal diameter, and the prelaminar hyperreflective lines are believed to be precursors of optic disc drusen. In 724 children examined first at the age of 11-12 years and then again 5 years later, the prevalence of optic disc drusen increased from 1.5%-2.2% (15), a prevalence close to that of 2% seen in histopathology studies in adults (18). Both numbers are higher than what has been recorded by Malmqvist et al: J Neuro-Ophthalmol 2020; 40: 315-321 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 2. Optical coherence tomography scans of optic nerve heads from 3 participants in the CCC2000 Study. A1, B1, C1. Baseline scans made at the age of 12 years. A2, B2, C2. Five-year follow-up scans tracked to the same locations as the baseline scans. A1 and A2. A case with hyperreflective lines (dotted arrows) and a large deep drusen just outside the rim of the Bruch membrane opening at baseline with progression to development of a deep drusen (oblique arrow pointing right) at the former location-with preservation of a hyperreflective line inside this new drusen-and expansion of the preexisting drusen (oblique arrow pointing left). An ovoid mass (vertical arrow) presumably represents nerve fibers that have herniated into the outer retina. B1 and B2. A case with a pronounced increase in the number and size of prelaminar hyperreflective lines (dotted arrows). C1 and C2. A case with increasing pseudopapilledema and presumed nerve fiber herniation into the outer retina (vertical lines) accompanying the development of an optic disc drusen (oblique arrow) and increasing numbers of hyperreflective lines (dotted arrows). fundus photography, indicating that fundus photography is inferior to OCT and insufficient as a stand-alone examination for optic disc drusen. Furthermore, our observations indicate that most optic disc drusen develop before the age of 18 years, which is in agreement with a prospective fundus photography study, (1). The use of OCT to assess optic disc drusen and related optic disc characteristics adds significantly to fundus photography and ophthalmoscopy (1,19-21), which show Malmqvist et al: J Neuro-Ophthalmol 2020; 40: 315-321 only disc surface drusen, by enabling the study of structural features far behind the surface of the disc, down to the lamina cribrosa. A third important imaging modality, autofluorescence fundus imaging, was not used because recruitment was given priority over pharmacological mydriasis in this study and because of the inability of the method to detect small and deeply buried optic disc drusen (6). Previously, B-scan ultrasound has been regarded as the gold standard in the diagnosis of optic disc drusen, but with 319 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology the increased imaging sensibility of the optic nerve head using EDI-OCT, optic disc drusen are now more reliably diagnosed using OCT (3). In agreement with our baseline findings, the 5-year follow-up found smaller scleral canal diameters in children with optic disc drusen than in those without drusen. This is strong support for what has already been suggested on the basis of smaller studies (12-14,16). We have followed our previous practice of reporting mean scleral diameters, but the constraints that nerve fibers experience on their way through the optic nerve head may be better described by the differences in its cross-sectional area. Compared with discs with drusen, discs without drusen had a 6.8% larger diameter but a 14% larger cross-sectional area (1.46 mm2 vs 1.67 mm2). For eyes with prelaminar lines compared with eyes without such lines, the diameter difference was 7.4% and the difference in area 19% (1.46 mm2 vs 1.73 mm2). Obviously, many factors other than a narrow scleral canal may induce nerve fiber compression, notably a small lamina cribrosa, the diameter of which is not necessarily proportional to that of the opening in the Bruch membrane, and a lamina cribrosa that is to stiff or fibrotic or otherwise mechanically unsuitable to safely accommodate the nerve fibers on their way through the optic nerve. All incident optic disc drusen had developed at locations where hyperreflective lines had been present, and 8 eyes with optic disc drusen at baseline had developed new optic disc drusen where there were hyperreflective lines at baseline. Thus, the association between prelaminar hyperreflective lines and optic disc drusen and the progression from prelaminar hyperreflective lines to optic disc drusen support that these lines are precursors of optic disc drusen. Additional support is found in the finding of a significantly smaller scleral canal in subjects with prelaminar lines but no disc drusen than in participants without prelaminar hyperreflective lines. A recent study of the prevalence and associated factors related to subclinical optic disc drusen found a prevalence of prelaminar hyperreflective lines in the optic disc of 14.6% (9). Three subjects (2.3%) with prelaminar hyperreflective lines had concomitant optic disc drusen according to newly published guidelines (4), in agreement with the prevalence found in this study. The remaining 16 subjects (12.3%) had isolated prelaminar hyperreflective lines with no hyporeflective areas. This is higher than the 3.4% found in this study. The difference could be caused by differences between scanning modalities or in difficulties in differentiating the hyperreflective lines from the lamina cribrosa. PHOMS has previously been described as the OCT finding corresponding to lateral bulges of retinal nerve fibers that herniate at the level of the Bruch membrane. They are not unique for optic disc drusen and can be seen in several acquired and dysplastic anomalies of the optic nerve head (4,17,22,23). The finding of PHOMS in children with 320 increasing optic disc drusen volumes is in agreement with disc crowding and axonal distension. This study, however, shows clear cases of increasing herniation in relation to the growth of optic disc drusen. The OCT scan density used in this study has been superseded by new scan patterns and faster instruments, and therefore, the prevalence and number of detectable drusen and hyperreflective lines per affected eye may be higher with newer scanning modalities. Comparison of OCT scans was performed using the follow-up scan feature on the OCT using the en-face view as reference for the follow-up scan. However, there might be inaccuracy in the follow-up function that could cause a slightly different location of the follow-up scan resulting in false interpretation of progression. This 5-year follow-up OCT study of 724 children in a population-based cohort is the first, to the best of our knowledge, to map long-term changes in optic nerve head anatomy associated with optic disc drusen. Scleral canal diameters were smaller in children with optic disc drusen or prelaminar hyperreflective lines, and the latter were found in close association with optic disc drusen. Thus, the study provides the first evidence from a prospective study that small optic discs and prelaminar lines on OCT are risk factors for the development of optic disc drusen. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: L. Malmqvist, X. Q. Li, A. M. Skovgaard, E. M. Olsen, M. Larsen, I. C. Munch, and S. Hamann; b. Acquisition of data: L. Malmqvist, X. Q. Li, M. H. Hansen, A. and K. Thomsen; c. Analysis and interpretation of data: L. Malmqvist, S. Hamann, and M. Larsen. Category 2: a. Drafting the manuscript: L. Malmqvist, S. Hamann, and M. Larsen; b. Revising it for intellectual content: L. Malmqvist, X. Q. Li, M. H. Hansen, A. K. Thomsen, A. M. Skovgaard, E. M. Olsen, M. Larsen, I. C. Munch, and S. Hamann. Category 3: a. Final approval of the completed manuscript: L. Malmqvist, X. Q. 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