Diagnostic accuracy of Bruch’s membrane opening minimum rim width for detecting glaucoma in Indian myopic eyes

Abstract

Purpose:

To analyze Bruch’s membrane opening minimum rim width (BMO–MRW) for detecting glaucoma in patients with myopia < −6D and assessment of peripapillary retinal nerve fiber layer thickness (pRNFLT).

Methods:

One eye was randomly selected from each of the 90 subjects (A-30 normal controls, B-30 with glaucoma suspect, and C-30 with primary open-angle glaucoma [POAG]). All patients underwent baseline ophthalmic evaluation. BMO– MRW and pRNFLT data were obtained using spectral-domain optical coherence tomography (Spectralis, Heidelberg Engineering GmbH, Heidelberg, Germany). The area under the receiver operating characteristic curves (AUC) for global and sectoral thickness parameters was calculated.

Results:

Sectoral analysis of BMO-MRW for the discrimination of early glaucoma in all myopic subjects showed significantly better diagnostic performance than pRNFLT in temporal (0.85 (0.77 to 0.94) P = 0.014), temporal superior (TS) (0.90 (0.83 to 0.98) P = 0.005), and nasal inferior quadrants (0.92 (0.86 to 0.97) P = 0.022) with 95% CI. When discriminating early glaucoma from the suspect, overall the diagnostic performance of BMO-MRW was higher than that of pRNFLT, with significant differences in the temperosuperior quadrant (0.85 (0.74 to 0.95) 95% CI, P = 0.047).

Conclusion:

BMO-MRW had better diagnostic performance than RNFL thickness and is a useful parameter for detecting glaucoma in myopic eyes (≤−6D) with POAG.

Myopia is a common ocular disorder worldwide. It is estimated that there will be 4,949 million people with myopia in 2050.[1,2] According to the Beijing Eye Study (2007), both marked and high myopia had a higher frequency of optic disc changes than moderate myopia and low myopia, emmetropia (−0.5D to + 2D), and hyperopia (>+2D).[3] Myopia is a risk factor for primary open-angle glaucoma (POAG) that can increase the risk of POAG by two- to three-fold.[1,2] Optic nerve head changes in myopia, like nasal insertion, tilted, or large disc, shallow cup, and peripapillary findings like scleral crescent and peripapillary atrophy (PPA), make the diagnosis of glaucoma difficult. Since POAG can cause asymptomatic vision loss, early diagnosis of POAG in myopic patients is important.

In myopic eyes, clinicians could face a diagnostic challenge due to the low accuracy of diagnosing glaucoma.[4,5,6] The average pRNFL thickness in cases of myopia is significantly thinner than that in emmetropic eyes.[7,8] A new parameter measuring the minimum distance between the Bruch membrane opening (BMO) and the internal limiting membrane (ILM), termed the Bruch membrane opening minimum rim width (BMO–MRW), has been proposed as an alternative to other rim parameters.[9,10] Spectralis OCT [Heidelberg Engineering GmbH, Heidelberg, Germany–Glaucoma module premium edition anatomical positioning system (GMPE APS)] Software’s analysis shows pRNFLT, BMO–MRW parameters. Studies have reported that BMO–MRW demonstrates better diagnostic accuracy and greater correlation with other structural and functional parameters compared with conventional neuroretinal rim parameters.[10,11,12] BMO-MRW measurements were not affected by axial myopia. Therefore, BMO-MRW measurements might be more suitable for myopic subjects when screening for glaucoma. A few studies were done for analysis of Bruch’s membrane opening minimum rim width of POAG in myopic patients by using Spectralis optical coherence tomography and no published study among the Indian population.

This study aimed to analyze the role of BMO-MRW for detecting glaucoma in myopia and also analyze the pRNFL thickness between glaucoma, glaucoma suspect, and normal subjects with ≤−6D spherical equivalent.

Methods

This prospective, cross-sectional, observational study was performed in a tertiary eye care center in South India and approved by the ethical committee. It adhered to the tenets of the Declaration of Helsinki. All patients were examined, and findings were recorded as per the standard proforma after obtaining written, detailed informed consent for inclusion in the proposed study. Participants aged 40 years and above with refractive error less than or equal to − 6D spherical equivalent (SE) were included in our study. Patients with SE >−6D myopia and media opacities in the visual axis such as posterior subcapsular polar cataracts, retinal pathologies, or patients who cannot maintain fixation during Spectralis OCT were excluded.

Study definition of patients

According to the Beijing Eye Study (2007), which was a cross-sectional population-based study, myopia was defined as low myopia (−0.5D to − 3.0D), moderate myopia (−3.0D to − 6.0D), marked myopia (−6D to − 8D), and high myopia (>−8D).[3]

Myopic participants were divided into three groups as per the following definitions: (A) Normal group: healthy myopic participants with refractive error ≤−6D SE. (B) Glaucoma suspect group: participants with suspected optic nerve damage such as neuroretinal rim thinning, increased excavation of the optic disc, higher vertical than horizontal cup-to-disc ratio, retinal nerve fiber loss but with normal visual field (VF), and no structural and functional progression during 2 years of follow-up, intraocular pressure (IOP) range up to 24 mmHg; (C) Glaucoma group: participants with findings of glaucomatous optic disc damage and corresponding VF defects and VF test results of mean deviation (MD) ≤−6.0 dB.

All participants underwent the following comprehensive ophthalmic examinations: best corrected visual acuity using an Early Treatment Diabetic Retinopathy Study chart, slit-lamp biomicroscopy, IOP measurement using Goldmann applanation tonometry (HAAG–STREIT 900, Haag–Streit, USA), gonioscopy using a four mirror Sussman gonio lens (Ocular Instruments Inc., Bellevue, WA), optic nerve head and RNFL (with red-free filter) evaluation with a Volk 90D lens, and VF examination was conducted using the Swedish interactive threshold algorithm standard program of Humphrey field analyzer (Carl Zeiss Meditec Inc, Dublin, CA) using the central 24–2 strategy. Spectral-domain optical coherence tomography (SD-OCT) imaging was performed using a GMPE APS (Heidelberg SD-OCT; Spectralis software version 6.9.4; Heidelberg Engineering GmbH, Heidelberg, Germany). For BMO–MRW, 24 radial B-scans (length: 158), for RNFLT, three circle B-scans (128/148/168 or 3.5/4.1/4.6 mm for the emmetropic eye with an axial length of 23 mm), inner, middle, and outer RNFLT, were acquired [Fig. 1]. The APS creates an axis from the fovea to the center of the BMO, called the FoBMO axis, which serves as a reference for the scans. The FoBMO angle was defined as the angle between the FoBMO axis and the horizontal axis of the acquired image frame. The scan protocol included 24 equally spaced radial B-scans, each with 768 A-scans covering a 15-degree region centered on the optic disc. For each B-scan, 25 (BMO–MRW) or 100 (RNFLT) B-scans were averaged. The software automatically segmented the ILM and the 48 BMO points from the 24 radial scans, and the BMO-MRW and pRNFL thickness were computed and calculated, globally and sectorally by reference to the Garway–Heath distribution maps relative to the FoBMO axis [superonasal (NS) (85 to 125 degrees), nasal (N) (125 to 235 degrees), inferonasal (NI) (235 to 275 degrees), inferotemporal (TI) (275 to 315 degrees), temporal (T) (315 to 45 degrees), and supero temporal (TS) (45 to 85 degrees)]. Bruch’s membrane opening and RNFLT segmentation were computed and reviewed by an experienced ophthalmologist to rule out segmentation errors. In cases of blood vessel shadowing, we optimized image contrast from standard settings to allow better visibility of BMO endpoints. In cases of bending of the BMO endpoint or Bruch’s membrane doubling phenomenon, we verified the endpoint by considering neighboring scans. Scans showing poor quality scores of less than 15 or any OCT-related artifacts such as mirror artifacts, out-of-register artifacts, or blink artifacts were excluded.[13]

Figure 1.

Representative images showing peripapillary RNFL and BMO-MRW thickness for groups A, B, and C. BMO-MRW = Bruch’s membrane opening minimum rim width; RNFLT = Retinal nerve fiber layer thickness

A sample size of 90 eyes (A-30, B-30, C-30) was required to analyze BMO-MRW thickness in the groups. The sample size was calculated with an estimated mean difference of global BMO–MRW, 48.2 µm between the normal and glaucoma suspect groups with 90% power and 5% level of significance. Statistical analysis was performed using the statistical software STATA 14.0 (StataCorp, USA). Statistical significance was set at 0.05. Descriptive statistics were reported in mean and standard deviation (SD) for the continuous measurement variables and frequency with percentage (%) for the categorical variables. The distribution of the variables was checked for normality using the Shapiro–Wilk test. The association between the categorical variables with the study groups was assessed using the Chi-square test or Fisher’s exact test. Differences in the clinical variables, such as RNFL thickness, were examined using a one-way analysis of variance test (ANOVA), and the subsequent posthoc analysis was carried out using the Bonferroni test. One-way analysis of variance was used to compare clinical factors, BMO–MRW, and RNFL thickness among the three groups. To determine the diagnostic ability of BMO-MRW and RNFL thickness, areas under the receiver operating characteristic curves (AUCs) and sensitivity at fixed specificities (90%, 95%) were calculated.

Results

In Group A, the mean age with a SD was 49.17 (7.4) with a range of 40–69, in Group B, it was 49.97 (8.2) with a range of 40–65, and in Group C, it was 58.23 (10.3) with a range of 40–78. The demographic details at the time of OCT measurement are shown in Table 1. The mean SE among the three groups was − 1.85 in Group A, −1.91 in Group B, and − 1.81 in Group C, which were not statistically significant. The global BMO-MRW thickness (µm) in Group A was 329.20 with a range of 246 to 445, in Group B, it was 240.87 with a range of 151 to 375, and in Group C, it was 172.27 with a range of 101 to 330, and global RNFL thickness (µm) in Group A was 105.47, in Group B, it was 100.07, and in Group C, it was 75.6 which were statistically significant among the three groups (P < 0.001). The sectoral analysis in both BMO-MRW and RNFL thickness was statistically significant [Table 2].

Table 1.

Demographic data and ocular characteristics of included eyes

Variables	Normal group (A)	POAG suspect group (B)	POAG group (C)	P
Subject (n)	30	30	30
Age in years (mean)	49.17±7.4	49.97±8.2	58.23±10.3	<0.001
Sex
Male (%)	11 (36.7)	13 (43.3)	19 (63.3)	0.009
Female (%)	19 (63.3)	17 (56.7)	11 (36.7)
Systemic illness
Diabetes mellitus (%)	6 (20.0)	9 (30.0)	12 (40.0)
Hypertension (%)	6 (20.0)	7 (23.3)	8 (26.7)
Hyperlipidemia (%)	1 (3.3)	1 (3.3)	2 (6.7)
Thyroid (%)	3 (10.0)	1 (3.3)	0
Intraocular pressure (mmHg) (mean)	15.62±2.43	16.51±3.25	15.93±3.58	0.303
Spherical equivalent (D) (mean)	−1.85±1.3	−1.9±11.6	−1.81±1.6	0.820
Cup disc ratio	0.36±0.11	0.71±0.06	0.79±0.08	<0.001

POAG=Primary open-angle glaucoma

Table 2.

Comparison of BMO-MRW and RNFLT between the study groups

	Normal (A), (n=30)		POAG suspect (B) (n=30)		POAG (C), (n=30)		P*
	BMO-MRW (μm)	RNFLT (μm)	BMO-MRW (μm)	RNFLT (μm)	BMO-MRW (μm)	RNFLT (μm)	BMO-MRW	RNFLT
G	329.20 (55.0) 308.65 to 349.75	105.47 (10.6) 101.51 to 109.42	240.87 (47.2) 223.24 to 258.49	100.07 (11.5) 95.78 to 104.35	172.27 (50.7) 153.34 to 191.20	75.60 (19.9) 68.18 to 83.02	<0.001	<0.001
T	231.73 (45.0) 214.94 to 248.53	65.83 (11.8) 61.42 to 70.24	182.73 (49.1) 164.39 to 201.07	69.43 (14.5) 64.00 to 74.87	140.50 (42.9) 124.50 to 156.50	57.70 (15.8) 51.82 to 63.58	<0.001	0.006
TS	317.03 (54.9) 296.54 to 337.53	135.50 (21.0) 127.67 to 143.33	239.10 (41.2) 223.72 to 254.48	126.63 (24.6) 117.44 to 135.83	165.23 (65.9) 140.63 to 189.83	100.43 (36.5) 86.81 to 114.05	<0.001	<0.001
TI	341.03 (66.0) 316.41 to 365.66	144.57 (12.9) 139.76 to 149.37	265.03 (57.0) 243.76 to 286.31	141.17 (19.1) 134.04 to 148.29	168.27 (72.9) 141.06 to 195.48	88.10 (41.0) 72.77 to 103.43	<0.001	<0.001
N	370.43 (77.1) 341.65 to 399.21	95.00 (16.5) 88.83 to 101.17	252.67 (71.8) 225.86 to 279.47	87.73 (13.7) 82.63 to 92.83	184.83 (65.8) 160.28 to 209.39	67.83 (20.1) 60.32 to 75.35	<0.001	<0.001
NS	371.60 (67.1) 346.54 to 396.66	132.20 (25.6) 122.63 to 141.77	255.10 (65.7) 230.56 to 279.64	120.90 (20.2) 113.37 to 128.43	198.60 (70.4) 172.32 to 224.88	95.83 (30.8) 84.34 to 107.33	<0.001	<0.001
NI	392.90 (78.5) 363.57 to 422.23	129.33 (23.5) 120.57 to 138.10	291.97 (60.7) 269.30 to 314.63	115.23 (27.4) 105.01 to 125.46	194.00 (68.5) 168.43 to 219.57	82.97 (36.0) 69.53 to 96.41	<0.001	<0.001

BMO-MRW=Bruch’s membrane opening minimum rim width; G=Global; T=Temporal; TS=Temporal superior; TI=Temporal inferior; N=Nasal; NS=Nasal superior; NI=Nasal inferior; POAG=Primary open-angle glaucoma; RNFLT=Retinal nerve fiber layer thickness; values were reported in mean with standard deviation and 95% confidence interval; P of <0.05 considered statistically significant; *ANOVA test

The correlation between BMO-MRW and its SE was observed in three groups. The temporal quadrant in Group A showed a negative correlation of − 0.44 (P = 0.015), while the TS quadrant in Group B had a negative correlation of − 0.42 (P = 0.020). Both correlations were statistically significant (P < 0.001). On the contrary, the nasal inferior quadrant in Group C showed a positive correlation of 0.38 (P = 0.041), which was also statistically significant (P < 0.001).

In terms of the correlation between RNFLT and SE, there was no significant correlation observed among the three groups except for the temporal quadrant in Group A, which showed a negative correlation of − 0.51 (P = 0.004), also statistically significant (P < 0.001) [Table 3].

Table 3.

Correlation between BMO-MRW and RNFLT with spherical equivalent

Sector	Normal				POAG suspect				POAG
	BMO-MRW		RNFLT		BMO-MRW		RNFLT		BMO-MRW		RNFLT
	Rho	P	Rho	P	Rho	P	Rho	P	Rho	P	Rho	P
G	−0.14	0.467	0.04	0.853	−0.29	0.127	−0.01	0.971	0.08	0.658	0.08	0.658
T	−0.44	0.015	−0.51	0.004	−0.16	0.389	−0.30	0.107	−0.11	0.579	−0.11	0.579
TS	−0.18	0.354	−0.10	0.590	−0.42	0.020	−0.14	0.446	−0.10	0.598	−0.10	0.598
TI	−0.08	0.658	−0.28	0.141	−0.28	0.136	0.15	0.432	0.16	0.410	0.16	0.410
N	0.004	0.985	0.20	0.285	−0.22	0.253	0.16	0.397	0.10	0.617	0.10	0.617
NS	−0.09	0.638	0.18	0.347	−0.28	0.141	0.26	0.173	0.01	0.948	0.01	0.948
NI	−0.01	0.949	0.05	0.799	−0.21	0.265	0.33	0.075	0.38	0.041	0.38	0.041

BMO-MRW=Bruch’s membrane opening minimum rim width; G=Global, T=Temporal, TS=Temporal superior, TI=Temporal inferior, N=Nasal, NS=Nasal superior, NI=Nasal inferior; POAG=Primary open-angle glaucoma; RNFLT=Retinal nerve fiber layer thickness. “Bold numbers indicate a significant correlation”

The study aimed to compare the diagnostic performance of BMO-MRW and pRNFLT in discriminating early glaucoma among all myopic subjects. The area under the receiver operating curves (AUROCs) were determined, and the values of BMO-MRW and RNFL thickness were compared. The sectoral analysis of BMO-MRW with pRNFLT for the discrimination of early glaucoma in all myopic subjects showed significantly better diagnostic performance than pRNFLT in temporal[0.85 (0.77 to 0.94) P = 0.014], TS [0.90 (0.83 to 0.98) P = 0.005], and nasal inferior quadrants [0.92 (0.86 to 0.97) P = 0.022] with 95% CI. When discriminating early glaucoma from the suspect, overall the diagnostic performance of BMO-MRW was higher than that of pRNFLT, with significant differences in the TS quadrant [0.85 (0.74 to 0.95) 95% CI, P = 0.047].

Discussion

The Spectralis OCT-derived parameters BMO-MRW and RNFL have gained more importance regarding the management and follow-up of glaucoma during the last years. It is difficult to detect early glaucoma in myopic eyes, and the pRNFL thickness may be underestimated and inaccurate. Disc tilting or PPA in myopia may have affected the RNFL distribution, resulting in inaccurate RNFL measurement.[14,15] The measurement of BMO-MRW is based on the edge of the optic disc, which would not be affected by the distance from the optic disc and the ocular magnification due to the axial length extension. In healthy tilted discs, BMO-MRW demonstrated a lower false-positive rate and higher specificity than RNFL thickness.[16] In patients with moderate myopia, the pRNFL was thinner, while the BMO-MRW values were similar compared with those in individuals with low or no myopia.[17] Recently, BMO-MRW was reported as the best parameter to detect early glaucoma as it has a stronger structure-function relationship compared with other ONH SD-OCT parameters.[12,18]

Our study prospectively analyzed the BMO-MRW parameters for the detection of early glaucoma in 90 eyes out of 169 eyes from 90 patients with SE ≤6, who satisfied the inclusion and exclusion criteria. We have used the Spectralis OCT–GMPE software with automatic eye-tracking technology and an automated segmentation algorithm for BMO-MRW and RNFL thickness analysis.

According to Do Hee Park et al.,[18] the diagnostic performance of BMO-MRW in all myopic subjects was significantly higher than that of pRNFL thickness in the inferonasal, inferotemporal, nasal, temporal, and superonasal sectors. Regarding the AUCs for discriminating early glaucoma from glaucoma suspects, the BMO-MRW showed generally higher diagnostic performance than pRNFL thickness. In our study, BMO-MRW showed better diagnostic performance than pRNFL thickness, with significant differences in the temporal, TS, and nasal inferior quadrants. Do Hee Park et al. reported a significantly higher AUC of BMO-MRW than that of pRNFL thickness in the inferonasal sector when discriminating early glaucoma from glaucoma suspect, where we found the TS quadrant was statistically significant.

Malik et al.[13] compared myopic patients with glaucoma to myopic normal controls, reporting that BMO-MRW performed better than pRNFL thickness for discriminating glaucoma in six sectors, although statistical significance was observed only for the inferonasal sector, and he proposed three explanations for this difference as follows: (1) The difference might be associated with a decrease in the reproducibility and diagnostic power of the nasal side pRNFL thickness. Since the reflectance of RNFL is highly directional and strongly dependent on the angle of illumination, pRNFL measurement of the nasal sector using a beam with a high entry angle might show reduced reproducibility and diagnostic power.[19] In contrast, BMO-MRW is more reliable in the nasal sector because the beam angle at the ONH is not as high as that at the pRNFL. (2) Previous results indicated that BMO enlargement occurs asymmetrically in myopic eyes, mainly at the inferior and nasal sectors.[20] Therefore, the MRW thins and glaucomatous thinning may have been detected earlier in the inferior and nasal sectors. (3) Imprecision in the spatial correlation between the points of measurement in the peripapillary retina and the ONH may result in large variations among the sectors in the relative diagnostic performance of SD-OCT indices. In this study, we also found a significantly higher AUC of BMO-MRW than that of pRNFL thickness in the inferonasal sector [Figs. 2 and 3].

Figure 2.

Area under the receiver operating curves (AUROCs) illustrating the diagnostic performance of BMO-MRW and RNFL thickness for the discrimination of POAG from all subjects. BMO-MRW = Bruch’s membrane opening minimum rim width; POAG = Primary open-angle glaucoma; RNFLT = Retinal nerve fiber layer thickness

Figure 3.

AUROC illustrating the diagnostic performance of BMO-MRW and RNFL thickness for the discrimination of POAG from POAG suspect eyes. BMO-MRW = Bruch’s membrane opening minimum rim width; POAG = Primary open-angle glaucoma; RNFLT = Retinal nerve fiber layer thickness

Chauhan et al.[10] reported a higher glaucoma diagnostic performance of BMO-MRW than that of pRNFL thickness in all regions except for the superonasal side, as well as the overall average value. In contrast, one study reported that pRNFL thickness measurements had a significantly higher diagnostic power than BMO-MRW in distinguishing preperimetric glaucoma from glaucoma suspect with suspicious glaucomatous appearance of the rim or cup; but this study was not focused on myopia.[21] But this same result was reported by Gmeiner et al.,[22] and also their study shows that the highest sectoral sensitivity of RNFLT for preperimetric glaucoma is in the nasal inferior sector. However, they concluded that BMO-MRW and RNFLT are comparably useful parameters for discrimination of preperimetric and perimetric glaucomatous eyes and show potential to assist each other in glaucoma diagnosis.

Sastre-Ibañez et al.[17] reported that BMO-MRW had no significant difference between moderate myopic subjects and low/nonmyopic subjects. They analyzed <−6D SE subjects only. In our study, we also analyzed the myopia patients having <−6D SE. There was a significant negative correlation between the SE and BMO-MRW in the temporal quadrant of normal eyes, the TS quadrant of glaucoma suspect eyes, and a positive correlation in the nasal quadrant of POAG eyes. No significant correlation between RNFL thickness and SE in glaucoma suspect and glaucoma eyes, except the temporal quadrant of normal myopic eyes, which had a significant negative correlation.

Geng Wang et al.[23] The study indicated that BMO-MRW measurement reduced the false-positive rate caused by myopia. They concluded that BMO-MRW had a lower percentage of eyes classified as outside normal limits/borderline in at least one quadrant than RNFL thickness in normal myopic subjects. In our study, we also found a significantly higher AUC of BMO-MRW than that of pRNFL thickness in the TS sector when discriminating early glaucoma from glaucoma-suspected eyes.

Sol La Bruna et al.[24] studied a topographic comparison of OCT minimum rim width (BMO–MRW) and circumpapillary retinal nerve fiber layer (cRNFL) thickness measures in eyes with or suspected glaucoma, which results that although BMO-MRW and cRNFL measures agreed in the majority of hemidiscs, they still disagreed in over 25% of the early glaucoma hemidiscs. These measures may be improved by comparing actual probability levels and accounting for blood vessel locations. But both can miss information available on retinal ganglion cell/retinal nerve fiber layer probability maps.

Clinical studies and morphometric investigations showed that the optic nerve head appearance varies between subjects with marked to high myopia and subjects with low to moderate myopia.[3,25,26] Thus, high myopia (>−6D) could act as a confounder due to associated structural changes in the retina and optic nerve. To avoid this bias, we limited our study population to eyes with refractive error less than 6D SE.

The limitations of our study were that it was conducted in an Indian population and included only patients with refractive error of less than 6D SE. Therefore, the findings may not be generalizable to other populations or to individuals with higher degrees of myopia.

To the best of our knowledge, this is the first study analyzing BMO-MRW in the myopic eyes of Indian patients.

Conclusion

In myopic eyes, BMO-MRW displayed a better diagnostic performance and correlation with SE compared to retinal nerve fiber layer thickness. BMO-MRW can thus be regarded as an important parameter, specifically for aiding the diagnosis of myopic glaucoma.

Authors' Contributions

All authors contributed to the study’s conception and design. MAK: Intellectual content, revision of the article, JT: Data collection, drafting the article, MRP: Conception, study design, formatting, and revising the article critically for important intellectual content, SG, RR: Revising the article critically for important intellectual content. All the authors read and approved the final manuscript.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Aravind Eye Care System, Tirunelveli, Tamil Nadu, India

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest: There are no conflicts of interest.

Funding Statement

Nil.