Exploring self-reported visual function and vision-related anxiety in patients with RPGR-associated retinal degeneration

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Henrique Alves, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4390545/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Variants in the retinitis pigmentosa GTPase regulator ( RPGR ) gene are responsible for the majority of X-linked retinitis pigmentosa cases, which not only affects male patients but also some heterozygous females. Vision-related disability and anxiety of patients with RPGR -associated retinal degeneration have never been explored before. This study aimed to evaluate self-reported visual function and vision-related anxiety in a Portuguese cohort of male and female patients with RPGR -associated retinal degeneration using two validated patient-reported outcome measures. Cross-sectional data of thirty-two genetically-tested patients was examined, including scores of the Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-related Anxiety Questionnaire (MVAQ). Patients were classified according to retinal phenotypes in males (M), females with male phenotype (FM), and females with radial or focal pattern (FRF). Both M and FM revealed higher rod-function and cone-function anxiety scores ( p < 0.017). Most MRDQ disability scores were higher in M and FM ( p < 0.004). Overall, positive correlations ( p < 0.004) were found between every MRDQ domain and both anxiety scores. In RPGR -associated retinal degeneration, males and females with male phenotype show similar levels of increased vision-related anxiety and disability. Every MRDQ visual function domain showed a strong correlation with anxiety scores. Patient-Reported Outcomes Retinitis Pigmentosa RPGR Anxiety Figures Figure 1 Figure 2 Figure 3 Introduction Retinitis pigmentosa (RP) encompasses a diverse group of inherited retinal disorders characterized by diffuse and irreversible retinal degeneration [ 1 , 2 ]. The initial stages manifest as night blindness and visual field constriction due to loss of rod photoreceptors [ 1 – 3 ]. Eventually, deterioration of cone photoreceptors occurs, which typically leads to loss of color vision, contrast sensitivity and central vision [ 1 – 3 ]. Retinitis pigmentosa stands as the most prevalent inherited retinal disease (IRD) globally, affecting an estimated 1 in 4000 individuals [ 4 ]. X-linked retinitis pigmentosa (XLRP) accounts for 5–15% of all RP cases [ 2 ]. It is one of the most severe forms of RP in males, with symptoms appearing in childhood and progressing rapidly to severe vision impairment by the fourth decade of life [ 4 ]. Clinically significant variants in the retinitis pigmentosa GTPase regulator ( RPGR ) gene are responsible for 70–80% of XLRP cases [ 1 ]. Despite the X-linked inheritance, which primarily affects hemizygous males, heterozygous females of RPGR variants may display varying degrees of severity, often with significant inter-eye asymmetry [ 5 ]. This phenotypic heterogeneity is thought to stem from differences in the X chromosome inactivation ratio (X lyonization), with some carriers exhibiting a phenotype akin to males, associated with significant visual impairment [ 4 , 6 ]. Fundus autofluorescence (FAF) serves as a valuable imaging technique for identifying retinal mosaicism and classifying the disease into four patterns of increasing severity: normal, radial, focal and male pattern [ 4 , 5 ]. Additionally, there is evidence correlating visual function to the observed retinal phenotype on FAF [ 5 ]. Patients with a normal, focal or radial pattern are more likely to retain good visual acuity, not reporting any symptoms [ 5 ]. The approval of Voretigene neparvovec for RPE65-associated retinal degeneration has promoted research into new treatments for other IRD, including RPGR -associated retinal degeneration [ 7 ]. Several clinical trials are underway, aiming to deliver a healthy RPGR gene copy using adeno-associated viral vectors [ 8 – 10 ]. Considering the potential severity and prevalence of this condition, there is a pressing need for effective treatment options [ 7 , 9 ]. These therapies have the potential to prevent, halt or even revert disease progression [ 9 ]. Taking into account that female carriers of RPGR variants may exhibit a severe male-like phenotype, some argue that this subgroup could benefit from gene replacement therapies and should be equally considered for future therapeutic approaches [ 5 , 9 ]. In fact, the phase 3 LUMEOS study (NCT04671433) on gene therapy for RPGR -associated retinal degeneration included female patients in its recruitment [ 11 ]. The inexorable vision impairment associated with IRD may profoundly impact a patient’s quality-of-life (QoL), leading to higher rates of depression and anxiety [ 12 , 13 ]. Studies have shown that vision-related anxiety correlates with disability in this population [ 14 ]. X-linked RP imposes a particularly heavy humanistic, economic and emotional burden due to its early onset and rapid progression to blindness [ 12 ]. Patient-reported outcome (PRO) measures play a crucial role in assessing treatment efficacy and understanding its association with patient-perceived treatment benefits in a standardized manner [ 3 , 15 , 16 ]. These clinical outcome assessments convey the patient’s viewpoint on the disease’s impact on their life, and which aspects of visual dysfunction affect their emotional well-being [ 15 , 16 ]. The Michigan Retinal Degeneration Questionnaire (MRDQ) and the Michigan Vision-related Anxiety Questionnaire (MVAQ) are two psychometrically validated PRO measures specifically developed for IRD patients, which were translated and linguistically validated for usage in Portuguese-speaking countries [ 17 ]. The MRDQ captures subjective disability across several domains representative of physiological visual function pathways [ 3 , 15 ]. Meanwhile, the MVAQ provides insight into vision-related anxiety, assessing the contributions of both cone and rod systems separately [ 16 ]. Patients’ QoL is one of the seven priorities of the 2021–2025 National Eye Institute (NEI) Strategic Plan [ 18 , 19 ]. The authors underline the importance of incorporating patient perspectives in clinical research studies using vision-related QoL assessments based on PRO measures [ 18 , 19 ]. To our knowledge, neither vision-related disability and anxiety nor any potential differences between males and females with RPGR -associated retinal degeneration have been explored before. The purpose of this study was to evaluate self-reported visual function and vision-related anxiety in a Portuguese cohort of male and female patients with RPGR -associated retinal degeneration using two validated PRO measures. Materials and methods Study design and participants Cross-sectional study conducted at an IRD referral center in Portugal. Male and female patients with genetically confirmed RPGR -associated retinal degeneration were identified using the IRD-PT registry ( www.retina.com.pt ) [ 20 ]. Ethical statement All patients provided written informed consent. The study was approved by the ethics committee of Coimbra University Hospital (protocol nº GER/001/2016) and followed the tenets of the Declaration of Helsinki for biomedical research. Measures We collected clinical data such as demographics (age and sex) and genetic testing results. Genetic variants were classified according to the guidelines of the American College of Medical Genetics and Genomics. The Early Treatment of Diabetic Retinopathy Study (ETDRS) introduced the ETDRS chart as a standardized visual acuity testing chart. Best corrected visual acuity (BCVA) was recorded as ETDRS letter score in the better-seeing eye. We used BCVA in the better-seeing eye as a surrogate for visual function since PRO measures typically reflect bilateral vision and in cases where there is a difference between eyes, visual function is primarily determined by the eye with better sight. Ultrawidefield fundus autofluorescence (UW-FAF) was used to classify retinal phenotype: normal pattern, radial pattern (radial spoke–shaped reflexes extending from the central macular area in a radial pattern), focal pattern (focal pigmentary retinopathy patchy pigmentation with a radial reflex pattern), and male pattern [4]. The Michigan Retinal Degeneration Questionnaire (MRDQ) and the Michigan Vision-Related Anxiety Questionnaire (MVAQ) are two psychometrically validated PRO measures specifically designed for IRDs [15, 16]. The MRDQ and MVAQ were developed using item response theory, factor analysis, and graded response models [3, 13]. MRDQ measures the impact of visual impairment in daily tasks, containing 59 Likert-scaled question items across seven different dimensions: central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity [3, 15]. On the other hand, MVAQ is a 14-item instrument with two domains: rod-function related anxiety, which included items like worrying about bumping into people/objects or walking on uneven ground at night, and cone-function related anxiety, with items such as worrying when reading or distinguishing colors [13, 16]. Item response theory analysis results in a theta score, which represents the functional ability or anxiety of a person in the measured domain [3]. Theta scores are mean-centered at zero and follow a normal distribution with variance of 1 [3]. They range between −3 and +3, where an increasing score indicates a higher severity in disability (MRDQ) or higher levels of anxiety (MVAQ) [21]. All participants completed the translated and linguistically validated Portuguese version of the Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-related Anxiety Questionnaire (MVAQ), where questions were read aloud by the interviewer, according to predefined guidelines. Statistical analysis Data normality was visually assessed and analyzed with the Shapiro–Wilk test. Normal distributed data was presented as mean and standard deviation (SD), and non-normal distributed data was presented as median and interquartile range (IQR). Using Kruskal-Wallis test, we searched for differences in age, BCVA of the better-seeing eye and all MRDQ and MVAQ theta scores between three groups based on FAF phenotype: males (M), females with male phenotype (FM) and females with radial or focal pattern (FRF). When a significant difference was detected, pairwise comparison was performed. Additionally, Spearman’s rank correlation was used to quantify the association between MVAQ theta scores and other variables such as age, BCVA of the better-seeing eye and MRDQ domains. Adjusted p -values according to Bonferroni correction for multiple comparison testing are presented. P -values were deemed significant if less than 0.05. All statistical analyses were performed using R 4.2.1 software (R Foundation for Statistical Computing). Results Thirty-two patients (50% female) with RPGR -associated retinal degeneration were included. The cohort’s clinical and demographic characteristics are shown in Table 1. Table 1 Clinical and Demographic Characteristics. Note: BCVA = best corrected visual acuity, ETDRS = early treatment of diabetic retinopathy study, FAF = fundus autofluorescence, IQR = interquartile range, SD = standard deviation, VUS = variant of uncertain significance. Characteristic Male Female Full sample Age in years, mean (SD) 36.56 (13.70) 44.688 (15.24) 40.62 (14.84) Variant classification, n (%) Pathogenic Likely pathogenic VUS 7 (43.8%) 5 (31.2%) 4 (25.0%) 8 (50%) 7 (43.8%) 1 (6.2%) 15 (46.9%) 12 (37.5%) 5 (15.6%) BCVA of better-seeing eye in ETDRS letters, median (IQR) 67 (60.75, 72) 83 (73.25, 85) 72 (65, 84.25) FAF phenotype of better-seeing eye, n (%) Radial pattern Focal pattern Male pattern - - 16 (100%) 7 (43.8%) 4 (25.0%) 5 (31.2%) 7 (21.9%) 4 (12.5%) 21 (65.6%) As expected, BCVA of the better-seeing eye was significantly higher in the FRF group compared to males and females with a male phenotype. There was no difference in BCVA between M and FM (Table 2). Males and females with male pattern presented higher MRDQ theta scores than the FRF group in central vision, color vision, contrast sensitivity, scotopic function, photopic and mesopic peripheral function domains (Table 2). There was no significant difference in theta scores between males and FM, except for the mesopic peripheral function domain, in which males revealed greater disability (median 0.999) than FM (median 0.014). Similarly, median MVAQ scores for rod- and cone-function related anxiety were equally higher in males and FM compared to FRF (Table 2). The distribution of MRDQ and MVAQ domain scores across the three groups are shown in Figure 1. Table 2 Comparison of Clinical Features and MRDQ and MVAQ Scores between Males, Females with a Male Phenotype and Females with a Radial or Focal Pattern. Note: BCVA = best corrected visual acuity, ETDRS = early treatment of diabetic retinopathy study, IQR = interquartile range, MRDQ = Michigan Retinal Degeneration Questionnaire, MVAQ = Michigan Vision-Related Anxiety Questionnaire. Asterisk (*) indicate a significant value (adjusted p-value < 0.05). Variable Males (M) Females with male phenotype (FM) Females with radial/focal pattern (FRF) Overall p -value Pairwise comparison p -value M vs FM FM vs FRF M vs FRF Age in years, median (IQR) 35.50 (26.00, 47.25) 59.00 (56.00, 62.00) 44.00 (31.00, 47.50) 0.115 - - - BCVA of better-seeing eye in ETDRS letters, median (IQR) 67.00 (60.75, 72.00) 71.00 (70.00, 74.00) 85.00 (83.00, 85.00) 0.002* 0.4316 0.009* 0.003* MRDQ theta scores, median (IQR) Central vision Color vision Contrast sensitivity Scotopic function Photopic peripheral function Mesopic peripheral function Photosensitivity 0.312 (-0.007, 0.995) 0.414 (-0.097, 0.972) 0.734 (0.358, 1.367) 0.859 (0.401, 1.133) 0.798 (0.211, 1.399) 0.999 (0.259, 1.239) 0.048 (-1.036, 0.520) 0.463 (-0.343, 0.770) -0.026 (-0.699, 0.640) 0.519 (-0.237, 0.836) -0.007 (-0.225, 0.592) 0.274 (-0.060, 0.412) 0.014 (-0.147, 0.496) -0.163 (-0.634, -0.084) -0.894 (-1.534, -0.664) -1.095 (-1.348, -0.842) -1.401 (-1.401, -0.862) -1.172 (-1.505, -0.935) -1.262 (-1.262, -1.262) -1.771 (-1.771, -1.159) -0.778 (-1.093, -0.527) 0.004* 0.001* 0.0001* <0.0001* <0.0001* <0.0001* 0.215 0.933 0.295 0.349 0.053 0.138 0.032* - 0.012* 0.035* 0.003* 0.004* 0.016* 0.004* - 0.008* 0.002* 0.0003* 0.0001* <0.0001* <0.0001* - MVAQ theta scores, median (IQR) Rod-function anxiety Cone-function anxiety 0.442 (-0.003, 1.630) 0.675 (0.207, 0.915) 0.180 (0.099, 0.881) 0.442 (0.359, 0.689) -1.197 (-1.197, -0.415) -0.563 (-0.861, -0.243) 0.003* 0.017* 0.835 0.780 0.014* 0.022* 0.006* 0.022* Regarding BCVA of the better-seeing eye, the higher the visual acuity, the lower the cone and rod anxiety thetas (Table 3). These negative correlations between BCVA and both rod- and cone-function anxiety scores are graphically depicted in Figure 2 and 3, respectively. Overall, positive correlations were found between every MRDQ domain and both rod- and cone-function related anxiety (Table 3). MRDQ mesopic peripheral function (r = 0.699; p <0.0001) and scotopic function (r = 0.684; p <0.0001) thetas had the strongest correlation with rod anxiety theta. MRDQ contrast sensitivity (r = 0.782; p <0.0001) and central vision (r = 0.773; p <0.0001) thetas had the strongest correlation with cone anxiety theta. Moreover, cone anxiety scores are positively correlated with concomitant rod anxiety scores and vice-versa (Table 3). Table 3 Spearman's Rank Correlation Coefficient Analysis between MVAQ Scores and Covariates. Note: BCVA = best corrected visual acuity, MRDQ = Michigan Retinal Degeneration Questionnaire, MVAQ = Michigan Vision-Related Anxiety Questionnaire. Asterisk (*) indicate a significant value (adjusted p-value < 0.05). Variable Correlation with rod-function anxiety Correlation with cone-function anxiety Correlation coefficient, r p -value Correlation coefficient, r p -value Age 0.114 0.534 0.378 0.093 BCVA -0.417 0.02* -0.581 0.0005* MRDQ domains Central vision Color vision Contrast sensitivity Scotopic function Photopic peripheral function Mesopic peripheral function Photosensitivity 0.511 0.570 0.635 0.684 0.665 0.699 0.524 0.004* 0.001* 0.0002* <0.0001* <0.0001* <0.0001* 0.003* 0.773 0.699 0.782 0.648 0.710 0.655 0.651 <0.0001* <0.0001* <0.0001* 0.0001* <0.0001* <0.0001* <0.0001* MVAQ domains Rod-function anxiety Cone-function anxiety 1.00 0.786 - <0.0001* 0.786 1.00 <0.0001* - Discussion By evaluating self-perceived vision-related disability and anxiety in both male and female patients, this study makes a significant and innovative contribution to the current knowledge and adds a new dimension to our understanding of RPGR -associated retinal degeneration. We highlight the importance of PRO measures in capturing the effect of visual loss on the patient’s function, mental health and QoL. In our cohort, both males and females with a male phenotype, presented increased disability scores in domains such as central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral function and mesopic peripheral function. Both rod and cone related functional domains were affected in our population, which is explained by the rapid progression of XLRP leading to secondary cone degeneration. In the male group, we found the highest perceived disability in the domains of scotopic function and mesopic peripheral function. This result is in line with data previously published by Karuntu et al. while evaluating visual function parameters in patients with RP using MRDQ [3]. Additionally, similar findings were described by Marques et al. in a cohort of EYS -associated retinal degeneration, where self-reported visual function and psychosocial impact of visual loss were evaluated using MRDQ and MVAQ [21]. On the other hand, in our group of females with male phenotype, highest perceived disability was observed in the domains of contrast sensitivity and central vision. Interestingly, the cohort of patients studied by Karuntu et al. also presented high scores of disability in contrast sensitivity and could be present at all stages of RP [3]. The lowest perceived disability score in our cohort of males and females with male phenotype was photosensitivity. This is consistent with the findings of Karuntu et al., whereas in the EYS cohort of Marques et al. color vision yielded the lowest disability score [3, 21]. Moreover, we observed that rod- and cone-function related anxiety scores were greater in males and females with male pattern, which is consistent with the self-perceived visual disability revealed by the MRDQ analysis. This hypothesis is supported by significant positive correlations found between anxiety scores and every MRDQ domain and BCVA. To date, very few studies have delved into the patient burden and psychosocial aspect of XLRP. In a review study, Chivers et al. described that people with RP reported a heavy psychosocial burden, having difficulty undertaking activities of daily living and maintaining independence [12]. Furthermore, they inferred from RP studies that XLRP ought to be associated with a greater burden than other forms of RP, with a greater impact on patients’ mental health due to the younger age of those affected and more rapid progression to advanced disease [12]. The significant correlations found in our study between self-perceived visual disability and vision-related anxiety are consistent with previous studies with IRD patients by Jayasundera et al. and Popova et al. [13, 14]. Furthermore, our findings suggesting a stronger correlation of scotopic function with rod-function anxiety, and central vision with cone-function anxiety, correspond to the results presented by Popova et al. [13]. By including female carriers of RPGR variants, this study enhances the understanding of phenotype heterogeneity, showing that females with a male phenotype may present similar levels of self-perceived disability and vision-related anxiety as males. In fact, it has been well documented that female carriers of RPGR variants presenting with the male pattern have a severe phenotype and visual impairment early in life [4, 5]. Several authors consider that including female carriers of RPGR variants in future studies is of the utmost importance to enhance the understanding of the disease and aid in developing targeted therapies not only for men but also for female patients [1, 4, 5]. There is an urgent need for inclusion of PRO measures in the design of clinical trials and future studies because of its relevance for patients and professionals, helping provide adequate support [1, 3]. These valuable instruments are capable of representing the impact of visual loss on the patients’ function and mental health in a standardized manner [1]. While it is well documented that male patients experience progressive decline in visual acuity, there is a knowledge gap regarding disease progression in heterozygous females [1]. In our cohort, there seems to be a difference in age between males and females with a male phenotype, albeit not significant. This difference may be attributed to a lower awareness of the disease in female patients. The resulting gender bias may lead to a delayed diagnosis in heterozygous female patients. One limitation of this study is its cross-sectional nature, which prevents us from inferring about disease progression. Secondly, although equally distributed between sex, the sample size is small as expected in a rare disease. Consequently, the statistical power to draw significant conclusions is inevitably hindered. Lastly, the cohort was obtained from an IRD referral center, thus our results may be affected by ascertainment bias. Nonetheless, to our knowledge this is the first study proposing to explore self-reported disability and vision-related anxiety using validated PRO measures in both males and females with RPGR -associated retinal degeneration. Our findings should help provide a more targeted and holistic approach to patient care, drawing attention to female carriers of RPGR variants, who can suffer from significant visual and psychological impairment. Ultimately, the results of MRDQ may be used to tailor low vision rehabilitation to each individual patient's needs. Similarly, identifying RP patients with higher levels of anxiety based on MVAQ can direct the need for psychological intervention. In conclusion, in RPGR -associated retinal degeneration, males and females presenting with a male phenotype show similar levels of increased vision-related anxiety and self-perceived visual disability. Both rod- and cone-function related anxiety correlate positively with every MRDQ domain and BCVA. The use of PRO measures in this study, such as MRDQ and MVAQ, adds a new dimension to our understanding of RPGR -associated retinal degeneration, enabling a more targeted and patient-centered therapeutic intervention. Declarations Authors contributions NG, OC and JPM were involved in study concept, design and acquisition of data. NG analyzed and interpreted the data, and wrote the draft of the manuscript. JPM, CO, CHA, RS and JM were contributors in writing and critically revising the manuscript. All authors edited and approved the final version of the manuscript for submission. Data availability statement The datasets generated and analyzed during the current study are not publicly available due to the sensitive nature of the research supporting data but are available from the corresponding author on reasonable request. Competing interests statement The authors declare no competing interests. References Lam, B.L. et al. A systematic literature review of disease progression reported in RPGR-associated X-linked retinitis pigmentosa. Retina (Philadelphia, Pa.) . 44 , 1-9 (2024). Nguyen, X.T. et al. RPGR-associated Dystrophies: Clinical, Genetic, and Histopathological Features. 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Self-reported visual function and psychosocial impact of visual loss in EYS-associated retinal degeneration in a Portuguese population. Ophthalmic genetics . 44 , 334–340 (2023). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editor invited by journal 15 May, 2024 Submission checks completed at journal 11 May, 2024 First submitted to journal 08 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4390545","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":304033820,"identity":"b49fb052-36f5-4806-9444-4a9e85e3a423","order_by":0,"name":"Nuno Gouveia","email":"","orcid":"","institution":"Coimbra University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nuno","middleName":"","lastName":"Gouveia","suffix":""},{"id":304033821,"identity":"6f835dd6-82ab-4030-a7b6-38324352f7f2","order_by":1,"name":"Oluji Chukwunalu","email":"","orcid":"","institution":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC)","correspondingAuthor":false,"prefix":"","firstName":"Oluji","middleName":"","lastName":"Chukwunalu","suffix":""},{"id":304033822,"identity":"0765bbac-9b81-43f2-b63e-c3e49290241b","order_by":2,"name":"Carolina Oliveira","email":"","orcid":"","institution":"University of Coimbra (FPCEUC)","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"","lastName":"Oliveira","suffix":""},{"id":304033823,"identity":"2ca56b04-5dde-47e4-b635-21a0c1277205","order_by":3,"name":"C. Henrique Alves","email":"","orcid":"","institution":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC)","correspondingAuthor":false,"prefix":"","firstName":"C.","middleName":"Henrique","lastName":"Alves","suffix":""},{"id":304033824,"identity":"32b17219-ee6d-49b5-baab-103b4251dcab","order_by":4,"name":"Rufino Silva","email":"","orcid":"","institution":"Coimbra University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rufino","middleName":"","lastName":"Silva","suffix":""},{"id":304033825,"identity":"de05cbb9-830d-467f-93e5-1e63dc7acb19","order_by":5,"name":"Joaquim Murta","email":"","orcid":"","institution":"Coimbra University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Joaquim","middleName":"","lastName":"Murta","suffix":""},{"id":304033826,"identity":"145eec40-0932-4df0-83d1-2d1bba29b07f","order_by":6,"name":"João Pedro Marques","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYBADZgjFxsDAD6ITCkjRItkA0mJAtGVALQYHQAw8WnTbzz68zVNRx87PfvjYgw9l9+SMz69O/PDAgEGeX+wAVi1mZ9KNrXnOHGaW7ElLN5xxrtjY7MbbzRJAhxnOnJ2AXcuBNDZp3rYDzAYHcsyAjITEbTfObgBpSTC4jUPL+WdALf/qmA3OvzGT/gvUsnnG2c0/8Gq5AbKlgZnZ4AbQFkaglg38vdvw23LjGbPlnGNAv8x4lm7Ycy7BWOIG7zaLBAMJ3H45n8Z4401NXTI/f/KxBz/KEuT4+89uvvmjwkaeXxq7FhCQAOJkBnCkgLkJMEHcACRrh9DCfwCv6lEwCkbBKBh5AAA9Zl3fSu+UDQAAAABJRU5ErkJggg==","orcid":"","institution":"Coimbra University Hospital","correspondingAuthor":true,"prefix":"","firstName":"João","middleName":"Pedro","lastName":"Marques","suffix":""}],"badges":[],"createdAt":"2024-05-08 16:15:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4390545/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4390545/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57036453,"identity":"9cf5b79a-c324-4002-9aaa-a0988888be6f","added_by":"auto","created_at":"2024-05-23 18:39:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":80066,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of MRDQ and MVAQ Scores between Males, Females with a Male Phenotype and Females with a Radial or Focal Pattern. Note: ACF = cone-function related anxiety, ARF = rod-function related anxiety, CNT = contrast sensitivity, COL = color vision, CV = central vision, FM = females with male phenotype, FRF = females with radial or focal pattern, M = males, MF = mesopic peripheral function, PF = photopic peripheral function, PS = photosensitivity, SF = scotopic function.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4390545/v1/92bbf38ced86e3294c5573e6.png"},{"id":57036454,"identity":"51a31ca5-b6da-4ea0-bdc1-950e5f5095fc","added_by":"auto","created_at":"2024-05-23 18:39:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30240,"visible":true,"origin":"","legend":"\u003cp\u003eNegative Correlation between MVAQ Rod-function Anxiety and BCVA. Note: ARF = rod-function related anxiety, BCVA = best corrected visual acuity.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4390545/v1/d396e04d7be02dc294679c08.png"},{"id":57036455,"identity":"b3fda8e3-d6b4-42c9-ad3b-ad80425a2917","added_by":"auto","created_at":"2024-05-23 18:39:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34701,"visible":true,"origin":"","legend":"\u003cp\u003eNegative Correlation between MVAQ Cone-function Anxiety and BCVA. Note: ACF = cone-function related anxiety, BCVA = best corrected visual acuity.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4390545/v1/5756646f37d57ed5d895a772.png"},{"id":57037366,"identity":"2c17cbf0-966b-409a-9e09-ae30ee1d6414","added_by":"auto","created_at":"2024-05-23 18:47:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":591244,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4390545/v1/90d6bc70-1268-49af-bdba-0770d44ac25a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring self-reported visual function and vision-related anxiety in patients with RPGR-associated retinal degeneration","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinitis pigmentosa (RP) encompasses a diverse group of inherited retinal disorders characterized by diffuse and irreversible retinal degeneration [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The initial stages manifest as night blindness and visual field constriction due to loss of rod photoreceptors [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Eventually, deterioration of cone photoreceptors occurs, which typically leads to loss of color vision, contrast sensitivity and central vision [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Retinitis pigmentosa stands as the most prevalent inherited retinal disease (IRD) globally, affecting an estimated 1 in 4000 individuals [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eX-linked retinitis pigmentosa (XLRP) accounts for 5\u0026ndash;15% of all RP cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It is one of the most severe forms of RP in males, with symptoms appearing in childhood and progressing rapidly to severe vision impairment by the fourth decade of life [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Clinically significant variants in the retinitis pigmentosa GTPase regulator (\u003cem\u003eRPGR\u003c/em\u003e) gene are responsible for 70\u0026ndash;80% of XLRP cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the X-linked inheritance, which primarily affects hemizygous males, heterozygous females of \u003cem\u003eRPGR\u003c/em\u003e variants may display varying degrees of severity, often with significant inter-eye asymmetry [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This phenotypic heterogeneity is thought to stem from differences in the X chromosome inactivation ratio (X lyonization), with some carriers exhibiting a phenotype akin to males, associated with significant visual impairment [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFundus autofluorescence (FAF) serves as a valuable imaging technique for identifying retinal mosaicism and classifying the disease into four patterns of increasing severity: normal, radial, focal and male pattern [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Additionally, there is evidence correlating visual function to the observed retinal phenotype on FAF [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Patients with a normal, focal or radial pattern are more likely to retain good visual acuity, not reporting any symptoms [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe approval of Voretigene neparvovec for RPE65-associated retinal degeneration has promoted research into new treatments for other IRD, including \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Several clinical trials are underway, aiming to deliver a healthy \u003cem\u003eRPGR\u003c/em\u003e gene copy using adeno-associated viral vectors [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Considering the potential severity and prevalence of this condition, there is a pressing need for effective treatment options [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These therapies have the potential to prevent, halt or even revert disease progression [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Taking into account that female carriers of \u003cem\u003eRPGR\u003c/em\u003e variants may exhibit a severe male-like phenotype, some argue that this subgroup could benefit from gene replacement therapies and should be equally considered for future therapeutic approaches [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In fact, the phase 3 LUMEOS study (NCT04671433) on gene therapy for \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration included female patients in its recruitment [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe inexorable vision impairment associated with IRD may profoundly impact a patient\u0026rsquo;s quality-of-life (QoL), leading to higher rates of depression and anxiety [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Studies have shown that vision-related anxiety correlates with disability in this population [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. X-linked RP imposes a particularly heavy humanistic, economic and emotional burden due to its early onset and rapid progression to blindness [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatient-reported outcome (PRO) measures play a crucial role in assessing treatment efficacy and understanding its association with patient-perceived treatment benefits in a standardized manner [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These clinical outcome assessments convey the patient\u0026rsquo;s viewpoint on the disease\u0026rsquo;s impact on their life, and which aspects of visual dysfunction affect their emotional well-being [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Michigan Retinal Degeneration Questionnaire (MRDQ) and the Michigan Vision-related Anxiety Questionnaire (MVAQ) are two psychometrically validated PRO measures specifically developed for IRD patients, which were translated and linguistically validated for usage in Portuguese-speaking countries [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The MRDQ captures subjective disability across several domains representative of physiological visual function pathways [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Meanwhile, the MVAQ provides insight into vision-related anxiety, assessing the contributions of both cone and rod systems separately [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients\u0026rsquo; QoL is one of the seven priorities of the 2021\u0026ndash;2025 National Eye Institute (NEI) Strategic Plan [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The authors underline the importance of incorporating patient perspectives in clinical research studies using vision-related QoL assessments based on PRO measures [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo our knowledge, neither vision-related disability and anxiety nor any potential differences between males and females with \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration have been explored before. The purpose of this study was to evaluate self-reported visual function and vision-related anxiety in a Portuguese cohort of male and female patients with \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration using two validated PRO measures.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eCross-sectional study conducted at an IRD referral center in Portugal. Male and female patients with genetically confirmed \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration were identified using the IRD-PT registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"https://orcid.org/0009-0005-1855-1964\" target=\"_blank\"\u003ewww.retina.com.pt\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.retina.com.pt\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients provided written informed consent. The study was approved by the ethics committee of Coimbra University Hospital (protocol n\u0026ordm; GER/001/2016) and followed the tenets of the Declaration of Helsinki for biomedical research.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eMeasures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe collected clinical data such as demographics (age and sex) and genetic testing results. Genetic variants were classified according to the guidelines of the American College of Medical Genetics and Genomics.\u003c/p\u003e\n\u003cp\u003eThe Early Treatment of Diabetic Retinopathy Study (ETDRS) introduced the ETDRS chart as a standardized visual acuity testing chart. Best corrected visual acuity (BCVA) was recorded as ETDRS letter score in the better-seeing eye. We used BCVA in the better-seeing eye as a surrogate for visual function since PRO measures typically reflect bilateral vision and in cases where there is a difference between eyes, visual function is primarily determined by the eye with better sight.\u003c/p\u003e\n\u003cp\u003eUltrawidefield fundus autofluorescence (UW-FAF) was used to classify retinal phenotype: normal pattern, radial pattern (radial spoke\u0026ndash;shaped reflexes extending from the central macular area in a radial pattern), focal pattern (focal pigmentary retinopathy patchy pigmentation with a radial reflex pattern), and male pattern [4].\u003c/p\u003e\n\u003cp\u003eThe Michigan Retinal Degeneration Questionnaire (MRDQ) and the Michigan Vision-Related Anxiety Questionnaire (MVAQ) are two psychometrically validated PRO measures specifically designed for IRDs [15, 16]. The MRDQ and MVAQ were developed using item response theory, factor analysis, and graded response models [3, 13]. MRDQ measures the impact of visual impairment in daily tasks, containing 59 Likert-scaled question items across seven different dimensions: central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity [3, 15]. On the other hand, MVAQ is a 14-item instrument with two domains: rod-function related anxiety, which included items like worrying about bumping into people/objects or walking on uneven ground at night, and cone-function related anxiety, with items such as worrying when reading or distinguishing colors [13, 16]. Item response theory analysis results in a theta score, which represents the functional ability or anxiety of a person in the measured domain [3]. Theta scores are mean-centered at zero and follow a normal distribution with variance of 1 [3]. They range between \u0026minus;3 and +3, where an increasing score indicates a higher severity in disability (MRDQ) or higher levels of anxiety (MVAQ) [21]. All participants completed the translated and linguistically validated Portuguese version of the Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-related Anxiety Questionnaire (MVAQ), where questions were read aloud by the interviewer, according to predefined guidelines.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData normality was visually assessed and analyzed with the Shapiro\u0026ndash;Wilk test. Normal distributed data was presented as mean and standard deviation (SD), and non-normal distributed data was presented as median and interquartile range (IQR). Using Kruskal-Wallis test, we searched for differences in age, BCVA of the better-seeing eye and all MRDQ and MVAQ theta scores between three groups based on FAF phenotype: males (M), females with male phenotype (FM) and females with radial or focal pattern (FRF). When a significant difference was detected, pairwise comparison was performed. Additionally, Spearman\u0026rsquo;s rank correlation was used to quantify the association between MVAQ theta scores and other variables such as age, BCVA of the better-seeing eye and MRDQ domains. Adjusted \u003cem\u003ep\u003c/em\u003e-values according to Bonferroni correction for multiple comparison testing are presented. \u003cem\u003eP\u003c/em\u003e-values were deemed significant if less than 0.05. All statistical analyses were performed using R 4.2.1 software (R Foundation for Statistical Computing).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-two patients (50% female) with \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration were included. The cohort\u0026rsquo;s clinical and demographic characteristics are shown in Table 1.\u003c/p\u003e\n\u003cp\u003eTable 1 Clinical and Demographic Characteristics. Note: BCVA = best corrected visual acuity, ETDRS = early treatment of diabetic retinopathy study, FAF = fundus autofluorescence, IQR = interquartile range, SD = standard deviation, VUS = variant of uncertain significance.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"619\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.65751211631664%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.609046849757675%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.447495961227787%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.2859450726979%\" valign=\"top\"\u003e\n \u003cp\u003eFull sample\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.65751211631664%\" valign=\"top\"\u003e\n \u003cp\u003eAge in years, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.609046849757675%\" valign=\"top\"\u003e\n \u003cp\u003e36.56 (13.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.447495961227787%\" valign=\"top\"\u003e\n \u003cp\u003e44.688 (15.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.2859450726979%\" valign=\"top\"\u003e\n \u003cp\u003e40.62 (14.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.65751211631664%\" valign=\"top\"\u003e\n \u003cp\u003eVariant classification, n (%)\u003c/p\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003eLikely pathogenic\u003c/p\u003e\n \u003cp\u003eVUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.609046849757675%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (43.8%)\u003c/p\u003e\n \u003cp\u003e5 (31.2%)\u003c/p\u003e\n \u003cp\u003e4 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.447495961227787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (50%)\u003c/p\u003e\n \u003cp\u003e7 (43.8%)\u003c/p\u003e\n \u003cp\u003e1 (6.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.2859450726979%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (46.9%)\u003c/p\u003e\n \u003cp\u003e12 (37.5%)\u003c/p\u003e\n \u003cp\u003e5 (15.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.65751211631664%\" valign=\"top\"\u003e\n \u003cp\u003eBCVA of better-seeing eye in ETDRS letters, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.609046849757675%\" valign=\"top\"\u003e\n \u003cp\u003e67 (60.75, 72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.447495961227787%\" valign=\"top\"\u003e\n \u003cp\u003e83 (73.25, 85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.2859450726979%\" valign=\"top\"\u003e\n \u003cp\u003e72 (65, 84.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.65751211631664%\" valign=\"top\"\u003e\n \u003cp\u003eFAF phenotype of better-seeing eye, n (%)\u003c/p\u003e\n \u003cp\u003eRadial pattern\u003c/p\u003e\n \u003cp\u003eFocal pattern\u003c/p\u003e\n \u003cp\u003eMale pattern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.609046849757675%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e16 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.447495961227787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (43.8%)\u003c/p\u003e\n \u003cp\u003e4 (25.0%)\u003c/p\u003e\n \u003cp\u003e5 (31.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.2859450726979%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (21.9%)\u003c/p\u003e\n \u003cp\u003e4 (12.5%)\u003c/p\u003e\n \u003cp\u003e21 (65.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAs expected, BCVA of the better-seeing eye was significantly higher in the FRF group compared to males and females with a male phenotype. There was no difference in BCVA between M and FM (Table 2).\u003c/p\u003e\n\u003cp\u003eMales and females with male pattern presented higher MRDQ theta scores than the FRF group in central vision, color vision, contrast sensitivity, scotopic function, photopic and mesopic peripheral function domains (Table 2). There was no significant difference in theta scores between males and FM, except for the mesopic peripheral function domain, in which males revealed greater disability (median 0.999) than FM (median 0.014). Similarly, median MVAQ scores for rod- and cone-function related anxiety were equally higher in males and FM compared to FRF (Table 2). The distribution of MRDQ and MVAQ domain scores across the three groups are shown in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 2 Comparison of Clinical Features and MRDQ and MVAQ Scores between Males, Females with a Male Phenotype and Females with a Radial or Focal Pattern. Note: BCVA = best corrected visual acuity, ETDRS = early treatment of diabetic retinopathy study, IQR = interquartile range, MRDQ = Michigan Retinal Degeneration Questionnaire, MVAQ = Michigan Vision-Related Anxiety Questionnaire. Asterisk (*) indicate a significant value (adjusted p-value \u0026lt; 0.05).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"739\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.10960757780785%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.561569688768607%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMales\u003c/p\u003e\n \u003cp\u003e(M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.373477672530445%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFemales\u003c/p\u003e\n \u003cp\u003ewith\u003c/p\u003e\n \u003cp\u003emale phenotype\u003c/p\u003e\n \u003cp\u003e(FM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.185385656292286%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFemales\u003c/p\u003e\n \u003cp\u003ewith\u003c/p\u003e\n \u003cp\u003eradial/focal pattern\u003c/p\u003e\n \u003cp\u003e(FRF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.930987821380244%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.83897158322057%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003ePairwise comparison\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.51948051948052%\" valign=\"top\"\u003e\n \u003cp\u003eM vs FM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.818181818181817%\" valign=\"top\"\u003e\n \u003cp\u003eFM vs FRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.66233766233766%\" valign=\"top\"\u003e\n \u003cp\u003eM vs FRF\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.10960757780785%\" valign=\"top\"\u003e\n \u003cp\u003eAge in years, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.561569688768607%\" valign=\"top\"\u003e\n \u003cp\u003e35.50 (26.00, 47.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.373477672530445%\" valign=\"top\"\u003e\n \u003cp\u003e59.00 (56.00, 62.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.185385656292286%\" valign=\"top\"\u003e\n \u003cp\u003e44.00 (31.00, 47.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.930987821380244%\" valign=\"top\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.359945872801083%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.630581867388362%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.848443843031123%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.10960757780785%\" valign=\"top\"\u003e\n \u003cp\u003eBCVA of better-seeing eye in ETDRS letters, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.561569688768607%\" valign=\"top\"\u003e\n \u003cp\u003e67.00 (60.75, 72.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.373477672530445%\" valign=\"top\"\u003e\n \u003cp\u003e71.00 (70.00, 74.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.185385656292286%\" valign=\"top\"\u003e\n \u003cp\u003e85.00 (83.00, 85.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.930987821380244%\" valign=\"top\"\u003e\n \u003cp\u003e0.002*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.359945872801083%\" valign=\"top\"\u003e\n \u003cp\u003e0.4316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.630581867388362%\" valign=\"top\"\u003e\n \u003cp\u003e0.009*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.848443843031123%\" valign=\"top\"\u003e\n \u003cp\u003e0.003*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.10960757780785%\" valign=\"top\"\u003e\n \u003cp\u003eMRDQ theta scores, median (IQR)\u003c/p\u003e\n \u003cp\u003eCentral vision\u003c/p\u003e\n \u003cp\u003eColor vision\u003c/p\u003e\n \u003cp\u003eContrast sensitivity\u003c/p\u003e\n \u003cp\u003eScotopic function\u003c/p\u003e\n \u003cp\u003ePhotopic peripheral function\u003c/p\u003e\n \u003cp\u003eMesopic peripheral function\u003c/p\u003e\n \u003cp\u003ePhotosensitivity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.561569688768607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.312 (-0.007, 0.995)\u003c/p\u003e\n \u003cp\u003e0.414 (-0.097, 0.972)\u003c/p\u003e\n \u003cp\u003e0.734 (0.358, 1.367)\u003c/p\u003e\n \u003cp\u003e0.859 (0.401, 1.133)\u003c/p\u003e\n \u003cp\u003e0.798 (0.211, 1.399)\u003c/p\u003e\n \u003cp\u003e0.999 (0.259, 1.239)\u003c/p\u003e\n \u003cp\u003e0.048 (-1.036, 0.520)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.373477672530445%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.463 (-0.343, 0.770)\u003c/p\u003e\n \u003cp\u003e-0.026 (-0.699, 0.640)\u003c/p\u003e\n \u003cp\u003e0.519 (-0.237, 0.836)\u003c/p\u003e\n \u003cp\u003e-0.007 (-0.225, 0.592)\u003c/p\u003e\n \u003cp\u003e0.274 (-0.060, 0.412)\u003c/p\u003e\n \u003cp\u003e0.014 (-0.147, 0.496)\u003c/p\u003e\n \u003cp\u003e-0.163 (-0.634, -0.084)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.185385656292286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-0.894 (-1.534, -0.664)\u003c/p\u003e\n \u003cp\u003e-1.095 (-1.348, -0.842)\u003c/p\u003e\n \u003cp\u003e-1.401 (-1.401, -0.862)\u003c/p\u003e\n \u003cp\u003e-1.172 (-1.505, -0.935)\u003c/p\u003e\n \u003cp\u003e-1.262 (-1.262, -1.262)\u003c/p\u003e\n \u003cp\u003e-1.771 (-1.771, -1.159)\u003c/p\u003e\n \u003cp\u003e-0.778 (-1.093, -0.527)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.930987821380244%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.004*\u003c/p\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003cp\u003e0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.359945872801083%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.933\u003c/p\u003e\n \u003cp\u003e0.295\u003c/p\u003e\n \u003cp\u003e0.349\u003c/p\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003cp\u003e0.138\u003c/p\u003e\n \u003cp\u003e0.032*\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.630581867388362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.012*\u003c/p\u003e\n \u003cp\u003e0.035*\u003c/p\u003e\n \u003cp\u003e0.003*\u003c/p\u003e\n \u003cp\u003e0.004*\u003c/p\u003e\n \u003cp\u003e0.016*\u003c/p\u003e\n \u003cp\u003e0.004*\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.848443843031123%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.008*\u003c/p\u003e\n \u003cp\u003e0.002*\u003c/p\u003e\n \u003cp\u003e0.0003*\u003c/p\u003e\n \u003cp\u003e0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.10960757780785%\" valign=\"top\"\u003e\n \u003cp\u003eMVAQ theta scores, median (IQR)\u003c/p\u003e\n \u003cp\u003eRod-function anxiety\u003c/p\u003e\n \u003cp\u003eCone-function anxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.561569688768607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.442 (-0.003, 1.630)\u003c/p\u003e\n \u003cp\u003e0.675 (0.207, 0.915)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.373477672530445%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.180 (0.099, 0.881)\u003c/p\u003e\n \u003cp\u003e0.442 (0.359, 0.689)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.185385656292286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-1.197 (-1.197, -0.415)\u003c/p\u003e\n \u003cp\u003e-0.563 (-0.861, -0.243)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.930987821380244%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.003*\u003c/p\u003e\n \u003cp\u003e0.017*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.359945872801083%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.835\u003c/p\u003e\n \u003cp\u003e0.780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.630581867388362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.014*\u003c/p\u003e\n \u003cp\u003e0.022*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.848443843031123%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.006*\u003c/p\u003e\n \u003cp\u003e0.022*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eRegarding BCVA of the better-seeing eye, the higher the visual acuity, the lower the cone and rod anxiety thetas (Table 3). These negative correlations between BCVA and both rod- and cone-function anxiety scores are graphically depicted in Figure 2 and 3, respectively.\u003c/p\u003e\n\u003cp\u003eOverall, positive correlations were found between every MRDQ domain and both rod- and cone-function related anxiety (Table 3). MRDQ mesopic peripheral function (r = 0.699; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001) and scotopic function (r = 0.684; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001) thetas had the strongest correlation with rod anxiety theta. MRDQ contrast sensitivity (r = 0.782; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001) and central vision (r = 0.773; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001) thetas had the strongest correlation with cone anxiety theta. Moreover, cone anxiety scores are positively correlated with concomitant rod anxiety scores and vice-versa (Table 3).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 3 Spearman\u0026apos;s Rank Correlation Coefficient Analysis between MVAQ Scores and Covariates. Note: BCVA = best corrected visual acuity, MRDQ = Michigan Retinal Degeneration Questionnaire, MVAQ = Michigan Vision-Related Anxiety Questionnaire. Asterisk (*) indicate a significant value (adjusted p-value \u0026lt; 0.05).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"536\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.73134328358209%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.26119402985075%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation with rod-function anxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.007462686567166%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation with cone-function anxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" height=\"28\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.74869109947644%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient, r\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.727748691099478%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.607329842931936%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient, r\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.916230366492147%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" height=\"28\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.73134328358209%\" valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.776119402985074%\" valign=\"top\"\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.485074626865671%\" valign=\"top\"\u003e\n \u003cp\u003e0.534\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.53731343283582%\" valign=\"top\"\u003e\n \u003cp\u003e0.378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.470149253731343%\" valign=\"top\"\u003e\n \u003cp\u003e0.093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.73134328358209%\" valign=\"top\"\u003e\n \u003cp\u003eBCVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.776119402985074%\" valign=\"top\"\u003e\n \u003cp\u003e-0.417\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.485074626865671%\" valign=\"top\"\u003e\n \u003cp\u003e0.02*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.53731343283582%\" valign=\"top\"\u003e\n \u003cp\u003e-0.581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.470149253731343%\" valign=\"top\"\u003e\n \u003cp\u003e0.0005*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.73134328358209%\" rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eMRDQ domains\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCentral vision\u003c/p\u003e\n \u003cp\u003eColor vision\u003c/p\u003e\n \u003cp\u003eContrast sensitivity\u003c/p\u003e\n \u003cp\u003eScotopic function\u003c/p\u003e\n \u003cp\u003ePhotopic peripheral \u0026nbsp; \u0026nbsp; function\u003c/p\u003e\n \u003cp\u003eMesopic peripheral function\u003c/p\u003e\n \u003cp\u003ePhotosensitivity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.776119402985074%\" rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.511\u003c/p\u003e\n \u003cp\u003e0.570\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.635\u003c/p\u003e\n \u003cp\u003e0.684\u003c/p\u003e\n \u003cp\u003e0.665\u003c/p\u003e\n \u003cp\u003e0.699\u003c/p\u003e\n \u003cp\u003e0.524\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.485074626865671%\" rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.004*\u003c/p\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003cp\u003e0.0002*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e0.003*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.53731343283582%\" rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.773\u003c/p\u003e\n \u003cp\u003e0.699\u003c/p\u003e\n \u003cp\u003e0.782\u003c/p\u003e\n \u003cp\u003e0.648\u003c/p\u003e\n \u003cp\u003e0.710\u003c/p\u003e\n \u003cp\u003e0.655\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.651\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.470149253731343%\" rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"12\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.73134328358209%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMVAQ domains\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRod-function anxiety\u003c/p\u003e\n \u003cp\u003eCone-function anxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.776119402985074%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.786\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.485074626865671%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.53731343283582%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.786\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.470149253731343%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001*\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\" height=\"24\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eBy evaluating self-perceived vision-related disability and anxiety in both male and female patients, this study makes a significant and innovative contribution to the current knowledge and adds a new dimension to our understanding of \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration.\u003c/p\u003e\n\u003cp\u003eWe highlight the importance of PRO measures in capturing the effect of visual loss on the patient\u0026rsquo;s function, mental health and QoL. In our cohort, both males and females with a male phenotype, presented increased disability scores in domains such as central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral function and mesopic peripheral function. Both rod and cone related functional domains were affected in our population, which is explained by the rapid progression of XLRP leading to secondary cone degeneration.\u003c/p\u003e\n\u003cp\u003eIn the male group, we found the highest perceived disability in the domains of scotopic function and mesopic peripheral function. This result is in line with data previously published by Karuntu et al. while evaluating visual function parameters in patients with RP using MRDQ [3]. Additionally, similar findings were described by Marques et al. in a cohort of \u003cem\u003eEYS\u003c/em\u003e-associated retinal degeneration, where self-reported visual function and psychosocial impact of visual loss were evaluated using MRDQ and MVAQ [21]. On the other hand, in our group of females with male phenotype, highest perceived disability was observed in the domains of contrast sensitivity and central vision. Interestingly, the cohort of patients studied by Karuntu et al. also presented high scores of disability in contrast sensitivity and could be present at all stages of RP [3]. The lowest perceived disability score in our cohort of males and females with male phenotype was photosensitivity. This is consistent with the findings of Karuntu et al., whereas in the \u003cem\u003eEYS\u003c/em\u003e cohort of Marques et al. color vision yielded the lowest disability score [3, 21].\u003c/p\u003e\n\u003cp\u003eMoreover, we observed that rod- and cone-function related anxiety scores were greater in males and females with male pattern, which is consistent with the self-perceived visual disability revealed by the MRDQ analysis. This hypothesis is supported by significant positive correlations found between anxiety scores and every MRDQ domain and BCVA. To date, very few studies have delved into the patient burden and psychosocial aspect of XLRP. In a review study, Chivers et al. described that people with RP reported a heavy psychosocial burden, having difficulty undertaking activities of daily living and maintaining independence [12]. Furthermore, they inferred from RP studies that XLRP ought to be associated with a greater burden than other forms of RP, with a greater impact on patients\u0026rsquo; mental health due to the younger age of those affected and more rapid progression to advanced disease [12]. The significant correlations found in our study between self-perceived visual disability and vision-related anxiety are consistent with previous studies with IRD patients by Jayasundera et al. and Popova et al. [13, 14]. Furthermore, our findings suggesting a stronger correlation of scotopic function with rod-function anxiety, and central vision with cone-function anxiety, correspond to the results presented by Popova et al. [13].\u003c/p\u003e\n\u003cp\u003eBy including female carriers of \u003cem\u003eRPGR\u003c/em\u003e variants, this study enhances the understanding of phenotype heterogeneity, showing that females with a male phenotype may present similar levels of self-perceived disability and vision-related anxiety as males. In fact, it has been well documented that female carriers of \u003cem\u003eRPGR\u003c/em\u003e variants presenting with the male pattern have a severe phenotype and visual impairment early in life [4, 5]. Several authors consider that including female carriers of \u003cem\u003eRPGR\u003c/em\u003e variants in future studies is of the utmost importance to enhance the understanding of the disease and aid in developing targeted therapies not only for men but also for female patients [1, 4, 5]. There is an urgent need for inclusion of PRO measures in the design of clinical trials and future studies because of its relevance for patients and professionals, helping provide adequate support [1, 3]. These valuable instruments are capable of representing the impact of visual loss on the patients\u0026rsquo; function and mental health in a standardized manner [1].\u003c/p\u003e\n\u003cp\u003eWhile it is well documented that male patients experience progressive decline in visual acuity, there is a knowledge gap regarding disease progression in heterozygous females [1]. In our cohort, there seems to be a difference in age between males and females with a male phenotype, albeit not significant. This difference may be attributed to a lower awareness of the disease in female patients. The resulting gender bias may lead to a delayed diagnosis in heterozygous female patients.\u003c/p\u003e\n\u003cp\u003eOne limitation of this study is its cross-sectional nature, which prevents us from inferring about disease progression. Secondly, although equally distributed between sex, the sample size is small as expected in a rare disease. Consequently, the statistical power to draw significant conclusions is inevitably hindered. Lastly, the cohort was obtained from an IRD referral center, thus our results may be affected by ascertainment bias.\u003c/p\u003e\n\u003cp\u003eNonetheless, to our knowledge this is the first study proposing to explore self-reported disability and vision-related anxiety using validated PRO measures in both males and females with \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration. Our findings should help provide a more targeted and holistic approach to patient care, drawing attention to female carriers of \u003cem\u003eRPGR\u003c/em\u003e variants, who can suffer from significant visual and psychological impairment. Ultimately, the results of MRDQ may be used to tailor low vision rehabilitation to each individual patient\u0026apos;s needs. Similarly, identifying RP patients with higher levels of anxiety based on MVAQ can direct the need for psychological intervention.\u003c/p\u003e\n\u003cp\u003eIn conclusion, in \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration, males and females presenting with a male phenotype show similar levels of increased vision-related anxiety and self-perceived visual disability. Both rod- and cone-function related anxiety correlate positively with every MRDQ domain and BCVA. The use of PRO measures in this study, such as MRDQ and MVAQ, adds a new dimension to our understanding of \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration, enabling a more targeted and patient-centered therapeutic intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NG, OC and JPM were involved in study concept, design and acquisition of data. NG analyzed and interpreted the data, and wrote the draft of the manuscript. JPM, CO, CHA, RS and JM were contributors in writing and critically revising the manuscript. All authors edited and approved the final version of the manuscript for submission.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The datasets generated and analyzed during the current study are not publicly available due to the sensitive nature \u0026nbsp;of \u0026nbsp;the \u0026nbsp; research \u0026nbsp;supporting \u0026nbsp;data but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLam, B.L. et al. A systematic literature review of disease progression reported in RPGR-associated X-linked retinitis pigmentosa. \u003cem\u003eRetina (Philadelphia, Pa.)\u003c/em\u003e. \u003cstrong\u003e44\u003c/strong\u003e, 1-9 (2024).\u003c/li\u003e\n\u003cli\u003eNguyen, X.T. et al. RPGR-associated Dystrophies: Clinical, Genetic, and Histopathological Features. \u003cem\u003eInternational journal of molecular sciences.\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 835 (2020).\u003c/li\u003e\n\u003cli\u003eKaruntu, J.S., Nguyen, X.T. \u0026amp; Boon, C.J.F. Correlations between the Michigan Retinal Degeneration Questionnaire and visual function parameters in patients with retinitis pigmentosa. \u003cem\u003eActa ophthalmologica\u003c/em\u003e. 10.1111/aos.16601 (2023).\u003c/li\u003e\n\u003cli\u003eNanda, A., Salvetti, A.P., Clouston, P., Downes, S.M. \u0026amp; MacLaren, R.E. Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy. \u003cem\u003eGenes.\u003c/em\u003e \u003cstrong\u003e9,\u003c/strong\u003e 643 (2018).\u003c/li\u003e\n\u003cli\u003eMarques, J.P. et al. Genetic spectrum, retinal phenotype, and peripapillary RNFL thickness in RPGR heterozygotes. \u003cem\u003eGraefe\u0026apos;s archive for clinical and experimental ophthalmology.\u003c/em\u003e \u003cstrong\u003e261\u003c/strong\u003e, 867\u0026ndash;878 (2023).\u003c/li\u003e\n\u003cli\u003eGocuk, S.A., Jolly, J.K., Edwards, T.L. \u0026amp; Ayton, L.N. Female carriers of X-linked inherited retinal diseases - Genetics, diagnosis, and potential therapies. \u003cem\u003eProgress in retinal and eye research.\u003c/em\u003e \u003cstrong\u003e96\u003c/strong\u003e, 101190 (2023).\u003c/li\u003e\n\u003cli\u003eWongchaisuwat, N. et al. Retinitis pigmentosa GTPase regulator-related retinopathy and gene therapy. \u003cem\u003eSaudi journal of ophthalmology: official journal of the Saudi Ophthalmological Society.\u003c/em\u003e \u003cstrong\u003e37\u003c/strong\u003e, 276\u0026ndash;286 (2023).\u003c/li\u003e\n\u003cli\u003eLam, B.L. et al. Assessment of Visual Function With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study. \u003cem\u003eOphthalmology\u003c/em\u003e. 10.1016/j.ophtha.2024.02.023 (2023).\u003c/li\u003e\n\u003cli\u003eMartinez-Fernandez de la Camara, C., Cehajic-Kapetanovic, J. \u0026amp; MacLaren, R.E. Emerging gene therapy products for RPGR-associated X-linked retinitis pigmentosa. \u003cem\u003eExpert opinion on emerging drugs\u003c/em\u003e. \u003cstrong\u003e27,\u003c/strong\u003e 431\u0026ndash;443 (2022).\u003c/li\u003e\n\u003cli\u003evon Krusenstiern, L. et al. Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations. \u003cem\u003eJAMA ophthalmology\u003c/em\u003e. \u003cstrong\u003e141,\u003c/strong\u003e 275\u0026ndash;283 (2022).\u003c/li\u003e\n\u003cli\u003eNational Library of Medicine. Gene Therapy Trial for the Treatment of X-linked Retinitis Pigmentosa Associated With Variants in the RPGR Gene https://www.clinicaltrials.gov/study/NCT04671433 (2024).\u003c/li\u003e\n\u003cli\u003eChivers, M. et al. The Burden of X-Linked Retinitis Pigmentosa on Patients and Society: A Narrative Literature Review. \u003cem\u003eClinicoEconomics and outcomes research: CEOR.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 565\u0026ndash;572 (2021).\u003c/li\u003e\n\u003cli\u003ePopova, L.T. et al. Effects of duration and number of symptoms on vision-related anxiety in patients with Inherited Retinal Diseases. \u003cem\u003eOphthalmic genetics,\u003c/em\u003e \u003cstrong\u003e44\u003c/strong\u003e, 11\u0026ndash;18 (2021).\u003c/li\u003e\n\u003cli\u003eJayasundera, K.T. et al. Construct Validity of Inherited Retinal Disease-Specific Patient-Reported Outcome Measures. \u003cem\u003eAmerican journal of ophthalmology.\u003c/em\u003e \u003cstrong\u003e248\u003c/strong\u003e, 116\u0026ndash;126 (2023).\u003c/li\u003e\n\u003cli\u003eLacy, G.D. et al. The Michigan Retinal Degeneration Questionnaire: A Patient-Reported Outcome Instrument for Inherited Retinal Degenerations.\u003cem\u003e American journal of ophthalmology\u003c/em\u003e. \u003cstrong\u003e222\u003c/strong\u003e, 60\u0026ndash;68 (2021).\u003c/li\u003e\n\u003cli\u003eLacy, G.D. et al. The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations. \u003cem\u003eAmerican journal of ophthalmology\u003c/em\u003e. \u003cstrong\u003e225\u003c/strong\u003e, 137\u0026ndash;146 (2021).\u003c/li\u003e\n\u003cli\u003eMarques, J.P. et al. Portuguese translation and linguistic validation of the Michigan Retinal Degeneration Questionnaire and the Michigan Vision-Related Anxiety Questionnaire in a cohort with inherited retinal degenerations. \u003cem\u003eOphthalmic genetics\u003c/em\u003e. \u003cstrong\u003e43\u003c/strong\u003e, 137\u0026ndash;139 (2022).\u003c/li\u003e\n\u003cli\u003eChiang, M.F. The 2021 National Eye Institute Strategic Plan-Relating Vision to Health and Quality of Life. \u003cem\u003eJAMA ophthalmology\u003c/em\u003e. \u003cstrong\u003e139,\u003c/strong\u003e 1263\u0026ndash;1265 (2021).\u003c/li\u003e\n\u003cli\u003eChiang, M.F. \u0026amp; Tumminia, S.J. The 2021 National Eye Institute Strategic Plan: Eliminating Vision Loss and Improving Quality of Life. \u003cem\u003eOphthalmology.\u003c/em\u003e \u003cstrong\u003e129\u003c/strong\u003e, 12\u0026ndash;14 (2022).\u003c/li\u003e\n\u003cli\u003eMarques, J.P. et al. Design, development and deployment of a web-based interoperable registry for inherited retinal dystrophies in Portugal: the IRD-PT. \u003cem\u003eOrphanet journal of rare diseases.\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 304 (2020).\u003c/li\u003e\n\u003cli\u003eMarques, J.P. et al. Self-reported visual function and psychosocial impact of visual loss in EYS-associated retinal degeneration in a Portuguese population. \u003cem\u003eOphthalmic genetics\u003c/em\u003e. \u003cstrong\u003e44\u003c/strong\u003e, 334\u0026ndash;340 (2023).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Patient-Reported Outcomes, Retinitis Pigmentosa, RPGR, Anxiety","lastPublishedDoi":"10.21203/rs.3.rs-4390545/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4390545/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVariants in the retinitis pigmentosa GTPase regulator (\u003cem\u003eRPGR\u003c/em\u003e) gene are responsible for the majority of X-linked retinitis pigmentosa cases, which not only affects male patients but also some heterozygous females. Vision-related disability and anxiety of patients with \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration have never been explored before. This study aimed to evaluate self-reported visual function and vision-related anxiety in a Portuguese cohort of male and female patients with \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration using two validated patient-reported outcome measures. Cross-sectional data of thirty-two genetically-tested patients was examined, including scores of the Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-related Anxiety Questionnaire (MVAQ). Patients were classified according to retinal phenotypes in males (M), females with male phenotype (FM), and females with radial or focal pattern (FRF). Both M and FM revealed higher rod-function and cone-function anxiety scores (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.017). Most MRDQ disability scores were higher in M and FM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.004). Overall, positive correlations (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.004) were found between every MRDQ domain and both anxiety scores. In \u003cem\u003eRPGR\u003c/em\u003e-associated retinal degeneration, males and females with male phenotype show similar levels of increased vision-related anxiety and disability. Every MRDQ visual function domain showed a strong correlation with anxiety scores.\u003c/p\u003e","manuscriptTitle":"Exploring self-reported visual function and vision-related anxiety in patients with RPGR-associated retinal degeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-23 18:39:36","doi":"10.21203/rs.3.rs-4390545/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvited","content":"","date":"2024-05-15T16:21:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-11T12:19:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-08T15:49:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5bf95fb5-2553-4784-8670-37e2b7077a29","owner":[],"postedDate":"May 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-27T16:21:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-23 18:39:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4390545","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4390545","identity":"rs-4390545","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}