==== Front PLoS One PLoS One plos PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0288170 PONE-D-23-08206 Research Article Medicine and Health Sciences Pharmacology Drugs Colchicine Biology and Life Sciences Anatomy Musculoskeletal System Skeleton Bone Bone Density Medicine and Health Sciences Anatomy Musculoskeletal System Skeleton Bone Bone Density Biology and Life Sciences Anatomy Biological Tissue Connective Tissue Bone Bone Density Medicine and Health Sciences Anatomy Biological Tissue Connective Tissue Bone Bone Density Medicine and Health Sciences Rheumatology Connective Tissue Diseases Osteoporosis Biology and Life Sciences Anatomy Digestive System Mouth Mandible Medicine and Health Sciences Anatomy Digestive System Mouth Mandible Physical Sciences Mathematics Geometry Fractals People and Places Population Groupings Age Groups Biology and Life Sciences Immunology Immune Response Inflammation Medicine and Health Sciences Immunology Immune Response Inflammation Medicine and Health Sciences Clinical Medicine Signs and Symptoms Inflammation Medicine and Health Sciences Diagnostic Medicine Diagnostic Radiology Bone Imaging Research and Analysis Methods Imaging Techniques Diagnostic Radiology Bone Imaging Medicine and Health Sciences Radiology and Imaging Diagnostic Radiology Bone Imaging Fractal dimension analysis of different mandibular regions in familial Mediterranean fever patients: A cross-sectional retrospective study Fractal dimension analysis on panoramic radiographs in familial Mediterranean fever patients https://orcid.org/0000-0001-7039-7099 Ersan Nilüfer Conceptualization Data curation Formal analysis Investigation Methodology Writing – original draft Writing – review & editing 1 * https://orcid.org/0000-0002-4917-6176 Özel Beliz Conceptualization Data curation Investigation Methodology Software Writing – original draft 2 ¤ 1 Yeditepe University Faculty of Dentistry, Department of Dentomaxillofacial Radiology, Istanbul, Turkiye 2 Yeditepe University Faculty of Dentistry, Department of Endodontics, Istanbul, Turkiye Tomaszewska Ewa Editor University of Life Sciences in Lublin, POLAND Competing Interests: The authors have declared that no competing interests exist. ¤ Current address: Department of Endodontics, Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, Netherlands * E-mail: yasenil@yahoo.com 30 6 2023 2023 18 6 e028817024 3 2023 20 6 2023 © 2023 Ersan, Özel 2023 Ersan, Özel https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Familial Mediterranean fever (FMF) is a genetic condition that may cause loss of bone mineral density (BMD) due to chronic inflammation. Previously, fractal dimension (FD) analysis values of mandibular cortical bone were shown to be lower in osteoporosis. Therefore, FD might be considered as an auxiliary tool to refer patients for dual-energy x-ray absorptiometry (DXA), which is the gold standard for BMD measurement. The purpose of this cross-sectional retrospective study was to evaluate trabecular and cortical microarchitecture of the mandible with FD analysis on panoramic radiographs in a subpopulation of FMF. Also, the effect of colchicine use was investigated. Forty-three FMF patients, aged between 10.8 and 71.2 years, and age- and gender-matched control group consisting of patients, who had no systemic diseases, were included. Demographic information such as age and gender, and colchicine use were recorded. In terms of age, the patients were classified as <30 and 30< years. On each panoramic radiographs five regions of interest were selected on the mandible as: 1- premolar, 2- molar, 3- angular, 4- condylar, and 5- basal cortical bone regions on right (R) and left (L) sides. Statistical significance was accepted at p<0.05 level. Intra- and inter-observer agreements demonstrated good to excellent consistency. In FMF patients, L3 and L4 values were higher, whereas L5 values were lower (p<0.05) than the control group. In terms of age, the difference between groups was insignificant in FMF patients (p>0.05), whereas in control group R3 and L4 values were higher in the 30< age group (p<0.05). Regarding gender and colchicine use, the difference between groups was insignificant (p>0.05). FMF disease might be a candidate for referral to DXA examination based on decreased bone density in the mandibular cortex detected by FD measurements on routine panoramic radiographs. Further studies are warranted to ascertain this relationship. The authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files. Additional data is available from the figshare repository (http://doi.org/10.6084/m9.figshare.23259770). Data Availability All relevant data are within the paper and its Supporting Information files. Additional data is available from the figshare repository (http://doi.org/10.6084/m9.figshare.23259770). ==== Body pmcIntroduction Familial Mediterranean fever (FMF), which was described by Heller in 1955, is among the most common monogenic autoinflammatory diseases [1]. The disease most commonly affects Jewish, Armenian, Turkish, and Arab populations [2]. Mutation of the MEFV gene was shown to be responsible for the development of FMF. The clinical hallmark of FMF is recurring fever attacks in relation with serositis with a frequency varying between weekly to once in several months that mostly takes 1–3 days that is followed by a spontaneous resolving [3]. The patient is mostly asymptomatic between febrile attacks, even though it was reported that subclinical inflammation continues between attacks [4,5]. Colchicine, which is the main drug used in the treatment of FMF, was approved in the United States by the Food and Drug Administration in 2009. Colchicine is mainly used to prevent FMF acute attacks caused by its several anti-inflammatory effects. It may as well prevent amyloidosis, which arises secondary to the chronic inflammatory conditions, and could also be seen in bones [4,6]. Although colchicine is considered to be a lifelong treatment for FMF, a recent study demonstrated that some physicians decide to discontinue the drug in patients, who were carriers of a pathogenic variant or variants of unknown significance and did not experience any attacks at least for six months [7,8]. As well, some of the patients needed to discontinue the drug due to colchicine resistance or adverse effects of the drug. Osteoporosis is characterized by decreased bone mass and microarchitectural deterioration of bony tissue that may subsequently lead to increased fragility and bone fracture [9]. Chronic subclinical inflammation in FMF patients might also give rise to decreased bone mineral density (BMD) and osteoporosis by affecting bone turnover and metabolism [10,11]. Many authors showed low levels of BMD and bone formation markers in individuals with FMF [11–13]. Colchicine decreases osteoclast numbers and inhibits resorption in bones [14,15], and therefore improve bone density and prevent osteoporosis [4,11,13]. Diagnosis of osteoporosis at an early stage is an important healthcare issue. The current principal method for diagnosing osteoporosis is measurement of BMD by dual energy X-ray absorptiometry (DXA) [16]. DXA is the gold standard for BMD measurements and is used for the diagnosis of osteopenia and osteoporosis, as well as prediction the fracture risk. The distribution of the equipment and cost of advanced imaging techniques, such as DXA, limit their access for screening of larger populations [17]. Another method to determine the changes related to bone mineral loss is fractal dimension (FD) analysis on panoramic radiographs. Panoramic radiography is one of the most used imaging modalities in dentistry and is an important part of routine dental care. It provides a valuable screening opportunity due to its lower cost and radiation dose, as well as a high access. Fractal analysis, which is a mathematical image analysis method, is used in the analysis of complex shapes and structural formations. The interpretation of the mandible on a panoramic image via computational analysis methods gives objective numerical results defined as the FD, and thus rules out the subjective judgment of the observer [18]. FD can assist in the quantification of complex structures and description of bone microarchitecture and demonstrate bone mineral loss on panoramic images [19]. And thus, FD is considered to be a distinctive parameter for the determination of the density of the osteoporotic and normal bone tissue [20,21]. The increased FD values have been linked to the increased complexity of the structure. A recent systematic review concluded that FD analysis on dental images is a reliable diagnostic tool for osteoporosis screening and could be a reference BMD test [22]. Even though both trabecular and cortical osseous tissue have a fractal structure, this structure is not visible to the naked eye for cortical bone [23]. In previous studies mostly trabecular bone regions were selected for the FD evaluation, while there are also studies including the cortical bone areas, as well [20,24–32]. Sindeaux et al. [30] demonstrated that FD values of the cortical bone were more accurate than those of the trabecular bone. They also reported that the patients with osteoporosis have higher probability of having lower mean FD values on the cortical bone compared to healthy counterparts and that cortical bone FD measurements might be considered as auxiliary tools to refer patients for DXA exam [30]. To the best of our knowledge, there is only one study that evaluates the bone microarchitecture of FMF patients using FD analysis that was performed on the trabecular structure of the mandible via panoramic radiographs of solely pediatric patients [33]. To date, no study exists, in which FD analysis was applied on panoramic radiographs of adult FMF patients, taking the colchicine use and mandibular cortical structure into consideration, as well. The hypothesis was that there were no differences in the microarchitecture of the mandible between FMF and healthy populations. Therefore, the aim of this cross-sectional retrospective study was to assess trabecular and cortical bone structures on panoramic radiographs in a subpopulation of FMF in order to find out whether significant differences exist in FMF patients and healthy individuals. Also, the effect of colchicine use on mandibular cortical and trabecular bone microarchitecture was investigated in FMF patients. Materials and methods All the procedures followed were in accordance with the ethical standards of the Helsinki Declaration and was approved by the Yeditepe University Non-interventional Research Ethics Committee (approval number: 202208Y0279). Written informed consent was obtained from the patients and/or their legal guardian at the time of panoramic imaging for the exposure and also for the possible use of the images for scientific purposes. However, for the study the requirement for patients’ informed consent was waived because of the retrospective nature of the study. All panoramic images were fully anonymized before the data collection and used in accordance with the relevant guidelines and ethical regulations. The individual in this manuscript has given written informed consent to publish these case details. Sample size calculation performed by G* Power 3.1.9.2 (Kiel, Germany) revealed that a total of minimum 50 panoramic radiographs from FMF and control patients (n = 25 in each group) was necessary (confidence interval: 95%, significance level: 0.05, effect size (d): 0.47). The database of the Department of Dentomaxillofacial Radiology of the Yeditepe University Faculty of Dentistry was retrospectively reviewed in August-September, 2022. Overall 75 self-reported FMF patients, who underwent panoramic imaging at Yeditepe University Faculty of Dentistry between January 2014 and November 2019 and have a panoramic radiograph with a good image quality, were identified. Among these patients, 32 of them, who had systemic diseases that affect bone metabolism (15 patients), and were using medications affecting the bone metabolism (3 patients), as well as the patients with a mixed dentition (13 patients) and severely atrophic alveolar crest (1 patient) that complicated the measurements on panoramic radiographs, were excluded. As a result, 43 FMF patients aged between 10–71 years and a control group consisting of the same number of randomly selected age-gender-matched patients, who had no systemic diseases, were included in the study. Control group, which was also subjected to the exclusion criteria, was selected randomly from the patients in the same database, depending on the matching characteristics of the patients in the FMF group, in terms of age and gender by filtering the data on Microsoft Excel sheet (Microsoft Office Professional Plus 2010 v14.0, Microsoft Corporation). The remaining patients were assigned a number consequently and control patients corresponding to the FMF patients were randomly selected by using a random number generator (random.org). Demographic information such as age and gender, and colchicine use were recorded. The patients were further classified into two age groups as <30 and 30< years. Besides, the patients with FMF were classified according to colchicine use. Self-reported colchicine use was recorded as ‘Yes’ or ‘No’, without taking the prior use or dose regimen into consideration. A flow chart of the study design demonstrating the eligibility and the numbers of individuals recruited at each stage of study (Fig 1). 10.1371/journal.pone.0288170.g001 Fig 1 Flow chart of the study design. A total of 86 panoramic radiographic images obtained with Planmeca 2002 cc Proline (Planmeca, Helsinki, Finland; 70 kVp, 10 mA, 8 s exposure time) and x1.34 magnification factor, were evaluated. Orientation of the head was arranged so that the Frankfort horizontal plane was parallel to the floor and the sagittal plane was parallel to the vertical plane. Digital images were exported in 8-bit depth grayscale high resolution ‘.tiff’ format from the Planmeca Romexis 3.8.3 (Helsinki, Finland). The FD measurements were performed on the ImageJ software (ImageJ 1.38; US National Institutes of Health, Bethesda, MD, USA) that was downloaded from https://imagej.nih.gov/ij/download.html. All sets of the fully anonymized panoramic images were imported into ImageJ software. Four different regions of interest (ROI) in 30x30 pixel size were selected from designated spots (rectangle tool) on right (R) and left (L) side of the mandible as follows (Fig 2); ROI1: Distal region of the premolar, next to the mental foramen, ROI2: mesial region of the apical part of second molar, ROI3: angular region of the mandible, and ROI4: mandibular condyle area. An additional fifth ROI was selected in differing pixel size depending on the ROI (polygon tool) on each side of the mandible as; ROI5: basal cortical bone of the mandible extending from distal to the mental foramen to the distal root of the first molar (Fig 2). The individual in this manuscript has given written informed consent to publish these case details. Each ROI was selected and the FD analysis was conducted as follows; duplication of the selected ROI, application of the Gaussian filter [34] to remove brightness alterations due to overlying soft and hard tissue, subtraction of the filtered image from the original cropped image, addition of a gray value of 128 to differentiate bone marrow spaces and trabeculae, binarization of the resulting image, steps of erosion, dilatation, inversion, and skeletonization. Lastly, the FD was calculated according to the fractal box counting method described by White & Rudolph [34]. The FD analysis was carried out by two independent observers (a dentomaxillofacial radiology specialist with 12-year of experience and an endodontist with an 8-year of experience). Prior to the FD analysis, the observers were calibrated by evaluating 15 panoramic radiographs, which were not included in the study, together. After the first independent readings 25% of the measurements were repeated after a two-week interval for intra- and inter-observer repeatability. Data collection was completed in November, 2022. FD analysis on panoramic radiographs was comparable for both FMF and control groups that all the fully anonymized panoramic images were evaluated in the same manner by two observers. The observers had access to patient information that could identify individual participants after data collection. 10.1371/journal.pone.0288170.g002 Fig 2 Designated region of interests (ROI) indicated on the panoramic radiograph. The fact that the information regarding the diagnosis of FMF and colchicine use, as well as other possible diseases and drug use questioned during taking anamnesis and evaluated in the exclusion criteria was based on the self-reported information was a potential confounder and a limitation of the study. Age was another confounder that we tried to overcome by selecting age and gender matched patients in the control group. Also, we classified the patients in two age groups as <30 and 30< years. SPSS software version 25.0 (IBM, USA) was used for the statistical analysis. Normality distribution of all variables was analyzed with histogram graphics and Kolmogorov-Smirnov tests. Mean, standard deviation, median, and IQR values were used for descriptive analysis. Analysis of the nonparametric variables that did not display a normal distribution among two groups was performed with Mann-Whitney U test, whereas Independent t-test was performed to analyze parametric variables that were normally distributed. Chi-square test was used to assess the distribution of categorical data between FMF and control groups. Intra- and inter-observer agreement was assessed with Intraclass Correlation Coefficient (ICC) [35]. Statistical significance was accepted at p<0.05 level. Results Demographic distribution of the patients is demonstrated on Table 1. 10.1371/journal.pone.0288170.t001 Table 1 Demographic distribution of the FMF and control patients. FMF Control Total P- value Mean±SD Median (min-max) Mean±SD Median (min-max) Mean±SD Median (min-max) Age 32.1±12.8 31.3 (10.8–71.2) 35.0±15.1 30.5 (11.3–70.7) 33.6±14.1 30.9 (10.8–71.2) 0.3541 n (%) n (%) n (%) P- value Gender Female 27 (62.8) 32 (74.4) 59 (68.6) 0.3522 Male 16 (37.2) 11 (25.6) 27 (31.4) Colchicine use No 13 (30.2) NA 13 (30.2) *** Yes 30 (69.8) NA 30 (69.8) 1 Independent t-test 2 Chi-square test p<0.05 NA: not available. Regarding all the ROI measurements, intra-observer agreement of the first and second observer, and inter-observer agreement that were determined using ICC test demonstrated a good to excellent agreement that ranged between 0.752–0.944, 0.802–0.958, and 0.765–0.962, respectively (p<0.05, Table 2). 10.1371/journal.pone.0288170.t002 Table 2 Intra- and inter-observer agreements determined using ICC test. 1st observer 1st & 2nd reading 2nd observer 1st & 2nd reading 1st & 2nd observer 1st readings 1st & 2nd observer 2nd readings ICC P- value ICC P- value ICC P- value ICC P- value R1 0.920 <0.001 * 0.811 0.010 * 0.897 0.001 * 0.865 0.003 * R2 0.915 0.001 * 0.802 0.012 * 0.831 0.007 * 0.881 0.002 * R3 0.921 <0.001 * 0.936 <0.001 * 0.962 <0.001 * 0.962 <0.001 * R4 0.902 0.001 * 0.879 0.002 * 0.912 0.001 * 0.807 0.011 * R5 0.885 0.002 * 0.900 0.001 * 0.765 0.021 * 0.853 0.004 * L1 0.867 0.003 * 0.805 0.012 * 0.868 0.003 * 0.877 0.002 * L2 0.910 0.001 * 0.868 0.003 * 0.934 <0.001 * 0.937 <0.001 * L3 0.752 0.026 * 0.958 <0.001 * 0.951 <0.001 * 0.917 0.001 * L4 0.804 0.012 * 0.952 <0.001 * 0.884 0.002 * 0.864 0.003 * L5 0.944 <0.001 * 0.907 0.001 * 0.869 0.003 * 0.841 0.006 * Intraclass Correlation Coefficient *p<0.05. Comparison of the FMF and control groups regarding right and left ROI measurements revealed that in FMF patients mean L3 and L4 values were found to be higher, whereas mean L5 values were less than the control group (p<0.05, Table 3). In terms of age groups, the difference between ROI measurements on both sides in FMF group was not significant (p>0.05), whereas in control group R3 and L4 values were found to be higher in 30< age group comparing to <30 age group (p<0.05, Table 4). In terms of gender in both groups and colchicine use in the FMF group, the difference between ROI measurements on right and left sides was insignificant (p>0.05, Tables 5 and 6). 10.1371/journal.pone.0288170.t003 Table 3 Comparison of fractal dimension measurements obtained on right and left sides on the panoramic radiographs of FMF and control groups. FMF (n = 43) Control (n = 43) P- value mean±SD median (IQR) mean±SD median (IQR) R1 1.241±0.117 1.262 (1.191–1.314) 1.260±0.089 1.255 (1.204–1.339) 0.8801 R2 1.277±0.076 1.299 (1.229–1.328) 1.243±0.111 1.255 (1.176–1.332) 0.1341 R3 1.227±0.113 1.226 (1.152–1.301) 1.246±0.112 1.255 (1.156–1.350) 0.4582 R4 1.221±0.134 1.250 (1.159–1.301) 1.201±0.104 1.218 (1.120–1.279) 0.4432 R5 1.115±0.094 1.119 (1.059–1.172) 1.130±0.096 1.133 (1.073–1.170) 0.4582 L1 1.234±0.117 1.255 (1.159–1.314) 1.182±0.163 1.195 (1.093–1.314) 0.0942 L2 1.254±0.105 1.271 (1.168–1.323) 1.208±0.121 1.217 (1.129–1.314) 0.1291 L3 1.236±0.119 1.240 (1.166–1.301) 1.144±0.171 1.147 (1.021–1.286) 0.013 1 * L4 1.273±0.131 1.264 (1.184–1.342) 1.162±0.154 1.214 (1.090–1.293) 0.002 1 * L5 1.110±0.072 1.105 (1.052–1.165) 1.154±0.076 1.160 (1.089–1.221) 0.007 2 * 1Mann Whitney U test 2 Independent t-test *p<0.05. 10.1371/journal.pone.0288170.t004 Table 4 Fractal dimension measurements in the FMF and control groups according to different age groups. FMF P- value Control P- value Age<30 (n = 20) Age>30 (n = 23) Age<30 (n = 21) Age>30 (n = 22) mean±SD median (IQR) mean±SD median (IQR) mean±SD median (IQR) mean±SD median (IQR) R1 1.240±0.126 1.258 (1.167–1.326) 1.241±0.112 1.262 (1.191–1.312) 0.8971 1.244±0.086 1.232 (1.187–1.306) 1.275±0.091 1.277 (1.226–1.341) 0.1941 R2 1.281±0.076 1.303 (1.231–1.328) 1.274±0.078 1.297 (1.224–1.320) 0.6891 1.220±0.112 1.227 (1.149–1.308) 1.265±0.108 1.261 (1.182–1.365) 0.2261 R3 1.223±0.121 1.214 (1.159–1.324) 1.231±0.108 1.257 (1.137–1.286) 0.8262 1.210±0.107 1.209 (1.131–1.296) 1.280±0.108 1.317 (1.192–1.364) 0.040 2 * R4 1.236±0.137 1.234 (1.173–1.332) 1.209±0.133 1.250 (1.153–1.285) 0.5202 1.180±0.111 1.188 (1.099–1.272) 1.222±0.094 1.237 (1.201–1.304) 0.1932 R5 1.107±0.107 1.111 (1.056–1.176) 1.121±0.083 1.131 (1.056–1.148) 0.6272 1.141±0.048 1.139 (1.099–1.185) 1.120±0.127 1.086 (1.050–1.161) 0.4852 L1 1.222±0.127 1.245 (1.174–1.294) 1.244±0.110 1.267 (1.158–1.314) 0.5632 1.156±0.116 1.149 (1.050–1.236) 1.207±0.197 1.235 (1.182–1.337) 0.3062 L2 1.276±0.109 1.309 (1.212–1.337) 1.235±0.100 1.248 (1.146–1.319) 0.1561 1.189±0.118 1.217 (1.072–1.292) 1.226±0.123 1.236 (1.136–1.319) 0.2301 L3 1.216±0.145 1.232 (1.153–1.300) 1.253±0.092 1.262 (1.184–1.301) 0.4301 1.098±0.175 1.125 (0.990–1.276) 1.187±0.159 1.213 (1.036–1.328) 0.1261 L4 1.264±0.104 1.261 (1.172–1.341) 1.281±0.153 1.264 (1.203–1.342) 0.7871 1.116±0.163 1.148 (1.066–1.224) 1.206±0.134 1.237 (1.137–1.314) 0.027 1 * L5 1.119±0.084 1.105 (1.039–1.194) 1.101±0.061 1.105 (1.052–1.144) 0.4302 1.154±0.075 1.160 (1.081–1.219) 1.154±0.079 1.158 (1.090–1.221) 0.9992 1Mann Whitney U test 2 Independent t-test *p<0.05. 10.1371/journal.pone.0288170.t005 Table 5 Fractal dimension measurements in the FMF and control groups according to gender. FMF P- value Control P- value Female (n = 27) Male (n = 16) Female (n = 32) Male (n = 11) mean±SD median (IQR) mean±SD median (IQR) mean±SD median (IQR) mean±SD median (IQR) R1 1.246±0.114 1.263 (1.226–1.313) 1.230±0.126 1.243 (1.166–1.317) 0.7041 1.266±0.092 1.257 (1.212–1.340) 1.242±0.078 1.232 (1.170–1.303) 0.3421 R2 1.272±0.079 1.293 (1.224–1.328) 1.286±0.071 1.305 (1.243–1.324) 0.4841 1.251±0.099 1.249 (1.190–1.324) 1.218±0.144 1.255 (1.153–1.332) 0.8101 R3 1.222±0.107 1.226 (1.144–1.278) 1.236±0.125 1.238 (1.178–1.324) 0.7032 1.249±0.112 1.249 (1.163–1.355) 1.235±0.118 1.255 (1.118–1.305) 0.7202 R4 1.195±0.130 1.250 (1.120–1.285) 1.265±0.134 1.260 (1.175–1.373) 0.1002 1.205±0.101 1.226 (1.132–1.273) 1.190±0.116 1.204 (1.082–1.279) 0.6772 R5 1.119±0.077 1.119 (1.059–1.172) 1.107±0.120 1.117 (1.049–1.164) 0.6842 1.133±0.108 1.136 (1.059–1.181) 1.120±0.049 1.127 (1.080–1.163) 0.7022 L1 1.242±0.139 1.267 (1.158–1.329) 1.220±0.070 1.221 (1.174–1.276) 0.5742 1.190±0.160 1.202 (1.130–1.303) 1.157±0.177 1.147 (1.017–1.352) 0.5652 L2 1.244±0.113 1.251 (1.146–1.320) 1.272±0.091 1.307 (1.182–1.347) 0.3131 1.225±0.122 1.258 (1.144–1.318) 1.160±0.107 1.177 (1.048–1.217) 0.0661 L3 1.239±0.100 1.242 (1.172–1.296) 1.230±0.151 1.225 (1.164–1.308) 0.9521 1.154±0.169 1.150 (1.030–1.290) 1.113±0.183 1.125 (0.973–1.273) 0.4351 L4 1.266±0.124 1.256 (1.203–1.325) 1.286±0.146 1.301 (1.148–1.406) 0.6531 1.163±0.170 1.205 (1.101–1.299) 1.160±0.101 1.214 (1.090–1.225) 0.5161 L5 1.111±0.076 1.110 (1.033–1.165) 1.108±0.068 1.094 (1.057–1.160) 0.8802 1.154±0.078 1.166 (1.086–1.218) 1.155±0.074 1.160 (1.095–1.223) 0.9802 1Mann Whitney U test 2Independent t-test p<0.05. 10.1371/journal.pone.0288170.t006 Table 6 Fractal dimension measurements in the FMF group according to colchicine use. Colchicine use P- value Yes (n = 30) No (n = 13) mean±SD median (IQR) mean±SD median (IQR) R1 1.243±0.118 1.265 (1.141–1.317) 1.235±0.120 1.253 (1.212–1.305) 0.6821 R2 1.273±0.074 1.274 (1.229–1.314) 1.288±0.082 1.309 (1.261–1.348) 0.3681 R3 1.236±0.116 1.251 (1.144–1.326) 1.207±0.107 1.204 (1.169–1.261) 0.4452 R4 1.218±0.137 1.226 (1.159–1.298) 1.229±0.131 1.279 (1.133–1.325) 0.8162 R5 1.106±0.096 1.111 (1.056–1.148) 1.135±0.089 1.137 (1.052–1.215) 0.3522 L1 1.242±0.113 1.256 (1.180–1.314) 1.215±0.130 1.238 (1.117–1.310) 0.5072 L2 1.257±0.105 1.263 (1.168–1.333) 1.248±0.109 1.310 (1.151–1.320) 0.9761 L3 1.223±0.134 1.228 (1.140–1.301) 1.266±0.072 1.255 (1.210–1.311) 0.2981 L4 1.269±0.130 1.260 (1.203–1.332) 1.284±0.140 1.270 (1.176–1.342) 0.8411 L5 1.103±0.073 1.104 (1.032–1.161) 1.125±0.071 1.105 (1.067–1.170) 0.3792 1Mann Whitney U test 2Independent t-test p<0.05. Discussion Fractal dimension analysis has been performed for the determination of the architectural structure of the trabecular and cortical bone on panoramic radiographs [20,24–32]. The inferior mandibular cortical bone is among the most commonly studied regions in osteoporosis detection on panoramic radiographs. Even though the mandibular cortical index has been shown to be a useful tool for osteoporosis screening [36], it is a subjective visual assessment and has a relatively limited reproducibility [37]. The current study aims to evaluate mandibular microarchitecture of the individuals with FMF in comparison with healthy population and determine a possible relationship between the FD values gathered on five different regions, including trabecular and cortical regions of the mandibular bone, on both sides on panoramic radiographs. Additionally, we investigated this relationship among the FMF patients regarding colchicine use. To date, no studies evaluated mandibular bone morphology on adult FMF patients using FD analysis and took colchicine use and mandibular cortical bone into consideration. In dental practice, panoramic radiography is routinely used and has been shown among the most useful tools to detect changes in the mandibular bone density, even if it is not primarily used for this purpose [21]. Therefore, panoramic radiography may be an important imaging modality to assess bone structures in individuals with FMF, as well. Previously, the effect of various systemic conditions affecting the jawbones have been evaluated on panoramic radiographs with FD. However, regarding FMF there is only one study, which has been conducted solely in children [33]. Besides, some studies demonstrated that colchicine treatment prevents osteoporosis [4,13]. Since in FMF chronic inflammation might give rise to a decreased bone density in the course of time during the disease process, it could be speculated that in adult FMF patients, especially in case they are not under colchicine treatment, FD analysis would assist in the detection of the expected changes. Not all the patients investigated in this study were under colchicine treatment, so that we could make a comparison between patients according to colchicine use. However, a significant difference was not observed in FMF patients, in terms of age groups or colchicine use. On the other hand, in terms of age, control patients revealed a greater R3 and L4 values in the patients aged 30< years. Different findings obtained on both sides might be the result of increased activity in the preferred side for chewing, asymmetrical skeleton of the face, the posture and functional relationship of the cheek, lips and tongue, and atrophy of the masticatory muscles in elderly people [38]. However, the evaluation of such instances was not the aim of the current study. Whilst it was previously shown that continuous inflammation decreases the rate of osteoblastic activity [39], osteoporosis could be anticipated as a result of chronic inflammation in FMF populations [40]. The fact that the clinical presentation of the FMF patient appears to be normal, unless there is an inflammatory attack, is considered to be the most important distinguishing characteristic of this chronic inflammatory disease [41]. Therefore, even though the disease is under control without exacerbations, osteoporosis might still be encountered, especially in case the patient is not under colchicine treatment. Altunok Ünlü et al. [33] reported that FD analysis results of children with FMF were close to healthy counterparts, and this could be a result of regular colchicine use. This finding was in correlation with those of Bayrak et al. [21], who also did not present significantly different FD measurements in the FMF group. Nevertheless, there is not an agreement in the literature regarding the osteoporotic effects of FMF. Only a small number of studies were performed regarding the effects on bone density in FMF populations, some of which have described a decrease [20,34,39], while others reported that there were not any effects on BMD in FMF populations [42,43]. In our study, in FMF patients similar FD values were demonstrated in terms of age, gender, and colchicine use. However, while in the left angulus and condylar area FD measurements were significantly greater, the left mandibular cortical area revealed lower FD measurements in the FMF patients. Mandibular cortical bone corresponds to a region with an increased bone density. Sindeaux et al. [30] demonstrated that patients with osteoporosis have a higher probability of having lower mean values of FD on the cortical bone. In our study, L5 value, which concerns the mandibular cortical bone, was lower in the FMF patients. This result was consistent with the study of Suyani et al. [12], who also presented lower bone density in adults with FMF in the other body parts. This difference between different regions of the mandible could be attributed to the different trabecular or cortical structure of these regions. As well, continuing inflammation may cause retardation of the development of the mandible in certain regions, subsequently affecting the craniofacial growth and the distribution of the mineralized tissue [44]. Overall, it might be speculated that the conflicting results between studies could be attributed to the bone tissue and ROI, of which the BMD was investigated, evaluation methods, different demographic features of study groups, such as age and gender, the type of mutation that resulted in FMF, and differences in the dose regimen of prior or current colchicine use. Regarding the studies performed on the mandible, Altunok Ünlü et al. [33], who investigated the effects of FMF on the mandible in children, reported a non-significantly different FD values in relation to gender of the children with FMF, which is in accordance with the current study performed on individuals, including adult FMF patients. They also reported that the highest intra-observer agreement for the FD measurements was found in the angulus area [33]. Besides, they did not observe significant differences between the FD values of this region in terms of laterality, age and gender. Consequently, they suggested that the mandibular angulus region could be selected for diagnosis or follow up of the disease using FD analysis. Even though, in the current study one of the highest intra- and inter-observer agreements was observed also in the angular region, FD values demonstrated significant differences between certain groups. In this study, the mean age of the FMF group was found as 32.1±12.8, which constitutes mostly an adult group. Different results obtained in these studies could be due to the difference in age range of the patient populations. The limitation of the study was that due to the retrospective cross-sectional nature of the study the gathered data depended on self-reported medical records obtained during questioning of the systemic anamnesis at a dental hospital and detailed information regarding FMF diagnosis, laboratory or imaging results of the test that are more accurately define BMD or treatment dosage and regimen, or previous colchicine use could not be obtained and evaluated. Additionally, information related to dental anamnesis such as dental status, parafunctional habits, and chewing side preference of the patients, as well as clinical findings which would affect the morphology of the bone also were not recorded and evaluated in this study. Conclusion Within the limitations of the study, FD analysis performed on the mandible demonstrated contradictory results on the trabecular and cortical regions. The basal cortical bone microarchitecture in a subpopulation of FMF patients revealed a decreased bone density. On the contrary, trabecular bone in the mandibular angle and condyle regions showed an increase in bone density. FMF disease might be a candidate for referral to DXA examination based on decreased bone density in the mandibular basal cortex detected by FD measurements on routine panoramic radiographs. According to our results, the relationship between colchicine use and the microarchitecture of mandibular bone is conjectural. Further studies performed on larger patient populations, in which the type of mutation resulted in FMF, the colchicine regimen and other factors affecting mandibular bone structure, such as parafunctional habits and chewing side preferences, were taken into consideration, are necessary to confirm these findings. Supporting information S1 Checklist STROBE statement—Checklist of items that should be included in reports of observational studies. (DOCX) Click here for additional data file. S1 Protocol Study protocol regarding fractal dimension analysis measurements. (DOCX) Click here for additional data file. S1 Dataset Data table. (XLSX) Click here for additional data file. 10.1371/journal.pone.0288170.r001 Decision Letter 0 Tomaszewska Ewa Academic Editor © 2023 Ewa Tomaszewska 2023 Ewa Tomaszewska https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version0 23 May 2023 PONE-D-23-08206Prediction of decreased mandibular bone density in familial Mediterranean fever via fractal dimension analysis: A cross-sectional retrospective studyPLOS ONE Dear Dr. Nilüfer Ersan, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. 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The signed consent form should not be submitted with the manuscript, but should be securely filed in the individual's case notes. Please amend the methods section and ethics statement of the manuscript to explicitly state that the patient/participant has provided consent for publication: “The individual in this manuscript has given written informed consent (as outlined in PLOS consent form) to publish these case details”.  If you are unable to obtain consent from the subject of the photograph, you will need to remove the figure and any other textual identifying information or case descriptions for this individual [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I have read carefully the manuscript entitled “Prediction of decreased mandibular bone density in familial Mediterranean fever via fractal dimension analysis: A cross-sectional retrospective study.” However, Authors didn't draft the paper well and I cannot recommend the publication of the article in its present form. The Authors should correct the manuscript before the re-submission of the work to Plos One. First of all, the title does not correspond to the content of the manuscript, as no "prediction" or "bone density" has been established. The study only focuses on the assessment of the FD (fractal dimension) in different regions of the mandibular bone. Secondly, there is no paragraph in which it is clearly stated that the method used to determine FD can be a measure of bone BMD (L66 and others). As indicated, FD is commonly used to assess the homogeneity of trabecular bone microarchitecture, not only in the mandible, and it is more accurately a measure of the regularity of the surface of the trabeculae. Therefore, measuring FD in the cortical bone area no longer aligns with the correct definition of FD provided in L67 and L206-208. Thus, additionally give additional references about measurements of FD of cortical bone. Minor comments: L56 In which country (countries) ? L102 n- 25 in each group L132 “grey scale” L173 According to the data in the tables, all variables lack normal distribution. Am I right? Also information about checking the groups with the Chi-square test is missing. Tables - correct the titles of tables 3-5, because you did not measure ROI, only FD in specific areas of the mandible ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0288170.r002 Author response to Decision Letter 0 Submission Version1 3 Jun 2023 Jun 3, 2023 Manuscript Reference No: PONE-D-23-08206 Title: Prediction of decreased mandibular bone density in familial Mediterranean fever via fractal dimension analysis: A cross-sectional retrospective study Dear Academic Editor and Reviewer(s), Please find the responses to your comments and suggestions below. We are deeply appreciated that they assisted us to turn our manuscript to a far better version. I have also made some additional corrections, such as grammatical or spelling errors and some other mistakes, that I have noticed during the revision of the manuscript. I would like to kindly ask you to consider them as a part of the revision process, as well. Thank you for your time and considerations. Kindest regards, Dr. Nilüfer Ersan   Comments from the Academic Editor and Reviewer(s): If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We do not have a laboratory protocol. However, we have deposited our study protocol along with the other supporting materials in https://doi.org/10.6084/m9.figshare.23259770. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Revised accordingly. 2. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. We have shared our supporting materials in https://doi.org/10.6084/m9.figshare.23259770. 3. We note that Figure (2) includes an image of a [patient / participant / in the study]. As per the PLOS ONE policy (http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research) on papers that include identifying, or potentially identifying, information, the individual(s) or parent(s)/guardian(s) must be informed of the terms of the PLOS open-access (CC-BY) license and provide specific permission for publication of these details under the terms of this license. Please download the Consent Form for Publication in a PLOS Journal (http://journals.plos.org/plosone/s/file?id=8ce6/plos-consent-form-english.pdf). The signed consent form should not be submitted with the manuscript, but should be securely filed in the individual's case notes. Please amend the methods section and ethics statement of the manuscript to explicitly state that the patient/participant has provided consent for publication: “The individual in this manuscript has given written informed consent (as outlined in PLOS consent form) to publish these case details”. If you are unable to obtain consent from the subject of the photograph, you will need to remove the figure and any other textual identifying information or case descriptions for this individual. We have successfully obtained consent from the individual and regarding this we inserted a statement in the Editorial Manager System and manuscript. We are keeping the file and did not submit it with the manuscript as instructed.   [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No There are no comments or suggestions to reply. ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes There are no comments or suggestions to reply. ________________________________________ 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No We have shared our supporting materials in https://doi.org/10.6084/m9.figshare.23259770. ________________________________________ 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes There are no comments or suggestions to reply. ________________________________________ 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I have read carefully the manuscript entitled “Prediction of decreased mandibular bone density in familial Mediterranean fever via fractal dimension analysis: A cross-sectional retrospective study.” However, Authors didn't draft the paper well and I cannot recommend the publication of the article in its present form. The Authors should correct the manuscript before the re-submission of the work to Plos One. First of all, the title does not correspond to the content of the manuscript, as no "prediction" or "bone density" has been established. The study only focuses on the assessment of the FD (fractal dimension) in different regions of the mandibular bone. The title was revised accordingly as ‘Fractal dimension analysis of different mandibular regions in familial Mediterranean fever patients: A cross-sectional retrospective study’. Secondly, there is no paragraph in which it is clearly stated that the method used to determine FD can be a measure of bone BMD (L66 and others). As indicated, FD is commonly used to assess the homogeneity of trabecular bone microarchitecture, not only in the mandible, and it is more accurately a measure of the regularity of the surface of the trabeculae. Therefore, measuring FD in the cortical bone area no longer aligns with the correct definition of FD provided in L67 and L206-208. Thus, additionally give additional references about measurements of FD of cortical bone. The manuscript was redrafted emphasizing the use of FD in the BMD evaluation and in assessment of cortical bone. Minor comments: L56 In which country (countries) ? Related information was inserted in the text. L102 n- 25 in each group The phrase ‘in each group’ was inserted. L132 “grey scale” The term ‘grayscale’ was inserted to the statement. L173 According to the data in the tables, all variables lack normal distribution. Am I right? In order to confirm the normality of the data, we have consulted to our statistician, who reevaluated the data in terms of different regions of interests and found that R3, R4, R5, L1, and L5 were normally distributed, while the others were not. As well, the data was reviewed and some minor corrections which did not affect the significance of the findings, were made. Abstract, Results section and related tables were revised accordingly. Thank you so much for your contribution. Also information about checking the groups with the Chi-square test is missing. Information regarding the Chi-square test was inserted to the Materials and methods section as: 'Chi-square test was used to assess the distribution of categorical data between FMF and control groups.’ Tables - correct the titles of tables 3-5, because you did not measure ROI, only FD in specific areas of the mandible Titles of the Tables 3-6 were corrected. ________________________________________ 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. Yes. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ________________________________________ [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] There were no additional attachment files to consider. While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. I have arranged the figures in the PACE system. Nevertheless, I have sent an email to figures@plos.org and waiting for approval for the appropriateness of the figures. Thank you for your time and consideration. Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0288170.r003 Decision Letter 1 Tomaszewska Ewa Academic Editor © 2023 Ewa Tomaszewska 2023 Ewa Tomaszewska https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 22 Jun 2023 Fractal dimension analysis of different mandibular regions in familial Mediterranean fever patients: A cross-sectional retrospective study PONE-D-23-08206R1 Dear Dr. Nilüfer Ersan, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I would like to thank the authors for reviewing and accepting all the comments and suggestions. In my opinion the article is now acceptable for publication. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ********** 10.1371/journal.pone.0288170.r004 Acceptance letter Tomaszewska Ewa Academic Editor © 2023 Ewa Tomaszewska 2023 Ewa Tomaszewska https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 23 Jun 2023 PONE-D-23-08206R1 Fractal dimension analysis of different mandibular regions in familial Mediterranean fever patients: A cross-sectional retrospective study Dear Dr. Ersan: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Ewa Tomaszewska Academic Editor PLOS ONE ==== Refs References 1 Heller H , Sohar E , Sherf L . Familial Mediterranean fever. AMA Arch Int Med. 1958;102 :50–71. doi: 10.1001/archinte.1958.00260190052007 13558745 2 Yaşar Bilge NŞ , Sarı İ , Solmaz D , Şenel S , Emmungil H , Kılıç L , et al . 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