Screening for oral potentially malignant disorders (OPMDs) with dysplasia in high-risk groups is suggested in countries with a high prevalence of the disorders. This study aimed to compare the accuracy of diagnoses of OPMDs with dysplasia made by a primary examiner  and a specialist  using the current Taiwanese Nationwide Oral Mucosal Screening Program (TNOMSP). A total of 134 high-risk participants were enrolled for oral mucosal screening via the TNOMSP. A primary examiner and a specialist examined each participant. Mucosal biopsies were obtained and subjected to histopathological analysis. The OPMD most frequently diagnosed by the primary examiner was thin homogeneous leukoplakia , and in 39/134 participants (29.1%) the diagnosis was uncertain, but abnormalities were suggested. The OPMDs most frequently diagnosed by the specialist were erythroleukoplakia  and thin homogeneous leukoplakia , and 51/134 participants (38.1%) were diagnosed with other diseases. Via histopathology, 70/134 participants (52.3%) were diagnosed with dysplasia, and 58/134 (43.3%) were diagnosed with benign conditions. The specialist’s diagnoses exhibited a higher specificity, positive predictive value, and accuracy than the primary examiners. A specialist using the current TNOMSP for high-risk participants diagnosed OPMDs with dysplasia more accurately than a primary examiner. Early diagnosis of high-risk OPMDs is crucial in countries with a high prevalence of the disorders. Proficient examination via the current TNOMSP by trained clinician is effective for the management of OPMDs with dysplasia. Several terms have been used to refer to the mucosal pathology that develops prior to oral cancer, such as “pre-cancerous”, “precancerous/premalignant lesions”, and “intraepithelial neoplasia” –3. WarnaThe histopathological diagnosis of OPMDs varies and can include hyperplasia, hyperkeratosis, and oral epithelial dysplasia (OED) . OEDs caRisk factors for OPMDs differ by country and region, and in Taiwan, the most common OPMDs are leukoplakia, erythroplakia, and oral submucous fibrosis –13. The One of the aims of conventional oral mucosa screening is early diagnosis of potentially malignant lesions, thus reducing malignancy-related mortality. Screening for OPMDs can facilitate preventive intervention , and it i.e., high-risk individuals), and being of Han Chinese descent. A total of 150 consecutive patients were initially screened for inclusion in the study, of which 16 were subsequently excluded; 10 because they declined to participate and 6 because they were not of Han Chinese descent.The study was approved by the Institutional Review Board of the Tri-Service General Hospital of National Defense Medical Center, Taipei, Taiwan (IRB: 1-107-05-010) and was conducted within the Department of Oral and Maxillofacial Surgery at that hospital. The inclusion criteria were age > 20 years, a history of tobacco and/or betel nut use , who recorded clinical diagnoses of erythroplakia, erythroleukoplakia, verrucous hyperplasia, non-homogeneous leukoplakia, homogeneous thick leukoplakia, submucosal fibrosis, lichen planus, unknown mass, unhealed ulceration for > 2 weeks , abnormaDiagnoses were made using the Taiwanese Nationwide Oral Mucosal Screening Program checklist. The primary examiner suspected a diagnosis of oral cancer but categorized the diagnosis into an unconfirmed diagnosis of an unhealed ulceration for > 2 weeks in the checklist. The specialist categorized the lesion as “other.” Biopsy histopathology indicated inflammation without dysplasia. The patient was advised to stop chewing betel nuts, rounding of the tooth attrition was performed, and a follow-up visit was arranged.Patients signed a standard informed consent form that is typically used at the hospital. A biopsy was performed for histopathological assessment, and the biopsy site was selected from the diagnosed lesion site. The presence or absence of dysplasia, oral cancer, or other abnormalities in the biopsy specimen was recorded in the pathology report and approved by a certified pathologist.p < 0.05 (two-tailed) was considered statistically significant.All statistical analyses were performed using the statistical software SPSS . Responses were numerically coded to facilitate data entry. The McNemar’s test was used to determine the difference between primary and the specialist in diagnosing OPMDs. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the clinical diagnoses made by the primary examiner and the specialist examiner were determined based on the gradings derived from the biopsies. The receiver operating characteristic (ROC) curve and area under the ROC curve were used to assess the accuracy of diagnoses of dysplasia and cancer made by the primary examiner and the specialist. In all analyses, Application of the inclusion and exclusion criteria resulted in 134/150 (89.3%) initially screened patients being included in the study; 117 men and 17 women with a mean age of 56.55 ± 12.93 years. Most participants  were unaware of their lesions. A history of chewing betel nuts was reported by 63.5% of participants, and current smoking or a history of smoking was reported by 76.8%. A total of 76/134 participants (56.7%) were diagnosed with dysplasia and/or cancer via histopathology, and 58/134 (43.2%) were diagnosed with benign conditions .The results of the conventional oral examinations are shown in The results of statistical evaluations performed to assess associations between clinical and histopathological diagnoses and examiner experience are shown in Identifying OED associated with OPMDs is crucial because of the potential for malignant transformation. OED is classified into three stages: mild, moderate, and severe. In mild OED, dysplastic changes are limited to basal or parabasal layers; in moderate OED, there is involvement of the middle or granular layer, and in severe OED, changes are evident from the basal layer of the epithelium to the middle and upper layers . The curIn the current study, we included high-risk individuals screened separately by both examiners based on the original design of TNOMSP. The TNOMSP was initiated in 1985, and thereafter it was gradually scaled up to include all of Taiwan, and to specifically target high-risk individuals. Unlike western countries, the incidence of oral mucosal malignant changes is approximately one-hundred times higher in high-risk individuals than the general population due to betel nut and tobacco use ,27. The The primary aim of the TNOMSP is early diagnosis of OPMDs and consequent prevention of progression to malignant transformation. Accordingly, appropriate education to facilitate the identification of such lesions is crucial . UnderstPatients with OPMDs are referred for biopsy and treated, and in abnormal cases, close follow-up by a specialist is recommended. In a recent large-scale retrospective cohort study conducted in Taiwan investigating associations between OPMDs and the early diagnosis of oral cancer, an oral mucosal screening program for the early identification of OPMDs contributed substantially to reducing mortality . InteresIn the current study, a clinical specialist, such as an oral and maxillofacial surgeon well trained and prepared to make a correct diagnosis for OPMDs, demonstrated a better outcome in diagnosing histopathologic OED. Our findings also suggest that, based on the design of the TNOMSP, the high-risk group can be properly diagnosed by the specialist for treatment. However, the limitation of this study is small sample size in a single medical center with limited examiners, but this provides a rationale for further comparative evaluation of the TNOMSP in diagnosis of OPMDs with dysplasia by more qualified examiners or specialists in a larger population base study.S1 Data(PDF)Click here for additional data file. 14 Oct 2020PONE-D-20-25840Comparison of the accuracy of diagnoses of oral potentially malignant disorders with dysplasia by a general dental clinician and a specialist using the Taiwanese Nationwide Oral Mucosal Screening ProgramPLOS ONEDear Dr. ChenThank 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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. 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Have the authors made all data underlying the findings in their manuscript fully available?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.The Reviewer #1: NoReviewer #2: Yes**********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: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease 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. Reviewer #1: 1.As you mention in the conculsion, a clinical specialist such as an oral and maxillofacial surgeon is well251 trained and prepared on making a correct diagnosis for OPMDs, which also revealed a better252 outcome in finding histopathologic OED.It is alreday a static and patient choosen bias. Since this is not a RCT, in clinical condition, symptomatic patient may go or refer to specialist already. It's not fair to compare the two group under this circumstances.2.Table 1. Patient characteristics and histopathological diagnoses should also be seperate into two different comparsion group.3.Table 3. should aslo present the real case number rather than the percentage only.4.What is the outcome of Screening for oral potentially malignant disorders (OPMDs) in Tawain and other hospital should be mention insie the article.5.Discussion part should be more organized and corrlated to the topic you want to discussion about. What kind of patient or lesion should be performed the screen should be mentioned inside discussion.6.The limitation of the study showed also be mentioned.Reviewer #2: In the present paper, the authors investigate the accuracy of diagnoses of OPMDs with dysplasia using Taiwanese Nationwide Oral 6 Mucosal Screening Program. Very interesting work but from reading the abstract and methods section, I was expecting to see some more proposed about the statistical analysis which was claimed by the author. And there are some parts of the research needed to be deliberate.1. What is the criterion for the receiver operating characteristic (ROC)?2.The author should deliberate about the description of using the receiver operating characteristic (ROC) curve for sensitivity, specificity, positive predictive value, negative predictive value, and accuracy .Cause there is not enough evidence to support the description of statistical analysis.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  25 Nov 2020Responses by the Author1. 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: PartlyReviewer #2: Partly2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: NoReviewer #2: Yes3. 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: NoReviewer #2: YesResponse: We appreciate Reviewer 1 for reminding us of the importance of making our original data open access. We have hereby uploaded our original data for the purpose of science.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: YesReviewer #2: Yes5. Review Comments to the AuthorPlease 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. Reviewer #1: 1.As you mention in the conculsion, a clinical specialist such as an oral and maxillofacial surgeon is well 251 trained and prepared on making a correct diagnosis for OPMDs, which also revealed a better252 outcome in finding histopathologic OED.It is alreday a static and patient choosen bias. Since this is not a RCT, in clinical condition, symptomatic patient may go or refer to specialist already. It's not fair to compare the two group under this circumstances.Response: We apologize for the misguiding figures and the text in the manuscript. This is a comparative study using paired data. We have revised our manuscript and figures to make them more understandable as follows:Fig 2. Oral mucosal screening protocol.Pg 2.AbstractEarly diagnosis of high-risk OPMDs is crucial in countries with a high prevalence. Stepwise examination via the current TNOMSP and appropriate subsequent referral is effective for the management of OPMDs with dysplasia. A specialist using the current TNOMSP for high-risk participants diagnosed OPMDs with dysplasia more accurately than a primary examiner. Early diagnosis of high-risk OPMDs is crucial in countries with a high prevalence of the disorders. Proficient examination via the current TNOMSP by trained clinician is effective for the management of OPMDs with dysplasia.Pg. 5Clinical examination procedureThe clinical examination checklist from procedure for the TNOMSP was used. Primary oral mucosal screening A diagnosis using the TNOMSP checklist was performed by a primary examiner , who recorded clinical diagnoses of erythroplakia, erythroleukoplakia, verrucous hyperplasia, non homogeneous leukoplakia, homogeneous thick leukoplakia, submucosal fibrosis, lichen planus, unknown mass, unhealed ulceration for > 2 weeks , abnormal mucosa without a diagnosis, suspected oral cancer, and other conditions. The same patient went through a A conclusive clinical examination was performed by a certified specialist examiner  who clinically diagnosed non-homogeneous leukoplakia, homogeneous thick leukoplakia, leukoplakia, erythroplakia, erythroleukoplakia, verrucous hyperplasia, submucosal fibrosis, lichen planus, suspected oral cancer, and other conditions. Mucosal biopsies of all lesions were performed and subjected to histopathological analysis .2.Table 1. Patient characteristics and histopathological diagnoses should also be seperate into two different comparsion group.Response: We thank reviewer 1 for this insightful suggestion; we have using paired data and revised our table 1 as following: Pg. 8Table 1. Patient characteristics and histopathological diagnosesVariable All PatientsN = 134 Primarya Specialist Histopathology OPMDsN = 82 CancerN = 5 OtherN = 8 OPMDsN = 73 CancerN = 10 OtherN = 51 DysplasiaN = 70 CancerN = 6 OtherN = 58Age 56.55 ± 12.93 56.28 ± 11.10 56.67 ± 8.49 40.99 ± 21.46 56.69 ± 10.24 61.11 ± 12.19 55.47 ± 16.17 58.71 ± 11.77 62.45 ± 13.07 53.34 ± 13.70Sex Female 17 (12.7%) 8 (9.8%) 0 (0%) 0 (0%) 10 (13.7%) 1 (10.0%) 6 (11.8%) 13 (18.6%) 1 (16.7%) 3 (5.2%)Male 117 (87.3%) 74 (90.2%) 5 (100%) 8 (100%) 63 (86.3%) 9 (90.0%) 45 (88.2%) 57 (81.4%) 5 (83.3%) 55 (94.8%)Awareness of the lesion No 114 (85.1%) 74 (90.2%) 3 (60.0%) 4 (50.0%) 65 (89.0%) 2 (20.0%) 47 (92.2%) 63 (90.0%) 0 (0%) 51 (87.9%)Yes 20 (14.9%) 8 (9.8%) 2 (40.0%) 4 (50.0%) 8 (11.0%) 8 (80.0%) 4 (7.8%) 7 (10.0%) 6 (100%) 7 (12.1%)Betel nut use Never used 49 (36.6%) 27 (32.9%) 1 (20.0%) 4 (50.0%) 31 (42.5%) 2 (20.0%) 16 (31.4%) 27 (38.6%) 2 (33.3%) 20 (34.5%)Ex-user 36 (26.9%) 27 (32.9%) 1 (20.0%) 4 (50.0%) 15 (20.5%) 1 (10.0%) 20 (39.2%) 12 (17.1%) 2 (33.3%) 22 (37.9%)Current user 49 (36.6%) 28 (34.1%) 3 (60.0%) 0 (0%) 27 (37.0%) 7 (70.0%) 15 (29.4%) 31 (44.3%) 2 (33.3%) 16 (27.6%)Tobacco use Never smoked 31 (23.1%) 14 (17.1%) 1 (20.0%) 4 (50.0%) 14 (19.2%) 1 (10.0%) 16 (31.4%) 15 (21.4%) 1 (16.7%) 15 (25.9%)Ex-smoker 31 (23.1%) 21 (25.6%) 1 (20.0%) 4 (50.0%) 19 (26.0%) 1 (10.0%) 11 (21.6%) 12 (17.1%) 2 (33.3%) 17 (29.3%)Current smoker 72(53.7%) 47 (57.3%) 3 (60.0%) 0 (0%) 40 (54.8%) 8 (80.0%) 24 (47.1%) 43(61.4%) 3 (50.0%) 26 (44.8%)a: participants diagnosed with an unexplained persistent mass, unhealed ulceration for more than 2 weeks, or abnormal mucosa without diagnosis by primary examiner were excluded. Data are presented as the mean ± standard deviation 3.Table 3. should aslo present the real case number rather than the percentage only.Response: We thank Reviewer 1 for this comment; We have revised the table as follows:Pg. 11Table 3-1. Accuracy of diagnoses of oral potentially malignant disorders with dysplasia by the primary examiner and the specialistPatients exclude due to cancerN = 88 Primary examiner OPMDsaN = 80 OtherN = 8Pathology report DysplasiaN = 47 47 (53.4%) 0 (0%) OtherN = 41 33 (37.5%) 8 (9.1%)Sensitivity 100Specificity 19.5Positive predictive value 58.8Negative predictive value 100Accuracy 62.5AUC 0.598a: Oral potentially malignant disorders (OPMDs) include erythroplakia, erythroleukoplakia, non-homogeneous leukoplakia, thick homogeneous leukoplakia, thin homogeneous leukoplakia, verrucous hyperplasia, submucous fibrosis, and lichen planus.Table 3-2. Accuracy of diagnoses of oral potentially malignant disorders with dysplasia by the specialistPatients exclude due to cancerN = 123 Specialist OPMDsaN = 72 OtherN = 51Pathology report DysplasiaN = 66 60 (48.8%) 6 (4.9%) OtherN = 57 12 (9.8%) 45 (36.6%)Sensitivity 90.9Specificity 78.9Positive predictive value 83.3Negative predictive value 88.2Accuracy 85.4AUC 0.870ba: Oral potentially malignant disorders (OPMDs) include erythroplakia, erythroleukoplakia, non-homogeneous leukoplakia, thick homogeneous leukoplakia, thin homogeneous leukoplakia, verrucous hyperplasia, submucous fibrosis, and lichen planus, b: log-rank test compared with AUC=0.5, p < 0.0014.What is the outcome of Screening for oral potentially malignant disorders (OPMDs) in Tawain and other hospital should be mention insie the article.Response: We thank reviewer 1 for helping us improve our manuscript. We have revised our discussion as follows:Pg. 15DiscussionPatients with OPMDs are referred for biopsy and treated, and in abnormal cases, close follow-up by a specialist is recommended. In a recent large-scale retrospective cohort study conducted in Taiwan investigating associations between OPMDs and the early diagnosis of oral cancer, an oral mucosal screening program for the early identification of OPMDs contributed substantially to reducing mortality [34]. Interestingly, OSF is a unique OPMDs in South-East Asia due to para-habits. A large national scale 10-year observation study conducted in Taiwan for OPMDs, targeting oral submucous fibrosis (OSF) with oral leukoplakia (OL), revealed a higher and faster malignant transformation rate then OSF alone [35]. Another study was conducted in a high-occurrence region within a single hospital in southern Taiwan, in which 555 individuals with OPMDs during a 5 year-period were examined for the relationship of its clinicopathological features and transformation. In this study, the annual malignant transformation rate was 1.16%, specifically for OSF, and that for homogenous leukoplakia and non-homogenous leukoplakia was 5.7%, 4.6%, and 12.1%, respectively [36]. A well-designed surveillance program could lead to early malignancy detection and reduced mortality and morbidity. This has been also demonstrated in a large scale cohort study using the Taiwan Cancer Registry to evaluate the relationship between OPMDs and malignancy, which showed a survival benefit due to early diagnosis of OPMDs to prevent oral malignancies [34]. For many years, this program has benefited the high-risk group, and there has been a 21% reduction in stage III or IV oral cancer diagnoses, and a 26% reduction in oral cancer mortality .5.Discussion part should be more organized and corrlated to the topic you want to discussion about. What kind of patient or lesion should be performed the screen should be mentioned inside discussion.Response: We thank reviewer 1 for helping us improve our manuscript. We have revised our discussion as follows:Pg. 13.DiscussionIn the current study, we included high-risk individuals screened separately by both examiners based on the original design of TNOMSP. The TNOMSP was initiated in 1985, and thereafter it was gradually scaled up to include all of Taiwan, and to specifically target high-risk individuals. Unlike western countries, the incidence of oral mucosal malignant changes is approximately one-hundred times higher in high-risk individuals than the general population due to betel nut and tobacco use [19-21]. The TNOMPS has been promoted by government health administrators and broadcast by media to highlight the importance of mucosal screening, which has been implanted for decades. Funding has been distributed through the Taiwan national health insurance system to first-line public health care providers, including dentists in general practice, oral and maxillofacial surgeons, otolaryngologists, and other related physicians. High-risk individuals are targeted for screening biennially, including those who currently use or have quit the use of betel nut and tobacco, as well as those above the age of 30. In 2015, there were 939,000 screenings conducted, and the percentage of the screened high-risk individuals rose from 28% in 2009 to 56.1% in 2015; the above-mentioned screening detected OPMDs in 4095 individuals and oral malignancy in 1361 individuals . Several international studies indicate that para-habit users are at high risk of OPMDs [29-31]. In Southeast Asia, approximately 90% of deaths resulting from oral malignancy occur in patients with habits known to be associated with enhanced risks of those malignancies; thus, the specific allocation of resources to screen individuals in high-risk groups is justifiable [32]. Due to the often-asymptomatic onset of OPMDs, the majority of patients with OED are evidently unaware of their condition, as was the case in the current study; thus, educating high-risk groups about their risks and encouraging them to engage in the TNOMSP may improve the prevention rates [33].6.The limitation of the study showed also be mentioned.Response: We thank reviewer 1 for helping us improve our manuscript. We have revised our conclusion as follows:Pg. 15ConclusionsIn the current study, a clinical specialist, such as an oral and maxillofacial surgeon well trained and prepared to make a correct diagnosis for OPMDs, demonstrated a better outcome in diagnosing histopathologic OED. Our findings also suggest that, based on the design of the TNOMSP, the high-risk group can be properly referred to diagnosed by the specialist for treatment. However, the limitation of this study is small sample size in a single medical center with limited examiners, but this provides a rationale for further comparative evaluation of the TNOMSP in diagnosis of OPMDs with dysplasia by more qualified examiners or specialists in a larger population base study.Reviewer #2: In the present paper, the authors investigate the accuracy of diagnoses of OPMDs with dysplasia using Taiwanese Nationwide Oral 6 Mucosal Screening Program. Very interesting work but from reading the abstract and methods section, I was expecting to see some more proposed about the statistical analysis which was claimed by the author. And there are some parts of the research needed to be deliberate.1. What is the criterion for the receiver operating characteristic (ROC)?Response: We thank reviewer 2 for the insightful instruction. We apologize for our previous technical mistakes; however, we have uploaded our original data as supplement, and revised table 3-1 and 3-2 to include additional details.Table 3-1. Accuracy of diagnoses of oral potentially malignant disorders with dysplasia by the primary examiner and the specialistPatients exclude due to cancerN = 88 Primary examiner OPMDsaN = 80 OtherN = 8Pathology report DysplasiaN = 47 47 (53.4%) 0 (0%) OtherN = 41 33 (37.5%) 8 (9.1%)Sensitivity 100Specificity 19.5Positive predictive value 58.8Negative predictive value 100Accuracy 62.5AUC 0.598a: Oral potentially malignant disorders (OPMDs) include erythroplakia, erythroleukoplakia, non-homogeneous leukoplakia, thick homogeneous leukoplakia, thin homogeneous leukoplakia, verrucous hyperplasia, submucous fibrosis, and lichen planus.Table 3-2. Accuracy of diagnoses of oral potentially malignant disorders with dysplasia by the specialistPatients exclude due to cancerN = 123 Specialist OPMDsaN = 72 OtherN = 51Pathology report DysplasiaN = 66 60 (48.8%) 6 (4.9%) OtherN = 57 12 (9.8%) 45 (36.6%)Sensitivity 90.9Specificity 78.9Positive predictive value 83.3Negative predictive value 88.2Accuracy 85.4AUC 0.870ba: Oral Potentially Malignant Disorders (OPMDs) includes erythroplakia, erythroleukoplakia, non-homogeneous leukoplakia, thick homogeneous leukoplakia, thin homogeneous leukoplakia, verrucous hyperplasia, submucous fibrosis, and lichen planus.b: log-rank test compared with AUC=0.5, p < 0.0012.The author should deliberate about the description of using the receiver operating characteristic (ROC) curve for sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Cause there is not enough evidence to support the description of statistical analysis.Response: We thank Reviewer 2 for this suggestion regarding the ROC curve. We have revised Fig. 3 based on our findings from table 3-1 and 3-2.Fig. 3 Receiver operating characteristic curve for comparison of the diagnostic accuracy of the primary examiner and the specialist.The area under the curve (AUC) for the specialist (blue) and primary examiner (green) are 0.870 and 0.598, respectively. The log-rank test comparing the specialist and primary examiner is significant (p < 0.001).AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 16 Dec 2020Comparison of the accuracy of diagnoses of oral potentially malignant disorders with dysplasia by a general dental clinician and a specialist using the Taiwanese Nationwide Oral Mucosal Screening ProgramPONE-D-20-25840R1Dear Dr. Chen,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.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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This survey analysis of randomized clinical trials registered within 100 days of the first reported case of coronavirus disease 2019 assessed recruitment and results reporting. We assessed whether trials recruited 75% or more of their target sample size, stopped before 75% recruitment, or were continuing to recruit (on schedule or delayed) but not yet 75% recruited. On October 19, we searched the Living Overview of Evidence platform2 for results posted as preprints, published in peer-reviewed journals, or reported in trial registries. The survey results were used to complement the information from our search. Associations of trial characteristics—location , planned sample size greater or less than the median , registered on or after the median registration date (March 15), and type of control group—with recruitment and results reporting were explored using logistic regressions. We used R version 3.6.2 . The P value threshold was <.05 in 2-tailed tests. Institutional review board approval and an informed consent waiver were not required for this study because the aggregated trial data collected are not subject to the health regulations of Switzerland.All RCTs registered in ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform between January 1 and April 9, 2020, were included. These trials had been previously identified in a systematic assessment.There were 516 trials identified. Seventy-six trial teams (14.7%) responded to the survey, and we found results reported for 53 trials (10.3%). Overall, 56 trials (10.8%) were completed, 24 (4.6%) terminated early, 111 (21.5%) were ongoing on schedule, 126 (24.4%) were ongoing but delayed, 39 (7.6%) were ongoing without reporting an expected end date, 155 (30%) had not started or were discontinued, and 5 (1.0%) had unknown status.P = .02) or when they were registered in China vs elsewhere  . Of 108 started trials with detailed recruitment information obtained from investigators and/or reported results, 38 (35.1%) reached at least 75% of their target sample size, 34 (31.5%) stopped before 75%, and 36 (33.3%) had not yet recruited 75% of their target. Median (interquartile range [IQR]) recruitment was 45.2% (19.6%-100%). Trials were less likely to begin recruitment when they were less than vs greater than median sample size  .P = .003) but more likely for trials registered before the median registration date  vs later . Type of control group was not associated with start of recruitment or results reporting.Of the 53 trials with reported results, 13 (24.5%) were posted as preprints, 39 (73.6%) were published in peer-reviewed journals, and 1 (1.9%) was posted on a registry. Results reporting was less likely for trials from China vs elsewhere  and emerging data raising concerns of safety  or futility .3 Delayed completion may be explained for some countries, such as China, by slow or halted recruitment due to decreasing COVID-19 cases after the first wave.Overall, 30% of COVID-19 RCTs initiated in the first 100 days of the pandemic did not begin recruitment, and only 10% had results reported by mid-October, suggesting the possibility of substantial research waste.4 and adaptive platform trials such as the RECOVERY trial5 are promising approaches to provide reliable and timely evidence.This study is limited by a low response rate to the survey and by unknown results because of inconsistent updates of trial registries and delayed publications. Successfully conducting a trial during a pandemic is challenging. Nevertheless, collaborative efforts such as consortiums of trials prospectively planning to pool their results


Objective: Early life is a critical period for gut microbial development. It is still controversial whether there is placental microbiota during a healthy pregnancy. Gestational diabetes mellitus (GDM) is associated with increased risk of metabolic syndrome in the offspring, and the mechanisms are unclear. We sought to explore whether microbiota in placenta and cord blood may be altered in GDM.Methods: Placenta and cord blood samples were collected from eight GDM and seven euglycemic (control) term pregnancies in cesarean deliveries without evidence of clinical infections. The Illumina MiSeq Sequencing System was used to detect the microbiota based on the V3–V4 hypervariable regions of the 16S ribosomal RNA gene.Results: The microbiota were detectable in all placental samples. Comparing GDM vs. controls, there were more operational taxonomic units (OTUs)  and higher ACE index  and Chao index . The placental microbiota was mainly composed of four phyla: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria at the phylum level and 10 dominant genera at the genus level in both GDM and controls. Despite the dominant similarity in microbiota composition, at the OTU level, the abundance of Ruminococcus, Coprococcus, Paraprevotella, and Lactobacillus were higher, whereas Veillonella was lower in the placentas of GDM vs. controls. The microbiota was detected in one of the 15 cord blood samples, and its components were similar as to the corresponding placental microbiota at both phylum and genus levels suggesting placental microbiota as the potential source.Conclusions: The most abundant phyla and genus of placental microbiota were similar in GDM and euglycemic pregnancies, but GDM was associated with higher diversity of placental microbiota. Further study is needed to confirm the existence of microbiota in cord blood in pregnancies without clinical infection. It was assumed historically that the placenta is sterile before birth, but in recent years, there is a controversy concerning whether bacteria exist in the placenta  was detected in people who had no biological signs of infection  is a common pregnancy complication with a prevalence ranging from 12.8 to 16.7% in China . GDM is with GDM . At the hout GDM . HoweverIn this study, we aimed to assess the existence, diversity, and composition of microbiota in placenta and cord blood in GDM and euglycemic (control) pregnancies and whether microbiota in placenta and cord blood may be altered in GDM.This was a cross-sectional study. We recruited eight GDM and seven euglycemic (control) singleton pregnant women who had prenatal care at Xinhua Hospital, a tertiary hospital in Shanghai, and were admitted to the hospital for cesarean deliveries.Exclusion criteria were any of the followings: (1) vaginal delivery; (2) preterm birth; (3) women who had preexisting diabetes before pregnancy, or hypertension/preeclampsia, clinical chorioamnionitis, or other severe pregnancy complication; (4) women having any clinical infection or who were treated with any antibiotics during pregnancy; (5) birth defects; and (6) any antepartum infection during pregnancy. Characteristics and clinical information of study participants were obtained from medical records. The study was approved by the Research Ethics Committee of Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine. Written informed consent was obtained from all participants.Cord blood and placenta specimens were collected following a strict aseptic protocol to control potential contamination –28. SpecMicrobial DNA was extracted from placenta and cord blood samples using beads-beating method . Alongsihttp://drive5.com/uparse/). The phylogenetic affiliation of each 16S rRNA gene sequence was analyzed by RDP Classifier (http://rdp.cme.msu.edu/) against the Silva (SSU123) 16S rRNA database using the confidence threshold of 70% (http://www.R-project.org/). For those placental microbiota OTUs that differed between GDM and non-GDM pregnancies, the Spearman correlation coefficients were calculated with maternal clinical parameters and birth outcomes.High-quality sequence alignments, sequence clustering, and operational taxonomic unit (OTU) delineation were conducted based on previously established method . On the d of 70% . The alpd of 70% , 36. SamP < 0.001) with R (version 3.4.0)  .SRA958249.The raw sequence data of the 16S rRNA gene supporting the results of this article are available in the NCBI Sequence Read Archive (SRA) under access number 2 or Fisher's exact test was used for categorical variables, and t-test or non-parametric Wilcoxon test was used for continuous variables where appropriate. All statistical analysis was carried out in SAS 9.3 software . Two-sided P < 0.05 was considered statistically significant.To compare the differences in characteristics of study participants between GDM and control groups, χ1c levels were all significantly higher in GDM vs. euglycemic pregnancies (This study included eight GDM and seven euglycemic (control) pregnant women and their newborns. All study participants were urban Shanghai residents and of Han ethnicity, and 46.67% had college education or more. The clinical characteristics of mothers and newborns are shown in gnancies  at mean Bacteria 16S rRNA can be detected in all of the 15 placental specimens, but in only one of the 15 cord blood specimens. Negative control sample from DNA isolation and blank PCR reagent were both negative after PCR step, which was considered as having no contamination from reagents and environment.Overall, 622,263 high-quality sequences were obtained in the 15 placental samples. The average number was 41,484.2 per placental sample. The Good's coverage of each sample was more than 97%, indicating that the sequences identified can represent the majority of bacteria in each of the placental samples. In one cord blood sample, 49,569 high-quality sequences were obtained.P = 0.024). Comparing GDM vs. control groups, the ACE indices were higher , and Chao indices were also higher  in GDM (P = 0.054).The mean number of OTUs was 373.63  in the placentas of women with GDM, higher than that of control women  in GDM , indicatP-value for the PCoA analysis is 0.383).To compare overall placenta microbiota composition between GDM and euglycemic pregnancies, PCoA analysis based on Bray–Curtis distance according to OTUs of each sample was implemented. Overall, in the total variation of all placental samples, the first principal component (PC1) could account for 56.53%, and PC2 could account for 17.63%. As shown in Bacteroidetes , Firmicutes , Actinobacteria , and Proteobacteria  :  = 0.78) .Prevotella (26.07% ± 6.00% in GDM vs. 25.23% ± 5.99% in control), Blautia (8.33% ± 2.44% vs. 7.90% ± 1.19%), Bacteroides (7.85% ± 1.78% vs. 7.62% ± 3.52%), Faecalibacterium (5.89% ± 0.90% vs. 6.33% ± 1.64%), Rhodococcus (4.30% ± 0.79% vs. 4.26% ± 0.97%), Bifidobacterium (4.16% ± 0.73% vs. 4.39% ± 0.95%), S24.7_norank (3.30% ± 1.06% vs. 2.59% ± 0.70%), Ruminococcaceae_uncultured (3.19% ± 0.77% vs. 2.44% ± 0.36%), Escherichia.Shigella (1.94% ± 0.52% vs. 3.51% ± 2.05%), and Lachnospiraceae_incertae_sedis (2.57% ± 0.46% vs. 2.34% ± 0.80%)  ± 0.80%) .Coprococcus (OTU 277), Prevotella (OTU 711), Anaerotruncus (OTU 5), S24–7_norank , Ruminococcus , Ruminococcaceae_uncultured , Lachnospiraceae_uncultured , Lachnospiraceae_unclassified , Paraprevotella (OTU 415), Dorea (OTU 588), and Defluviitaleaceae_Incertae_Sedis (OTU 494) were all higher, whereas Veillonella (OTU 601) was lower in the placentas of women with GDM than those of controls (n = 18) at the OTU level that differed between the GDM and control groups (P < 0.05).Despite above similarity, this study also identified 18 OTUs of placental microbiota that differed between GDM and non-GDM pregnancies . The relcontrols . Table 3Lachnospiraceae_uncultured) was positively correlated with maternal age. OTU 100 (S24-7_norank) was positively correlated with gestational age. OUT 471 (S24-7_norank) was positively correlated with fasting blood glucose in late pregnancy; OTU 471 (S24-7_norank), OTU 711 (Prevotella), OTU 155 (Ruminococcaceae_uncultured), OTU 160 (Lachnospiraceae_unclassified), OTU 381 (Lachnospiraceae_uncultured), and OTU 494  were positively correlated with maternal serum triglycerides concentration at late pregnancy. OTU 601 (Veillonella) was negatively correlated with maternal serum triglycerides concentration at late pregnancy and prepregnancy BMI. None of the OTUs was correlated with infant birth weight and Ponderal index , Bacteroidetes (32.7%), Proteobacteria (6.3%), and Actinobacteria (4.6%). The microbiota at the genus level were mainly composed of Blautia (21.6%), Bacteroides (10.5%), Ruminococcaceae_uncultured (8.2%), S24-7_norank (8.1%), Alistipes (5.4%), Lachnospiraceae_uncultured (5.2%), and Rhodococcus (4.1%). At both phylum and genus levels, the detectable bacteria in the cord blood sample were similar as those detected in the corresponding placental sample from the same woman , which was consistent with our study finding. In contrast, another study reported reduced OTUs in placenta microbiota of GDM pregnancies (n = 11 GDM and 11 controls)  , 39. Preontrols) , and steontrols) , 40, 41.a phylum . Our finBacteroides in placental tissue has been associated with the expression of genes that were important for nutrient transport and immunity in pregnant women' placenta , whereas le there was a positive association between the genus Sediminibacterium and T2DM  of cord blood samples . In 2011and T2DM . In our The main study limitation is the relatively small sample size. The preliminary finding requires confirmation in larger studies. Importantly, our study revealed the differences in the placental microbiota between GDM and non-GDM pregnancies at the OTU level. In this study, we did not collect the exact housing and living situation of each woman in the study. Housing characteristics  may have an impact on household microbial diversity . Living In conclusion, this study confirmed that microbiota existed in the placenta and had higher diversity in GDM compared with euglycemia pregnancy. Future studies are needed to uncover the roles of placental microbiota for long-term metabolic health in children.SRA958249.The raw sequence data of the 16S rRNA gene supporting the results of this article are available in the NCBI Sequence Read Archive (SRA) under access number The studies involving human participants were reviewed and approved by Research Ethics Committee of Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine. The patients/participants provided their written informed consent to participate in this study.FO conceived and designed the study. FO, NT, LZ, TZ, and YT coordinated and conducted the study. FO and NT analyzed, interpreted data, and drafted the manuscript. Z-CL and PF intensively reviewed and revised the manuscript. All authors have approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To determine and evaluate the rate of diplopia after Ahmed glaucoma valve (AGV) implantation surgery.The records of patients who underwent AGV implantation in our hospital between the years of 2010 and 2017 were retrospectively reviewed. Patients who were referred to our strabismus department due to binocular diplopia after AGV implantation surgery were included. The details of postoperative day 1, day 7, day 15, and 1 month examinations were recorded. In the postoperative period, the onset time of diplopia complaints, diplopia type, and the presence of diplopia at distance and near fixation were noted. Ocular motility examination and deviation measurements were evaluated.Ten (47%) of 211 patients who underwent AGV implantation in our hospital between 2010 and 2017 met the study inclusion criteria. Six of the 10 patients were men (60%) and 4 were women (40%). The mean age of the patients was 44.5 (34-63) years. Complaints of diplopia developed at a mean of 14.5±12.3 (1-30) days after AGV implantation. The prism measurements of the patients were found to be 8.4±1.4 prism diopters (PD) exotropia and 7.1±8.8 PD hypotropia. While 8 patients had diplopia only at near distance, 2 patients had diplopia at both distance and near. Three patients were treated with prismatic glasses, and their complaints of diplopia recovered spontaneously in 5.11±4.10 months. The other 7 patients were followed up without treatment, and their diplopia complaints resolved spontaneously in 6.11±4.40 months.Although most of the diplopia that develops after AGV implant surgery resolves without treatment, prismatic glasses might be considered as a treatment option in patients whose diplopia affects their daily lives. Seton implantation is one of the most commonly performed procedures, especially in cases where trabeculectomy surgery has failed.2 As with any surgery, some complications may be observed after AGV implantation. Complications such as choroidal effusion, hyphema, shallow anterior chamber, suprachoroidal hemorrhage, vitreous hemorrhage, positive Seidel test, cataract, corneal edema, hypotony, tube erosion, and endophthalmitis may occur in the early postoperative period.4The Ahmed glaucoma valve (AGV) is one of the most frequently used devices in seton implant surgery. AGV implantation is preferred in patients that are non-responsive to medical treatment and have not had successful outcomes from other glaucoma surgeries.5 In the literature, prevalence rates between 2.1% and 77% have been reported for strabismus 8 and between 1.4% and 23% for diplopia.10 Although patients often recover spontaneously, cases requiring intervention have also been reported.12Strabismus and diplopia are also among the known complications following glaucoma drainage implant (GDI) surgery.The aim of this study was to determine the incidence of diplopia in patients who underwent AGV implantation.The files of patients who underwent AGV implantation in our hospital between 2010 and 2017 were screened retrospectively. Patients who were referred to our strabismus unit due to binocular diplopia following AGV implantation were included in the study. Patients who had diplopia prior to AGV implantation, other extraocular muscle and/or neurological pathologies that may cause binocular diplopia, or monocular diplopia were excluded from the study.13 at a distance of 30 cm. BCVA values were converted to logMAR for statistical analysis. IOP values measured by applanation tonometry and detailed optic disc head examinations were noted from the patient records.From the records of the patients included in the study, we recorded their epidemiological characteristics and the distance and near best-corrected visual acuity (BCVA), IOP values, and biomicroscopic and fundus examination results of the eye to undergo AGV implantation, measured at the last preoperative examination. Distance BCVA was evaluated using a Snellen chart at a distance of 6 m, and near BCVA was evaluated using a near reading chart developed by Eğrilmez et al.The Ahmed FP7  device was used as the AGV implant.A fornix-based flap of the conjunctiva and Tenon’s capsule was raised in the superotemporal quadrant. Before implantation, the system was primed by injecting balanced salt solution through the tip of the tube using a 26-gauge (G) blunt cannula, and the valve was checked. The tube body was then sutured to the sclera 8-10 mm from the limbus. The tube was trimmed, bevel up, to a length not exceeding the pupil margin and inserted into the anterior chamber through an incision made 2-3 mm from the limbus using a 22G needle. The tube was secured to the sclera at two points using 10/0 nylon sutures. The tube was covered with pericardium, which was sutured to the sclera with 10/0 nylon sutures. The conjunctiva was closed with 10/0 nylon sutures.14 gaze limitations were classified as 0 , -1 (up to 75% of full rotation), -2 (up to 50% of full rotation), -3 (up to 25% of full rotation), or -4 (up to midline). For patients with visual acuity worse than 0.7 logMAR, the angle of deviation was determined by distance and near Krimsky prism test using prism bars due to inadequate fixation of the eye. For patients with visual acuity better than 0.7 logMAR, the angle of deviation was recorded using prism bars at distance and near fixation. Deviation angles were recorded in prism diopters (PD).Any complications that occurred perioperatively were recorded. The findings from detailed examinations performed on postoperative day 1, day 7, day 15, and 1 month were recorded. For patients with complaints of diplopia, the time from surgery to diplopia onset, type of diplopia, and presence of diplopia at distance and near. Ocular motility examination findings and deviation measurements were noted. Using the duction grading described by Scott and Kraft All patients’ results from the Hess test, distance Worth 4 dot test (6 m), and near Worth 4 dot test with appropriate refractive correction at 30 cm distance were recorded. Patients who could not perform the Hess test and the distant and near Worth 4 dot tests were noted.Patients whose diplopia persisted or did not improve for more than 3 months were identified. The follow-up records of patients who underwent medical intervention were evaluated to determine whether the intervention was adequate and whether the diplopia persisted. We evaluated whether the patients’ complaints of diplopia changed during approximately 1 year of follow-up and the time of diplopia resolution was determined.As per routine protocol, the patients were informed preoperatively about the possible risks of surgery, and verbal and written informed consent were obtained for the AGV implantation procedure. The study received ethics committee approval and was designed in accordance with the principles of the Declaration of Helsinki. Statistical analysis was not performed in this study.Of the 211 patients who underwent AGV implantation in our hospital between 2010 and 2017, 10 patients (4.7%) presented to our strabismus unit due to binocular diplopia and met the study criteria. Of these, 6 patients were men (60%) and 4 were women (40%). The mean age was 44.5 (34-63) years. The preoperative mean distance BCVA was 0.81±0.27 logMAR, preoperative mean near BCVA was 0.9±0.35 logMAR, and mean IOP was 34.0±14.2 (26-46) mmHg. Postoperative mean distance BCVA was 0.90±0.41 on day 1, 0.87±0.45 on day 7, 0.82±0.52 on day 15, and 0.8±0.34 logMAR at 1 month. Postoperative mean IOP was 8.2±3.1 on day 1, 7.9±2.1 on day 7, 12.3±4.7 on day 15, and 12.4±5.6 mmHg at 1 month.The Ahmed FP7  was used in all cases and was positioned in the superotemporal region between 10 and 11 o’clock in the right eye and between 1 and 2 o’clock in the left eye. The procedures were performed under general anesthesia and written and verbal consent was obtained from all patients preoperatively. The preoperative epidemiological and clinical findings of all patients are shown in Diplopia developed after a mean of 14.5±12.3 (1-30) days after AGV implantation. On ocular motility examination of these patients, -2 abduction limitation was observed in 4 patients, -2/-2 abduction/elevation limitation in 2 patients, -1/-2 abduction/elevation limitation in 1 patient, -2/-1 abduction/elevation limitation in 1 patient; and -2 elevation limitation was observed in 2 patients. The mean prism measurements of the patients were 8.4±1.4 PD exophoria and 7.1±8.8 PD hypotropia. Near diplopia alone was detected in 8 patients, while both distance and near diplopia were detected in 2 patients. The mean near visual acuity of the 10 patients with near diplopia was 0.8 logMAR. The visual acuity of the 2 patients with distance diplopia was 1.0 logMAR. Hess tests performed by these 2 patients during their complaints and after their complaints resolved are shown in Three patients were treated with prism glasses and their diplopia complaints resolved spontaneously after a mean of 5.11±4.10 months. Seven patients were followed up without treatment and their diplopia complaints resolved spontaneously after a mean of 6.11±4.40 months.15GDIs are used in the treatment of patients with refractory glaucoma for whom trabeculectomy has failed or is believed to have a very low chance of success. The Molteno implant, AGV, and Baerveldt glaucoma implant (BGI) are among the implants used.4As with any surgical procedure, some complications may occur after these implant surgeries. These complications can include cataract, corneal edema, hypotonia, tube erosion, hyphema, suprachoroidal hemorrhage, endophthalmitis, and diplopia.9 Strabismus and diplopia may result from a mass effect caused by a very large bleb, muscle tension, adipose tissue herniation, Faden effect due to scarring under the rectus muscles, and acquired superior oblique syndrome.16 There are various studies in the literature on diplopia after placement of a GDI .17Diplopia and strabismus are complications that develop following GDI surgery.11 found that the incidence of diplopia within the first year was 1.4%. Their study also included diplopia due to other GDIs, and unlike our study, the implants were placed in different regions . Only 2 of the patients that developed diplopia had AGV implants. In this study, 17 of 32 patients who developed diplopia received prism glasses, while 13 patients did not undergo any treatment. In addition, 3 patients who did not respond to treatment with prism glasses were treated surgically.In their study evaluating diplopia after GDI surgery , Abdelaziz et al.18, diplopia was detected in 4 (2.5%) of 159 patients who underwent AGV implant surgery. Diplopia was corrected by surgical intervention in 3 of these 4 cases, while the AGV implant had to be removed in the other patient.In a retrospective study by Huang et al.10 reported temporary diplopia in 4 (4.7%) of 85 patients who underwent AGV implant surgery, and 50% of these cases spontaneously resolved within 3 months after surgery.In addition, Ayyala et al.19 reported a case of acquired Brown’s syndrome following AGV implantation, and prism glasses were used to correct the patient’s diplopia.Kartı et al.In our study, correction with prism glasses was used in 3 of 10 patients who developed diplopia following AGV implantation, whereas 7 patients were followed up without any treatment. The patients treated with prism glasses were those who could not tolerate diplopia, and in a mean of 5 months, these patients no longer needed prism glasses and their diplopia resolved. We observed that the complaints of untreated patients could resolve spontaneously within a mean of 6 months.12 showed that restriction caused by the fibrous capsule around the implant was responsible for strabismus after GDI surgery. As surgical treatment, they performed adjustable suture surgery and capsule extraction.There are also publications in the literature in which surgical methods were preferred for the treatment of diplopia after GDI surgery. Roizen et al.In the present study, none of the patients underwent surgical procedures and we observed that their diplopia complaints resolved within a 1-year follow-up period. We believe that their diplopia may have been caused by intraoperative manipulation of the rectus muscles and restriction of rectus muscle action due to the implant itself. Therefore, we believe that if local edema resulting from manipulation resolves within the weeks or months after surgery, the diplopia may also resolve spontaneously.The retrospective design of this study is one of its main limitations. Another limitation is the relatively small number of patients included in the study.In this study, the incidence of binocular diplopia following AGV implantation was 4.5%, and in all cases the diplopia resolved without the need for surgical treatment. The mean resolution time of diplopia was 6.5 months. Although most cases of diplopia after AGV implant surgery resolve without treatment, prism glasses may be considered as a treatment option in patients whose diplopia adversely affects their daily lives. In routine examination practice, diplopia and strabismus evaluation is not commonly performed for patients who have undergone and/or will undergo glaucoma surgery. However, a standard pre- and postoperative diplopia and strabismus examination may be beneficial for patients undergoing glaucoma surgery.


R0) of coronavirus disease from publicly reported data that lack information such as onset of symptoms, presence of importations or known super-spreading events. Using data from the Republic of Korea, we illustrated how estimates of R0 can be biased and provided improved estimates with more detailed data. We used COVID-19 contact trace system in Korea, which can provide symptom onset date and also serial intervals between contacted people. The total R0 was estimated as 2.10  1.84–2.42). Also, early transmission of COVID-19 differed by regional or social behaviours of the population. Regions affected by a specific church cluster, which showed a rapid and silent transmission under non-official religious meetings, had a higher R0 of 2.40 (95% CI 2.08–2.77).Previous studies have reported the basic reproduction number ( R0) of COVID-19 should be discussed with some concerns. First, the symptom onset date should be used to estimate R0 mathematically, instead of the date of the positive test result for accurate estimation but many researchers used the diagnosed date as a proxy [R0 of COVID-19 through the epidemic curve of early COVID-19 transmission using the measured serial intervals, which is defined as the time interval between the onset dates of symptom(s) in the infector and the infectee, and symptom onset date of not-imported cases.The epidemic characteristics of coronavirus disease COVID-19) are reported by many countries 9 are rep; however a proxy . In addi a proxy  by invesData regarding the study population were derived from the COVID-19 surveillance system in Korea Centers for Disease Control and Prevention (KCDC) , collectR0’ package of R version 3.4.2 [R0 using the exponential growth method, which is one of the popular methods used in infectious disease dynamics studies when the growth rate and the serial interval are available in the data [R0 as total and as four different regions, Daegu, Gyeongbuk, Gyeonggi and Seoul, are reported since they showed early epidemics in Korea. Since one large specific church cluster (SCC) in Daegu showed rapid and silent transmission based on broad but non-official religious meetings, they are reported separately [After collecting the frequencies of symptomatic cases daily, we used the ‘on 3.4.2  to creatthe data . Estimats.d.): 19.72) years. The mean age in SCC cases was 40.11 (s.d.: 17.22) years, while that in without SCC cases was 51.43 (s.d.: 20.21) years. Men accounted for 3841 (40.32%) overall cases, 1514 (39.42%) SCC cases and 2327 (60.58%) other cases. Women accounted for 5686 (59.68%) overall cases, 2871 (50.49%) SCC cases and 2815 (49.51%) other cases.Of the 14 423 confirmed cases in the Republic of Korea until 3 August, 10 870 (75.38%) cases were symptomatic. In total, 1347 cases were excluded because they were classified as imported cases. The mean age in the remaining 9526 cases was 46.22  days was fitted into γ distribution, which was calculated by symptomatic infector–infectee pairs including 969 infectors and 1567 infectees in the Republic of Korea until 3 August 2020. The total R0 was estimated as 2.10  1.84–2.42). SCC cases had an R0 of 2.40 (95% CI 2.08–2.77) and non-SCC cases had an R0 of 1.92 (95% CI 1.42–2.59). Regional differences in R0 are shown in R0 of 1.76 (95% CI 1.20–2.54). Daegu and Geyongbuk showed different R0 values, regardless of SCC cases; SCC cases in Daegu and Geyongbuk had a higher R0 than overall of 2.49 (95% CI 2.14–2.91) and 2.37 (95% CI 1.32–4.22), respectively. If we use the publicly reported dates instead of the onset date for the comparison, R0 for overall was estimated as 3.14 (95% CI 3.04–3.25).The mean serial interval of 4.02 (R0 was 2.10 (95% CI 1.84–2.42). This is lower than 3.14, which is estimated by the reported dates in the Republic of Korea for the comparison. Although estimations through mathematical models or confirmed dates may have advantages in pandemic situation when the onset date is not available [R0 might have been overestimated. Also, due to rapid transmission of SCC group, all members of SCC group were tested for screening, resulting in congestion of confirmed dates which was the date they were tested. Similarly, there was some screening of hospitals also. These tests may have led to an overestimation of R0 by estimating the larger growth rate than the reality. Therefore, using symptom onset dates is essential for accuracy. Nevertheless, if patients' date of onset is not available, there should be some alternative methods [The study showed that the vailable , it is mR0 values were estimated in SCC cases, which caused silent transmission in Daegu and Gyeongbuk as confirmations were delayed by uncooperative behaviours of the religious group [R0 by region indicates that the transmission characteristics of COVID-19 may differ based on various factors such as social distancing guidelines or specific clusters showing different characteristics to the general population.Higher us group . The difR0 values ranging from 1.53 to 2.41 in different regions using only the onset date of domestic symptomatic cases. We suggest that the countries should not only report a case by date of symptom onset but also distinguish imported or local transmission, and perhaps even large clusters should be highlighted. Otherwise, estimates of R0 may be higher than reality.In conclusion, this study estimated


To remove the oxygen from the SiC, it was essential to add C. Two different mixture method were used, dry mixing (specktromill) and wet mixing . The effect of different levels of carbon additive and mixture method on density, microstructure, elastic modulus, polytype of SiC, Vickers hardness, and fracture toughness were examined. Precisely, 1.5 wt.% C addition was sufficient to remove oxide layer from SiC and improve the properties of dense SiC ceramics. The highest hardness and elastic modulus values were 27.96 and 450 GPa, respectively. Results showed that the 4H polytype caused large elongated grains, while the 6H polytype caused small coaxial grains. It has been observed that it was important to remove oxygen to achieve high density and improve properties of SiC. Other key factor was to include sufficient amount of carbon to remove oxide layer. The results showed that excess carbon prevented to achieve high density with high elastic modulus and hardness.High dense (>99% density) SiC ceramics were produced with addition of C and B This oxide layer inhibits to achieve high density and causes grain coarsening [Silicon carbide (SiC) is widely used in the defense industry (bulletproof vests), turbine engines, nozzles, heat conducting tube, and aerospace applications ,4,5,6,7.xpansion ,15,16,17g method ,26,27,28arsening ,29,30,31arsening ,25,26,32arsening ,21,27,33arsening ,35,36,374C were added to SiC, and powders were mixed with dry mixing and wet mixing. Dense SiC ceramics were produced by spark plasma sintering method.The aim of this study is to optimize the properties of SiC by adding different amounts of carbon to SiC and mixing powders with different methods. To achieve these goals, from 0.5 to 5.0 wt.% C and 0.5 wt.% BIn this research, the starting powder was commercially available submicron α-silicon carbide (SiC)  with the major impurity being oxygen 1.7 wt.%, and trace amounts of the Fe, Al, and Ca. The chemical and physical characteristics of SiC powder can be seen in The effect of the mixture method on the microstructural and mechanical properties of the silicon carbide was investigated using two different methods which were dry mixing by Specktromill  and wet mixing by ball milling.4C, 0.5–5 wt.% with 0.5 increment C and SiC. Powders were weighted and place in a small bottle without media and blended with Specktromill for 5 min.For the dry mixing series, 6.5 g of mixture were prepared with 0.5 wt.% B4C and 0.5–5 wt.% with 0.5 increment C and SiC. Powders were weighted and put into a Nalgane bottle with SiC ball and ball milled for 24 h. After that, to separate the media from the liquid mixture, the slurries were sieved using 1.4 mm mesh sieve. The liquid mixture had been put on a hot plate at 275 °C and allowed to dry. Then, the powder chunks were ground with mortar and pestle to prevent agglomeration.For the wet mixing series, 20 g of dry powders mixtures were prepared with 0.5 wt.% BFor densification, 6.5 g of every powder mixture were used for one sample. The powder was placed in a graphite die with an internal diameter of 20 mm. Graphite foil was lined between powders and the die as well as the punches to avoid samples reacting with the die set. Then, samples were densified with two-stage sintering using spark plasma sintering . The SPS was heated to 1400 °C with a 200 °C/min heating rate under vacuum with a 50 MPa applied pressure. The SPS was held for 1 min intermediate dwell to allow the carbon to react with oxide layer on the SiC, and then, the SPS was heated to 1950 °C with 200 °C/min heating rate under 50 MPa applied pressure and held for 5 min. After dwelling for 5 min at sintering temperature, SPS furnace was naturally cooled down to room temperature.After sintering, the dense samples required sandblasting to remove excess graphite foil from the surface. Then, to produce a smooth and clean surface, both sides of dense samples surface were ground down using a surface grinder with a 120-grit diamond wheel with a lubricant:water solution (1:20 vol%) to keep the specimen surface wet while grinding to prevent possible damage from friction.After that, the density of sintered samples was measured with Archimedes principle using DI water as the immersion medium and elastic properties were measured using ultrasound analysis method. Polytype of SiC was determined using X-ray diffraction. Phase identification and quantification were estimated via a PANalytical X’Pert X-ray diffraction unit, and a Cu Kα X-ray source at 45 kV and 40 mA was used for analysis. Scan range was from 10° to 90° 2θ. The virtual step size was 0.0131° and rotation was 16 rpm for each scan. All scans were recorded by Data Collector, and after that, Rietveld analysis was done using MDI Jade 9 software to determine the phase of the SiC. Especially, the free carbon peak present at 26.6° 2θ was important to understand if the addition of carbon was reacted during sintering processing or not.3Fe(CN)6 in 60 mL DI water).Using LECO Vari/Cut 50 diamond saw, the samples were sectioned and mounted in epoxy using a Buehler SimpliMet 1000 Mounting Press. Then, samples were polished to 0.25 µm finish using Buehler EcoMet 250 Grinder-Polisher. To highlight SiC grain boundaries, one piece of polished samples was etched by a modified Murakami method (20 g KOH and 20 g KField emission scanning electron microscope (Zeiss Sigma FESEM with Oxford EDS System) was used to examine pores, inhomogeneity, and shape of grains. Average grain sizes of the dense samples were estimated by linear intercept procedure using minimum of 100 intersections. Microhardness was performed on polished surfaces using LECO M-400-G3 microhardness tester with Vickers diamond tip. Specifically, 9.8 N load was applied for 10 s on polished sample surfaces. At least 10 acceptable indentations were made. Via Keyence VHX 5000 digital microscope, indent sizes were measured.P (kgf) is a force and d (mm) is the average length of the two diagonals of the indentation. Each hardness value presents the mean of the 10 calculated hardness.According to the following equation, Vickers hardness value was calculated to refer to ASTM C1327-15 :(1)HvKc=0.For 1.0 wt.% (8.79 μm) and 1.5 wt.% C (10.74 μm) dry mixed samples, large grain sizes and irregular shape porosities were observed. With increasing the carbon content from 2.0 to 5.0 wt.%, surplus carbon started appearing on the FESEM images. All samples had large, elongated grains and large quantity of porosity. Additionally, the images showed that the dry mixing method was not the way to have well disperse, similar grains.On the other hand, wet mixed sample with 1.0 wt.% C (3.79 μm) had some slight porosity. The pores tented to decrease until the specimen reached the full density. Wet mixed 1.5 wt.% C (4.11 μm) sample have reached almost full density with only occasional small pores; it can be suggested that addition of carbon was enough to remove oxide layer. Both 1.0 and 1.5 wt.% samples had combined with small equiaxed grains and some elongation of grains. As seen in 4C (0.5 wt.%) and 0.5–5.0 wt.% C were added to SiC. Addition of 0.5–2.5 wt.% carbon showed higher than 99% relative density. However, addition of carbon after 2.5 wt.% decreased the relative densities of samples.The densities of the dry mixing and wet mixing series samples were determined using Archimedes’ method. They are shown below in Looking at the wet mixed series sample densities, it was clear that addition of 0.5 wt.% carbon was insufficient for removing the surface oxygen and reached the full densification. Addition of 1.0–1.5 wt.% carbon was enough carbon to efficiently removed the oxide layer from SiC surface, so that the density increased but as carbonaceous inclusions do not leave anything in the microstructure.For all series, with higher levels of carbon, there is more than enough carbon to react with and eliminate oxygen and surplus carbon remained. Since the theoretical density of C is less than SiC and excess carbon caused porosities in the structure, the density of the samples decreased. Addition of less or large amount of carbon affects the SiC properties and prevents it from having high density. Maitre et. al. sintered SiC without sintering aids at 1950 °C under applied pressure of 100 MPa for 5 min by SPS. Despite the very high pressure at the same sintering temperature, only 97.5% density was achieved .Elastic modulus is especially an important property for ceramics and can be used in special applications like SiC, since it tells when the material will deform. The material may require greater force to deform when the material has higher elastic modulus. Elastic modulus of dry mixed and wet mixed series can be seen in The elastic modulus of wet mixed series changed between 432 and 351 GPa. The elastic modulus had the same trend with the dry mixed samples. The values first increased with increasing the carbon content, then decreased with increasing carbon addition. The highest elastic modulus value was obtained at 1.5 wt.% C, which was 450 GPa. The lowest elastic modulus value was obtained again at 5.0 wt% C, which was 351 GPa.It was clear that there was a relationship between the density and the elastic module. Results showed that the elastic modulus increased with increasing the density of the samples. This result was found because of two reasons. First, carbon has lower elastic modulus value, so the surplus carbon affect the SiC ceramics, and it reduced the elastic modulus of dense SiC. Second, addition of carbon from 0.5 to 1.5 wt.% C helped to reduce porosity and SiC reached the high elastic modulus, however, addition of more than 1.5 wt.% of carbon caused porosity. Due to the porous structure, elastic modulus decreased. To achieve high dense SiC with high elastic modulus, sufficiently carbon should be added.4C was not found in XRD analysis of any samples. For both series, from 0.5 to 1.5 wt.% C samples did not have any excess carbon; it showed that all addition carbon was reached with oxygen. Free carbon started to appear when more carbon was added. The same amounts of carbon were added to dry mixed and wet mixed samples, but when looking at the free carbon’s amount, it can be seen that dry mixed samples had more surplus carbon in dense SiC. It may suggest that poor mixing (dry mixing) caused these results. It was clearly seen in FESEM images that specimens had agglomerates carbon.Rietveld refinement  of the XRD patterns of the samples may be seen in Looking at the phase fraction of 4H/6H, we see that when samples had mainly 4H polytype, sample had larger averages grain sizes. It can be seen in For the wet mixed samples, with increasing the carbon content from 0.5 to 1.5 wt.%, the amount of 4H polytype was higher than 6H polytype. In addition, the average grain size was enhanced until 1.5 wt.% C. However, as the amount of added carbon increased, both the average grain size and the 4H ratio decreased. Ayguzer Yasar et al. also was mentioned that 4H polytype displayed elongated grains, whereas 6H polytype showed small equiaxed grains . Liu et 1/2. However, due to the poor mixing, carbon was not well distributed, so it was hard to make inferences about effect of carbon content.Hardness and calculated fracture toughness values can be seen in Wet mixed SiC samples hardness values changed from 24.06 to 27.96 GPa. Having oxide layer on the SiC had negative effect on hardness of SiC ceramics. Since 0.5 wt.% C was not enough to remove all oxygen, SiC did not reach high hardness. However, 1.5 wt.% C addition was enough to remove oxide layer, hardness reached the highest value. Hardness increased from 26.27 to 27.96 GPa when the carbon content increased from 0.5 to 1.5 wt.%. Then with increasing the carbon content from 2.0 to 5.0 wt.%, hardness reduced from 27.75 to 25.48 GPa. Since carbon’s hardness is lower than SiC, surplus carbon caused drop in the hardness value of SiC ceramics. Excess carbon acts like oxygen, and it has detrimental effect on SiC. Sufficient carbon should be added to SiC in order to improve the properties of SiC. To compare the hardness values, in the study of Lomello et al., SiC samples were sintered at 1900 °C with a high applied pressure of 70 MPa. However, a hardness value of maximum 25 GPa could be obtained. This was because the sintering temperature was not sufficient, and the samples only reached 96% density, resulting in a lower hardness value [1/2. Silicon carbide has a low fracture toughness, and the addition of different amounts of carbon has not been sufficiently modified to improve this feature.Fracture toughness values vary in between 2.26 and 2.52 MPa.m4C and 0.5–5.0 wt.% C with dry mixing (specktromill) and wet mixing  was done and samples were sintered at 1950 °C under applied pressure of 50 MPa for 5 min by SPS. Mixing method was found to be significant in properties of SiC ceramics. Dry mixing method showed poor mixing and detrimental effect of microstructural and mechanical properties of SiC ceramics. Samples mixed with dry mixing showed large grain sizes and large irregular shape pores. On the other hand, wet mixing showed well distribution of carbon. The highest density (99%) was reached in the sample with 1.5% C addition with wet milling method. The highest hardness and elastic modulus were achieved at 1.5 wt.% C, and the values were 27.96 and 450 GPa, respectively. Rietveld analysis showed that the samples had mainly 6H polytype when the high density was reached. In addition, it was found from the results of the analysis that the 4H polytype caused large elongated grains, whereas the 6H polytype caused small coaxial grains. Last but not least, 1.5 wt.% C addition was sufficient to remove the oxide layer from SiC and improve the properties of dense SiC ceramics. It has been observed that excess carbon affects the material as bad as oxygen. Surplus carbon inhibited to achieve high density with high elastic modulus and hardness.In this study, to produce SiC ceramics, SiC powder mixed addition of 0.5 wt.% B