Emerging worldwide in the past decade, there has been a significant increase in multidrug-resistant bacteria from serious nosocomial infections, especially carbapenemase-producing Gram-negative bacilli that have emerged worldwide. The objective of this study is to investigate carbapenem resistance in Gram-negative bacilli bacteria using phenotypic detection, antimicrobial resistance profiles and genotypic characterisation methods.200 Gram-negative bacilli isolates were collected from different clinical specimens. All clinical samples were exposed to isolation and identification of significant pathogens applying bacteriological examination and an automated Vitek-2 system. The isolates were subjected to susceptibility tests by the Vitek-2 automated system and those isolates that were resistant to beta-lactam drugs, including carbapenems, third-generation cephalosporines or cefoxitin, were selected for phenotyping using Carba plus disc system assay for detection of carbapenemase-producing isolates. These isolates were further confirmed by molecular detection. PCR was used for the detection carbapenem-resistant genes .blaNDM 83% (44/53) followed by blaOXA-48 75% (40/53), blaVIM 49% (26/53) and blaIMP 43% (23/53), while the gene blaKPC was least frequent 7% (4/53). 92% (46/51) of isolates were involved in the production of more than one carbapenemase gene.110 (55%) of 200 Gram-negative bacilli were identified as beta-lactam-resistant isolates. The frequency of carbapenem-resistant isolates was calculated to be 30.9% (n = 34/110). A collection totalling 65/110 (59%) isolates were identified as carbapenemase producers by phenotypic method. Moreover, among the 65 carbapenemase-producing Gram-negative isolates with a positive phenotype-based result, 30 (46%), 20 (30%) and 18 (27%) isolates were positive for OXA-48, KPC and MBL enzymes, respectively, as well as the production of 27% of AmpC with porin loss. Tigecycline was the most effective antibiotic that affected 70% of MDR isolates, but high rates of resistance were detected to other tested antimicrobials. Of interest, a high incidence of MDR, XDR and PDR profiles were observed among all carbapenemase-producing isolates. 36% (24/65) of the tested isolates were MDR to 3 to 5 antimicrobial classes. 29% (17/65) of the recovered isolates were XDR to 6 to 7 antimicrobial classes. Alarmingly, 24% (16/65) of isolates displayed PDR to all the tested 8 antimicrobial classes. Genotype assay, including 53 phenotypically confirmed carbapenemase-producing isolates of Gram-negative bacilli, found 51(96%) isolates were harbouring one or more genes. The most common carbapenemase gene was This study demonstrated the emergence of carbapenemase-producing Gram-negative pathogens implicated in healthcare-related infections. Accurate identification of carbapenem-resistant bacterial pathogens is essential for patient treatment, as well as the development of appropriate contamination control measures to limit the rapid spread of pathogens. Tigecycline exhibited potent antimicrobial activity against MDR, XDR and PDR-producing strains that establish a threatening alert which indicates the complex therapy of infections caused by these pathogens. Multidrug resistance has increased globally and is considered a public health threat. Several recent studies have reported the existence of multidrug-resistant bacterial pathogens from different origins including humans, poultry, cattle and fish. This has increased the need for routine application of antimicrobial susceptibility testing to detect the antibiotic of choice as well as screening of the emerging MDR strains , 2.In general, the phenomenon of MDR is primarily attributed to the recurrent and indiscriminate use of antibiotics as well as coding for some antimicrobial resistance genes .Enterobacteriaceae Reviewers' comments:Reviewer's Responses to QuestionsComments to 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: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: NoReviewer #2: No**********3. 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: YesReviewer #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: Comments to authors:- The current study is very interesting; however, the authors should address the following comments to improve the quality of the manuscript:- The manuscript should be revised for language editing and grammar mistakes by a native English speaker.- Please write the genes name in correct form all over the manuscript Title:I think the work would benefit from the title that contains main conclusion of the study (should be derived from the conclusion), please modify the title.Abstract:- The abstract must illustrates the used methods and the most prevalent results (give more hints about methods and results). Besides, rephrase the main conclusion of your findings.Introduction:-Give a hint about different infections caused by common pathogenic members of Enterobacteriaceae (such as E. coli and K. pneumonia) and Pseudomonas aeruginosa, their virulence factors, and the mechanism of disease occurrence.- The introduction needs to be more informative:-The authors should illustrate the public heath importance concerning the emergence of multidrug-resistant (MDR) bacterial pathogens that reflecting the necessary of new potent and safe antimicrobial agents. Several studies proved the widespread MDR- bacterial pathogens;Authors could add the following paragraph:Multidrug resistance has been increased globally that is considered public health threat. Several recent studies reported the existence of multidrug-resistant bacterial pathogens from different origins including humans, poultry, cattle, and fish that increase the need for routine application of the antimicrobial susceptibility testing to detect the antibiotic of choice as well as screening of the emerging MDR strains. You should cite the following valuable studies:1-PMID: 331778492-PMID: 324979223-PMID:330614724-PMID: 339478755-PMID: 324722096-PMID: 32994450-Rephrase the aim of work to be clear and better sound.Material and methods-Table 1 must be placed in the results section.-It is not acceptable to illustrate the prevalence of the bacterial pathogens in the methods; it should be placed to the results section.-Where are the methods of the isolation and identification of 200 Gram-negative bacteria?? You must illustrate in details and support your methods with specific references.- Phenotype-based method for carbapenemases: should be modified to be: Phenotypedetection carbapenemases using Disc diffusion method. Rephrase this section; add more details, discuss in details and specific references.- Confirmation of carbapenemase production using commercialcombination disk assay; add specific references to this section.-Molecular detection of genes should be modified:PCR-based detection of carbapenemase genes. Besides, add specific references.-Where are the statistical analyses?-Results:- Where are the results of phenotypic characters and the prevalence of the isolated bacterial pathogens from the examined samples? You must illustrate their prevalence in a new table.-Table 1 must be placed in the results section.- Illustrate in a new table the test results of the phenotypic MDR .-Illustrate the distribution of the carbapenemase genes among the recovered isolates in a new table.- Please increase the resolution of all figures (1200 dpi).-Where are the statistical analyses?-Discussion:-The discussion is too long and poor; the authors are advised to illustrate the real impact of their findings without repetition of results.-Conclusion- Should be rephrased to be sounded. A real conclusion should focus on the question or claim you articulated in your study, whose resolution has been the main objective of your paper?Reviewer #2: - The current study has a significant impact, but it needs a major revision:- The manuscript should be revised for grammar mistakes.-The title is broad, please modify the title.-In the introduction: discuss the public health importance of the members of Enterobacteriaceae and other Gram negative bacterial pathogens.-Improve the aim of work.Methods:-Transfer Table 1 to the results.-Transfer the prevalence of bacterial species to the results section.-Discuss the isolation and identification of the bacterial pathogens.-Specific references should be added to all the used methods and techniques.-Where is the statistical analysis?-Results:- Discuss the prevalence of the retrieved isolates in a new table.- Transfer Table 1 to the results- Please increase the resolution of all figures (1200 dpi).-Where is the statistical analysis?-Discussion:-Very long; please improve**********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,  4 Sep 2021Dear Dr. Abdelazeem Thank you for reviewing my manuscript. I appreciate your efforts and the efforts of the reviewers.I have worked hard to edit the revised manuscript and I hope I have done wellI look forward to having my research accepted in PLOS ONE journal.Sayran H. HajiAuthor Journal Requirements:When submitting your revision, we need you to address these additional requirements.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 athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfI tried to be in accordance with the requirements of PLOS ONE style------------------------------------------------------------------------------------2. In your Methods section, please provide additional information on the verbal consent provided by the patients, including as to how this verbal consent was documented or witnessed. I added regarding oral consent in the ethical issues section------------------------------------------------------------------------------------https://journals.plos.org/plosone/s/figures#loc-blot-and-gel-reporting-requirements and https://journals.plos.org/plosone/s/figures#loc-preparing-figures-from-image-files. When you submit your revised manuscript, please ensure that your figures adhere fully to these guidelines and provide the original underlying images for all blot or gel data reported in your submission. See the following link for instructions on providing the original image data: https://journals.plos.org/plosone/s/figures#loc-original-images-for-blots-and-gels.3. PLOS ONE now requires that authors provide the original uncropped and unadjusted images underlying all blot or gel results reported in a submission’s figures or Supporting Information files. This policy and the journal’s other requirements for blot/gel reporting and figure preparation are described in detail at plosone@plos.org if you have any questions.In your cover letter, please note whether your blot/gel image data are in Supporting Information or posted at a public data repository, provide the repository URL if relevant, and provide specific details as to which raw blot/gel images, if any, are not available. Email us at My cover letter contains the DOI of the original, uncropped, unedited images of the blot /gel data published in a public data repository.https://data.mendeley.com/datasets/fhnkrf3jdr/1------------------------------------------------------------------------------------http://journals.plos.org/plosone/s/data-availability.4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see The minimal data set is available in public repository and include the relevant DOIs, within my revised cover letter. https://data.mendeley.com/datasets/dp7g8rntyb/1Dataset: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: I don’t have any ethical or legal restrictionsWe will update your Data Availability statement to reflect the information you provide in your cover letter.------------------------------------------------------------------------------------5. Please ensure that you refer to Figure 1 in your text as, if accepted, production will need this reference to link the reader to the figure.I referenced all the Figures in my text to link the reader to the figure.------------------------------------------------------------------------------------6. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 1 in your text; if accepted, production will need this reference to link the reader to the Table.I referenced all the tables in my script to connect the reader to the figure.------------------------------------------------------------------------------------Reviewer #1: Comments to authors:- The current study is very interesting; however, the authors should address the following comments to improve the quality of the manuscript:- The manuscript should be revised for language editing and grammar mistakes by a native English speaker.I have checked for language editing and grammatical errors by native British speakers using online proofreading;Professional editing and proofreadingservices at your fingertipshttps://app.proofreadmyessay.co.uk/my-documents/------------------------------------------------------------------------------------- Please write the genes name in correct form all over the manuscript I corrected the name of the genes throughout the manuscript------------------------------------------------------------------------------------Title:I think the work would benefit from the title that contains main conclusion of the study (should be derived from the conclusion), please modify the title.I modified the title that contains main conclusion------------------------------------------------------------------------------------Abstract:- The abstract must illustrates the used methods and the most prevalent results (give more hints about methods and results). Besides, rephrase the main conclusion of your findings.More hints were given about the methods and results. Besides, I reformulated the main conclusion of the results.------------------------------------------------------------------------------------Introduction:-Give a hint about different infections caused by common pathogenic members of Enterobacteriaceae (such as E. coli and K. pneumonia) and Pseudomonas aeruginosa, their virulence factors, and the mechanism of disease occurrence.Hints were given about the common pathogenic members of Enterobacteriaceae in the introduction part------------------------------------------------------------------------------------- The introduction needs to be more informative:-The authors should illustrate the public heath importance concerning the emergence of multidrug-resistant (MDR) bacterial pathogens that reflecting the necessary of new potent and safe antimicrobial agents. Several studies proved the widespread MDR- bacterial pathogens;Authors could add the following paragraph:Multidrug resistance has been increased globally that is considered public health threat. Several recent studies reported the existence of multidrug-resistant bacterial pathogens from different origins including humans, poultry, cattle, and fish that increase the need for routine application of the antimicrobial susceptibility testing to detect the antibiotic of choice as well as screening of the emerging MDR strains. You should cite the following valuable studies:1-PMID: 331778492-PMID: 324979223-PMID:330614724-PMID: 339478755-PMID: 324722096-PMID: 32994450I have illustrated the public health importance of the emergence of multidrug-resistant (MDR) bacterial pathogens by adding your paragraph, and I really appreciate your help in providing these valuable studies, which I used as references.-------------------------------------------------------------------------------------Rephrase the aim of work to be clear and better sound. I paraphrased the aim of the workMaterial and methods-Table 1 must be placed in the results section. I have moved the table to the resulting part-------------------------------------------------------------------------------------It is not acceptable to illustrate the prevalence of the bacterial pathogens in the methods; it should be placed to the results section. I have moved the prevalence of bacterial pathogens to the results section.-------------------------------------------------------------------------------------Where are the methods of the isolation and identification of 200 Gram-negative bacteria?? You must illustrate in details and support your methods with specific references.The methods for isolating and identifying 200 Gram-negative bacteria have been explained with adding specific references. Furthermore, I added a new table to identify 200 Gram-negative bacteria.------------------------------------------------------------------------------------ Phenotype-based method for carbapenemases: should be modified to be: Phenotypedetection carbapenemases using Disc diffusion method. Rephrase this section; add more details, discuss in details and specific references.I have modified the phenotypic-based method for carbapenemes to the phenotype detection of carbapenemes using the disc diffusion method, and more details have been added to this section with references.------------------------------------------------------------------------------------- Confirmation of carbapenemase production using commercialcombination disk assay; add specific references to this section. The phenotypic-based method has been combined with confirmation of carbapenemase production using commercial combination disk checked, because I think it was duplicated, and specific references were added-------------------------------------------------------------------------------------Molecular detection of genes should be modified:PCR-based detection of carbapenemase genes. Besides, add specific references.Molecular gene detection was changed to PCR-based detection of carbapenemase genes. Besides, specific references have been added.-------------------------------------------------------------------------------------Where are the statistical analyses? Statistical analyzes for this study were designed using GraphPad Prism . The Chi-square test was applied to analyze the obtained data.-------------------------------------------------------------------------------------Results:- Where are the results of phenotypic characters and the prevalence of the isolated bacterial pathogens from the examined samples? You must illustrate their prevalence in a new table.The results of the phenotypic characteristics and prevalence of bacterial pathogens isolated from the examined samples were added to a new table with a clear explanation of the correlation in the text. -------------------------------------------------------------------------------------Table 1 must be placed in the results section. Table 1 has been converted to Table 2 and moved to the result section. ------------------------------------------------------------------------------------ Illustrate in a new table the test results of the phenotypic MDR . I have developed a new table of MDR phenotypic test results identifying the antimicrobial classes of the antimicrobial agents used.-------------------------------------------------------------------------------------Illustrate the distribution of the carbapenemase genes among the recovered isolates in a new table. The distribution of carbapenemase genes among the recovered isolates is illustrated in a new table------------------------------------------------------------------------------------- Please increase the resolution of all figures (1200 dpi). I have increased the resolution. Hope it is clear now-------------------------------------------------------------------------------------Where are the statistical analyses?Statistical analyzes for this study were designed using GraphPad Prism . The Chi-square test was applied to analyze the obtained data.-------------------------------------------------------------------------------------Discussion:-The discussion is too long and poor; the authors are advised to illustrate the real impact of their findings without repetition of results. I've shortened the discussion and deleted all the duplicates as much as I can-------------------------------------------------------------------------------------Conclusion- Should be rephrased to be sounded. A real conclusion should focus on the question or claim you articulated in your study, whose resolution has been the main objective of your paper? The conclusion has been reformulated to be presented and includes the main resolution of my study.------------------------------------------------------------------------------------Reviewer #2: - The current study has a significant impact, but it needs a major revision:- The manuscript should be revised for grammar mistakes. I have checked for language editing and grammatical errors by native British speakers using online proofreading;Professional editing and proofreadingservices at your fingertipshttps://app.proofreadmyessay.co.uk/my-documents/-------------------------------------------------------------------------------------The title is broad, please modify the title. I have modified and shortened the title -------------------------------------------------------------------------------------In the introduction: discuss the public health importance of the members of Enterobacteriaceae and other Gram-negative bacterial pathogens. The public health importance of the members of Enterobacteriaceae and other Gram-negative bacterial pathogens was discussed in the introduction part-------------------------------------------------------------------------------------Improve the aim of work. The purpose of the work has improved------------------------------------------------------------------------------------Methods:-Transfer Table 1 to the results. I have moved the table to the resulting part-------------------------------------------------------------------------------------Transfer the prevalence of bacterial species to the results section. I have moved the prevalence of bacterial pathogens to the results section.-------------------------------------------------------------------------------------Discuss the isolation and identification of the bacterial pathogens. The methods for isolating and identifying Gram-negative bacteria have been explained with adding specific references. Furthermore, I added a new table to identify 200 Gram-negative bacteria.-------------------------------------------------------------------------------------Specific references should be added to all the used methods and techniques. I added specific references to all the methods and techniques used-------------------------------------------------------------------------------------Where is the statistical analysis?Statistical analyzes for this study were designed using GraphPad Prism . The Chi-square test was applied to analyze the obtained data.-------------------------------------------------------------------------------------Results:- Discuss the prevalence of the retrieved isolates in a new table.The results of the prevalence of bacterial pathogens isolated from the examined samples were added to a new table with a clear explanation in the text.------------------------------------------------------------------------------------- Transfer Table 1 to the results Table 1 has been converted to Table 2 and moved to the result section.------------------------------------------------------------------------------------- Please increase the resolution of all figures (1200 dpi). I have increased the resolution. Hope it is clear now------------------------------------------------------------------------------------Discussion:-Very long; please improveI've shortened and improved the discussion as much as I can________________________________________AttachmentResponse to Reviewers30.08.docxSubmitted filename: Click here for additional data file. 7 Sep 2021PONE-D-21-22590R1Prevalence and characterisation of carbapenemase encoding genes in multidrug-resistant Gram-negative bacilliPLOS ONEDear Dr. haji,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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Oct 22 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.Please include the following items when submitting your revised manuscript:If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.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.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: We look forward to receiving your revised manuscript.Kind regards,Abdelazeem Mohamed Algammal, Prof, Ph.DAcademic EditorPLOS ONE[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. 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: (No Response)**********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?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: Yes**********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 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: The authors have addressed some of my comments; however the haveignored a major comment concerning the introduction.Please address the following comment:The introduction needs to be more informative:-The authors should illustrate the public heath importance concerning the emergenceof multidrug-resistant (MDR) bacterial pathogens that reflecting the necessary of newpotent and safe antimicrobial agents. Several studies proved the widespread MDRbacterial pathogens;Authors could add the following paragraph:Multidrug resistance has been increased globally that is considered public healththreat. Several recent studies reported the existence of multidrug-resistant bacterialpathogens from different origins including humans, poultry, cattle, and fish thatincrease the need for routine application of the antimicrobial susceptibility testing todetect the antibiotic of choice as well as screening of the emerging MDR strains. Youshould cite the following valuable studies:1-PMID: 331778492-PMID: 324979223-PMID:330614724-PMID: 339478755-PMID: 324722096-PMID: 32994450**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  11 Sep 2021Journal Requirements:When submitting your revision, we need you to address these additional requirements.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 athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfI tried to be in accordance with the requirements of PLOS ONE style------------------------------------------------------------------------------------2. In your Methods section, please provide additional information on the verbal consent provided by the patients, including as to how this verbal consent was documented or witnessed. I added regarding oral consent in the ethical issues section------------------------------------------------------------------------------------https://journals.plos.org/plosone/s/figures#loc-blot-and-gel-reporting-requirements and https://journals.plos.org/plosone/s/figures#loc-preparing-figures-from-image-files. When you submit your revised manuscript, please ensure that your figures adhere fully to these guidelines and provide the original underlying images for all blot or gel data reported in your submission. See the following link for instructions on providing the original image data: https://journals.plos.org/plosone/s/figures#loc-original-images-for-blots-and-gels.3. PLOS ONE now requires that authors provide the original uncropped and unadjusted images underlying all blot or gel results reported in a submission’s figures or Supporting Information files. This policy and the journal’s other requirements for blot/gel reporting and figure preparation are described in detail at plosone@plos.org if you have any questions.In your cover letter, please note whether your blot/gel image data are in Supporting Information or posted at a public data repository, provide the repository URL if relevant, and provide specific details as to which raw blot/gel images, if any, are not available. Email us at My cover letter contains the DOI of the original, uncropped, unedited images of the blot /gel data published in a public data repository.https://data.mendeley.com/datasets/fhnkrf3jdr/1------------------------------------------------------------------------------------http://journals.plos.org/plosone/s/data-availability.4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see The minimal data set is available in public repository and include the relevant DOIs, within my revised cover letter. https://data.mendeley.com/datasets/dp7g8rntyb/1Dataset: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: I don’t have any ethical or legal restrictionsWe will update your Data Availability statement to reflect the information you provide in your cover letter.------------------------------------------------------------------------------------5. Please ensure that you refer to Figure 1 in your text as, if accepted, production will need this reference to link the reader to the figure.I referenced all the Figures in my text to link the reader to the figure.------------------------------------------------------------------------------------6. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 1 in your text; if accepted, production will need this reference to link the reader to the Table.I referenced all the tables in my script to connect the reader to the figure.------------------------------------------------------------------------------------Reviewer #1: Comments to authors:- The current study is very interesting; however, the authors should address the following comments to improve the quality of the manuscript:- The manuscript should be revised for language editing and grammar mistakes by a native English speaker.I have checked for language editing and grammatical errors by native British speakers using online proofreading;Professional editing and proofreadingservices at your fingertipshttps://app.proofreadmyessay.co.uk/my-documents/------------------------------------------------------------------------------------- Please write the genes name in correct form all over the manuscript I corrected the name of the genes throughout the manuscript------------------------------------------------------------------------------------Title:I think the work would benefit from the title that contains main conclusion of the study (should be derived from the conclusion), please modify the title.I modified the title that contains main conclusion------------------------------------------------------------------------------------Abstract:- The abstract must illustrates the used methods and the most prevalent results (give more hints about methods and results). Besides, rephrase the main conclusion of your findings.More hints were given about the methods and results. Besides, I reformulated the main conclusion of the results.------------------------------------------------------------------------------------Introduction:-Give a hint about different infections caused by common pathogenic members of Enterobacteriaceae (such as E. coli and K. pneumonia) and Pseudomonas aeruginosa, their virulence factors, and the mechanism of disease occurrence.Hints were given about the common pathogenic members of Enterobacteriaceae in the introduction part------------------------------------------------------------------------------------- The introduction needs to be more informative:-The authors should illustrate the public heath importance concerning the emergence of multidrug-resistant (MDR) bacterial pathogens that reflecting the necessary of new potent and safe antimicrobial agents. Several studies proved the widespread MDR- bacterial pathogens;Authors could add the following paragraph:Multidrug resistance has been increased globally that is considered public health threat. Several recent studies reported the existence of multidrug-resistant bacterial pathogens from different origins including humans, poultry, cattle, and fish that increase the need for routine application of the antimicrobial susceptibility testing to detect the antibiotic of choice as well as screening of the emerging MDR strains. You should cite the following valuable studies:1-PMID: 331778492-PMID: 324979223-PMID:330614724-PMID: 339478755-PMID: 324722096-PMID: 32994450I have illustrated the public health importance of the emergence of multidrug-resistant (MDR) bacterial pathogens by adding your paragraph, and I really appreciate your help in providing these valuable studies, which I used as references.-------------------------------------------------------------------------------------Rephrase the aim of work to be clear and better sound. I paraphrased the aim of the workMaterial and methods-Table 1 must be placed in the results section. I have moved the table to the resulting part-------------------------------------------------------------------------------------It is not acceptable to illustrate the prevalence of the bacterial pathogens in the methods; it should be placed to the results section. I have moved the prevalence of bacterial pathogens to the results section.-------------------------------------------------------------------------------------Where are the methods of the isolation and identification of 200 Gram-negative bacteria?? You must illustrate in details and support your methods with specific references.The methods for isolating and identifying 200 Gram-negative bacteria have been explained with adding specific references. Furthermore, I added a new table to identify 200 Gram-negative bacteria.------------------------------------------------------------------------------------ Phenotype-based method for carbapenemases: should be modified to be: Phenotypedetection carbapenemases using Disc diffusion method. Rephrase this section; add more details, discuss in details and specific references.I have modified the phenotypic-based method for carbapenemes to the phenotype detection of carbapenemes using the disc diffusion method, and more details have been added to this section with references.------------------------------------------------------------------------------------- Confirmation of carbapenemase production using commercialcombination disk assay; add specific references to this section. The phenotypic-based method has been combined with confirmation of carbapenemase production using commercial combination disk checked, because I think it was duplicated, and specific references were added-------------------------------------------------------------------------------------Molecular detection of genes should be modified:PCR-based detection of carbapenemase genes. Besides, add specific references.Molecular gene detection was changed to PCR-based detection of carbapenemase genes. Besides, specific references have been added.-------------------------------------------------------------------------------------Where are the statistical analyses? Statistical analyzes for this study were designed using GraphPad Prism . The Chi-square test was applied to analyze the obtained data.-------------------------------------------------------------------------------------Results:- Where are the results of phenotypic characters and the prevalence of the isolated bacterial pathogens from the examined samples? You must illustrate their prevalence in a new table.The results of the phenotypic characteristics and prevalence of bacterial pathogens isolated from the examined samples were added to a new table with a clear explanation of the correlation in the text. -------------------------------------------------------------------------------------Table 1 must be placed in the results section. Table 1 has been converted to Table 2 and moved to the result section. ------------------------------------------------------------------------------------ Illustrate in a new table the test results of the phenotypic MDR . I have developed a new table of MDR phenotypic test results identifying the antimicrobial classes of the antimicrobial agents used.-------------------------------------------------------------------------------------Illustrate the distribution of the carbapenemase genes among the recovered isolates in a new table. The distribution of carbapenemase genes among the recovered isolates is illustrated in a new table------------------------------------------------------------------------------------- Please increase the resolution of all figures (1200 dpi). I have increased the resolution. Hope it is clear now-------------------------------------------------------------------------------------Where are the statistical analyses?Statistical analyzes for this study were designed using GraphPad Prism . The Chi-square test was applied to analyze the obtained data.-------------------------------------------------------------------------------------Discussion:-The discussion is too long and poor; the authors are advised to illustrate the real impact of their findings without repetition of results. I've shortened the discussion and deleted all the duplicates as much as I can-------------------------------------------------------------------------------------Conclusion- Should be rephrased to be sounded. A real conclusion should focus on the question or claim you articulated in your study, whose resolution has been the main objective of your paper? The conclusion has been reformulated to be presented and includes the main resolution of my study.------------------------------------------------------------------------------------Reviewer #2: - The current study has a significant impact, but it needs a major revision:- The manuscript should be revised for grammar mistakes. I have checked for language editing and grammatical errors by native British speakers using online proofreading;Professional editing and proofreadingservices at your fingertipshttps://app.proofreadmyessay.co.uk/my-documents/-------------------------------------------------------------------------------------The title is broad, please modify the title. I have modified and shortened the title -------------------------------------------------------------------------------------In the introduction: discuss the public health importance of the members of Enterobacteriaceae and other Gram-negative bacterial pathogens. The public health importance of the members of Enterobacteriaceae and other Gram-negative bacterial pathogens was discussed in the introduction part-------------------------------------------------------------------------------------Improve the aim of work. The purpose of the work has improved------------------------------------------------------------------------------------Methods:-Transfer Table 1 to the results. I have moved the table to the resulting part-------------------------------------------------------------------------------------Transfer the prevalence of bacterial species to the results section. I have moved the prevalence of bacterial pathogens to the results section.-------------------------------------------------------------------------------------Discuss the isolation and identification of the bacterial pathogens. The methods for isolating and identifying Gram-negative bacteria have been explained with adding specific references. Furthermore, I added a new table to identify 200 Gram-negative bacteria.-------------------------------------------------------------------------------------Specific references should be added to all the used methods and techniques. I added specific references to all the methods and techniques used-------------------------------------------------------------------------------------Where is the statistical analysis?Statistical analyzes for this study were designed using GraphPad Prism . The Chi-square test was applied to analyze the obtained data.-------------------------------------------------------------------------------------Results:- Discuss the prevalence of the retrieved isolates in a new table.The results of the prevalence of bacterial pathogens isolated from the examined samples were added to a new table with a clear explanation in the text.------------------------------------------------------------------------------------- Transfer Table 1 to the results Table 1 has been converted to Table 2 and moved to the result section.------------------------------------------------------------------------------------- Please increase the resolution of all figures (1200 dpi). I have increased the resolution. Hope it is clear now------------------------------------------------------------------------------------Discussion:-Very long; please improveI've shortened and improved the discussion as much as I canAttachmentResponse to Reviewers30.08.docxSubmitted filename: Click here for additional data file. 29 Sep 2021PONE-D-21-22590R2Prevalence and characterisation of carbapenemase encoding genes in multidrug-resistant Gram-negative bacilliPLOS ONEDear Dr. haji,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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.==============================ACADEMIC EDITOR: Please address all the reviewer comments, it is your last chance./>==============================plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Nov 13 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. 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For instructions see: We look forward to receiving your revised manuscript.Kind regards,Abdelazeem Mohamed Algammal, Prof, Ph.DAcademic EditorPLOS ONE[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. 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: (No Response)**********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?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: Yes**********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 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: In the introduction section the authors reported several recent studies in the following paragraph,however they have cited only one reference.. How??Please cite all references:Multidrug resistance has been increased globally that is considered public healththreat. Several recent studies reported the existence of multidrug-resistant bacterialpathogens from different origins including humans, poultry, cattle, and fish thatincrease the need for routine application of the antimicrobial susceptibility testing todetect the antibiotic of choice as well as screening of the emerging MDR strains. Youshould cite the following valuable studies:1-PMID: 331778492-PMID: 324979223-PMID:330614724-PMID: 339478755-PMID: 324722096-PMID: 32994450Lines 438- 505; please add specific references. The following sentence is found instead of refrences; please revise and correct.Error! Reference source not found..**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  7 Oct 2021Reviewer #1: In the introduction section the authors reported several recent studies in the following paragraph,however they have cited only one reference.. How??Please cite all references:________________________________________With my appreciation, I have referred to all of the following valuable studies as references in the introduction, material methods, and results in the manuscript.1-PMID: 33177849 reference number 302-PMID:33061472 reference number 33-PMID: 33947875 reference number 1 4-PMID: 32472209 reference number 225-PMID: 32994450 reference number 2________________________________________Lines 438- 505; please add specific references. The following sentence is found instead of refrences; please revise and correct. Error! Reference source not found. ________________________________________I have revised and corrected the error related to the reference source on lines 438-505.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 11 Oct 2021Prevalence and characterisation of carbapenemase encoding genes in multidrug-resistant Gram-negative bacilliPONE-D-21-22590R3Dear Dr. haji,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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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?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: Yes**********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 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: The authors have carried out a significant changes to the manuscript. They have addressed all the suggested corrections and comments. Really, it's an interesting study that has a significant impact. Now, the manuscript could be accepted.Congratulations.**********what does this mean?). If published, this will include your full peer review and any attached files.7. 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Where you have provided it, we have included your ORCID, so your contribution can be unambiguously assigned to you.https://orcid.org/0000-0002-2576-7959Acosta-Serrano A https://orcid.org/0000-0002-1095-8445Ahmad K https://orcid.org/0000-0003-2285-5133Aldred N Ali FAllen Ahttps://orcid.org/0000-0003-0868-8578Alvarsson A https://orcid.org/0000-0002-4395-5232Andersen J Arimura YAzem ABallestrem CBarrachina FBerridge Mhttps://orcid.org/0000-0003-1853-1494Besteiro S https://orcid.org/0000-0003-0857-495XBeynon R Bharti PBin ZBin ZBizard ABlanco-Aparicio CBloom KBodas MBoschetti CBose RBoukhatmi HBrown NBuchwalter Ahttps://orcid.org/0000-0002-3780-8164Bulgakova N https://orcid.org/0000-0003-0038-1985Bunch H Caceres JCallaini GCamins ACampbell CCancio Ihttps://orcid.org/0000-0003-2372-4848Čapková Frydrychová R Carmena ACasali Ahttps://orcid.org/0000-0002-3572-7598Catic A https://orcid.org/0000-0002-8701-4995Chamberlain L https://orcid.org/0000-0002-5974-1650Chan K-Y Chen FChen XChen XCheng C-WCheng Y-CClaereboudt Ehttps://orcid.org/0000-0002-0789-2633Claessen D Cohen NColgren Jhttps://orcid.org/0000-0002-8722-9371Contreras O https://orcid.org/0000-0002-9197-8041Cooper C Crow ACyert Mhttps://orcid.org/0000-0001-6671-7600D'Arcy P Deschenes Rhttps://orcid.org/0000-0002-2263-363XDougan S https://orcid.org/0000-0002-1028-7397Du L-L Ducatelle Rhttps://orcid.org/0000-0002-9305-3982Duclos M Dundee MDyson PEl-Danaf RElia Mhttps://orcid.org/0000-0003-1436-5759Engstler M Erhardt SEstévez Rhttps://orcid.org/0000-0003-3238-6692Etich J Farge GField CField MFiorani FFisher DFisher RForth J-HFranco SFukagawa TFukata Mhttps://orcid.org/0000-0002-5883-4433Fuller W https://orcid.org/0000-0003-4831-4087Funabiki H Galasko Dhttps://orcid.org/0000-0002-8914-7740Gallego-Delgado J Ganz JGardlik RGazouli MGershenzon JGodinho SGondim KGravholt Chttps://orcid.org/0000-0001-9668-6497Gray R Griffiths Ghttps://orcid.org/0000-0002-4738-0173Grose R Gruneberg Uhttps://orcid.org/0000-0002-7580-5124Hadjantonakis A-K Hammarlund-Udenaes MHamza IHarwood JHemler MHiraoka YHochegger HHolehouse AHolmes MHolthoff Khttps://orcid.org/0000-0003-4332-1640Hoskisson P https://orcid.org/0000-0003-0444-1017Hougland J Hunter TIlan NInestrosa NIsokawa MItzhaki LSJadavji Nhttps://orcid.org/0000-0002-7857-064XJakimowiz D Jin WJin ZJulien EKalsbeek AKathayat RKawaguchi S-YKawashima SKe HKeller SKerr I DKhan FHKim CKim JYhttps://orcid.org/0000-0002-6776-2451Kim JH Kloxin AMKoletas EKuan Y-SKuil Lhttps://orcid.org/0000-0003-4281-5884Kurita T Lackner KLanyon-Hogg TLax GLeigh Nhttps://orcid.org/0000-0001-7317-5651Liang S https://orcid.org/0000-0001-8097-7222Lin G https://orcid.org/0000-0002-7166-9233Loppin B https://orcid.org/0000-0002-7803-8442Lu Z Luty AJFMadrid MMakumi AMarasco DMarco AMartin FMartinez PMartinho RMassana RMcDougall Ahttps://orcid.org/0000-0002-4478-7584Knafo S Min Rhttps://orcid.org/0000-0001-9928-9294Moran Y Morrow ZMullin JMNetherton CNichols JNielsen ONodwell JNorton LOdone APawelec Ghttps://orcid.org/0000-0002-1425-9879Pestov D Pfanner NPlotkin MPolishchuk Rhttps://orcid.org/0000-0003-1507-0936Polymenis M Ranjit MRavindran VRhind NRigden DRikhy RRobinson DRoig Ihttps://orcid.org/0000-0003-2493-3748Rudolph C https://orcid.org/0000-0003-2583-7299Sadej R Sakai DSapio RSanes JSango KSantocanale Chttps://orcid.org/0000-0002-0311-0710Sarkar DS Sarko DSauer J-Dhttps://orcid.org/0000-0001-8999-5451Scheele C Schniepp HCSemenkovich CSeutin VShcherbata HSheng NShenolikar SShu XShutt TSidhu GSobrado PSoldati-Favre DSpencer SStülke JSudhof TSusi PSwan ASwelum AA-ATan KTanaka KTandon RTate Ehttps://orcid.org/0000-0002-7757-1739Thatcher GRJ Thomas GTirloni LTodd Rhttp://orcid.org/0000-0001-5779-2449Tommasino M Tsubouchi Hhttps://orcid.org/0000-0003-3048-9241Utrilla J https://orcid.org/0000-0002-1033-1335van der Giezen M van der Goot GVega JLVeit MVendetti SVincent BVlodavsky Ihttps://orcid.org/0000-0001-8730-0003Wang F Wang QWeissman KWeller SWestermann SWilkie Ihttps://orcid.org/0000-0002-4610-8397Williams RS Witte OWWolfner MYan AYan Bhttps://orcid.org/0000-0002-0969-5748Yuan X Zanetti GZechiedrich LZhang BZhang Fhttps://orcid.org/0000-0001-9733-8494Zhang X Zhao YZhu Ghttps://orcid.org/0000-0002-0609-8956Zille M The team really does appreciate all the work our reviewers do on behalf of the journal, and we look forward to working with you again in future.


Prostate cancer has been shown to be susceptible to significant stigmatisation, because to a large extent it is concealable, it has potentially embarrassing sexual symptoms and has significant impact on the psychosocial functioning.Opengrey.eu, were screened. We used thematic analysis, with narrative synthesis to analyse these data. We assessed risk of bias in the included studies using the RoBANS.This review included studies that focused on qualitative and/or quantitative data, where the study outcome was prostate cancer and included a measure of stigmatization. Electronic databases  and one database for grey literature In total, 18 studies met review inclusion criteria, incorporating a total of 2295 participants. All studies recruited participants with prostate cancer, however four studies recruited participants with other cancers such as breast cancer and lung cancer. Of the 18 studies, 11 studies evaluated perceived or felt stigma; four studies evaluated internalised or self-stigma; three studies evaluated more than one stigma domain.We found that patients living with prostate cancer encounter stigmatisation that relate to perception, internalisation, and discrimination experiences. We also identified several significant gaps related to the understanding of prostate cancer stigmatization, which provides an opportunity for future research to address these important public health issues.CRD42020177312.This systematic review protocol is registered with PROSPERO, the international prospective register of systematic reviews in health and social care. Registration number:  The SIS was used by five studies within the review , 42, 48 An additional limitation was a reliance on Western literature, many of the studies reported in this review were conducted in Western countries, therefore the voice of Eastern or other cultural settings is missing. This apparent bias in the literature could be accounted for by the incidence rate reported in different cultures for prostate cancer. A man living in North America is far more likely to be diagnosed with prostate cancer then a man living in South Central Asia for example . Hsing, This systematic review is the first to comprehensively review disease related stigmatization in patients living with prostate cancer, encompassing both qualitative and quantitative studies. Based on the results of this review, prostate cancer has been shown to be susceptible to significant stigmatisation, because to a large extent it is concealable, it has potentially embarrassing sexual symptoms and has potentially significant impact on the psychosocial functioning.Stigma has been a growing concern in cancer literature, and this study aimed to illuminate how prostate cancer stigmatisation relates to the lives of individuals experiencing the condition. Based on this research, there is clear rationale for further research exploring factors that influence or impede quality of life for prostate cancer patients, as a consequence of stigma.S1 Checklist(DOCX)Click here for additional data file. 29 Oct 2021
 PONE-D-21-26750

 A Systematic Review of Disease Related Stigmatization in Patients Living with Prostate Cancer

 PLOS ONEDear Dr. Larkin,

 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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Dec 06 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at
 A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.
 If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.Please include the following items when submitting your revised manuscript: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.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. 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We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: DL received funding from Edge Hill University to undertake this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Please include your amended statements within your cover letter; we will change the online submission form on your behalf. plosone@plos.org with a request to remove this option.3. Please note that in order to use the direct billing option the corresponding author must be affiliated with the chosen institute. Please either amend your manuscript to change the affiliation or corresponding author, or email us at http://journals.plos.org/plosone/s/supporting-information. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to Questions  Comments to 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: YesReviewer #2: Yes**********   2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #2: N/A**********   3. 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: YesReviewer #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 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. Reviewer #1: Well constructed and written paper on an important topic.On page 3 the statement combining watchful waiting and active surveillance is not quite accurate. Watchful waiting is applicable to all cancer risk groups.Reviewer #2: Please update referencing style as per journal guidelines.Abstract:Please do not begin your background paragraph with a statement about your methodology.Introduction:“Although some men are diagnosed after the cancer has spread beyond the prostate, , advances in treatment options ensure that 78% of men survive prostate cancer for 10 or more years .”What are the references for these stats?The second half of the introduction is informative and well-written.Methods:I enjoyed reading the methods section and the journey to final analysis and narrative-style review. Well done for a clear and transparent account of your search strategy and methods.Results and Discussion:Very little to fault. I have thoroughly enjoyed reading this review and am better informed as a result.I would suggest presenting the 3 major themes and sub-themes in a pictorial or easily accessible format as a figure so that readers can get a grasp of your findings rapidly. This will be the most effective and efficient way to get your message across.https://bjui-journals.onlinelibrary.wiley.com/doi/full/10.1111/bju.15159The second suggestion is to consider where your findings surrounding stigmatisation in prostate cancer fits into the survivorship essentials framework Limitations:I am interested in the authors’ thoughts on stigmatisation around this chronic disease in a predominantly western culture and literature compared with an eastern or other cultural setting.Overall, I commend the authors on tackling this oft overlooked aspects of a very common disease.**********   6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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 While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  29 Nov 2021Response to Reviewers We would like to thank the editorial team for taking the time and effort in considering our manuscript. We would particularly like to thank the two reviewers for their insightful comments. We have now taken on board all the comments from both reviewers and addressed each issue in turn below, without exception we have accepted and adopted the recommended changes. We now feel that the manuscript has been fundamentally improved, we therefore sincerely hope that with the changes made to the manuscript it can be once again considered for publication in PLOS ONE1. 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.pdf1. Response: Manuscript now meets PLOS ONE style requirements. Both the main body of the text and author affiliations have been updated. Larkin, D*1 ¶Birtle, A. J2&, Bradley, L1&, Dey, P3¶, Martin, C.R4&, Pilkington, M5&, and Romero-Rivas, C6&1 Department of Psychology, Edge Hill University, Lancashire, UK2 Department of Oncology, Rosemere Cancer Centre, Lancashire Teaching  Hospitals, Preston, UK3 Faculty of Health, Social Care and Medicine, Edge Hill University, Lancashire, UK4 Institute for Clinical and Applied Health Research (ICAHR), University of Hull, Hull, UK5 Department of Psychology, Manchester Metropolitan University, Manchester, UK6 Department of Evolutive and Educational Psychology, AUM, Madrid, Spain *Corresponding author information: Derek.Larkin@edgehill.ac.ukE-mail: ¶These authors contributed equally to this work& These authors also contributed equally to this work--------------------------------------------------------------------------------------------------------------------------------------------2. 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Labels have been labelled as Table 1, 2 & 3 Figure 1 & 2 These have I’ve also been updated within the text.--------------------------------------------------------------------------------------------------------------------------------------------5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.5. Response: To the best of the authors knowledge none of the papers have been retracted and none of the references have been removed, we have however included a subsequent reference in response to reviewers’ comments. References have been updated to conform to PLOS ONE citations, using the downloadable plug-in for Endnote. Additional references added in response to reviewer’s comment. 60. Dunn J, Green A, Ralph N, Newton RU, Kneebone A, Frydenberg M, et al. Prostate cancer survivorship essentials framework: guidelines for practitioners. BJU International 2020. doi:10.1111/bju.15159.63. Taitt HE. Global trends and prostate cancer: a review of incidence, detection, and mortality as influenced by race, ethnicity, and geographic location. Am J Men's Health. 2018;12(6):1807-23. doi:10.1177/1557988318798279.64. Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer. 2000;85(1):60-7. doi:10.1002/(SICI)1097-0215(20000101)85:1<60::AID-IJC11>3.0.CO;2-B.65. Akin-Odanye EO, Husman AJ. Impact of stigma and stigma-focused interventions on screening and treatment outcomes in cancer patients. Ecancermedicalscience. 2021. doi:10.3332/ecancer.2021.1308.66. Nyblade L, Stockton M, Travasso S, Krishnan S. A qualitative exploration of cervical and breast cancer stigma in Karnataka, India. BMC women's health. 2017;17(1):1-15. doi:10.1186/s12905-017-0407-x.--------------------------------------------------------------------------------------------------------------------------------------------Comments to the Author6 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: YesReviewer #2: YesResponse: no response required--------------------------------------------------------------------------------------------------------------------------------------------7. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: N/AResponse: no response required--------------------------------------------------------------------------------------------------------------------------------------------8. 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: YesReviewer #2: YesResponse: no response required--------------------------------------------------------------------------------------------------------------------------------------------9. 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: YesResponse: no response required-------------------------------------------------------------------------------------------------------------------------------------------- 10. Review Comments to the AuthorReviewer #1: Well-constructed and written paper on an important topic.10A On page 3 the statement combining watchful waiting and active surveillance is not quite accurate. Watchful waiting is applicable to all cancer risk groups.10A Response: Thank you for this helpful comment we have now removed the phrase “active surveillance” from the sentence. --------------------------------------------------------------------------------------------------------------------------------------------10B Reviewer #2: Please update referencing style as per journal guidelines.10B Response: References have been updated to conform to PLOS ONE citations, using the downloadable plug-in for Endnote. --------------------------------------------------------------------------------------------------------------------------------------------10C Abstract:Please do not begin your background paragraph with a statement about your methodology.10C Response: The sentence “We systematically review the scientific literature on stigma as it relates to prostate cancer across three principal domains: perception, internalisation, and discrimination experiences.” Has now been removed from the background paragraph. --------------------------------------------------------------------------------------------------------------------------------------------10D Introduction:“Although some men are diagnosed after the cancer has spread beyond the prostate, , advances in treatment options ensure that 78% of men survive prostate cancer for 10 or more years .”What are the references for these stats?https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer10D Response: These stats came from cancer research UK Additional reference added in response to reviewer’s comment. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer- type/prostate-cancer5. Cancer Research UK. Prostate Cancer Statistics 2021 [cited 2021 August]. Available from: The second half of the introduction is informative and well-written.Methods:I enjoyed reading the methods section and the journey to final analysis and narrative-style review. Well done for a clear and transparent account of your search strategy and methods.Results and Discussion:Very little to fault. I have thoroughly enjoyed reading this review and am better informed as a result.Response: no response required--------------------------------------------------------------------------------------------------------------------------------------------10E I would suggest presenting the 3 major themes and sub-themes in a pictorial or easily accessible format as a figure so that readers can get a grasp of your findings rapidly. This will be the most effective and efficient way to get your message across.10E Response: Thank you for this helpful suggestion we have now designed a figure that outlines the three major themes Labelled Figure 2-------------------------------------------------------------------------------------------------------------------------------------------https://bjui-journals.onlinelibrary.wiley.com/doi/full/10.1111/bju.1515910F The second suggestion is to consider where your findings surrounding stigmatisation in prostate cancer fits into the survivorship essentials framework 10F Response: Many thanks for this suggestion we have considered the framework and have added an extra passage linking the framework to the current review. “In 2020 a framework in which six major descriptions for men's current prostate cancer survivorship experience emerged: dealing with side effects; challenging; medically focused; uncoordinated; unmet needs; and anxious [60]. There was a total of 26 survivorship elements determined across six domains: health promotion and advocacy; shared management; vigilance; personal agency; care coordination; and evidence-based survivorship interventions. Stigmatisation is not directly addressed in the framework, however, topics raised within the current review are, such as psychosocial functioning, masculinity, social support, and quality of life. Stigmatisation therefore maps across a number of the domains within Dunn et al. [60] framework, clearly demonstrating the pervasive and encompassing nature of prostate cancer stigmatisation.” --------------------------------------------------------------------------------------------------------------------------------------------10G Limitations:I am interested in the authors’ thoughts on stigmatisation around this chronic disease in a predominantly western culture and literature compared with an eastern or other cultural setting.10G Response: Would like to thank the reviewer for the suggestion. We have added a small section within the limitations section of the paper, discussing the lack of literature on prostate cancer stigmatisation across different cultures. “An additional limitation was a reliance on Western literature, many of the studies reported in this review were conducted in Western countries, therefore the voice of Eastern or other cultural settings is missing. This apparent bias in the literature could be accounted for by the incidence rate reported in different cultures for prostate cancer. A man living in North America is far more likely to be diagnosed with prostate cancer then a man living in South Central Asia for example [63]. Hsing, Tsao and Devesa [64] hypothesised that differences in incidence and mortality rates reported for numerous countries could be the result of underdiagnosis, underreporting, disparities in screening practices, disparities in health-care access, gaps in knowledge and awareness, and attitudes toward prostate cancer and associated screening, and cancer stigma. This last point is a very important issue, since for example in African countries such as Nigeria, patients with cancer who faced stigma were more likely to conceal their diagnosis and seek medical care later, while cancer stigma primarily resulted in adverse psychosocial outcomes for patients Akin-Odanye and Husman [65]. In addition, experiences related to stigmatization may change across cultures. For example, in a study conducted in Karnataka, India, breast or cervical cancer stigma was defined in terms of both actual (enacted) stigma, such as seclusion or verbal stigma, and perceived (fear of) stigma, in the event that a cancer diagnosis was reported [66]. But, in short, there is a gap in the scientific literature about how cancer-related stigmatization is modulated across cultures, and on how interventions could be carried out in non-Western cultures.”--------------------------------------------------------------------------------------------------------------------------------------------10H Overall, I commend the authors on tackling this oft overlooked aspects of a very common disease.Response: no response required--------------------------------------------------------------------------------------------------------------------------------------------AttachmentResponse to reviewers.docxSubmitted filename: Click here for additional data file. 6 Dec 2021A Systematic Review of Disease Related Stigmatization in Patients Living with Prostate Cancer.PONE-D-21-26750R1Dear Dr. Larkin,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. 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