Targeted antiviral treatment using non-ionizing radiation therapy for SARS-CoV-2 and viral pandemics preparedness: Technique, methods and practical notes for clinical application

Ayan Barbora; Refael Minnes

doi:10.1371/journal.pone.0251780

Peer Review History

Original SubmissionOctober 7, 2020
25 Mar 2021 Decision Letter - Balveen Kaur, Editor PONE-D-20-31505 Targeted antiviral treatment using Non-ionizing Radiation Therapy for SARS-CoV-2 and viral pandemics preparedness: Technique, methods and practical notes for Clinical Application PLOS ONE Dear Dr. Minnes, 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. Please submit your revised manuscript by May 09 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 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. 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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 Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #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: Yes Reviewer #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. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The method part should be detailed. theoretical information should be made understandable by giving examples. The type of radiation to be applied should be given clearly. Other parts of the article contain very nice and useful information. Reviewer #2: Ayan Barbora and colleague present the feasible application of Non-ionizing Radiation therapy for SARS-COV-2 treatment. This study addresses an interesting aspect of SARS-COV-2 treatment during the pandemic outbreak. The authors present data of Non-Ionizing Radiation therapy in the treatment of EV71 and influenza A to devise the theoretical condition for SARS-COV-2 treatment using SRET. Major point: - The novel treatment for SARS-COV-2 by using Non-ionizing Radiation Therapy is calculated from the procedure used in the treatment of EV71 and influenza virus. If the author can test the procedure in SARS-COV-2, the conclusion will be more convincing. Minor points: - The authors devise a new treatment based on the virus physical properties, such as the virus’ particle size and charge. Does SARS-COV-2 biological characteristics, such as anatomical site of virus entry and replication, affect the efficacy of the new procedure proposed in this study? The authors should discuss this aspect in the discussion section. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0251780.r001
Revision 1
8 Apr 2021 Author Response Point-by-Point Response to Reviewers and Editor In the following, we address all the reviewers’ and editor’s comments: Reviewers’ and editor’s comments in red, our response in black. Reviewer #1: The method part should be detailed. theoretical information should be made understandable by giving examples. The type of radiation to be applied should be given clearly. Other parts of the article contain very nice and useful information. Our article presents a novel and fast antiviral treatment method that was developed based on published experimental evidence. Since the PLOS One guidelines demand that the Methods section come before the Results section, kindly refer to: 1. Results section containing the documented experimental examples, background information, theoretical basis of our technique and the type (frequency) and power dosage of radiation to be used; and 2. Methods section containing the mathematical formulations and derivatives 3. Discussion section containing details on how clinicians can derive appropriate treatment durations of the radiation involved by using the standard Ct values from viral swab tests done universally today. To make our argument clearer, we added some points in Introduction. We rewrote the following: "For enveloped viruses (viruses that are surrounded by a continuous bilayer membrane studded with viral proteins), such as the SARS-CoV-2 virus, the biophysical properties of the envelope are determined according to the composition of the membrane and its dimensions [6, 7, 8]. For such viruses, the infectivity of the virus is physically inactivated by membrane lysis. Viral genomes released from solubilized/ruptured membranes in itself remains incapable of infecting eukaryotic cells as demonstrated by the historically successful disease control afforded by alcohol, soap, etc. [9, 10]." and: "Although non-ionizing radiation penetration into the body is low compared to ionizing radiation exposure from external sources, recent advances in endoscopic Super High Frequency (SHF) (3-30 GHz) medical devices [18] allow delivery of such radiation deep within the human body. Such developments encourage the adaptation of this antiviral method [15] for viral pandemic(s) response." Details on the type and doses of the radiation can be found in Conclusions: " The equation y = -3.308x + 42.9 [3134]; provides a relation between 〖log〗_10 number of virus particles and clinical throat swab Ct values represented by x and y respectively. Patient-specific exposure durations of ~15x minutes can be derived for providing 100 % inactivation of SARS-CoV-2 virus particles by 10 – 17 GHz simultaneous irradiations at 14.5 ± 1 W/m2. For SARS-CoV-2 pandemic with an eclipse period of 10 hours between cellular entry and the release of new particles with a typical burst size of ∼103 virions [4] this method can reduce viral loads significantly enhancing patient recoveries and reducing pandemic mortality rates." Reviewer #2: Ayan Barbora and colleague present the feasible application of Non-ionizing Radiation therapy for SARS-COV-2 treatment. This study addresses an interesting aspect of SARS-COV-2 treatment during the pandemic outbreak. The authors present data of Non-Ionizing Radiation therapy in the treatment of EV71 and influenza A to devise the theoretical condition for SARS-COV-2 treatment using SRET. Major point: - The novel treatment for SARS-COV-2 by using Non-ionizing Radiation Therapy is calculated from the procedure used in the treatment of EV71 and influenza virus. If the author can test the procedure in SARS-COV-2, the conclusion will be more convincing. We present an innovative method of in situ antiviral treatment based on the physical phenomenon of SRET which has been experimentally demonstrated to be highly effective in inactivating other viruses previously (ref. EV71 and influenza virus examples). Being a physical phenomenon based on particle dimensions it is directly applicable with the currently available medical device technologies (ref. 18). However, since we currently do not have authorization/access to work with SARS-COV-2 viruses we are unable to test it out. Minor points: - The authors devise a new treatment based on the virus physical properties, such as the virus’ particle size and charge. Does SARS-COV-2 biological characteristics, such as anatomical site of virus entry and replication, affect the efficacy of the new procedure proposed in this study? The authors should discuss this aspect in the discussion section. We have added a new paragraph addressing these issues in the Discussion: " Conventional pharmaceutical/biological remedies being biochemical solutions are subject to evolution of mutant strains often rendering them ineffective, thereby necessitating constant production of stronger antidotes besides driving drug resistance. In contrast the non-ionizing radiation therapy antiviral treatment presented here works on resonant frequency and appropriate power dose [14, 15] determined solely by the physical particle dimensions of the viruses. As such, this technique is advantageous over other treatments given its dynamic adaptability which allows tuning the radiation parameters to particle dimensions of any virus concerned. Further, being a radiation-based therapy, this treatment can effectively reach deep tissues endoscopically [18], wherein any and all virus particles within the targeted resonant frequency range [14, 15] get their membranes ruptured during irradiation as soon as they form or are lying dormant. And viruses with membranes ruptured via this SRET based method are incapable of causing further infection upon introduction to other non-infected cells [15]." PLOS One Comments: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_titleauthors_affiliations.pdf The manuscript's style was changed according to the style requirements of PLOS ONE. We would like to thank the reviewers for their comments. We honestly believe that these comments helped us improve our manuscript. Sincerely, Dr. Refael Minnes (corresponding author) Department of Physics, Ariel University. 40700, Ariel, Israel Cell: (972)-54-6254094 Office: (972)-3-6453140 Email: refaelm@ariel.ac.il https://doi.org/10.1371/journal.pone.0251780.r002
4 May 2021 Decision Letter - Eric Charles Dykeman, Editor Targeted antiviral treatment using Non-ionizing Radiation Therapy for SARS-CoV-2 and viral pandemics preparedness: Technique, methods and practical notes for Clinical Application PONE-D-20-31505R1 Dear Dr. Minnes, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Eric Charles Dykeman, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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 Reviewer #2: 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 Reviewer #2: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (No Response) ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: (No Response) ****** 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 Reviewer #2: (No Response) ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: All corrections were made. This article can be accepted. Although non-ionizing radiation penetration into the body is low compared to ionizing radiation exposure from external sources, recent advances in endoscopic Super High Frequency (SHF) (3-30 GHz) medical devices [18] allow delivery of such radiation deep within the human body. Such developments encourage the adaptation of this antiviral method [15] for viral pandemic(s) response." Details on the type and doses of the radiation can be found in Conclusions: " The equation y = -3.308x + 42.9 [3134]; provides a relation between 〖log〗_10 number of virus particles and clinical throat swab Ct values represented by x and y respectively. Patient-specific exposure durations of ~15x minutes can be derived for providing 100 % inactivation of SARS-CoV-2 virus particles by 10 – 17 GHz simultaneous irradiations at 14.5 ± 1 W/m2. For SARS-CoV-2 pandemic with an eclipse period of 10 hours between cellular entry and the release of new particles with a typical burst size of ∼103 virions [4] this method can reduce viral loads significantly enhancing patient recoveries and reducing pandemic mortality rates." 2.Methods section containing the mathematical formulations and derivatives 3.Discussion section containing details on how clinicians can derive appropriate treatment durations of the radiation involved by using the standard Ct values from viral swab tests done universally today. To make our argument clearer, we added some points in Introduction. Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Suleyman GOKMEN Reviewer #2: Yes:** Bangxing Hong https://doi.org/10.1371/journal.pone.0251780.r003
Formally Accepted
6 May 2021 Acceptance Letter - Eric Charles Dykeman, Editor PONE-D-20-31505R1 Targeted antiviral treatment using Non-ionizing Radiation Therapy for SARS-CoV-2 and viral pandemics preparedness: Technique, methods and practical notes for Clinical Application Dear Dr. Minnes: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Eric Charles Dykeman Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0251780.r004

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