biophBiomedical PhotonicsBiomedical Photonics2413-9432Non-profit partnership for development of domestic photodynamic therapy and photodiagnosis10.24931/2413-9432-2024-13-3-4-13bioph-657Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВлияние фотобиомодуляционной терапии c использованием лазера (650 нм) на состояние десен после кюретажаEffect of photobiomodulation therapy with low level laser on gingival in post-curettage patientsWahyuningtyaD. T.WahyuningtyaD. T.

Surabaya

Surabaya

AstutiS. D.AstutiS. D.

Surabaya

Surabaya

suryanidyah@fst.unair.ac.idWidiyantiP.WidiyantiP.

Surabaya

Surabaya

SetiawatieE. M.SetiawatieE. M.

Surabaya

Surabaya

GuspiariK.GuspiariK.

Surabaya

Surabaya

AmirM. S.AmirM. S.

Surabaya

Surabaya

ArifiantoD.ArifiantoD.

Surabaya

Surabaya

YaqubiA. K.YaqubiA. K.

Surabaya

Surabaya

ApsariA.ApsariA.

Surabaya

Surabaya

SusiloY.SusiloY.

Surabaya

Surabaya

SyahromA.SyahromA.

Johor Bahru

Johor Bahru

Airlangga UniversityИндонезияAirlangga UniversityIndonesiaHang Tuah UniversityИндонезияHang Tuah UniversityIndonesiaSoetomo UniversityИндонезияSoetomo UniversityIndonesiaUniversiti Teknologi MalaysiaМалайзияUniversiti Teknologi MalaysiaMalaysia202401112024133413Copyright © Wahyuningtya D.T., Astuti S.D., Widiyanti P., Setiawatie E.M., Guspiari K., Amir M.S., Arifianto D., Yaqubi A.K., Apsari A., Susilo Y., Syahrom A., 20242024Wahyuningtya D.T., Astuti S.D., Widiyanti P., Setiawatie E.M., Guspiari K., Amir M.S., Arifianto D., Yaqubi A.K., Apsari A., Susilo Y., Syahrom A.Wahyuningtya D.T., Astuti S.D., Widiyanti P., Setiawatie E.M., Guspiari K., Amir M.S., Arifianto D., Yaqubi A.K., Apsari A., Susilo Y., Syahrom A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pdt-journal.com/jour/article/view/657

Изучено влияние лазера, излучающего в красной области спектра, на способность к заживлению ран после химиотерапии. В исследовании участвовали 60 человек, которые были разделены на две группы: лечения и контрольная. Пациенты из группы лечения получали 60-секундную световую биомодуляционную терапию с использованием красного лазера с длиной волны 650 нм и световой дозой 3,5 Дж/см2. Были измерены десневой индекс, уровни простагландина E2, человеческого дефензина 2 и интерлейкина-1β в слюне пациентов из обеих групп. Принятый уровень значимости p кюретажа у пациентов группы лечения наблюдались более низкие уровни простагландина Е2, человеческого дефензина 2 и интерлейкина-1β, чем в контрольной группе. Десневой индекс у пациентов после кюретажа не выявил существенных различий между группами лечения и контрольной группой в день лечения, но значительно отличался на 3-й и 5-й дни. В эти сроки в группе лечения наблюдалось уменьшение признаков воспаления и ускорение выздоровления. Результаты указывают на возможные преимущества лечения лазером, излучающим в красной области спектра, для восстановления после химиотерапии. Фотобиомодуляционная терапия красным лазером может способствовать процессам заживления у пациентов после кюретажа согласно результатам анализа десневого индекса, простагландина Е2, человеческого дефенсина 2 и интерлейкина-1β.

This research investigate how red laser treatment affects individuals who have had chemotherapy’s ability to heal their wounds. The sixty individuals were split up into groups for treatment and control. On the third and fifth days, the treatment group had reduced signs of inflammation and enhanced recovery. The results point to possible advantages of red laser treatment for recovery after a cure. 60 patients were divided into 30 therapy groups and 30 control groups to investigate the role of photo biomodulation therapy in wound healing. The therapy groups had 60 seconds of light biomodulation therapy utilizing a 650 nm red laser at a dose of 3,5 J/cm2. The gingival index, prostaglandin E2, human defensin 2, and interleukin-1β levels in the laser-treated and control groups’ saliva were measured. The level of significance was set at p <0.05. The result of this study on day zero after curettage showed that subjects treated with 650 nm laser levels of prostaglandin E2, human defensin 2, and interleukin-1β remained essentially the same as the control group subjects without therapy. On the third and fifth days after curettage, subjects treated with 650 nm laser showed lower levels of prostaglandin E2, human defensin 2, and interleukin-1β. They exhibited substantial differences from the control group subjects without therapy. The gingival index on post-curettage patients showed no significant differences between laser therapy and control groups on day zero but significantly differed on the third and fifth days. Photobiomodulation therapy with a red laser can help the healing of post-curettage subjects according to the analysis’ findings of the gingival index, prostaglandin E2, human defensin 2, and interleukin-1β.

заживление ран после кюретажалазер 650 нмфотобиомодуляцияпровоспалительный медиаторpost curettage wound healing650 nm red laserphoto biomodulationpro-inflammatory mediatorReferencesAstuti S. D. et al. An in-vivo study of photobiomodulation using 403 nm and 649 nm diode lasers for molar tooth extraction wound healing in wistar rats // Odontology. –2022. – Vol. 110 (2). – P. 240-253. doi: https://doi.org/10.1007/s10266-021-00653-wAstuti S. D. et al. An in-vivo study of photobiomodulation using 403 nm and 649 nm diode lasers for molar tooth extraction wound healing in wistar rats. Odontology, 2022, vol. 110 (2), рр. 240-253. doi: https://doi.org/10.1007/s10266-021-00653-wSağlam M. et al. Combined application of Er: YAG and Nd: YAG lasers in treatment of chronic periodontitis. A split‐mouth, single‐blind, randomized controlled trial // Journal of periodontal research. – 2017. – Vol 52(5). – P. 853-862. doi: https://doi.org/10.1111/jre.12454Sağlam M. et al. Combined application of Er: YAG and Nd: YAG lasers in treatment of chronic periodontitis. A split‐mouth, single‐blind, randomized controlled trial. Journal of periodontal research, 2017, vol 52(5), рр. 853-862. doi: https://doi.org/10.1111/jre.12454Astuti S.D. et al. The efficacy of photodynamic inactivation with laser diode on Staphylococcus aureus biofilm with various ages of biofilm // Infectious disease reports. – 2020. – Vol. 12(S1). – P. 68-74. doi: https://doi.org/10.4081/idr.2020.8736Astuti S.D. et al. The efficacy of photodynamic inactivation with laser diode on Staphylococcus aureus biofilm with various ages of biofilm. Infectious disease reports, 2020, vol. 12(S1), рр. 68-74. doi: https://doi.org/10.4081/idr.2020.8736Astuti S.D. et al. Chlorophyll mediated photodynamic inactivation of blue laser on Streptococcus mutans // In AIP Conference Proceedings. – 2016. –Vol. 1718(1). – P. 120001.Astuti S.D. et al. Chlorophyll mediated photodynamic inactivation of blue laser on Streptococcus mutans. In AIP Conference Proceedings, 2016, vol. 1718(1), рр. 120001.Daigo Y. et al. Wound healing and cell dynamics including mesenchymal and dental pulp stem cells induced by photobiomodulation therapy: an example of socket-preserving effects after tooth extraction in rats and a literature review // International Journal of Molecular Sciences. – 2020. – Vol. 21(18). – P. 6850. doi: https://doi.org/10.3390/ijms21186850Daigo Y. et al. Wound healing and cell dynamics including mesenchymal and dental pulp stem cells induced by photobiomodulation therapy: an example of socket-preserving effects after tooth extraction in rats and a literature review. International Journal of Molecular Sciences, 2020, vol. 21(18), рр. 6850. doi: https://doi.org/10.3390/ijms21186850de Paula Eduardo C. et al. Laser phototherapy in the treatment of periodontal disease. A review // Lasers in medical science. – 2010. – Vol. 25 (6). – P. 781-792. doi: DOI 10.1007/s10103-010-0812-yde Paula Eduardo C. et al. Laser phototherapy in the treatment of periodontal disease. A review. Lasers in medical science, 2010, vol. 25 (6), рр. 781-792. doi: DOI 10.1007/s10103-010-0812-yEming S.A. et al. Wound repair and regeneration: mechanisms, signaling, and translation // Science translational medicine. – 2014. – Vol. 6 (265). – P. 265sr6-265sr6. doi: DOI: 10.1126/scitranslmed.3009337Eming S.A. et al. Wound repair and regeneration: mechanisms, signaling, and translation. Science translational medicine, 2014, vol. 6 (265), рр. 265sr6-265sr6. doi: DOI: 10.1126/scitranslmed.3009337Mardianto A.I. et al. Photodynamic Inactivation of Streptococcus mutan Bacteri with Photosensitizer Moringa oleifera Activated by Light Emitting Diode (LED) // In Journal of Physics: Conference Series. – 2020. – Vol. 1505 (1). – P. 012061Mardianto A.I. et al. Photodynamic Inactivation of Streptococcus mutan Bacteri with Photosensitizer Moringa oleifera Activated by Light Emitting Diode (LED). In Journal of Physics: Conference Series, 2020, vol. 1505 (1), рр. 012061Sutherland J.C. et al. Biological Effects of Polychromatic Light // Photochemistry and photobiology. – 2002. – Vol. 76 (2). – P. 164-170. doi: https://doi.org/10.1562/0031-8655(2002)0760164BEOPL2.0.CO2Sutherland J.C. et al. Biological Effects of Polychromatic Light. Photochemistry and photobiology, 2002, vol. 76 (2), рр. 164-170. doi: https://doi.org/10.1562/0031-8655(2002)0760164BEOPL2.0.CO2Astuti S.D. et al. Photodynamic effectiveness of laser diode combined with ozone to reduce Staphylicoccus aureus biofilm with exogenous chlorophyll of Dracaena angustifolia leaves // Biomedical Photonics. – 2019. – Vol. 8 (2). – P. 4-13.Astuti S.D. et al. Photodynamic effectiveness of laser diode combined with ozone to reduce Staphylicoccus aureus biofilm with exogenous chlorophyll of Dracaena angustifolia leaves. Biomedical Photonics, 2019, vol. 8 (2), рр. 4-13.Correia J.H. et al. Photodynamic therapy review: Principles, photosensitizers, applications, and future directions // Pharmaceutics. – 2021. – Vol. 13 (9). – P. 1332. doi: https://doi.org/10.3390/pharmaceutics13091332Correia J.H. et al. Photodynamic therapy review: Principles, photosensitizers, applications, and future directions. Pharmaceutics, 2021, vol. 13 (9), рр. 1332. doi: https://doi.org/10.3390/pharmaceutics13091332Astuti S.D. et al. Combination effect of laser diode for photodynamic therapy with doxycycline on a wistar rat model of periodontitis // BMC oral health. – 2021. – Vol. 21(1). – P. 1-15.Astuti S.D. et al. Combination effect of laser diode for photodynamic therapy with doxycycline on a wistar rat model of periodontitis. BMC oral health, 2021, vol. 21(1), рр. 1-15.Hung C.M. et al. Gingyo-san enhances immunity and potentiates infectious bursal disease vaccination. Evid // Based Complementary Altern Med. – 2011. doi: https://doi.org/10.1093/ecam/nep021Hung C.M. et al. Gingyo-san enhances immunity and potentiates infectious bursal disease vaccination. Evid. Based Complementary Altern Med, 2011. doi: https://doi.org/10.1093/ecam/nep021Plaetzer K. et al. Photophysics and photochemistry of photodynamic therapy: fundamental aspects // J Lasers Med Sci. – 2009. – Vol. 24 (2). – P. 259-268.Plaetzer K. et al. Photophysics and photochemistry of photodynamic therapy: fundamental aspects. J Lasers Med Sci, 2009, vol. 24 (2), рр. 259-268.Ren C. et al. The effectiveness of low-level laser therapy as an adjunct to non-surgical periodontal treatment: a meta-analysis // J. Periodontal Res. – 2017. – Vol. 52 (1). – P. 8-20. doi: https://doi.org/10.1111/jre.12361Ren C. et al. The effectiveness of low-level laser therapy as an adjunct to non-surgical periodontal treatment: a meta-analysis. J. Periodontal Res, 2017, vol. 52 (1), рр. 8-20. doi: https://doi.org/10.1111/jre.12361Gilowski L. et al. Amount of interleukin-1β and interleukin-1 receptor antagonist in periodontitis and healthy patients // Arch. Oral Biol. – 2014. – Vol. 59 (7). – P. 729-734. doi: https://doi.org/10.1016/j.archoralbio.2014.04.007Gilowski L. et al. Amount of interleukin-1β and interleukin-1 receptor antagonist in periodontitis and healthy patients. Arch. Oral Biol, 2014, vol. 59 (7), рр. 729-734. doi: https://doi.org/10.1016/j.archoralbio.2014.04.007Harvey J.D. et al. Periodontal microbiology // Dent. Clin. – 2017. – Vol. 61 (2). – P. 253-269. doi: https://doi.org/10.1016/j.cden.2016.11.005Harvey J.D. et al. Periodontal microbiology. Dent. Clin, 2017, vol. 61 (2), рр. 253-269. doi: https://doi.org/10.1016/j.cden.2016.11.005Iglesias-Bartolome R. et al. Transcriptional signature primes human oral mucosa for rapid wound healing // Sci. Transl. Med. – 2018. – Vol. 10 (451). – P. eaap8798. doi: 10.1126/scitranslmed.aap8798Iglesias-Bartolome R. et al. Transcriptional signature primes human oral mucosa for rapid wound healing. Sci. Transl. Med, 2018, Vol. 10 (451), рр. eaap8798. doi: 10.1126/scitranslmed.aap8798Savitt E.D. et al. Distribution of certain subgingival microbial species in selected periodontal conditions // J Periodontal Res. – 1984. – Vol. 19 (2). – P. 111-23. doi: https://doi.org/10.1111/j.1600-0765.1984.tb00800.xSavitt E.D. et al. Distribution of certain subgingival microbial species in selected periodontal conditions. J Periodontal Res, 1984, vol. 19 (2), рр. 111-23. doi: https://doi.org/10.1111/j.1600-0765.1984.tb00800.xIsmiyatin K. et al. Different 650 nm laser diode irradiation times affect the viability and proliferation of human periodontal ligament fibroblast cells // Dent. J (Majalah Kedokteran Gigi. – 2019. – Vol. 52 (3). – P. 142-142.Ismiyatin K. et al. Different 650 nm laser diode irradiation times affect the viability and proliferation of human periodontal ligament fibroblast cells. Dent. J (Majalah Kedokteran Gigi, 2019, vol. 52 (3), рр. 142-142.Politis C. et al. Wound healing problems in the mouth // Front. Physiol. – 2016. – Vol. 7. – P. 507. doi: https://doi.org/10.3389/fphys.2016.00507Politis C. et al. Wound healing problems in the mouth. Front. Physiol, 2016, vol. 7, рр. 507. doi: https://doi.org/10.3389/fphys.2016.00507Popova C. et al. Correlation Between Healing Parameters and PGE2 Expression Levels in Non-Surgical Therapy of Chronic Periodontitis // J of IMAB – Annual Proceeding Scientific Papers. – 2017. – Vol. 23 (4). – P. 1758-1764. doi: 10.5272/jimab.2017234.1758Popova C. et al. Correlation Between Healing Parameters and PGE2 Expression Levels in Non-Surgical Therapy of Chronic Periodontitis. J of IMAB – Annual Proceeding Scientific Papers, 2017, vol. 23 (4), рр. 1758-1764. doi: 10.5272/jimab.2017234.1758Arjmand B. et al. Low-Level Laser Therapy: Potential and Complications // J Lasers Med Sci. – 2021. – Vol. 12. doi: 10.34172/jlms.2021.42Arjmand B. et al. Low-Level Laser Therapy: Potential and Complications. J Lasers Med Sci, 2021, vol. 12. doi: 10.34172/jlms.2021.42Rosso M.P.D.O. et al. Photobiomodulation therapy (PBMT) in peripheral nerve regeneration: a systematic review // J. Biomed. Eng. – 2018. – Vol. 5 (2). – P. 44. doi: https://doi.org/10.3390/bioengineering5020044Rosso M.P.D.O. et al. Photobiomodulation therapy (PBMT) in peripheral nerve regeneration: a systematic review. J. Biomed. Eng, 2018, vol. 5 (2), рр. 44. doi: https://doi.org/10.3390/bioengineering5020044Farivar S. et al. Biological effects of low-level laser therapy // J Lasers Med Sci. – 2014. – Vol. 5 (2). – P. 58.Farivar S. et al. Biological effects of low-level laser therapy. J Lasers Med Sci, 2014, vol. 5 (2), рр. 58.Suhariningsih D. et al. The effect of electric field, magnetic field, and infrared ray combination to reduce HOMA-IR index and GLUT 4 in diabetic model of Mus musculus // Lasers in Medical Science. – 2020. – Vol. 35 (6). – P. 1315-1321.Suhariningsih D. et al. The effect of electric field, magnetic field, and infrared ray combination to reduce HOMA-IR index and GLUT 4 in diabetic model of Mus musculus. Lasers in Medical Science, 2020, vol. 35 (6), рр. 1315-1321.Astuti S.D. et al. Effectiveness Photodynamic Inactivation with Wide Spectrum Range of Diode Laser to Staphylococcus aureus Bacteria with Endogenous Photosensitizer: An in vitro Study // Journal of International Dental and Medical Research. – 2019. – Vol. 12 (2). – Р. 481-486.Astuti S.D. et al. Effectiveness Photodynamic Inactivation with Wide Spectrum Range of Diode Laser to Staphylococcus aureus Bacteria with Endogenous Photosensitizer: An in vitro Study. Journal of International Dental and Medical Research, 2019, vol. 12 (2), рр. 481-486.Ren C. et al. The effectiveness of low-level laser therapy as an adjunct to non-surgical periodontal treatment: a meta-analysis // J. Periodontal Res. – 2017. – Vol. 52 (1). – P. 8-20. doi: https://doi.org/10.1111/jre.12361Ren C. et al. The effectiveness of low-level laser therapy as an adjunct to non-surgical periodontal treatment: a meta-analysis. J. Periodontal Res, 2017, vol. 52 (1), рр. 8-20. doi: https://doi.org/10.1111/jre.12361Setiawatie E.M. et al. An in vitro Anti-microbial Photodynamic Therapy (APDT) with Blue LEDs to activate chlorophylls of Alfalfa Medicago Sativa L on Aggregatibacter actinomycetemcomitans // J. Int. Dent. Medical Res. – 2016. – Vol. 9 (2). – P. 118-125.Setiawatie E.M. et al. An in vitro Anti-microbial Photodynamic Therapy (APDT) with Blue LEDs to activate chlorophylls of Alfalfa Medicago Sativa L on Aggregatibacter actinomycetemcomitans. J. Int. Dent. Medical Res, 2016, vol. 9 (2), рр. 118-125.Sidharthan S. et al. Gingival crevicular fluid levels of Interleukin-22 (IL-22) and human β Defensin-2 (hBD-2) in periodontal health and disease: A correlative study // J Oral Biol Craniofac Res. – 2020. – Vol. 10 (4). – P. 498-503. doi: https://doi.org/10.1016/j.jobcr.2020.07.021Sidharthan S. et al. Gingival crevicular fluid levels of Interleukin-22 (IL-22) and human β Defensin-2 (hBD-2) in periodontal health and disease: A correlative study. J Oral Biol Craniofac Res, 2020, vol. 10 (4), рр. 498-503. doi: https://doi.org/10.1016/j.jobcr.2020.07.021Tang E. et al. Laser-activated transforming growth factor-β1 induces human β-defensin 2: implications for laser therapies for periodontitis and peri-implantitis // J. Periodontal Res. – 2017. – Vol. 52 (3). – P. 360-367. doi: https://doi.org/10.1111/jre.12399Tang E. et al. Laser-activated transforming growth factor-β1 induces human β-defensin 2: implications for laser therapies for periodontitis and peri-implantitis. J. Periodontal Res, 2017, vol. 52 (3), рр. 360-367. doi: https://doi.org/10.1111/jre.12399Muliani Izat W.O.A. et al. The Effectiveness of Sea Cucumber Extract (Holothuroidae Sp) on Interleukin-1β (IL-1β) Expression in Periodontitis (Research on Wistar Rats) // (Doctoral dissertation, Hasanuddin University). – 2020.Muliani Izat W.O.A. et al. The Effectiveness of Sea Cucumber Extract (Holothuroidae Sp) on Interleukin-1β (IL-1β) Expression in Periodontitis (Research on Wistar Rats). (Doctoral dissertation, Hasanuddin University), 2020.Genco R.J. et al. Periodontal disease and overall health: a clinician’s guide // Yardley, Pennsylvania, USA: Professional Audience Communications Inc. – 2010. – P. 254-263.Genco R.J. et al. Periodontal disease and overall health: a clinician’s guide. Yardley, Pennsylvania, USA: Professional Audience Communications Inc, 2010, рр. 254-263.Santosa B. et al. Elisa Method for Measurement of Metallothionein Protein in Rice // Leaves Ir Bagendit. – 2020.Santosa B. et al. Elisa Method for Measurement of Metallothionein Protein in Rice. Leaves Ir Bagendit, 2020.Sakurai Y. et al. Inhibitory effect of low-level laser irradiation on LPS stimulated prostaglandin E2 production and cyclooxygenase 2 in human gingival fibroblasts // Eur. J. Oral Sci. – 2000. – Vol. 108 (1). – P. 29-34. doi: https://doi.org/10.1034/j.1600-0722.2000.00783.xSakurai Y. et al. Inhibitory effect of low-level laser irradiation on LPS stimulated prostaglandin E2 production and cyclooxygenase 2 in human gingival fibroblasts. Eur. J. Oral Sci, 2000, vol. 108 (1), рр. 29-34. doi: https://doi.org/10.1034/j.1600-0722.2000.00783.xHanna R. et al. Phototherapy as a rational antioxidant treatment modality in COVID-19 management; new concept and strategic approach: a critical review // Antioxidants. – 2020. – Vol. 9 (9). – P. 875. doi: https://doi.org/10.3390/antiox9090875Hanna R. et al. Phototherapy as a rational antioxidant treatment modality in COVID-19 management; new concept and strategic approach: a critical review. Antioxidants, 2020, vol. 9 (9), рр. 875. doi: https://doi.org/10.3390/antiox9090875Ebrahimi P. et al. Effect of photobiomodulation in secondary intention gingival wound healing a systematic review and meta-analysis // BMC Oral Health. – 2021. – Vol. 21 (1). – P. 1-16.Ebrahimi P. et al. Effect of photobiomodulation in secondary intention gingival wound healing a systematic review and meta-analysis. BMC Oral Health, 2021, vol. 21 (1), рр. 1-16.Astuti S.D. et al. Effectiveness of 650 nm red laser photobiomodulation therapy to accelerate wound healing post tooth extraction // Biomedical Photonics. – 2024. – Vol. 13 (1). – P. 4-15. https://doi.org/10.24931/2413-9432-2024-13-1-4-15Astuti S.D. et al. Effectiveness of 650 nm red laser photobiomodulation therapy to accelerate wound healing post tooth extraction. Biomedical Photonics, 2024, vol. 13 (1), рр. 4-15. https://doi.org/10.24931/2413-9432-2024-13-1-4-15Genco R.J. et al. Periodontal disease and overall health: a clinician’s guide // Yardley, Pennsylvania, USA: Professional Audience Communications Inc. – 2010. – P. 254-263.Genco R.J. et al. Periodontal disease and overall health: a clinician’s guide. Yardley, Pennsylvania, USA: Professional Audience Communications Inc, 2010, рр. 254-263.Avci P. et al. Low-level laser (light) therapy (LLLT) in skin: stimulating, healing, restoring // Semin Cutan Med Surg. – 2013. – Vol. 32 (1). – P. 41.Avci P. et al. Low-level laser (light) therapy (LLLT) in skin: stimulating, healing, restoring. Semin Cutan Med Surg, 2013, vol. 32 (1), рр. 41.Rasouli M. et al. The interplay between extracellular matrix and progenitor/stem cells during wound healing: Opportunities and future directions // Acta Histochemica. –2021. – Vol. 123 (7). – P. 151785. doi: https://doi.org/10.1016/j.acthis.2021.151785.Rasouli M. et al. The interplay between extracellular matrix and progenitor/stem cells during wound healing: Opportunities and future directions. Acta Histochemica, 2021, Vol. 123 (7), рр. 151785. doi: https://doi.org/10.1016/j.acthis.2021.151785.

The authors declare that there are no conflicts of interest present.