helmholtzeyeinstituteРоссийский офтальмологический журналRussian Ophthalmological Journal2072-00762587-5760Real time Publishers10.21516/2072-0076-2019-12-3-43-49helmholtzeyeinstitute-301Research ArticleКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯCLINICAL STUDIESОКТ-ангиография в комплексной оценке эффективности гипотензивной терапии у больных с первичной открытоугольной глаукомойOCT angiography in a comprehensive assessment of hypotensive therapy effectiveness in patients with primary open-angle glaucomaЮрьеваТ. Н.YurievaT. N.

д-р мед. наук, профессор, заместитель директора по научной работе1, профессор кафедры офтальмологии

664049, Иркутск, мкр. Юбилейный, д. 100

Dr. Med. Sci., Professor, deputy director for science1, professor in chair of ophthalmology 

100, Yubileynyj district, Irkutsk, 664049

ЖуковаС. И.ZhukovaS. I.

канд. мед. наук, заведующая диагностическим отделением

664043, Иркутск, ул. Лермонтова, д. 337

Cand. Med. Sci., head diagnostics department

337, Lermontova St., Irkutsk, 664043

ГБОУ ДПО «Иркутская государственная медицинская академия — филиал РМАНПО МЗ РФ»РоссияIrkutsk State Medical Academy – branch of Russian Medical Academy of Continuous EducationRussian FederationИркутский филиал ФГАУ «НМИЦ МНТК “Микрохирургия глаза" им. акад. С.Н. Федорова» Минздрава России,РоссияIrkutsk Branch of S. Fyodorov Eye Microsurgery Federal State InstitutionRussian Federation2019310820191234349Copyright © Юрьева Т.Н., Жукова С.И., 20192019Юрьева Т.Н., Жукова С.И.Yurieva T.N., Zhukova S.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://roj.igb.ru/jour/article/view/301

Дегенеративные изменения в сетчатке у больных с первичной открытоугольной глаукомой (ПОУГ) развиваются в ответ на ишемию и хроническую гипоксию на фоне нетолерантного внутриглазного давления (ВГД), поэтому анализ изменений глазного кровотока в мониторинге глаукомы, наряду с «базисными» тестами, следует рассматривать как неотъемлемую часть алгоритма их комплексного обследования.

Цель работы — оценить эффективность гипотензивной терапии больных с ПОУГ фиксированной комбинацией Дорзоламид/Тимолол (Дорзопт Плюс) и выявить наиболее информативные маркеры заболевания и эффективности лечения.

Материал и методы

Материал и методы. Обследовано 34 пациента (средний возраст — 68,44 ± 4,26 года) с развитой стадией ПОУГ и суб- и декомпенсированным ВГД. В комплекс стандартного диагностического обследования включена оптическая когерентная томография в режиме ангиографии.

Результаты

Результаты. На фоне проводимой терапии достигнуто стойкое снижение ВГД на 35,1 % (в среднем на 8,6 ± 0,7 мм рт. ст., р < 0,05) по сравнению с исходным. Нормализация офтальмотонуса сопровождалась стабильным повышением показателей корнеального гистерезиса и перфузионного давления, уменьшением средней глубины периметрического дефекта, изменениями хориоретинального кровотока.

Заключение

Заключение. Дорзопт Плюс обладает достаточным гипотензивным эффектом и снижает ВГД в среднем на 35 % от исходного уровня, способствует сохранению зрительных функций и улучшению показателей хориоретинального кровотока. Изменение толщины хориоидеи и плотности капилляров ретинального перипапиллярного слоя могут быть информативными биомаркерами в диагностике глаукомы и оценке эффективности гипотензивной терапии. 

Degenerative changes in the retina of primary open-angle glaucoma (POAG) patients are developing as response to ischemia and chronic hypoxia accompanied by intolerant IOP. For this reason, the analysis of ocular blood flow changes in glaucoma monitoring, as well as the basic tests, should be considered an integral part of comprehensive examination of such patients.

The purpose is to identify the most informative markers of the disease and to assess the effectiveness of its antihypertensive therapy by the fixed combination Dorzolamide / Timolol (Dorzopt Plus).

Material and methods

Material and methods. 34 patients aged 68.44 ± 4.26 years with an advanced POAG stage and sub- or decompensated IOP were examined. The examination included optical coherence tomography in the angiography mode.

Results

Results. A stable average reduction in IOP by 35.1 % (by 8.6 ± 0.7 mm Hg, p < 0.05) as compared with the baseline was achieved. IOP normalization was accompanied by a stable increase in corneal hysteresis and perfusion pressure, a decrease in the average depth of the perimetric defect, and changes in chorioretinal blood flow.

Conclusion

Conclusion. Changes in the choroid thickness and capillary density of the retinal peripapillary layer may be considered as the most informative biomarkers in the diagnosis of glaucoma and the evaluation of antihypertensive therapy effectiveness. 

первичная открытоугольная глаукомаОКТ-ангиографияретинальный кровотокрадиальное перипапиллярное сплетениеprimary open-angle glaucomaOCT angiographyretinal blood flowradial peripapillary plexusReferencesTham Y.C., Li X., Wong T.Y., et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014; 121: 2081–90.Tham Y.C., Li X., Wong T.Y., et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014; 121: 2081–90.Нестеров А.П. Глаукома: основные проблемы, новые возможности. Вестник офтальмологии. 2008; 124 (1): 3–7.Nesterov A.P. Glaucoma: major problems, new opportunities. Vestnik oftal'mologii. 2008; 124 (1): 3–7 (in Russian).Краснов М.М. О целевом внутриглазном давлении. Клиническая офтальмология. 2003; 4 (2): 49.Krasnov M.M. On the target intraocular pressure. Klinicheskaya oftal'mologiya. 2003; 4 (2): 49 (in Russian).Курышева Н.И. Глаукомная оптическая нейропатия. Москва: МЕДпресс-информ; 2006.Kurysheva N.I. Glaucoma optic neuropathy. Moscow: MEDpressinform; 2006 (in Russian).Нестеров А.П. Патогенез и проблемы патогенетического лечения глаукомы. Клиническая офтальмология. 2003; 4 (2): 47–9.Nesterov A.P. Pathogenesis and problems of the pathogenetic treatment of glaucoma. Klinicheskaya oftal'mologiya. 2003; 4 (2): 47–9 (in Russian).Dong Z.M., Wollstein G., Schuman J.S. Clinical utility of optical coherence tomography in glaucoma. Invest. Ophthalmol. Vis. Sci. 2016; 57: OCT556–OCT567. doi:10.1167/iovs.16-19933Dong Z.M., Wollstein G., Schuman J.S. Clinical utility of optical coherence tomography in glaucoma. Invest. Ophthalmol. Vis. Sci. 2016; 57: OCT556–OCT567. doi:10.1167/iovs.16-19933Kim J.S., Ishikawa H., Gabriele M.L., et al. Retinal nerve fiber layer thickness measurement comparability between time domain optical coherence tomography (OCT) and spectral domain OCT. Invest. Ophthalmol. Vis. Sci. 2010; 5: 896-902. doi 10.1167/iovs.09-4110Kim J.S., Ishikawa H., Gabriele M.L., et al. Retinal nerve fiber layer thickness measurement comparability between time domain optical coherence tomography (OCT) and spectral domain OCT. Invest. Ophthalmol. Vis. Sci. 2010; 5: 896-902. doi 10.1167/iovs.09-4110Takayama K., Hangai M., Kimura Y., et al. Three-dimensional imaging of lamina cribrosa defects in glaucoma using swept-source optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 2013; 54: 4798807. doi.org/10.1167/iovs.13-11677Takayama K., Hangai M., Kimura Y., et al. Three-dimensional imaging of lamina cribrosa defects in glaucoma using swept-source optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 2013; 54: 4798807. doi.org/10.1167/iovs.13-11677Wang B., Nevins J.E., Nadler Z., et al. In vivo lamina cribrosa microarchitecture in healthy and glaucomatous eyes as assessed by optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 2013; 54: 8270–4. doi.org/10.1167/iovs.13-13109Wang B., Nevins J.E., Nadler Z., et al. In vivo lamina cribrosa microarchitecture in healthy and glaucomatous eyes as assessed by optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 2013; 54: 8270–4. doi.org/10.1167/iovs.13-13109Pechauer A., Liu L., Gao S., et al. Optical coherence tomography angiography of peripapillary retinal blood flow response to hyperoxia. Invest. Ophthalmol. Vis. Sci. 2015; 56: 328–9. doi.org/10.1167/iovs. 15-16655Pechauer A., Liu L., Gao S., et al. Optical coherence tomography angiography of peripapillary retinal blood flow response to hyperoxia. Invest. Ophthalmol. Vis. Sci. 2015; 56: 328–9. doi.org/10.1167/iovs. 15-16655Pinhas A., Linderman R., Mo S., et al. A method for age-matched OCT angiography deviation mapping in the assessment of disease- related changes to the radial peripapillary capillaries. PLOS ONE. 2018; 13 (5): e0197062. https: //doi.org/10.1371/ journal. pone. 0197062Pinhas A., Linderman R., Mo S., et al. A method for age-matched OCT angiography deviation mapping in the assessment of disease- related changes to the radial peripapillary capillaries. PLOS ONE. 2018; 13 (5): e0197062. https: //doi.org/10.1371/ journal. pone. 0197062Yu P.K., Cringle S.J., Yu D.Y. Correlation between the radial peripapillary capillaries and the retinal nerve fiber layer in the normal human retina. Exp. Eye. Res. 2014; 129: 83–92. doi: 10.1016/j.exer.2014.10.020Yu P.K., Cringle S.J., Yu D.Y. Correlation between the radial peripapillary capillaries and the retinal nerve fiber layer in the normal human retina. Exp. Eye. Res. 2014; 129: 83–92. doi: 10.1016/j.exer.2014.10.020Tan P.E., Yu P.K., Cringle S.J., Yu D.Y. Quantitative assessment of the human retinal microvasculature with or without vascular comorbidity. Invest. Ophthalmol. Vis. Sci. 2014; 55 (12): 8439–52. doi: 10.1167/ iovs. 14-15056Tan P.E., Yu P.K., Cringle S.J., Yu D.Y. Quantitative assessment of the human retinal microvasculature with or without vascular comorbidity. Invest. Ophthalmol. Vis. Sci. 2014; 55 (12): 8439–52. doi: 10.1167/ iovs. 14-15056Tan P.E., Balaratnasingam C., Xu J., et al. Quantitative comparison of retinal capillary images derived by speckle variance optical coherence tomography with histology. Invest. Ophthalmol. Vis. Sci. 2015; 56 (6): 3989–96. doi: 10.1167/iovs.14-15879Tan P.E., Balaratnasingam C., Xu J., et al. Quantitative comparison of retinal capillary images derived by speckle variance optical coherence tomography with histology. Invest. Ophthalmol. Vis. Sci. 2015; 56 (6): 3989–96. doi: 10.1167/iovs.14-15879Campbell J.P., Zhang M., Hwang T.S., et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci. Rep. 2017; 7: 42201. doi: 10.1038/srep42201Campbell J.P., Zhang M., Hwang T.S., et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci. Rep. 2017; 7: 42201. doi: 10.1038/srep42201Cassani S., Arciero J., Guidoboni G., Siesky B., Harris A. Theoretical predictions of metabolic flow regulation in the retina. Journal for Modeling in Ophthalmology. 2016; 2: 70–8. https://www.modelingophthalmology.com/index.php/JMO/article/view/32Cassani S., Arciero J., Guidoboni G., Siesky B., Harris A. Theoretical predictions of metabolic flow regulation in the retina. Journal for Modeling in Ophthalmology. 2016; 2: 70–8. https://www.modelingophthalmology.com/index.php/JMO/article/view/32Rahimy E., Sarraf D. Paracentral acute middle maculopathy spectraldomain optical coherence tomography feature of deep capillary ischemia. Curr. Opin. Ophthalmol. 2014; 25 (3): 207–12. doi: 10.1097/ ICU.0000000000000045Rahimy E., Sarraf D. Paracentral acute middle maculopathy spectraldomain optical coherence tomography feature of deep capillary ischemia. Curr. Opin. Ophthalmol. 2014; 25 (3): 207–12. doi: 10.1097/ ICU.0000000000000045Nemiroff J., Kuehlewein L., Rahimy E., et al. Assessing deep retinal capillary ischemia in paracentral acute middle maculopathy by optical coherence tomography angiography. Amer. J. Ophthalmology. 2016; 162: 121132.e121. doi: 10.1016/j.ajo.2015.10.026Nemiroff J., Kuehlewein L., Rahimy E., et al. Assessing deep retinal capillary ischemia in paracentral acute middle maculopathy by optical coherence tomography angiography. Amer. J. Ophthalmology. 2016; 162: 121132.e121. doi: 10.1016/j.ajo.2015.10.026Ghasemi Falavarjani K., Phasukkijwatana N., Freund K.B., et al. En face optical coherence tomography analysis to assess the spectrum of perivenular ischemia and paracentral acute middle maculopathy in retinal vein occlusion. Amer. J. Ophthalmology. 2017; 177: 131–8. doi: 10.1016/j.ajo.2017.02.015Ghasemi Falavarjani K., Phasukkijwatana N., Freund K.B., et al. En face optical coherence tomography analysis to assess the spectrum of perivenular ischemia and paracentral acute middle maculopathy in retinal vein occlusion. Amer. J. Ophthalmology. 2017; 177: 131–8. doi: 10.1016/j.ajo.2017.02.015Yu S., Pang C., Gong Y., et al. The spectrum of superficial and deep capillary ischemia in retinal artery occlusion. Am. J. Ophthalmology. 2015; 159 (1): 53–63.e1–2. doi: 10.1016/j.ajo.2014.09.027Yu S., Pang C., Gong Y., et al. The spectrum of superficial and deep capillary ischemia in retinal artery occlusion. Am. J. Ophthalmology. 2015; 159 (1): 53–63.e1–2. doi: 10.1016/j.ajo.2014.09.027Hayreh S.S. Blood flow in the optic nerve head and factors that may influence it. Prog. Retin. Eye Res. 2001; 20 (5): 595–624. doi: 10.1016/ s1350-9462(01)00005-2Hayreh S.S. Blood flow in the optic nerve head and factors that may influence it. Prog. Retin. Eye Res. 2001; 20 (5): 595–624. doi: 10.1016/ s1350-9462(01)00005-2Hayreh S.S. Ischemic optic neuropathies. Luxemburg: Springer, 2011: 456. doi: 10.1007/978-3-642-11852-4Hayreh S.S. Ischemic optic neuropathies. Luxemburg: Springer, 2011: 456. doi: 10.1007/978-3-642-11852-4Hayreh S.S., Bill A., Sperber G.O. Effects of high intraocular pressure on the glucose metabolism in the retina and optic nerve in old atherosclerotic monkeys. Graefes Arch. Clin. Exp. Ophthalmol.1994; 232 (12): 745–52. doi: 10.1007/bf00184278Hayreh S.S., Bill A., Sperber G.O. Effects of high intraocular pressure on the glucose metabolism in the retina and optic nerve in old atherosclerotic monkeys. Graefes Arch. Clin. Exp. Ophthalmol.1994; 232 (12): 745–52. doi: 10.1007/bf00184278Duijm H.F., van den Berg T.J., Greve E.L. A comparison of retinal and choroidal hemodynamics in patients with primary open-angle glaucoma and normal-pressure glaucoma. Am J Ophthalmol.1997; 123 (5): 644–56. doi: 10.1016/s0002-9394(14)71077-3Duijm H.F., van den Berg T.J., Greve E.L. A comparison of retinal and choroidal hemodynamics in patients with primary open-angle glaucoma and normal-pressure glaucoma. Am J Ophthalmol.1997; 123 (5): 644–56. doi: 10.1016/s0002-9394(14)71077-3Bayir H., Kagan V.E. Bench-to-bedside review: Mitochondrial injury, oxidative stress and apoptosis – there is nothing more practical than a good theory. Crit. Care. 2008; 12 (1): 206. doi: 10.1186/cc6779Bayir H., Kagan V.E. Bench-to-bedside review: Mitochondrial injury, oxidative stress and apoptosis – there is nothing more practical than a good theory. Crit. Care. 2008; 12 (1): 206. doi: 10.1186/cc6779Bakhoum M.F., Freund K.B., Dolz-Marco R. Paracentral acute middle maculopathy and the ischemic cascade associated with retinal vascular occlusion. Amer. J. Ophthalmology. 2018 Nov; 195: 143–53. S00029394(18)30424-0. doi: 10.1016/j.ajo.2018.07.031Bakhoum M.F., Freund K.B., Dolz-Marco R. Paracentral acute middle maculopathy and the ischemic cascade associated with retinal vascular occlusion. Amer. J. Ophthalmology. 2018 Nov; 195: 143–53. S00029394(18)30424-0. doi: 10.1016/j.ajo.2018.07.031Sossi N., Anderson D.R. Blockage of axonal transport in optic nerve induced by elevation of intraocular pressure. Effect of arterial hypertension induced by angiotensin I. Arch. Ophthalmol. 1983; 101 (1): 94–7. doi:1 0.1001/archopht. 1983. 01040010096017Sossi N., Anderson D.R. Blockage of axonal transport in optic nerve induced by elevation of intraocular pressure. Effect of arterial hypertension induced by angiotensin I. Arch. Ophthalmol. 1983; 101 (1): 94–7. doi:1 0.1001/archopht. 1983. 01040010096017Hayreh S.S., March W., Anderson D.R. Pathogenesis of block of rapid orthograde axonal transport by elevated intraocular pressure. Exp. Eye Res. 1979; 28: 515–23. doi: 10.1016/0014-4835(79)90039-3Hayreh S.S., March W., Anderson D.R. Pathogenesis of block of rapid orthograde axonal transport by elevated intraocular pressure. Exp. Eye Res. 1979; 28: 515–23. doi: 10.1016/0014-4835(79)90039-3Bernacki J., Dobrowolska A., Nierwinska K., et al. Physiology and pharmacological role of the blood-brain barrier. Pharmacol. Rep. 2008; 60 (5): 600–22. PMID:19066407Bernacki J., Dobrowolska A., Nierwinska K., et al. Physiology and pharmacological role of the blood-brain barrier. Pharmacol. Rep. 2008; 60 (5): 600–22. PMID:19066407Еричев В.П., Дугина А.Е., Мазурова Ю.В. Фиксированные лекарственные формы: современный подход к терапии глаукомы. Глаукома. 2010; 1: 62–5.Erichev V.P., Dugina A.E., Mazurova Yu.V. Fixed dosage forms: modern approach to glaucoma therapy. Glaucoma. 2010; 1: 62–5 (in Russian).Куроедов А.В. Перспективы применения комбинированных антиглаукомных препаратов (обзор литературы). Клиническая Офтальмология. 2007; 4: 176–81.Kuroedov A.V. Prospects for the use of combined antiglaukoma drugs (literature review). Klinicheskaja oftal’mologija. 2007; 4: 176–81 (in Russian).Bacharach J., Delgado M.F., Iwach A.G. Comparison of efficacy of the fixed–combination timolol/dorzolamide versus concomitant administration of timolol and dorzolamide. Ocul. Pharm. Ther. 2003; 19: 93–6.Bacharach J., Delgado M.F., Iwach A.G. Comparison of efficacy of the fixed–combination timolol/dorzolamide versus concomitant administration of timolol and dorzolamide. Ocul. Pharm. Ther. 2003; 19: 93–6.Henderer J.D., Wilson R.P., Moster M.R., et al. Timolol/dorzolamide combination therapy as initial treatment for intraocular pressure over 30 mm Hg. J. Glaucoma. 2005; 14: 267–70.Henderer J.D., Wilson R.P., Moster M.R., et al. Timolol/dorzolamide combination therapy as initial treatment for intraocular pressure over 30 mm Hg. J. Glaucoma. 2005; 14: 267–70.Martinez A., Sanchez M. A comparison of the effects of 0.005 % latanoprost and fixed combination dorzolamide/timolol on retrobulbar haemodynamics in previously untreated glaucoma patients. Cur. Med. Res. Opin. 2006. 22: 67–73.Martinez A., Sanchez M. A comparison of the effects of 0.005 % latanoprost and fixed combination dorzolamide/timolol on retrobulbar haemodynamics in previously untreated glaucoma patients. Cur. Med. Res. Opin. 2006. 22: 67–73.Martinez A., Sanchez M. Effects of dorzolamide 2 % added to timolol maleate 0.5 % on intraocular pressure, retrobulbar blood flow, and the progression of visual field damage in patients with primary open–angle glaucoma: a single-center, 4-year, open-label study. Clin. Ther. 2008; 30: 1120–34.Martinez A., Sanchez M. Effects of dorzolamide 2 % added to timolol maleate 0.5 % on intraocular pressure, retrobulbar blood flow, and the progression of visual field damage in patients with primary open–angle glaucoma: a single-center, 4-year, open-label study. Clin. Ther. 2008; 30: 1120–34.Ozturk F., Ermis S.S., Inan U.U. Comparison of the ocular hypotensive effects of bimatoprost and timololdorzolamide combination in patients with elevated intraocular pressure: a 6-month study. Acta Ophthalmol. Scand. 2007; 85: 1: 80–3.Ozturk F., Ermis S.S., Inan U.U. Comparison of the ocular hypotensive effects of bimatoprost and timololdorzolamide combination in patients with elevated intraocular pressure: a 6-month study. Acta Ophthalmol. Scand. 2007; 85: 1: 80–3.Ловпаче Д.Н. Опыт применения фиксированной комбинации дорзопт плюс у пациентов с различными клиническими разновидностями ПОУГ. Российский офтальмологический журнал. 2013; 1: 92–5.Lovpache D.N. An experience of using a fixed combination Dorzopt Plus in patients with various clinical forms of primary open angle glaucoma. Russian ophthalmological journal. 2013; 1: 92–5 (in Russian).Ловпаче Д.Н. Опыт применения фиксированной комбинации дорзопт плюс (Rompharm company) у пациентов с различными клиническими разновидностями глаукомы. Срок наблюдения — 18 месяцев. Российский офтальмологический журнал. 2014; 1: 69–72.Lovpache D.N. Using a fixed combination Dorzopt Plus in patients with various clinical forms of primary open angle glaucoma: the results of an 18-month follow-up. Russian ophthalmological journal. 2014; 1: 69–72 (in Russian).Козлова И.В., Акопян А.И., Рещикова В.С. Опыт применения новой фиксированной формы дорзопт плюс в лечении пациентов с ПОУГ. Глаукома. Журнал НИИ глазных болезней РАМН. 2012; 2: 48–52.Kozlova I.V., Akopyan A.I., Reshchikova V.S. Experience of application of the new fixed Dorzopt plus form in treatment of patients with primary open-angle glaucoma. Glaucoma. 2012; 2: 48–52 (in Russian).Курышева Н.И., Азизова О.А., Пирязев А.П. Сравнительное исследование антиоксидантной активности комбинированных препаратов для местного гипотензивного лечения глаукомы. Российский офтальмологический журнал. 2013; 2: 41–4.Kurysheva N.I., Azizova O.A., Piryazev A.P. A comparative study into antioxidant activity of fixed combinations in topical glaucoma treatment. Russian ophthalmological journal. 2013; 2: 41–4 (in Russian).Fuchjager-Mayer G. Direct costs of glaucoma and severity of the disease: a multinational long-term study of resource utilisation in Europe. Br. J. Ophthalmol. 2005; 89: 1293–7.Fuchjager-Mayer G. Direct costs of glaucoma and severity of the disease: a multinational long-term study of resource utilisation in Europe. Br. J. Ophthalmol. 2005; 89: 1293–7.Frampton J.E., Perry Caroline M. Topical Dorzolamide 2 %/Timolol 0.5 % ophthalmic solution. Drugs & Aging December. 2006; 23 (12): 977–95.Frampton J.E., Perry Caroline M. Topical Dorzolamide 2 %/Timolol 0.5 % ophthalmic solution. Drugs & Aging December. 2006; 23 (12): 977–95.

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