REVIEWS
Interest in studying tissue microcirculation both from a researcher and a clinical specialist perspective is determined by the role of microcirculatory disorders in the development and progression of pathology and the possibility of using the obtained data to diagnose and control the disease treatment. Disorders of regulation and the structural and functional characteristics of the microcirculatory vessels are a link in the pathogenesis of most known pathological processes and conditions. Currently, there are a large number of methods that allow us to study the features of microvascular blood flow in norm and pathology. The review provides information on the most common modern non-radiological methods for microvascular blood flow research. We discuss the options, basic principles, advantages and limitations of individual methods based on the principles of plethysmography, Dopplerography, and changes in the optical properties of the tissue. Major trends in the improvement of approaches to the study of microcirculation are also noted.
Primary open-angle glaucoma (POAG) is a neurodegenerative disease causing glaucomatous damage of the optic nerve with characteristic visual field defects. Vascular theory of the glaucoma pathogenesis considers glaucomatous optic neuropathy (GON) as a result of changes in impaired ocular blood flow (OBF). Ultrasound examination with the assessment of OBF using multifunctional ultrasonic diagnostic devices is used for evaluation of hemodynamic parameters in the retrobulbar vessels: ophthalmic artery (OA), central retinal artery (CRA) and short posterior ciliary arteries (sPCA). This review presents the results of ocular blood flow studies using Doppler Ultrasound methods in patients with POAG and normal tension glaucoma (NTG). Many researchers have emphasized the important role of these methods in diagnosing and monitoring the optic nerve damage progression in glaucoma. In clinical practice, the standardization of the vascular Doppler Ultrasound technique and development of a suitable study protocol should improve the informativeness of the method and obtain reliable and reproducible results.
ORIGINAL ARTICLES (CLINICAL INVESTIGATIONS)
Introduction. Skin microcirculation is characterized by natural spatial and temporal variation of perfusion due to the structure of the cutaneous microvasculature and the influence of regulatory factors.
Objective. To evaluate spatial heterogeneity of skin perfusion and inter day individual reproducibility of Laser Doppler flowmetry (LDF) with local thermal tests in healthy volunteers.
Materials and methods. The study included 51 healthy volunteers (female/man – 35/16; age 25 [24; 26] years). The study protocol included 2 days of measurements with an interval of 3–7 days. After measuring basic anthropometric and physiological parameters, all subjects underwent LDF on the dorsal and ventral side of the forearm at rest (Mbaseline), then during cooling (Mcold) and heating (Mheat). Comparison of variables on the dorsal and ventral sides of the forearm, as well as assessment of the dynamics of skin perfusion during thermal tests were carried out using the Wilcoxon matched pairs test. The inter-day individual reproducibility of skin perfusion was measured by using the intraclass correlation coefficient (ICC) and coefficient of variation (CV, %). Data are expressed as median and interquartile range.
Results. Mbaseline (7.8 [4.8; 11.1]), Mcold (7.5 [4.8; 10.5]) and Mheat 7.5 [4.2; 10.9] in the skin of the dorsum of the forearm were statistically significantly lower (p<0.001) than on the ventral side: Mbaseline 10.4 [5.9; 13.0], Mcold 9.9 [5.6; 13.3], Mheat 9.5 [5.2; 12.5]. When assessing the dynamics of skin perfusion during the thermal tests, statistically significant changes in skin blood flow were revealed, both during cooling and heating on both sides of the forearm (p<0.01 vs Mbaseline). Mcold (CV=8.3 %, ICC=0.56) and Mheat (CV=19.9 %, ICC=0.563) on the dorsal forearm had the best inter-day reproducibility.
Conclusion. Skin perfusion, assessed by LDF is statistically significantly higher on the ventral side of the forearm compared to the dorsum . The inter-day reproducibility of LDF during local heating and cooling tests is higher on the skin of the dorsal side of the forearm than on the ventral side.
Aim. To study the nature of shifts in the nonlinear dynamics parameters of blood microcirculation (BMC) in patients with obliterating atherosclerosis of the arteries of the lower limbs (OAALL) and concomitant diabetes mellitus (DM).
Materials and Methods. Sixty male patients with OAALL, median age 63.0 [59.0; 68.0] years, who were divided into 2 groups equal in age and basic clinical and anamnestic data, were studied: 1 – patients without DM (n=45) and 2 – with concomitant DM (n=15). Nonlinear dynamic processes of BMC of the foot skin of the affected limb were assessed by laser Doppler flowmetry. The study included determination of fractal dimension (Do, R/S), entropy (Ho, Hi) and phase portrait analysis (D2, D2H).
Results. The analysis of nonlinear-dynamic processes of BMC has shown a statistically significant decrease of median values of fractal dimension parameters (Do, R/S) by 30 % and entropy indices (Hi) by 33 % in OAALL patients with concomitant DM in comparison with the group of patients without DM. This indicates a decrease in the number of factors involved in the coordination of microvascular system activity, growth of its functional rigidity, limitation of situational lability and reduction of chaotic behavior.
Conclusion. The study of nonlinear dynamics parameters provides additional data of important clinical significance for the assessment of pathophysiology of the disease. The results obtained indicate a reduction in the reserve of adaptive regulation of BMC in the combination of OAALL with DM and are associated with a worse prognosis of the disease.
The aim. To perform a comparative analysis of microcirculatory bed (MCB) response in patients with viral pneumonia (COVID-19), severe course, aggravated by arterial hypertension on artificial lung ventilation (ALV) and thermal oxygen-helium mixture (OHM) therapy.
Materials and methods. 9 patients were on mask ALV and 13 received OHM therapy. The OHM therapy was performed at gas concentration: O2 – 30 %, He – 70 %; the OHM temperature at the heater output was +95 оС (patients received it with t= up to +65 оС). The blood flow parameters in the MCB were recorded by ultrasound dopplerograph, 20 MHz sensor on the nail shaft of the thumb.
Results. The study has shown that the blood flow parameters in MCB were variable in patients on ALV. The increase in the blood flow velocity in MCB was due to blood inflow through the arteriolar link as a result of high values of HR (up to 100 beats/min), which ranged 0.741 – 2.428 cm/s on different days of observation. The PI index was high – 1.332 , some days its value increased by 13.7–26.7 %. Capillary blood flow indicators were low and averaged 0.181 cm/s. After OHM therapy, the blood flow velocity increased in all links of MCB: in the arteriolar and capillary by 7 %, in the venular almost 3 times as compared to the primary study. The PI index decreased from 1.56 to 1.155, vascular tone RI from 0.87 to 0.714. The positive effect of OHM therapy was observed after 30 min, 60 min and on subsequent days of MCB monitoring.
Introduction. Diagnostics of blood circulation in skin microvessels and oxidative metabolism of biological tissue allows predicting the presence of microcirculatory disorders in the body, assessing their severity and monitoring therapy. The use of a functional test related to the change in the position of the entire human body in space is a well-known method for studying the functions of the autonomic nervous system and diagnosing cardiovascular diseases.
Purpose. To study a set of parameters characterizing oxidative metabolism and dynamics of blood microcirculation in the finger during a sequence of tests with the change in the position of the upper limb using fluorescence spectroscopy and laser Doppler flowmetry.
Materials and Methods. The study was conducted on a group of volunteers consisting of 10 people aged 21–40 years. The LAZMA PF device (Russia), implementing the methods of laser Doppler flowmetry and fluorescence spectroscopy, was placed on the pad of the middle finger. Each volunteer’s microcirculation parameters were measured in two arm positions: «at heart level» and with the limb vertically raised in the «up» position. Blood flow oscillations were continuously measured during all stages: three times in two positions.
Results. A change in the limb position from the «at heart level» to «up» state leads to a decrease in the average values of microcirculation indices by 12 perfusion units (p. u.) and oxidative metabolism by 7 relative units (r. u.) with a simultaneous increase in the NADH coenzyme by 3 r. u., i.e. there is a unidirectional change in the microcirculation and oxidative metabolism parameters and an oppositely directed change of the NADH coenzyme values. According to the results of NADH coenzyme measurements, based on the analysis of statistical data, a statistically significant difference was found between the «at heart level» and «up» arm positions. This difference was not revealed only in the first cycle of the study, the reliability of p was greater than 0.05, between the arm positions 1–2, when the arm was «at heart level» and then raised «up». It was also found that with each new measurement cycle, the probability value of p for NADH indicators steadily decreased with a change in the arm position, at a significance level of p<0.05. The probability value of p became statistically significant starting from the second cycle of the study. Based on the results of oxidative metabolism indicator measurements, it was found that the probability value of p had a statistical significance of p<0.05 at each change of arm position in each cycle.
Conclusion. The studies have shown that in order to obtain reliable information about the results of the limb position test, it is not enough to perform one-time measurements of the microcirculation indicator or the oxidative metabolism of biological tissue using laser Doppler flowmetry. The position of the limb and its change leads to significant changes in microcirculation and oxidative metabolism indicators, which should be taken into account when conducting medical and physiological studies
Introduction. This study aimed to assess blood microcirculation changes in the skin of the forehead, cheeks and lower extremities before, during and after performing a yoga inverted pose, using wearable laser Doppler flowmetry analyzers in healthy volunteers.
Materials and methods. The study involved 25 volunteers, with an average age of 37 [35–44] years. Blood microcirculation changes were evaluated by laser Doppler flowmetry using six LAZMA PF wireless wearable devices, placed in pairs on the supraorbital artery regions of the forehead, cheeks and on the first toes of the feet, symmetrically on the right and left. A three-phase study protocol included a supine position before the inverted pose (6 minutes), the inverted pose (3 minutes), and a supine position after the inverted pose (6 minutes). Measurements included the index of microcirculation (Im), nutritive blood flow (Imn), the amplitude of endothelial (Ae), neurogenic (An), myogenic (Am), respiratory (Ar) and cardiac (Ac) oscillations for each investigated area.
Results. Transitioning from the supine position to the inverted pose increases the forehead Im by 21.7 %; when returning to the supine position, Im decreases but remains significantly above the baseline. Imn in the forehead area remains stable. Ae, An, Am and Ac before and after the inversion show no significant changes. Ar shows a statistically significant change while maintaining the median values. In the cheek area, when transitioning from the supine position to the inverted pose, there is a 35.6 % increase in Im, and upon returning to the supine position, Im continues to rise while Imn tends to increase. There is a significant increase in Ar (by 50 %) and Ac (by 42.9 %), as well as a tendency to increase Ae, An, Am. Im in the feet area decreases by 55.6 %, but after returning to the horizontal position, compared to the initial state, it increases by 27.4 % and Imn increases by 42.9 %. There is a statistically significant increase in Ae (by 28.6 %), Am (by 40 %), Ar (by 50 %) and Ac (by 50 %).
Conclusion. Findings revealed significant impacts of the inversion position on the blood microcirculation in all investigated areas. The index of microcirculation significantly increases after performing the inverted pose both in the skin of the forehead and cheeks. However, the respiratory and cardiac oscillation amplitudes increases only in the skin of the cheeks, without changing significantly or with a median shift in the forehead skin, which confirms the peculiarities of microcirculatory regulation in the supraorbital artery area. In the toe skin after performing the inverted position, the index of microcirculation and nutritive blood flow, as well as the amplitudes of myogenic, respiratory and cardiac oscillations of tissue perfusion increase significantly. We can assume that inverted yoga poses may be beneficial in clinical practice for rehabilitating individuals with lower extremity circulatory disorders.
Introduction. Operations on the abdominal cavity organs and the anterior abdominal wall account for about 23.5–25.5 % of all surgical interventions. The incidence of infectious inflammatory complications after them varies widely and reaches 67 %. The role of adequate functioning of the microcirculation system in wound healing has been repeatedly confirmed by the literature. To interpret the pathology, it is necessary to determine the features of the physiological functional status of the anterior abdominal wall microcirculation. Purpose of the study. Study the features of local blood microcirculation in various areas of the anterior abdominal wall and their age-related changes.
Materials and methods. Two groups of volunteers were examined: 30 young conditionally healthy persons (average age 21±0.7 years) and 30 patients of the Surgical Department of the Semashko Clinical Hospital without pathology of abdominal organs and abdominal wall (average age 62±5,9 years). Laser Doppler flowmetry (LDF) technique was used on the LAZMA PF device (OOO NPP LAZMA, Russia). Measurements were performed on the skin of the anterior surface of the middle third of the left forearm and in 9 regions of the anterior abdominal wall.
Results. In the first group, the maximum microcirculation index was determined in the suprapubic region – 7.24±1.99 perfusion units (p. u.). A statistically significant difference occurred between the indices of basal blood flow of the upper and lower floors of the abdominal wall with the average (p<0.05). Among elderly patients, the forearm microcirculation index (5.19±0.78 p. u.) was comparable to the values in all areas of the anterior abdominal wall. The values of microcirculation index in nine regions of the anterior abdominal wall did not differ from each other, being in range of 4.25–4.94 p. u.
Conclusion. When planning studies of blood microcirculation in the abdominal wall tissues, the specific anatomical region and age of patients should be taken into account.
Introduction. Spondyloarthritis (SpA) associated with inflammatory bowel disease (IBD) is a disease in the SpA group developing in patients with Crohn’s disease (CD) and ulcerative colitis. Gut-vascular barrier impairments, including increased epithelial permeability and endothelial glycocalyx (EGc) damage, have been demonstrated in both CD and axial SpA (axSpA), and can serve as a pathogenetic basis for the joint development and progression of these diseases.
Aim. To evaluate the significance of EGc damage and epithelial permeability markers in patients with CD-associated axSpA.
Materials and methods. We examined 22 patients with axSpA associated with CD (group A), 29 patients with axSpA without IBD (group B), 27 patients with CD (group C) and 28 conditionally healthy controls (group D). Calprotectin (FC) and zonulin (FZ) in feces, hyaluronan and syndecan 1 in serum were studied. Perfusion boundary region (PBR) and the Microvascular Health Index (MVHS) were measured by dark-field microscopy in the sublingual region.
Results. In patients with CD-associated axSpA, an increase in PBR (p<0.001) and a decrease in MVHS (p=0.001) were revealed in comparison with healthy individuals. Only CD patients revealed decreased serum hyaluronan (p=0.006) associated with colitis and deep ulcers on endoscopy. Increased PBR allowed to identify very high axSpA activity in group A with a sensitivity of 100 % and specificity of 83.3 %. In group A patients, a correlation between hyaluronan and FC was found (ρ=–0.541; p=0.030). A classification tree, including FC, FZ, hyaluronan, and MVHS, was constructed to determine the presence of CD in axSpA patients with an accuracy of 90.2 %.
Conclusions. The study of the gut-vascular barrier damage markers allows to improve the methods of diagnosis and assessment of the integral activity of axSpA associated with CD.
Introduction. One of the urgent problems of modern obstetrics is gestational arterial hypertension (GAH), which entails a whole range of complications for both mother and fetus. In this regard, it is necessary to search for economically accessible, informative and safe methods for early diagnosis of uteroplacental blood flow disorders in pregnant women.
The aim of the study was to investigate the features of peripheral and uteroplacental blood flow in pregnant women with GAH, to assess the state of the vascular wall of pregnant women using photoplethysmography and to determine its association with uteroplacental blood flow disorders.
Materials and methods. A total of 78 patients with 22 to 40 weeks of pregnancy, divided into two groups, were clinically examined: the first group (n=42) were pregnant women with GAH, the second group the control group (n=36) consisted of patients with physiological course of gestation. The study included assessment of the objective clinical status of the pregnant woman, recording and contour analysis of photoplethysmograms, ultrasound examination of the uteroplacental and fetoplacental blood flow, and statistical processing of the results.
Results. When comparing the anthropometric characteristics of the studied groups, an increase in BMI was found in the group of pregnant women with GAG (p<0.05). Contour analysis of photoplethysmography (PPG) data showed an increase in the augmentation index in pregnant women with GAG by 73.47 % (p=0.054), an increase in central arterial pressure by 3.6 % (p<0.05). Changes in peripheral hemodynamics in pregnant women with hypertensive disorder were associated with impaired fetoplacental blood flow (rxy = 0.52-0.86, p < 0.05), which was accompanied by lower fetal biometry parameters (p<0.05).
Conclusion. Hemodynamic disturbances in the mother-placenta-fetus system correlate with changes in the parameters of peripheral circulation, which allows us to consider the additional use of the photoplethysmography method as promising in terms of early diagnostics and prevention of perinatal complications in mother and fetus.
Introduction. The aim of the study was to evaluate the diagnostic capabilities of various modifications of portable analyzers LAZMA-PF when studying the state of microcirculation depending on the tasks set.
Materials and methods. Synchronous assessment of lower extremity microcirculation using a distributed system of single-channel analyzers LAZMA-PF, was performed in patients with unilateral coxarthrosis (n=37) in the initial state and after hip joint replacement. In patients with colorectal cancer (n=27) and in the healthy control group (n=30), a comparative assessment of microcirculation and oxidative metabolism was performed using a multimodal analyzer LAZMA-PF combining two diagnostic technologies – laser Doppler flowmetry and fluorescence spectroscopy.
Results. The perfusion level in the damaged limb in patients with unilateral coxarthrosis, reduced by 57 % (p<0.01) compared to the contralateral limb, was maintained due to a significant tension on the regulatory mechanisms of microcirculation, as evidenced by a more than twofold (p<0.001) increase in the coefficient of variation and increased amplitudes of regulatory rhythms of microcirculation (from 21 % up to 30 %, p<0.05). In the postoperative period, a decrease in perfusion by 10 % (p<0.05) was noted in the intact limb due to increased neurogenic influences and suppression of endothelial oscillations by 24 %, p<0.05. In patients with colorectal cancer, decreased perfusion (by 23 %, p<0.05), microcirculation variability (by 21 %, p<0.05) and amplitudes of tone-forming (from 36 % up to 52 %, p<0.05) and respiratory (by 29 %, p<0.05) microcirculation rhythms were recorded; a decrease in nutritive blood flow (by 40 %, p<0.01) and oxidative metabolism (by 43 %, p<0.01) in comparison with the norm were fixed.
Conclusion. The use of portable laser analyzers on symmetrical areas of the body made it possible to identify a decrease in perfusion in the affected limb with unilateral coxarthrosis and redistribution of microcirculation in favor of the operated limb after hip joint endoprosthesis. When using a multimodal analyzer in patients with colorectal cancer, microcirculation violation of ischemia type and decrease in oxidative metabolism of tissues were recorded.
Introduction. Early detection of arterial remodeling in patients with arterial hypertension (AH) allows to timely activate prevention of complications and implement a personalized approach to therapy.
Objective. To evaluate arterial remodeling using instrumental and laboratory markers in men with AH of I and II grade.
Materials and methods. The study included 207 men aged 30-49 years, of whom 67 were healthy individuals and 140 patients with AH, who were divided into 6 groups depending on age and grade of AH. Instrumental assessment of arterial remodeling was performed using volumetric sphygmography with VaSera VS-1500N sphygmograph, duplex scanning of the brachiocephalic arteries with SonoScape S20Exp ultrasound device and rheography to assess the speed of pulse wave propagation with Impecard-M computer rheograph. The content of endothelin-1, transforming growth factor β1, type IV collagen in blood was determined by enzyme immunoassay.
Results. At the age of 30–39 years, CAVI and vascular age were higher in patients with AH grade II compared with both practically healthy men (p=0.01 and p=0.003 respectively) and patients with AH grade II (p=0.002 and p=0.004 respectively), while at the age of 40–49 years, CAVI and vascular age were higher in patients with AH grade II only when compared with basically healthy men (p=0.04 and p=0.04 respectively). The augmentation index and intima-media complex thickness at the age of 30–39 years were higher in patients with AH grade II (p=0.004 and p=0.03) compared to healthy men; at 40–49 years of age, the augmentation index did not differ in the studied groups, while the intima-media thickness in patients with AH grades I and II was higher than in healthy men (p=0.04 and p=0.00001 respectively). The incidence of atherosclerotic plaques in brachiocephalic arteries in 40–49 years old men was 46.2 % in patients with AH grade I and 43.8 % in patients with AH grade II. The content of transforming growth factor β1 and type IV collagen was comparable in the studied groups.
Conclusion. Patients with AH grade I and II exhibit different phenotypes of arterial remodeling. Men with AH grade II have the most pronounced changes in parameters during instrumental examination.
ORIGINAL ARTICLES (EXPERIMENTAL INVESTIGATIONS)
Introduction. One of the topical issues of modern circulatory physiology is the study of the peculiarities of the influence of chronic stress on the hepatic hemodynamics. The effect of stress on the liver microvessels has not been practically studied.
The aim was to study the parameters of liver microcirculation in rats when modeling chronic stress.
Materials and methods. The study was conducted on 60 male Wistar rats weighing 220-370 g, divided into control and experimental groups of 30 rats each. In animals of the experimental group, chronic predatory stress was simulated by exposure to predator (cat) urine smell for 10 days according to the method of V. E. Zeilikman et al. (2021). Median laparotomy was performed under anesthesia with Zoletil and Xylazine. The study of rat liver microcirculation was performed using laser Doppler flowmeter LAKK-02 (Russia) on the visceral surface of the liver. The study of liver tissue perfusion parameters was carried out before and after stress modelling in rats of the experimental group, before and after laparotomy in rats of the control group (falsely operated animals). Digital data were processed by methods of variation statistics.
Results. When modeling chronic emotional stress, a decrease in the basic microcirculation parameters on the visceral surface of the liver was revealed: microcirculation index – by 28.35 %, coefficient of variation – by 55.92 %, which is probably due to vasoconstriction of the vessels of the microcirculatory link. To the greatest extent, there was a decrease in the mean square deviation (by 100 %), which indicates the deterioration in the mechanisms of modulation of liver tissue perfusion.
Conclusion. Chronic stress has a significant effect on the microcirculation system of the rat liver, which is manifested by a marked decrease in the basic parameters of tissue perfusion and a reduction in the mechanisms of blood flow modulation.
BRIEF SURVEY
The clinical observation presents a rare case of a patient with arterial tortuosity syndrome, with a 9-year follow-up of the clinical picture dynamics.
LECTURES
The article presents the stages of development of radiological research methods from the discovery of radioactive elements to modern methods of radionuclide diagnostics. The main attention is paid to methods of studying blood circulation in the lungs, with indication of their advantages, disadvantages, indications and contraindications for research, options for processing the results and their interpretation. The possibilities of differential diagnostics of lung diseases, for example, histiocytosis X and lymphangioleiomimatosis are also discussed. The article does not address the issues of PET-CT diagnostics.
MESSAGES FROM YOUNG SCIENTISTS
Background. In microinvasive surgery of aneurysms of the ophthalmic segment of the internal carotid artery (AOS-ICA), flow-diverting stents are often used, which overlap the area of the ophthalmic artery origin. This type of treatment may be accompanied by visual acuity decrease in the intraas well as in the early and late postoperative period.
Aim – to evaluate ocular hemodynamics indices in patients with AOS-ICA before and after the ophthalmic segment of the internal carotid artery stenting.
Materials and methods. The study group consisted of 17 patients (16 women and 1 man), age median being 48.5 years (from 23 to 68), admitted to the Polenov Neurosurgical Institute during the period from April, 2022, through November, 2024. Inclusion criteria: age more than 18 years, unilateral AOS-ICA of no less than 4 mm diameter, absence of CT-signs of visual pathway compression and of ophthalmic complaints, absence of retinal and optic nerve pathologic condition, and sufficient transparency of the optical media. To visualize the aneurysm, the reconstruction of 3D images obtained from rotational angiography was used. Angiographic images were obtained in anteroposterior, lateral, and working projections before and immediately after treatment. The treatment consisted in stenting of the ICA ophthalmic segment by a flow-diverting stent DERIVO 2 (Acandis Pforzheim, Germany). The ophthalmic examination was carried out before and after surgery and included standard diagnostic methods and OCT, OCTA of the macular area and the optic disc area. Additionally, a calibrometry of arteries and veins with estimation of their average diameter (ADA, ADV).
Results. After stenting, in 4 out of 17 patients, on the AOS-ICA side, within the period from 3 to 14 days, visual disturbances were noted in form of multiple episodes of transitory monocular blindness, their duration being from 30 seconds to several hours. In patients with such complications, at comparison with the contralateral eye indices, on the involved side, a reduced perfusion density in all plexuses was noted (by 1.0–4.2 % in the superficial, by 1.3–7.2 % in the deep, and in the radial peripapillary – by 2.1–3.0 %). On the involved side, in comparison to the contralateral eye, there was also a significant ADA decrease (79.4 μm versus 85.3 μm, P<.001), ADV however had no significant differences (102.6 μm versus104.23 μm, Р=.580).
Conclusions. The carried-out pilot study showed that preoperative detection of local defects of retinal and optic disc capillary perfusion, as well as asymmetry of peripapillary arterioles in AOS-ICA, could be markers of collateral blood flow insufficiency manifesting itself by transitory episodes of monocular blindness after stenting.
ISSN 2712-9756 (Online)