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Neurology, Neuropsychiatry, Psychosomatics

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Vol 11, No 2 (2019)
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https://doi.org/10.14412/2074-2711-2019-2

LECTURES

4-11 216
Abstract

The paper considers the actual problem of cryptogenic stroke and patent foramen ovale (PFO). It highlights the issues of pathogenesis and role of paradoxical embolism in the development of cerebral circulation disorders. The features of clinical manifestations and neuroimaging pattern of stroke in the presence of PFO are described. Ultrasound diagnostic techniques used to verify a cardiac anomaly are characterized. Approaches to establishing a cause-and-effect relationship between the presence of PFO and the development of stroke are presented. The current possibilities of secondary prevention in this category of patients, in particular the results of studies of percutaneous PFO occlusion, are discussed.

ORIGINAL INVESTIGATIONS

12-21 219
Abstract

Objective: to assess the risk of hemorrhagic transformation (HT), by taking into account an appropriate scale (the hemorrhagic transformation index (HTI)) to clarify the possible timing of anticoagulant therapy (AT) initiation in patients with atrial fibrillation (AF) and ischemic stroke (IS) in the middle cerebral artery (MCA) bed.

Patients and methods. The admission data of 304 consecutively selected patients (111 men and 193 women aged 32 to 94 years (mean age, 72.7 years) with any form of AF and IS in the MCA basin were analyzed. The end point of the study was any HT according to brain computed tomography findings in the first 2 weeks after the development of IS. The HTI scores were divided into categories based on their predicted HT probabilities, thus yielding four models. Their comparison with the standard (the Diener rule) and the choice of the most appropriate model were done using the binary logistic regression and appropriate analysis (receiver operating characteristic, ROC). The final HTI model and the Diener rule were further used in the Royston–Parmar survival analysis to predict the risk of HT by days after the onset of IS. This was used to plot hazard function and survival, as well as the number of patients to be treated (number needed to treat, NNT) and the number of patients who can be harmed (number needed to harm, NNH). Possible periods for AT initiation were determined by the NNT and NNH plots.

Results and discussion. All the HTI models under study were superior to the Diener's rule in the accuracy of HT prediction. However, the HTI model with 0–1, 2–3, 4–5, 6–8 score arrangements was found to be the best one, as shown by the results of tests; it could additionally identify patients at very high (>0.8) risk for HT and somewhat better differentiate patients at low (0.05–0.1) risk. A survival analysis showed that the hazard function peaked on 1 and 3 days after the onset of IS. There was a progressive NNT drop in patients with a HTI score of 0–1 on 1 to 3 days; their curves reached a plateau on day 4. In patients with a HTI score of 2–3, NNT declined on days 1 to 4, with a plateau on day 5. In those with a HTI score of 4–5, NNH was minimal within the first 3 days following the onset of IS, and then there was a significant NNH rise until the end of the second week. In patients with a HTI score of 6–8, NNH remained very low throughout the follow-up period with a significant increase on days 4 to 9, with a subsequent exit to the plateau.

Conclusion. The greatest risk of HT is observed on 1 and 3 days after the onset of IS. AT is recommended to patients with a HTI score of 0–1 on day 4 after the onset of IS, to those with a HTI score of 2–3 on day 5, and to those with a HTI score of 4–5 following 2 weeks. AT may be initiated in patients at very high risk for HT (a HTI score of 6–8) on 9 days, provided that HT is absent.

22-29 100
Abstract

Objective: to evaluate the significance of insomnia and chronobiological patterns in the development of headache (HA) attacks for the formation of clinical features of migraine and for the elaboration of strategies for its prevention.

Patients and methods. A prospective comparative study was conducted in 60 patients aged 18–65 years who were diagnosed as having migraine (with or without aura) with comorbid sleep disorder. Group 1 consisted of 30 patients with migraine and insomnia; Group 2 comprised 30 patients with migraine without insomnia. The study participation included four visits to a physician for 12 months.

Results and discussion. Persistent sleep disorders in patients with migraine were shown to worsen the course of the underlying disease: HA attacks had a greater intensity, mainly left-sided localization and a longer duration. Group 1 patients were observed to have a chronic course of the disease with a frequency of ≥8 attacks per month in 33% of cases. Analysis of biological rhythms revealed that individuals with evening and mildly evening chronotypes were characterized by the greatest changes in the sleep-wake cycle, by sleep deprivation and its reduced efficiency. Analysis of the data of HA and sleep diaries kept by the patients for 12 months showed that Group 1 had four peaks of the daily distribution of HA attacks; 13.4% of attacks occurred during sleep and early morning.

Conclusion. The coexistence of sleep disorders and HA is not only manifested as the overlapping of clinical manifestation, but also largely determines their natural course and prognosis, i.e. their progression into a chronic form. Therefore, it is imperative to identify sleep disorders in migraines, since their correction is effective and, in most cases, allows chronic HA to progress to an episodic form.

30-36 90
Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and the first one among the nosological entities of parkinsonism. Susceptibility-weighted imaging (SWI), magnetic resonance imaging (MRI) pulse sequence, which allows the in vivo estimation of the values of iron deposition in different areas of the brain, is a potential technique for the early diagnosis of PD and for the study of the pathogenesis of its complications.

Objective: to compare the values of iron deposition in the basal ganglia in Stages II and III PD and to determine the relationship of clinical findings to the level of iron deposition according to the SWI findings.

Patients and methods. Twenty-four patients with Hoehn and Yahr Stages II (n=24) and III (n=12) PD were examined. All the patients underwent brain MRI on a Siemens TrioTim (3T) MRI scanner by using pulse sequences T1, T2, SWI and subsequently quantifying the iron deposition (SPIN software). The accumulation of iron is visualized as an area of reduced signal intensity on SWI, and its estimation in accordance with the SPIN program has accordingly a smaller value. The regions of interest on both sides were the dentate nucleus, substantia nigra, red nucleus, putamen, globus pallidus, and head of the caudate nucleus. The examination protocol also included tests using the following scales: the Unified Parkinson's Disease Rating Scale (UPDRS), the Mini-Mental State Examination (MMSE), Frontal Assessment Batter (FAB), Freezing of Gait (FOG), Gait and Balance Scale (GABS), the Epworth Daytime Sleepiness Scale, the Parkinson's Disease Quality of Life Questionnaire (PDQ), the Beck Depression Inventory, and the Clock-Drawing Test.

Results and discussion. The investigators found significant (p<0.05) correlations between the clinical picture and the level of iron deposition in the regions of interest in patients with Stage II PD: FOG – left caudate nucleus (r=-0.94); GABS – left caudate nucleus (r=-0.94); and in patients with stage III of the disease: UPDRS (full) – left red nucleus (r=-0.82), right globus pallidus (r=-0,80), left putamen (r=-0,96); UPDRS (Section 2) – left red nucleus (r=-0.77), left globus pallidus (r=-0.84); UPDRS (Section 3) – right putamen (r=-0,85), right globus pallidus (r=-0.78), left globus pallidus (r=-0,92); FOG – left globus pallidus (r=-0.81); GABS – left red nucleus (r=-0.96), left putamen (r=0.82), right putamen (r=-0.89), left globus pallidus (r=-0.82), right globus pallidus (r=-0.85), left caudate nucleus (r=-0.82), right caudate nucleus (r=-0.89); Beck Depression Inventory – right substantia nigra (r=-0.82).

Conclusion. SWI measurement of the values of iron deposition in the structures of the extrapyramidal system in PD provides an additional insight into the pathological processes occurring in them.

37-41 59
Abstract

Objective: to study the association of DRD2/ANKK1 Taq1A polymorphism with depression in an open 45–64-year-old male population from Novosibirsk.

Patients and methods. A representative sample of an open 45–64-year-old male population (n=781) was surveyed within Screening IV of the international HAPIEE program and the WHO MONICA-psychosocial program in 2003–2005. All the study participants filled out the WHO MONICA-psychosocial Program Depression Scale. The DRD2/ANKK1 Taq1A C32806T (rs 1800497) polymorphism was genotyped using the published methods within the budgeting topic. The Pearson's chi-square (2) test was applied to test the statistical significance of differences between the groups. Significance in all types of analysis was taken at p ≤0.05.

Results and discussion. The prevalence of depression in the open 45–64-year-old male population was 36.3%: 13.5% of the examinees had severe depression (SD) and 22.8% had moderate depression (MD). A comparative intergroup analysis showed that the odds ratio (OR) for the incidence of SD was 3.86 times higher in the T/C genotype carriers than in the C/C genotype ones, who, on the contrary, had no depression; the OR for the incidence of SD was also 3.28 times higher in the T/C genotype carriers, while MD was more common in the homozygous C/C genotype carriers. The OR for the incidence of SD was 2.63 times higher in the DRD2 T allele carriers than in the C allele carriers who did not suffer from depression in most cases.

Conclusion. A significant association was established between the carriage of Taq1A (T allele) and depression in 45–64-year-old males.

42-45 125
Abstract

Fejerman syndrome, a benign nonepileptic myoclonus of infancy (BNMI), is a rare type of paroxysmal events, which mimics epileptic spasms. It is difficult to determine the nature of myoclonus without video electroencephalography (VEEG) monitoring.

Objective: to present the clinical and electroencephalographic characteristics of new cases of benign nonepileptic myoclonus of infancy and early childhood.

Patients and methods. The data of 33 children (19 boys and 14 girls) aged 5 months to 3 years with BNMI, who had been followed in 2011 to 2017, were analyzed.

Results and discussion. The age at onset of paroxysms ranged from 4 to 24 months and that was 5–8 months in most cases. The most common movements were extensor muscle jerks (30.3%), head titubation with rotation (27.3%), axial spasms (27.3%), and nods (24.2%). The same child may have different types of paroxysms. Motor paroxysms were sporadic in all the patients and formed into clusters in 33.3% of cases. The frequency of clusters was up to 10 times daily. There were 2 to 50 paroxysms in the cluster. There was delayed psychomotor development in 5 of the 33 children and hyperexcitability was present in 10. VEEG monitoring indicated that the brain bioelectrical activity conformed to the age in 97% of cases; none of the children showed abnormal movements accompanied by EEG pathological activity. The duration of the disease was 2 to 19 months, averaging 7 months. In all cases paroxysms were stopped without using antiepileptic drugs.

Conclusion. It is extremely important to timely recognize BNMI, since anti-epileptic therapy can be unreasonably prescribed in cases of an erroneous diagnosis. VEEG monitoring plays a crucial role in diagnosing nonepileptic and epileptic myoclonus.
46-51 102
Abstract

Temporal lobe epilepsy (TLE) is one of the most common and refractory forms of epilepsy, which has different etiologies. Experimental and clinical studies have demonstrated that transformation of the normal brain neuron activity pattern into paroxysmal one is accompanied by changes in the expression of cytokines and neurotrophins in the hippocampus and temporal cortex. Modulation of the expression of brainderived neurotrophic factor (BDNF) may be associated with the carriage of the single nucleotide polymorphism (SNP) rs6265 in the BDNF gene. Groups of investigators have shown the increased expression of BDNF in the hippocampus and temporal cortex of patients with drugresistant epilepsy. Independent studies have demonstrated the role of the IL-1B gene encoding the proinflammatory cytokine interleukin (IL) 1in the development of inflammatory responses and structural mediobasal TLE with hippocampal sclerosis.

Objective: to study the association of the carriage of the SNPs rs16944 and rs1143634 in the IL-1B gene and rs6265 in the BDNF gene with the development of TLE.

Patients and methods. Real-time polymerase chain reaction was used to conduct a molecular genetic study of the carriage of the SNPs rs1143634 and rs16944 in the IL-1B gene and rs6265 in the BDNF gene in 84 patients with TLE and in 203 healthy Caucasian volunteers, who lived in the Siberian Federal District.

Results and discussion. The carriage of the high-producing C allele (odds ratio (OR)=2.01; 95% confidence interval (CI), 1.31–3.08; p=0.001) and the homozygous CC genotype (OR=2.48; 95% CI, 1.47–4.17; p=0.001) of SNP rs1143634 in the IL-1B gene was found to be statistically significantly associated with the development of TLE in the examined population. There were no statistically significant differences in the carriage of the SNPs rs1143634 and rs16944 in the IL-1B gene and rs6265 in the BDNF gene with the clinical presentations and course of TLE (p>0.05). The carriage of the SNP rs6265 in the BDNF gene was ascertained to be unassociated with the development of TLE (2=0.3; p =0.86).

Conclusion. The authors have established an association of the carriage of the high-producing C allele and the homozygous CC genotype of the SNP rs1143634 in the IL-1B gene with TLE.
52-59 83
Abstract

Objective: to investigate the prevalence of cognitive impairment (CI) and possibilities of its pharmacological correction in hypertensive patients, by comparatively evaluating the efficiency of different treatment options: antihypertensive therapy and its combinations with vasoactive drugs and the dopamine receptor agonist piribedil.

Patients and methods. At the first stage of the investigation, the prevalence of CI was assessed in a continuous sample of hypertensive patients (n=350). The second stage included a naturalistic comparative study of the efficiency of various therapeutic strategies for moderate CI (MCI) in patients with Stage 1–2 hypertension (n=91). This investigation lasted 48 weeks and consisted of a 24-week treatment period and a 24-weeks follow-up period.

Results and discussion. CI was diagnosed in 83.4% of patients in the continuous sample, while it reached the level of dementia in 16.9%. Therapy aimed at achieving and maintaining blood pressure (BP) targets did not lead to the regression of MCI. However, BP correction in combination with a 24-week piribedil therapy cycle was optimal in patients with CI. By the end of treatment, the Montreal Cognitive Assessment (MoCa) scores increased from 24.5Ѓ}0.8 to 27.5Ѓ}0.6 (p<0.05) and from 24.9Ѓ}0.7 to 27.1Ѓ}0.8 (p<0.05) in the groups of patients randomized to supplemental piribedil alone or in combination with nootropic and/or vascular drugs, respectively. There were no intergroup differences in the groups of patients randomized to supplemental piribedil. The time course of cognitive changes in the further follow-up period showed a longterm positive effect of piribedil on cognitive function.

Conclusion. It is necessary to regularly screen for cognitive dysfunction in hypertensive patients. The most effective treatment in combination with a long-term piribedil therapy cycle for hypertension-associated MCI was to promote the achievement and retention of blood pressure targets.

60-64 68
Abstract

Objective: to establish the characteristics of location for cerebral aneurysms according to ethnicity in the population of Yakutia.

Patients and methods. A total of 433 patients with aneurysmal hemorrhagic stroke (AHS) who had been admitted consecutively to the regional vascular center (Yakutsk) were examined. Group 1 included representatives of the indigenous ethnic groups of the Asian race in Yakutia (n=331; 33.8% of men); Group 2 comprised patients of the Caucasian race (n=102; 45.1% of men). The diagnosis was made by digital subtraction cerebral angiography (77.6%) and multislice computed tomography angiography (22.4%).

Results. A total of 433 ruptured saccular aneurysms, including the latter in the anterior cerebral and anterior communicating arteries (ACAAcoA) (33.8%), middle cerebral artery (MCA) (38.7%), internal carotid artery (ICA) (21.6%), and vertebrobasilar arteries (5.8%), were diagnosed. In Group 1, the most common location for aneurysms was MCA (41.1 and 39.7% in men and women, respectively); in Group 2, that was ACA-AcoA (52.2%) in men and ICA (42.8%) in women. The ethnic groups showed significant differences in the incidence of MCA aneurysms (40.2 and 26.4% in Groups 1 and 2; respectively (p=0.014)); (odds ratio (OR = 1.866; 95% confidence interval (CI), 1.111–3.146). In Group 1, the incidence of MCA aneurysms was higher in women than in those in Group 2 (p=0.012) (OR=2.417; 95% CI, 1.155–5.141).

Conclusion. The location for cerebral aneurysms differs according to ethnicity. In Yakutia among AHS patients, the most frequent location for aneurysms is MCA among indigenous Asians, while that is ACA-AcoA in Caucasian men and ICA is in Caucasian women. The incidence of MCA aneurysms is significantly higher in indigenous Asian women than in Caucasian ones.

65-70 75
Abstract

Objective: to evaluate the efficiency of a training method using special infant formulas as part of combined rehabilitation for patients with ischemic stroke and neurogenic dysphagia.

Patients and methods. The investigation enrolled 55 patients (30 men and 25 women) aged 45–80 years with dysphagia during the acute period of ischemic stroke. Thirty patients used special astringent formulas as part of combined therapy and 25 patients did not. The investigators studied the time of course of changes in the restoration of swallowing function, by using the Penetration-Aspiration Scale (PAS) and the Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS), as well as the transition from probe feeding to independent one.

Results and discussion. The best restoration of swallowing function was shown to be achieved through training using formulas with different astringency. Stronger astringent formulas, like solid foods, stimulate better the pharyngeal receptor apparatus; the most active restoration of a dynamic swallowing stereotype occurs. The gradual transition to a milder astringent formula allows restoration of the skill to swallow thinner liquid foods. It takes 10 days to achieve a significant clinical effect in most patients, mainly in those with pseudobulbar disorders. Training may be prolonged to 2 weeks or more in severe cases, in bulbar dysfunctions.

Conclusion. The training rehabilitation method using special infant formulas in combination with electrical stimulation in patients with ischemic stroke and neurogenic dysphagia allows achieving the significantly better indicators of restoration of swallowing function in accordance with the PAS scale. The application of the method contributes to the significantly better transition from probe feeding to independent one.

71-77 98
Abstract

Objective: to develop and justify differentiated indications for the use of agomelatine (valdoxan) to treat the typological variants of endogenous depressions with varying severity on the basis of an analysis of its therapeutic efficacy.

Patients and methods. An open prospective study was conducted using the clinical, psychopathological, and psychometric rating scales: the Hamilton Depression Rating Scale (HAMD-21); Udvalg for Kliniske Undersњgelser Scale (UKU); the Snaith-Hamilton Pleasure Scale (SHAPS) for assessing anhedonic disorders, and statistical methods. Examinations were made in 56 patients (mean age, 34.9 years) with moderate and severe endogenous depression within affective psychosis (n=42) and shift-like schizophrenia (n=14) (ICD-10 items F31.3–4; F32.1–2, and F33.1–2). The patients received a cycle treatment with agomelatine (valdoxan) 25–50 mg once a day in the evening for 4–8 weeks. The patients' status was evaluated over time on fixed days from a reduction in the mean total score (MTS) of the respective scales as insignificant (less than 19% reduction in disorders), moderate (20–49%), good (50–69%), and excellent (70% or more) effects. The effect of agomelatine was analyzed in two patient groups. The specific features of the antidepressive effect and its dynamics in the presence of endogenous depressions of different typologies (melancholic, anxious, and adynamic depressions) were studied in Group 1 (n=26); the effect of agomelatine on anhedonic endogenous depressions and manifestations of anhedonia in different mental activity areas (interests, social activity, emotional engagement and eating/drinking) was investigated in Group 2 (n=30).

Results and discussion. There was a good tolerance and a high antidepressant activity of agomelatine during its treatment cycle for moderate and severe endogenous depressions. A significant improvement (an 84.4% reduction in HAMD-21 MTS) was noted in patients at 3 and 4 weeks of the treatment cycle and consistently persisted at a subsequent follow-up. Agomelatine showed a good effect (a 50% or more reduction in HAMD-21 MTS) just at 14 days of therapy. The drug was observed to have a balanced antidepressant effect, significant thymoleptic, stimulant, anxiolytic, and antianhedonic activities (reductions in the MTS of depressive disorders by 90.83, 84.9, 82.39, and 78.9%, respectively).

Conclusion. The universal spectrum of the antidepressive effect of agomelatine, its good tolerability, high efficacy, and rapid improvement makes it the drug of choice in treating a wide range of psychopathological endogenous depressions: melancholic, apatho-adynamic, anxious, and anhedonic ones.

78-85 86
Abstract

The concurrent use of muscle relaxants and nonsteroidal anti-inflammatory drugs (NSAIDs) is a promising treatment for painful muscle hypertonia and convulsive states.

Objective: to identify the most effective and safe synergist combinations of tolperisone and NSAIDs.

Material and methods. A differential chemoreactome analysis was employed to evaluate the effects of the muscle relaxant tolperisone and five NSAIDs (dexketoprofen, etoricoxib, meloxicam, naproxen, and diclofenac). The biological activities of the molecules under study were assessed in five sections: 1) inhibition of the proteins of prostaglandin and leukotriene metabolism; 2) inhibition of the effects of the transcription factor nuclear factor kappa, tumor necrosis factor-, and other anti-inflammatory mechanisms; 3) inhibition of excessive blood coagulation and platelet aggregation; 4) vasodynamic effects; 5) antitumor properties on cell lines in culture.

Results and discussion. Based on the differences in the pharmacological activity profiles of tolperisone and NSAIDs under study, the investigators identified the most promising synergistic combinations, in which both active ingredients complemented each other as effectively and safely as possible. The obtained estimates of the degree of synergism of various combinations of tolperisone and NSAIDs hold that the most promising antithrombotic, and antitumor effects.

Conclusion. The results of this study will help adequately choose combinations of muscle relaxants and NSAIDs in patients with muscle hypertonia, which will be able to improve the efficiency and safety of treatment.

CLINICAL OBSERVATIONS

86-88 161
Abstract

Wilson's (Wilson–Konovalov) disease (WD) is a chronic progressive disease resulting from impaired body copper metabolism with damages to target organs (liver, brain, and kidneys). The paper describes a clinical case of organic delusional (schizophrenia-like) disorder in a patient with WD. The characteristic feature of its psychiatric onset in the patient is schizophrenia-like disorders in the absence of neurological and gastroenterological symptoms. Because of this onset of WD, patients have not received specific treatment for a long time (frequently before the appearance of the Kayser–Fleischer rings or the occurrence of cirrhosis). Thus, the diagnostic search should include WD in young patients with a primary psychotic episode. The search for early effective methods for WD verification is of interest for further investigations.

89-92 130
Abstract

The paper describes a clinical case of transient global amnesia (TGA) in a male patient who has experienced prolonged stress at work and at home. The middle-aged man was admitted to hospital disoriented, constantly repeating the same questions. The patient did not remember what had happened that morning before his admission to the hospital. Brain magnetic resonance imaging revealed bilateral punctate hippocampal DWI hyperintensity. The patient has not been observed to have risk factors for cerebrovascular events. Neuropsychological examination has shown that the patient does not have adequate strategies to cope with the sequels of long-term intense stress accompanied with emotion suppression. The described case confirms that psychological instability may be one of the precipitating factors for TGA.

REVIEWS

93-99 130
Abstract

Depression is the most common non-motor manifestation of Parkinson's disease (PD), which significantly affects the rate of disease progression and increases the risk of motor complications and dementia. The paper considers the etiology and pathogenesis, cause-and-effect factors of depression in PD, and features of its diagnosis and treatment. Attention is paid to the algorithm for a physician's actions in the detection of depressive disorder in a patient with PD, to the choice of an antidepressant, and to the promising areas of therapy.

100-105 88
Abstract

Diabetic polyneuropathy (DPN) is the most common chronic complication of diabetes mellitus and can develop just at the prediabetes stage. As DPN progresses and, in the absence of its adequate treatment, leads to worse quality of life and its shorter expectancy in patients. The paper discusses current clinical guidelines for the examination and management of patients with DPN, diagnostic methods, and pathogenetic treatment of this disease.

106-114 92
Abstract

The review considers the problem of cognitive impairment (CI) and dementia in patients from older age groups, as well as the safety of antidementia agents with a focus on adverse cardiovascular drug reactions. Special attention is paid to the role of cardiovascular risk factors in the genesis of CI and all types of dementia. It is emphasized that the treatment of patients with CI is primarily aimed at monitoring vascular risk factors, preventing stroke and progression of chronic cerebrovascular disease, and, therefore, improving cognitive functions. Postoperative cognitive dysfunction in elderly patients, in particular during coronary artery bypass surgery, is highlighted. Non-drug and drug measures to prevent the progression of CI and dementia are described in detail. The significant importance of multimorbidity and polypragmasia in elderly patients with dementia is noted; data on the cardiovascular safety of anti-dementia drugs are presented.

115-120 63
Abstract

This review considers the clinical and pathogenetic aspects of an association between tobacco smoking dependence and depressive spectrum disorders. The comorbidity of these disorders has been established to be to a large extent determined by their common genetic bases. This association substantially affects the efficiency of treatment. Resistance to anti-nicotine and antidepressant medications is associated precisely with the comorbidity of these diseases. To enhance the efficiency of treatment, it is promising to include non-drug methods into the therapeutic complex. This makes it possible to achieve a gradual reduction in tobacco withdrawal syndrome and to prevent an exacerbation of comorbid depression.



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ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)