Browsing by Author "Petrović, Igor (7004083314)"

Objectives: Adherence to medication is an important factor that can influence Parkinson's disease (PD) control. We aimed to explore patients' adherence to antiparkinsonian medication and determine factors that might affect adherence to medications among PD patients. Methods: A cross-sectional, exploratory survey of PD patients treated with at least one antiparkinsonian drug and with a total score of MoCA (Montreal Cognitive Assessment) ≥26 was conducted. The final sample included 112 PD patients. A patient's adherence was assessed through ARMS (Adherence to Refills and Medications Scale). ARMS scores higher than 12 were assumed lower adherence. In addition, each patient underwent neurological examination, assessment of depression, anxiety, and evaluation of the presence of PD nonmotor symptoms. Results: The mean ARDS value in our cohort was 14.9 ± 2.5. Most PD patients (74.1%) reported lower adherence to their medication. Participants in the lower adherence group were younger at PD onset, had significantly higher UPDRS (Unified PD Rating Scale) scores, as well as UPDRS III and UPDRS IV subscores, HARS (Hamilton Anxiety Rating Scale), and NMSQuest (Non-Motor Symptoms Questionnaire for PD) scores compared to the fully adherent group (p=0.013, p=0.017, p=0.041, p=0.043, and p=0.023, respectively). Among nonmotor PD symptoms, the presence of cardiovascular, apathy/attention-deficit/memory disorders, hallucinations/delusions, and problems regarding changes in weight, diplopia, or sweating were associated with lower adherence. Multivariate regression analysis revealed depression as the strongest independent predictor of lower adherence. Conclusion: Depressed PD patients compared to PD patients without clinical depression had a three times higher risk for lower adherence to pharmacotherapy. Recognition and adequate treatment of depression might result in improved adherence. Copyright © 2022 Branislava Radojević et al.

[No abstract available]

[No abstract available]

Background: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). Methods: Following the MDSGene protocol, we systematically investigated genotype–phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. Results: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. Conclusions: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). Methods: Following the MDSGene protocol, we systematically investigated genotype–phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. Results: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. Conclusions: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective: Differentiating Parkinson's disease (PD) from atypical parkinsonian disorders (APD) such as Multiple System Atrophy, parkinsonian type (MSA-p) or Progressive Supranuclear Palsy (PSP-RS) can be challenging. Early signs of postural Instability and gait disability (PIGD) are considered clues that may signal presence of APD. However, it remains unknown which PIGD test – or combination of tests – can best distinguish PD from APD. We evaluated the discriminative value of several widely-used PIGD tests, and aimed to develop a short PIGD evaluation that can discriminate parkinsonian disorders. Methods: In this multicentre cohort study patients were recruited by 11 European MSA Study sites. Patients were diagnosed using standardized criteria. Postural instability and gait disability was evaluated using interviews and several clinical tests. Results: Nineteen PD, 21 MSA-p and 25 PSP-RS patients were recruited. PIGD was more common in APD compared to PD. There was no significant difference in axial symptoms between PSP-RS and MSA-p, except for self-reported falls (more frequent in PSP-RS patients). The test with the greatest discriminative power to distinguish APD from PD was the ability to perform tandem gait (AUC 0.83; 95% CI 71–94; p < 0.001), followed by the retropulsion test (AUC 0.8; 95% CI 0.69–0.91; p < 0.001) and timed-up-and-go test (TUG) (AUC 0.77; 95% CI 0.64–0.9; p = 0.001). The combination of these three tests yielded highest diagnostic accuracy (AUC 0.96; 95% CI 0.92–1.0; p < 0.001). Conclusions: Our study suggests that simple “bedside” PIGD tests – particularly the combination of tandem gait performance, TUG and retropulsion test – can discriminate APD from PD. © 2018 Elsevier Ltd

Objective: Differentiating Parkinson's disease (PD) from atypical parkinsonian disorders (APD) such as Multiple System Atrophy, parkinsonian type (MSA-p) or Progressive Supranuclear Palsy (PSP-RS) can be challenging. Early signs of postural Instability and gait disability (PIGD) are considered clues that may signal presence of APD. However, it remains unknown which PIGD test – or combination of tests – can best distinguish PD from APD. We evaluated the discriminative value of several widely-used PIGD tests, and aimed to develop a short PIGD evaluation that can discriminate parkinsonian disorders. Methods: In this multicentre cohort study patients were recruited by 11 European MSA Study sites. Patients were diagnosed using standardized criteria. Postural instability and gait disability was evaluated using interviews and several clinical tests. Results: Nineteen PD, 21 MSA-p and 25 PSP-RS patients were recruited. PIGD was more common in APD compared to PD. There was no significant difference in axial symptoms between PSP-RS and MSA-p, except for self-reported falls (more frequent in PSP-RS patients). The test with the greatest discriminative power to distinguish APD from PD was the ability to perform tandem gait (AUC 0.83; 95% CI 71–94; p < 0.001), followed by the retropulsion test (AUC 0.8; 95% CI 0.69–0.91; p < 0.001) and timed-up-and-go test (TUG) (AUC 0.77; 95% CI 0.64–0.9; p = 0.001). The combination of these three tests yielded highest diagnostic accuracy (AUC 0.96; 95% CI 0.92–1.0; p < 0.001). Conclusions: Our study suggests that simple “bedside” PIGD tests – particularly the combination of tandem gait performance, TUG and retropulsion test – can discriminate APD from PD. © 2018 Elsevier Ltd

Background/Aim. Botulinum toxin-A (BTX-A) is known to block the release of acetylcholine from motor and autonomic nerve terminals and may significantly decrease saliva production when injected intraglandulary. The aim of this study was to evaluate effects of BTX-A injections in the treatment of disabling sialorrhea in various neurological disorders. Methods. This study included 19 consecutive patients with significant sialorrhea associated with various neurological disorders. Out of them 13 patients were with Parkinson's disease, two with pantothenate kinase-associated neurodegeneration, two with multiple system atrophy, one with Wilson's disease, and one patient with postoperative sialorrhea. Botulinum toxin-A (Dysport®, Ipsen Pharma) was injected into the parotid glands with (n = 7 patients) or without (n = 12 patients) ultrasound guidance. All the patients were scored before and after the treatment and in weekly intervals thereafter using the salivation item of the part II (Activities of Daily Living) of the Unified Parkinson's Disease Rating Scale (UPDRS). Results. Thirteen patients (68%) reported beneficial effect of BTX-A injection, while 6 of them (32%) had no response at all. The sialorrhea scores before and after the treatment were 3.1 ± 0.1 (range 2-4) and 1.8 ± 0.1 (range 0-3), respectively (t = 5.636; p < 0.001). There was no difference in the magnitude of response between the groups with (t = 4.500; p = 0.004) and without (t = 3.674; p = 0.005) ultrasound control of injection sites. Adverse effects were registered in 5 patients (26%). Conclusions. Botulinum toxin-A injections to easily accessible parotid glands, without necessity for ultrasound guidance, are safe and efficaceous treatment for sialorrhea in different neurological disorders.

Background: The neural basis of task specificity in dystonia is still poorly understood. This study investigated gray and white matter (WM) brain alterations in patients with task-specific dystonia (TSD) and non-task-specific dystonia (NTSD). Methods: Thirty-six patients with TSD (spasmodic dysphonia, writer's cramp), 61 patients with NTSD (blepharospasm, cervical dystonia), and 83 healthy controls underwent 3D T1-weighted and diffusion tensor magnetic resonance imaging (MRI). Whole brain cortical thickness and voxel-based morphometry; volumes of basal ganglia, thalamus, nucleus accumbens, amygdala, and hippocampus; and WM damage were assessed. Analysis of variance models were used to compare MRI measures between groups, adjusting for age and botulinum toxin (BoNT) treatment. Results: The comparison between focal dystonia patients showed cortical thickness and gray matter (GM) volume differences (ie, decreased in NTSD, increased in TSD) in frontal, parietal, temporal, and occipital cortical regions; basal ganglia; thalamus; hippocampus; and amygdala. Cerebellar atrophy was found in NTSD patients relative to controls. WM damage was more severe and widespread in task-specific relative to NTSD patients. TSD patients receiving BoNT, relative to nontreated patients, had cortical thickening and increased GM volume in frontoparietal, temporal, and occipital regions. NTSD patients experiencing pain showed cortical thickening of areas involved in pain-inhibitory mechanisms. Conclusions: TSD and NTSD are characterized by opposite alterations of the main cortical and subcortical sensorimotor and cognitive-controlling brain structures, suggesting the possible presence of different pathophysiological and/or compensatory mechanisms underlying the complexity of the two clinical phenotypes of focal dystonia. © 2020 International Parkinson and Movement Disorder Society. © 2020 International Parkinson and Movement Disorder Society

Background: The neural basis of task specificity in dystonia is still poorly understood. This study investigated gray and white matter (WM) brain alterations in patients with task-specific dystonia (TSD) and non-task-specific dystonia (NTSD). Methods: Thirty-six patients with TSD (spasmodic dysphonia, writer's cramp), 61 patients with NTSD (blepharospasm, cervical dystonia), and 83 healthy controls underwent 3D T1-weighted and diffusion tensor magnetic resonance imaging (MRI). Whole brain cortical thickness and voxel-based morphometry; volumes of basal ganglia, thalamus, nucleus accumbens, amygdala, and hippocampus; and WM damage were assessed. Analysis of variance models were used to compare MRI measures between groups, adjusting for age and botulinum toxin (BoNT) treatment. Results: The comparison between focal dystonia patients showed cortical thickness and gray matter (GM) volume differences (ie, decreased in NTSD, increased in TSD) in frontal, parietal, temporal, and occipital cortical regions; basal ganglia; thalamus; hippocampus; and amygdala. Cerebellar atrophy was found in NTSD patients relative to controls. WM damage was more severe and widespread in task-specific relative to NTSD patients. TSD patients receiving BoNT, relative to nontreated patients, had cortical thickening and increased GM volume in frontoparietal, temporal, and occipital regions. NTSD patients experiencing pain showed cortical thickening of areas involved in pain-inhibitory mechanisms. Conclusions: TSD and NTSD are characterized by opposite alterations of the main cortical and subcortical sensorimotor and cognitive-controlling brain structures, suggesting the possible presence of different pathophysiological and/or compensatory mechanisms underlying the complexity of the two clinical phenotypes of focal dystonia. © 2020 International Parkinson and Movement Disorder Society. © 2020 International Parkinson and Movement Disorder Society

Introduction: Functional movement disorders (FMD) refer to a group of movement disorders that present with clinical characteristics incongruent to those due to established pathophysiologic processes, as for example in the case of neurodegeneration or lesions. The aim of this study was to assess clinical features that contribute to the specific phenotypic presentations and disease course of FMD. Methods: The study consisted of 100 patients with FMD treated at Clinic for Neurology, Clinical Center of Serbia, who were longitudinally observed. Comprehensive clinical and psychiatric assessment was performed at the baseline, when initial FMD phenotype was defined. Follow-up assessment of phenotypic pattern over the time and clinical course was done after 3.2 ± 2.5 years at average. Results: We showed that 48% of FMD patients were prone to changes of phenotypic pattern during the disease course. Dystonia had tendency to remains as single and unchanged phenotype over the time (68.2%), while patients initially presented with Tremor, Gait disorder, Parkinsonism and Mixed phenotype were more susceptible to developing additional symptoms (62.5, 50, and 100%, respectively). Higher levels of somatoform experiences (p = 0.033, Exp(B) = 1.082) and higher motor severity (p = 0.040, Exp(B) = 1.082) at baseline assessment were associated with an increased likelihood of further enriching of FMD phenotype with additional functional symptoms. Also, these patients more frequently reported pain, and had higher scores on majority of applied psychiatric scales, together with more frequent presence of major depressive disorder. Conclusion: Results from this prospective study suggested tendency for progression and enrichment of functional symptoms in FMD patients over time. Besides functional core symptoms, other key psychological and physical features (like pain or multiple somatisations) were quite relevant for chronicity and significant dysability of FMD patients. © Copyright © 2020 Tomić, Ječmenica Lukić, Petrović, Svetel, Dragašević Mišković, Kresojević, Marković and Kostić.

Introduction: Functional movement disorders (FMD) refer to a group of movement disorders that present with clinical characteristics incongruent to those due to established pathophysiologic processes, as for example in the case of neurodegeneration or lesions. The aim of this study was to assess clinical features that contribute to the specific phenotypic presentations and disease course of FMD. Methods: The study consisted of 100 patients with FMD treated at Clinic for Neurology, Clinical Center of Serbia, who were longitudinally observed. Comprehensive clinical and psychiatric assessment was performed at the baseline, when initial FMD phenotype was defined. Follow-up assessment of phenotypic pattern over the time and clinical course was done after 3.2 ± 2.5 years at average. Results: We showed that 48% of FMD patients were prone to changes of phenotypic pattern during the disease course. Dystonia had tendency to remains as single and unchanged phenotype over the time (68.2%), while patients initially presented with Tremor, Gait disorder, Parkinsonism and Mixed phenotype were more susceptible to developing additional symptoms (62.5, 50, and 100%, respectively). Higher levels of somatoform experiences (p = 0.033, Exp(B) = 1.082) and higher motor severity (p = 0.040, Exp(B) = 1.082) at baseline assessment were associated with an increased likelihood of further enriching of FMD phenotype with additional functional symptoms. Also, these patients more frequently reported pain, and had higher scores on majority of applied psychiatric scales, together with more frequent presence of major depressive disorder. Conclusion: Results from this prospective study suggested tendency for progression and enrichment of functional symptoms in FMD patients over time. Besides functional core symptoms, other key psychological and physical features (like pain or multiple somatisations) were quite relevant for chronicity and significant dysability of FMD patients. © Copyright © 2020 Tomić, Ječmenica Lukić, Petrović, Svetel, Dragašević Mišković, Kresojević, Marković and Kostić.

Introduction: Levodopa-induced dyskinesias (LID) appears in more than 50% of Parkinson’s disease patients after 5 years of treatment and clinicians always have to ensure that there is a balance between the beneficial effect of the treatment and the potential complications. Areas covered: In this review, the authors discuss the treatment of LID. Treatment can be divided into strategies for preventing their occurrence, modification of dopaminergic therapy, and providing more continuous dopaminergic stimulation as well as the use of nondopaminergic drugs. Expert opinion: Amantadine is currently considered the most effective drug for the treatment of LID. Several compounds developed to target adenosine, adrenergic, glutamatergic, and serotonergic receptors have shown to significantly decrease dyskinesias in animal models. However, despite promising preclinical results, translation to clinical practice remains challenging and majority of these compounds failed to decrease LID in randomized controlled trials with moderate–to-advanced parkinsonian patients. Despite promising results with nondopaminergic drugs, treatment of dyskinesias is still challenging and largely due to their side effects. Future research should focus on developing treatments that can provide continuous dopaminergic delivery throughout the day in a noninvasive manner. Studies on the impact of the early administration of long-acting formulations of levo-3,4-dihydroxy-phenylalanine on dyskinesias are also necessary. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Introduction: Levodopa-induced dyskinesias (LID) appears in more than 50% of Parkinson’s disease patients after 5 years of treatment and clinicians always have to ensure that there is a balance between the beneficial effect of the treatment and the potential complications. Areas covered: In this review, the authors discuss the treatment of LID. Treatment can be divided into strategies for preventing their occurrence, modification of dopaminergic therapy, and providing more continuous dopaminergic stimulation as well as the use of nondopaminergic drugs. Expert opinion: Amantadine is currently considered the most effective drug for the treatment of LID. Several compounds developed to target adenosine, adrenergic, glutamatergic, and serotonergic receptors have shown to significantly decrease dyskinesias in animal models. However, despite promising preclinical results, translation to clinical practice remains challenging and majority of these compounds failed to decrease LID in randomized controlled trials with moderate–to-advanced parkinsonian patients. Despite promising results with nondopaminergic drugs, treatment of dyskinesias is still challenging and largely due to their side effects. Future research should focus on developing treatments that can provide continuous dopaminergic delivery throughout the day in a noninvasive manner. Studies on the impact of the early administration of long-acting formulations of levo-3,4-dihydroxy-phenylalanine on dyskinesias are also necessary. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson's disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson's Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score > 14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies. © 2021 - IOS Press. All rights reserved.

Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson's disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson's Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score > 14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies. © 2021 - IOS Press. All rights reserved.

[No abstract available]

[No abstract available]

Introduction: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with a progressive clinical course. In addition to symptomatic therapy, DBS has been increasingly recognized as a potential therapeutic strategy, especially in severe cases. Therefore, we wanted to report our experience regarding benefits of DBS in five PKAN cases in 3-year follow-up study. Methods: Five genetically confirmed PKAN patients from Serbia underwent GPi-DBS. To assess clinical outcome, we reviewed medical charts and applied: Schwab and England Activities of Daily Living Scale (S&E), EQ-5D questionnaire for quality of life, Patient Global Impression of Improvement (GPI-I), Functional Independence Measure (FIM), Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), Barry Albright Dystonia Scale (BAD). Patients were evaluated in five visits: at the disease onset, 5 years after the onset, before surgery, 6 months and 14–36 months after the surgery. Improvement of 20% was accepted as significant. Results: Overall, dystonia significantly improved after GPi-DBS at 6 and 14–36 months postoperatively, when assessed by the BFMDRS and BAD. However, two patients failed to improve considerably. Four patients reported improvement on GPI-I, while one remained unchanged. Three patients reported significant improvement, when assessed with S&E and FIM. EQ-5D showed the most prominent improvement in the domains of mobility and pain/discomfort. Conclusion: Three out of our five patients experienced beneficial effects of the GPi-DBS, in up to 36 months follow-up. Two patients who had not reached significant improvement had longer disease duration; therefore, it might be reasonable to recommend GPi-DBS as soon as dystonia became disabling. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Introduction: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with a progressive clinical course. In addition to symptomatic therapy, DBS has been increasingly recognized as a potential therapeutic strategy, especially in severe cases. Therefore, we wanted to report our experience regarding benefits of DBS in five PKAN cases in 3-year follow-up study. Methods: Five genetically confirmed PKAN patients from Serbia underwent GPi-DBS. To assess clinical outcome, we reviewed medical charts and applied: Schwab and England Activities of Daily Living Scale (S&E), EQ-5D questionnaire for quality of life, Patient Global Impression of Improvement (GPI-I), Functional Independence Measure (FIM), Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), Barry Albright Dystonia Scale (BAD). Patients were evaluated in five visits: at the disease onset, 5 years after the onset, before surgery, 6 months and 14–36 months after the surgery. Improvement of 20% was accepted as significant. Results: Overall, dystonia significantly improved after GPi-DBS at 6 and 14–36 months postoperatively, when assessed by the BFMDRS and BAD. However, two patients failed to improve considerably. Four patients reported improvement on GPI-I, while one remained unchanged. Three patients reported significant improvement, when assessed with S&E and FIM. EQ-5D showed the most prominent improvement in the domains of mobility and pain/discomfort. Conclusion: Three out of our five patients experienced beneficial effects of the GPi-DBS, in up to 36 months follow-up. Two patients who had not reached significant improvement had longer disease duration; therefore, it might be reasonable to recommend GPi-DBS as soon as dystonia became disabling. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.