Ataxia subaguda asociada a ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS) / Subacute ataxia associated with cerebellar ataxia, neu ropathy and vestibular areflexia (CANVAS)

Resumen El síndrome de ataxia cerebelosa, neuropatía y arre flexia vestibular (CANVAS) es un trastorno neurodege nerativo progresivo que se manifiesta en etapas tardías de la vida. Su base genética ha sido recientemente identificada en el gen que codifica la subunidad 1 del factor C de replicación (RFC1). Presentamos el caso de una mujer de 62 años con una historial de desequilibrio y deterioro de la marcha de presentación bifásica, con un inicio rápido de los sínto mas seguido de un deterioro neurológico lento y progre sivo. El proceso diagnóstico fue complejo y se realizaron numerosas pruebas para descartar causas adquiridas y genéticas de la ataxia, arribando al diagnóstico de ataxia cerebelosa de inicio tardío idiopática. Ulteriormente, las pruebas de función vestibular identificaron una grave vestibulopatía bilateral. Esto llevó a considerar el CANVAS entre los diagnósticos, que finalmente fue confirmado mediante pruebas genéticas (expansión bialélica del penta-nucleótido AAGGG en el gen RFC1). Este caso subraya la importancia de esta nueva enfer medad genética y su variante de presentación subaguda y enfatiza la relevancia de las pruebas objetivas de fun ción vestibular en las ataxias consideradas idiopáticas para lograr un diagnóstico adecuado y un eventual asesoramiento genético a la descendencia.

Abstract Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Fac tor C (RFC1). We present the case of a 62-year-old woman who expe rienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cer ebellar ataxia. Subsequently, vestibular function tests iden tified severe bilateral vestibulopathy. This led to consider ing CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new de scribed genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibu lar function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.

[Subacute ataxia associated with cerebellar ataxia, neuropathy and vestibular areflexia (CANVAS)]. / Ataxia subaguda asociada a ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS).

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Factor C (RFC1). We present the case of a 62-year-old woman who experienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cerebellar ataxia. Subsequently, vestibular function tests identified severe bilateral vestibulopathy. This led to considering CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new described genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibular function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.

El síndrome de ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS) es un trastorno neurodegenerativo progresivo que se manifiesta en etapas tardías de la vida. Su base genética ha sido recientemente identificada en el gen que codifica la subunidad 1 del factor C de replicación (RFC1). Presentamos el caso de una mujer de 62 años con una historial de desequilibrio y deterioro de la marcha de presentación bifásica, con un inicio rápido de los síntomas seguido de un deterioro neurológico lento y progresivo. El proceso diagnóstico fue complejo y se realizaron numerosas pruebas para descartar causas adquiridas y genéticas de la ataxia, arribando al diagnóstico de ataxia cerebelosa de inicio tardío idiopática. Ulteriormente, las pruebas de función vestibular identificaron una grave vestibulopatía bilateral. Esto llevó a considerar el CANVAS entre los diagnósticos, que finalmente fue confirmado mediante pruebas genéticas (expansión bialélica del penta-nucleótido AAGGG en el gen RFC1). Este caso subraya la importancia de esta nueva enfermedad genética y su variante de presentación subaguda y enfatiza la relevancia de las pruebas objetivas de función vestibular en las ataxias consideradas idiopáticas para lograr un diagnóstico adecuado y un eventual asesoramiento genético a la descendencia.

Cranial Nerve Thinning Distinguishes RFC1-Related Disorder from Other Late-Onset Ataxias.

BACKGROUND: RFC1-related disorder (RFC1/CANVAS) shares clinical features with other late-onset ataxias, such as spinocerebellar ataxias (SCA) and multiple system atrophy cerebellar type (MSA-C). Thinning of cranial nerves V (CNV) and VIII (CNVIII) has been reported in magnetic resonance imaging (MRI) scans of RFC1/CANVAS, but its specificity remains unclear. OBJECTIVES: To assess the usefulness of CNV and CNVIII thinning to differentiate RFC1/CANVAS from SCA and MSA-C. METHODS: Seventeen individuals with RFC1/CANVAS, 57 with SCA (types 2, 3 and 6), 11 with MSA-C and 15 healthy controls were enrolled. The Balanced Fast Field Echo sequence was used for assessment of cranial nerves. Images were reviewed by a neuroradiologist, who classified these nerves as atrophic or normal, and subsequently the CNV was segmented manually by an experienced neurologist. Both assessments were blinded to patient and clinical data. Non-parametric tests were used to assess between-group comparisons. RESULTS: Atrophy of CNV and CNVIII, both alone and in combination, was significantly more frequent in the RFC1/CANVAS group than in healthy controls and all other ataxia groups. Atrophy of CNV had the highest sensitivity (82%) and combined CNV and CNVIII atrophy had the best specificity (92%) for diagnosing RFC1/CANVAS. In the quantitative analyses, CNV was significantly thinner in the RFC1/CANVAS group relative to all other groups. The cutoff CNV diameter that best identified RFC1/CANVAS was ≤2.2 mm (AUC = 0.91; sensitivity 88.2%, specificity 95.6%). CONCLUSION: MRI evaluation of CNV and CNVIII using a dedicated sequence is an easy-to-use tool that helps to distinguish RFC1/CANVAS from SCA and MSA-C.

Nigrostriatal dysfunction in RFC1-related disorder/CANVAS.

INTRODUCTION: Parkinsonism is now recognized as an additional feature in RFC1/CANVAS syndrome; however, no systematic evaluation of nigrostriatal dopaminergic function has been published so far. METHODS: This is an observational, single-center study, which analyzed 13 patients with molecular confirmation of RFC1/CANVAS. Disease severity was assessed with the SARA scale. Each subject was carefully evaluated for the presence of parkinsonian features. Dopamine transporter (DAT) imaging was acquired and reconstructed in the transverse, coronal and sagittal planes 4 h after venous injection of 99mTc-TRODAT-1. An experienced nuclear physician performed the visual analysis of all images. RESULTS: Patients had a mean age of 62.3 ± 8.8 years, and there were 9 women. The mean SARA score was 15.5 ± 5.8. Nine patients had abnormal DAT imaging results. The putamen was more frequently affected than the caudate nucleus on both sides. Considering all regions, uptake of 99mTc-TRODAT-1 did not correlate with disease duration or SARA scores. Parkinsonism was noticed in 3/13 patients, all of which had abnormal DAT scans. Interestingly, six subjects had reduced DAT imaging uptake, but no clinical signs of parkinsonism. CONCLUSION: Nigrostriatal dysfunction is frequent in RFC1/CANVAS even in the absence of clinical parkinsonism and may occur early in the disease course.

CANVAS: una nueva etiología de la ataxia del adulto. La asociación con tos orienta al diagnóstico. Comunicación de 2 pacientes / Late-Onset Cerebellar Ataxia with Neuropathy: Uncovering the Role of RFC1 Gene Mutations

Presentamos dos pacientes no relacionados con ataxia cerebelosa de inicio tardío asociada con neuropatía y tos seca de larga data. Un paciente tenía dos hermanos afectados con neuropatía sensorial y tos. Ambos probandos tuvieron investigaciones extensas que incluyó pruebas genéticas negativas para las ataxias más comunes, así como pruebas paraneoplásicas y otras causas inmunológicas. Ambos pacientes mostraron una expansión intrónica anormal en el pentanucleótido AAGGG del gen RFC1. Esta etiología se informa como causa frecuente de ataxia de inicio en adultos; la presencia de tos puede conducir al diagnóstico correcto.

We report two unrelated patients with late-onset cerebellar ataxia associated with neuropathy and a long-standing dry cough. One patient had two siblings affected with sensory neuropathy and cough. Both probands had extensive investigations including genetics testing negative for most common ataxias as well as testing for paraneoplasic and other immunologic causes. Both patients showed an abnormal intronic expansion in the pentanucleotide AAGGG of the gene RFC1. This etiology is being reported as frequent cause of adult-onset ataxia; the presence of cough may lead to the correct diagnosis.

Dysautonomia in RFC1-related disorder: Clinical and neurophysiological evaluation.

OBJECTIVE: To characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy. METHODS: We enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests. RESULTS: In the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs. CONCLUSIONS: Autonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy. SIGNIFICANCE: Dysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.

RFC1-Related Disorder: In Vivo Evaluation of Spinal Cord Damage.

BACKGROUND: RFC1-related disorder is a novel heredodegenerative condition with a broad phenotypic spectrum. Its neuropathological bases are not yet fully understood, particularly regarding the pattern, extent, and clinical relevance of spinal cord (SC) damage. OBJECTIVES: The objectives were to determine the SC structural signature in RFC1-related disorder in vivo and to identify potential clinical correlates for these imaging abnormalities. METHODS: We enrolled 17 subjects with biallelic RFC1 (AAGGG)n expansions and 11 age- and sex-matched healthy controls that underwent multimodal magnetic resonance imaging SC acquisitions in a 3T Philips Achieva scanner. Both global morphometry and tract-specific analyses were then performed across all cervical levels. Between-group comparisons were assessed using nonparametric tests. RESULTS: In the patient group, mean age and disease duration were 62.9 ± 9.3 and 9.3 ± 4.0, respectively. Compared to controls, patients had remarkable SC cross-sectional area reduction along all cervical levels but anteroposterior flattening only in the lower cervical levels. There was also prominent SC gray matter atrophy. Diffusivity abnormalities were identified in the dorsal columns but not in the lateral corticospinal tracts. Disease severity did not correlate with these imaging parameters. CONCLUSION: SC damage is a hallmark of RFC1-related disorder and characterized by gray as well as white matter involvement. In particular, dorsal columns are severely and diffusely affected. The clinical correlates of these imaging abnormalities still deserve additional investigations. © 2022 International Parkinson and Movement Disorder Society.

Using design science research to propose an IT governance model for higher education institutions.

The increasing use of, and dependence on, Information Technology (IT) to support operational teaching, research, and management activities in Higher Education Institutions (HEI)-mainly due to their multi-unit organizational structure-have evidenced the need of encouraging managers to focus more on IT Governance (ITG) effectiveness, which has been an issue for many of these institutions. In this sense, we aim to develop a specific ITG model for Higher Education Institutions, by following the methodological principles of Design Science Research (DSR). The model was developed based on a robust theoretical basis that took into account different approaches substantiated by both the alignment of good practices and ITG focus areas as well as addressing the current ITG context of the Brazilian higher education institutions. The validation of the ITG model was based on its presentation to members of the IT Steering Committee of a Brazilian HEI, who confirmed its usefulness and applicability.

Hybridization of the Kano model and business model canvas: aeronautical and metalworking industry in Bogota, Colombia.

The aeronautical and metalworking industrial sector lies within an active environment, which is a characteristic of globalization as well as the implementation of new, innovative, and revolutionary technologies that allow for the dynamization of endogenous and exogenous processes of organizations, thus reaping benefits for such companies. This study aimed to generate a generalized methodology that led to the hybridization of the Kano model and Business Model Canvas. A Kano questionnaire was implemented in 105 organizations of the aeronautical and metalworking sector in Bogota, Colombia to assess the attributes of a technology-based product (digital platform) to be offered by the company Aerospace Business Group LLC; its results were integrated into the Business Model Canvas. It was ascertained that all attributes contributed to customer satisfaction and were distributed into three blocks of the Business Model Canvas. This hybridization aids in the development of better structured businesses, thus reducing risks and maximizing opportunities.

Brain Structural Signature of RFC1-Related Disorder.

BACKGROUND: The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition. OBJECTIVE: The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. METHODS: We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls. RESULTS: The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. CONCLUSION: This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.

Modelo de avaliação da viabilidade econômico-financeira da implantação de usinas de reciclagem de resíduos da construção civil em municípios brasileiros / Economic and financial viability evaluation model for the implementation of waste recycling plants construction in Brazilian municipalities

RESUMO Este trabalho teve como objetivo geral desenvolver um modelo de avaliação da viabilidade econômico-financeira da implantação de usinas de reciclagem de resíduos da construção civil e demolição (URRCD) em municípios brasileiros. O modelo de avaliação proposto para cada projeto de investimento (PI) em estudo uniu o modelo de negócio Canvas, o plano de negócios, a metodologia multi-índice proposta por Souza e Clemente (2009) e ampliada por Lima et al. (2015) por meio do aplicativo web $AVEPI. Também foi realizada uma análise de sensibilidade por meio de limites de elasticidade e valores-limite, bem como uma análise estocástica utilizando a simulação de Monte Carlo (SMC). Com base na proposição desse modelo, este foi aplicado em um estudo de caso no município de Pato Branco (PR). Os resultados mostram que há viabilidade econômico-financeira na implantação desse PI, uma vez que o valor presente líquido médio é de aproximadamente R$ 583.919,87, e a recuperação do investimento se concretizará em 12 anos (payback). Por meio da SMC, visualizou-se que há alta probabilidade (99,78%) de que o investimento na URRCD de Pato Branco seja rentável. Entretanto, os índices de elasticidade mostraram que é preciso monitorar as receitas esperadas e os custos estimados com mais atenção. Assim, será preciso um trabalho, por parte dos gestores da URRCD, em prol de sempre estarem buscando aumentar a demanda pelos agregados reciclados, como maneira de aumentar a receita da usina, desde que se respeite a sua capacidade de produção.

ABSTRACT This work had as main objective to develop an evaluation model for analyzing the economic and financial feasibility of implementing Construction and Demolition Waste Recycling Plants (URRCD) in Brazilian municipalities. The evaluation model proposed for the Investment Project (IP) under study was performed using the business model Canvas, the business plan, the multi-index method proposed by Souza and Clemente (2009) and expanded by Lima et al. (2015) through the $AVEPI Web app. Also, a sensitivity analysis was performed, through the elasticity limits and limit values as well as a stochastic analysis using the Monte Carlo Simulation (MCS). From the proposition of this model, it was applied in a case study in Pato Branco, Paraná. The results showed that there is economic and financial viability in the implementation of this IP, since the average Net Present Value (NPV) is about R$ 583,919.87 and the investment recovery will materialize in 12 years (Payback). Through MCS, it was observed that there is a high probability (99.78%) that the investment in the URRCD of Pato Branco, Paraná, be profitable. However, the elasticity indices showed that it is necessary to monitor the expected revenues and the estimated costs with more attention. Thus, it will require a work by the managers of the URRCD, in favor of always seeking to increase the demand for recycled aggregates, as a way to increase the revenue of the plant, as long as it does not exceed its production capacity.

Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations.

A biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences. However only the biallelic AAGGG expansions were reported to cause late-onset ataxia. In this study, we aimed to assess the prevalence and nature of RFC1 repeat expansions in three cohorts of adult-onset ataxia cases: Brazilian (n = 23) and Canadian (n = 26) cases that are negative for the presence of variants in other known ataxia-associated genes, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the biallelic AAGGG expansion in only one Brazilian family which presented two affected siblings, and in one Canadian case. We also observed two new repeat conformations, AAGAG and AGAGG, which suggests the pentanucleotide expansion sequence has a dynamic nature. To assess the frequency of these new repeat conformations in the general population, we screened 163 healthy individuals and observed the AAGAG expansion to be more frequent in cases than in control individuals. While additional studies will be necessary to asses the pathogenic impact of biallelic genotypes that include the novel expanded conformations, their occurrence should nonetheless be examined in future studies.

Designing a Model of a Digital Ecosystem for Healthcare and Wellness Using the Business Model Canvas.

Wellness is a term often used to talk about optimal health as "dynamic balance of physical, emotional, social, spiritual, and intellectual health." While healthcare is a term about care offered to patients for improving their health. We use both terms, as well as the Business Model Canvas (BMC) methodology, to design a digital ecosystem model for healthcare and wellness called DE4HW; the model considers economic, technological, and legal asymmetries, which are present on e-services beyond geographical regions. BMC methodology was embedded into the global project strategy called: IBOT (Initiate, Build, Operate and Transfer); it is a methodology to establish a functional, integrated national telemedicine network and virtual education network; of which we took its phases rationale. The results in this work illustrate the design of DE4HW model, into the first phase of IBOT, enriched with the BMC, which enables us to define actors, their interactions, rules and protocols, in order to build DE4HW, while IBOT strategy manages the project goal, up to the transfer phase, where an integral service platform of healthcare and wellness is turned over to stakeholders.