Patient and Public Involvement and Engagement in the Development of a Platform Clinical Trial for Parkinson's Disease: An Evaluation Protocol.

Background: Patient and public involvement and engagement (PPIE) in the design of trials is important, as participant experience critically impacts delivery. The Edmond J Safra Accelerating Clinical Trials in PD (EJS ACT-PD) initiative is a UK consortium designing a platform trial for disease modifying therapies in PD. Objective: The integration of PPIE in all aspects of trial design and its evaluation throughout the project. Methods: PwP and care partners were recruited to a PPIE working group (WG) via UK Parkinson's charities, investigator patient groups and participants of a Delphi study on trial design. They are supported by charity representatives, trial delivery experts, researchers and core project team members. PPIE is fully embedded within the consortium's five other WGs and steering group. The group's terms of reference, processes for effective working and PPIE evaluation were co-developed with PPIE contributors. Results: 11 PwP and 4 care partners have supported the PPIE WG and contributed to the development of processes for effective working. A mixed methods research-in-action study is ongoing to evaluate PPIE within the consortium. This includes the Patient Engagement in Research Scale -a quantitative PPIE quality measure; semi-structured interviews -identifying areas for improvement and overall impressions of involvement; process fidelity- recording adherence; project documentation review - identifying impact of PPIE on project outputs. Conclusions: We provide a practical example of PPIE in complex projects. Evaluating feasibility, experiences and impact of PPIE involvement in EJS ACT-PD will inform similar programs on effective strategies. This will help enable future patient-centered research.

Elevated Bile Acid 3ß,5α,6ß-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann-Pick Type C.

Ataxia is a common neurological feature of Niemann-Pick disease type C (NPC). In this disease, unesterified cholesterol accumulates in lysosomes of the central nervous system and hepatic cells. Oxidation by reactive oxygen species produces oxysterols that can be metabolised to specific bile acids. These bile acids have been suggested as useful biomarkers to detect NPC. Concentrations of 3ß,5α,6ß-trihydroxycholanyl glycine (3ß,5α,6ß-triOH-Gly) and 3ß,7ß-dihydroxy-5-cholenyl glycine (3ß,7ß-diOH-Δ5-Gly) were measured in plasma of 184 adults with idiopathic ataxia. All patients were tested with whole genome sequencing containing hereditary ataxia panels, which include NPC1 and NPC2 mutations and other genetic causes of ataxia. Plasma 3ß,5α,6ß-triOH-Gly above normal (>90 nM) was found in 8 out of 184 patients. One patient was homozygous for the p.(Val1165Met) mutation in the NPC1 gene. The remaining seven included one patient with Friedreich's ataxia and three patients with autoimmune diseases. Oxidative stress is known to be increased in Friedreich's ataxia and in autoimmune diseases. Therefore, this subset of patients possibly shares a common mechanism that determines the increase of this bile acid. In a large cohort of adults with ataxia, plasma 3ß,5α,6ß-triOH-Gly was able to detect the one patient in the cohort with NPC1 disease, but also detected oxidation of cholesterol by ROS in other disorders. Plasma 3ß,7ß-diOH-Δ5-Gly is not a potential biomarker for NPC1.

Vertebrates can be more important pollinators than invertebrates on islands: the case of Malva (=Lavatera) arborea L.

Premise of the study: On islands, flowering plants tend to be more generalist in their pollination needs, as insects (the main pollinators of flowering plants) are underrepresented in these ecosystems compared to the mainland. In addition, some vertebrate species that are typically insectivorous or granivorous on the mainland are forced to broaden their diet and consume other resources such as nectar or pollen on the islands. The shrub Malva arborea, with its large and colourful flowers, attracts different groups of potential pollinators. This study aimed to compare the effectiveness of vertebrates versus insects in an insular population of M. arborea and to investigate its reproductive system. Methods: For three groups of taxa (insects, birds and lizards), we assessed the two components of pollination effectiveness: (i) the quantitative component (i.e. number of visits and number of flowers contacted) through direct observations of flowers; and (ii) the qualitative component (fruit and seed set, number and size of seeds and proportion of seedling emergence) through pollinator exclusion experiments. Key results: Vertebrates (birds and lizards) were quantitatively the most effective pollinators, followed by insects. However, when all three groups visited the flowers, fruit and seed set were higher than when any of them were excluded. We also found that M. arborea has hermaphrodite flowers and is able to reproduce by autogamy, although less efficiently than when pollinated by animals. Conclusions: Both vertebrates and insects play an important role in the reproduction of M. arborea. Although the plant does not need pollinators to produce seeds, its reproductive success increases when all pollinators are allowed to visit the flowers. Besides providing new information on M. arborea, these findings may help to better understand the role of different pollinator groups in the reproduction of other plant species, especially on islands where the co-occurrence of vertebrate and invertebrate pollination in the same plant species is usual.

Proxy measures for the assessment of psychotic and affective symptoms in studies using electronic health records.

BACKGROUND: There is a lack of standardised psychometric data in electronic health record (EHR)-based research. Proxy measures of symptom severity based on patients' clinical records may be useful surrogates in mental health EHR research. AIMS: This study aimed to validate proxy tools for the short versions of the Positive and Negative Syndrome Scale (PANSS-6), Young Mania Rating Scale (YMRS-6) and Montgomery-Åsberg Depression Rating Scale (MADRS-6). METHOD: A cross-sectional, multicentre study was conducted in a sample of 116 patients with first-episode psychosis from 12 public hospitals in Spain. Concordance between PANSS-6, YMRS-6 and MADRS-6 scores and their respective proxies was evaluated based on information from EHR clinical notes, using a variety of statistical procedures, including multivariate tests to adjust for potential confounders. Bootstrapping techniques were used for internal validation, and an independent cohort from the Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne, Switzerland) for external validation. RESULTS: The proxy versions correlated strongly with their respective standardised scales (partial correlations ranged from 0.75 to 0.84) and had good accuracy and discriminatory power in distinguishing between patients in and not in remission (percentage of patients correctly classified ranged from 83.9 to 91.4% and bootstrapped optimism-corrected area under the receiver operating characteristic curve ranged from 0.76 to 0.89), with high interrater reliability (intraclass correlation coefficient of 0.81). The findings remained robust in the external validation data-set. CONCLUSIONS: The proxy instruments proposed for assessing psychotic and affective symptoms by reviewing EHR provide a feasible and reliable alternative to traditional structured psychometric procedures, and a promising methodology for real-world practice settings.

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.

Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials.

BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative.

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.

Functional unknomics: Systematic screening of conserved genes of unknown function.

The human genome encodes approximately 20,000 proteins, many still uncharacterised. It has become clear that scientific research tends to focus on well-studied proteins, leading to a concern that poorly understood genes are unjustifiably neglected. To address this, we have developed a publicly available and customisable "Unknome database" that ranks proteins based on how little is known about them. We applied RNA interference (RNAi) in Drosophila to 260 unknown genes that are conserved between flies and humans. Knockdown of some genes resulted in loss of viability, and functional screening of the rest revealed hits for fertility, development, locomotion, protein quality control, and resilience to stress. CRISPR/Cas9 gene disruption validated a component of Notch signalling and 2 genes contributing to male fertility. Our work illustrates the importance of poorly understood genes, provides a resource to accelerate future research, and highlights a need to support database curation to ensure that misannotation does not erode our awareness of our own ignorance.

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson's disease.

An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson's disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson's disease, a multi-arm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson's disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson's disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson's disease.

Assessing the Role of Lizards as Potential Pollinators of an Insular Plant Community and Its Intraspecific Variation.

The role of lizards as potential pollinators on islands has been documented for either one or a few plants in different parts of the world, but it has never been assessed for an entire plant community. Here, we quantified interaction rate by lizards and evaluated intraspecific differences in the use of flowers on Cabrera Gran (Cabrera archipelago, Balearic Islands) by means of visual observations, automated cameras and the analysis of pollen grain samples. Overall, we recorded interactions of the Balearic wall lizard (Podarcis lilfordi) with flowers of 44 plant species, 72.7% of which were unknown to date. Although florivory occurs in some of these species (35%), the majority of visits were legitimate (65%); in addition, we found intraspecific differences in the interactions related to the sex and age of lizards. Our findings support the role of Balearic wall lizards as potential pollinators across the entire plant community, and their contribution to particular plant species, for instance the endangered Cistus heterophyllus carthaginensis. This study also documents the first record of another sympatric lizard (Tarentola mauritanica) visiting flowers and contributes to the few existing records of flower interactions involving geckos in the Paleartic ecozone.

A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models.

Friedreich's ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.

Altered pituitary morphology as a sign of benign hereditary chorea caused by TITF1/NKX2.1 mutations.

Benign hereditary chorea (BHC) is a rare genetically heterogeneous movement disorder, in which conventional neuroimaging has been reported as normal in most cases. Cystic pituitary abnormalities and features of empty sella have been described in only 7 patients with BHC to date. We present 4 patients from 2 families with a BHC phenotype, 3 of whom underwent targeted pituitary MR imaging and genetic testing. All four patients in the two families displayed a classic BHC phenotype. The targeted pituitary MR imaging demonstrated abnormal pituitary sella morphology. Genetic testing was performed in three patients, and showed mutations causing BHC in three of the patients, as well as identifying a novel nonsense mutation of the TITF1/NKX2-1 gene in one of the patients. The presence of the abnormal pituitary sella in two affected members of the same family supports the hypothesis that this sign is a distinct feature of the BHC phenotype spectrum due to mutations in the TITF1 gene. Interestingly, these abnormalities seem to develop in adult life and are progressive. They occur in at least 26% of patients affected with Brain-lung-thyroid syndrome. As a part of the management of these patients we recommend to perform follow-up MRI brain with dedicated pituitary imaging also in adult life as the abnormality can occur years after the onset of chorea.

Examining the relationship between psychosis and immigration in Spain: The effect of cannabis use and language barrier in a large psychosis sample.

The main aim of this study is to examine the association between psychosis and immigration, independent of the language barrier, drug consumption, and the social support index. The second aim is to explore the clinical and demographic characteristics of the immigrants in the catchment area, compared with the native Spanish population suffering from psychosis. All consecutive patients admitted to a hospital in Spain during 2018 and 2019 (n = 1484) were identified through the hospital's clinical records. The general representative sample (n=1484) was divided into two groups: immigrants (n=131) and non-immigrants (n=1353). Demographic, clinical, and social variables were then obtained and included in a logistic regression model. A subsample with all consecutive cases with psychosis (93 immigrants and 543 no immigrants) was also analysed to describe the diagnosis and evolution after admission. Our results show that there is higher significant prevalence of admissions due to psychosis in the immigrant population than in the non-immigrant population. This association is prominent in the population of Sub-Saharans, and is independent of cannabis use, a low social support index, or a language barrier. Understanding the specificities not only in the social context of this population but also the clinical needs is determinant for being able to shape the therapeutic intervention.

From Collar to Coccyx: Truncal Movement Disorders: A Clinical Review.

BACKGROUND: Movement disorders affecting the trunk remain a diagnostic challenge even for experienced clinicians. However, despite being common and debilitating, truncal movement disorders are rarely discussed and poorly reviewed in the medical literature. OBJECTIVES: To review common movement disorders affecting the trunk and provide an approach for clinicians based on the truncal region involved (shoulder, chest, diaphragm, abdomen, pelvis, and axial disorders). For each disorder, clinical presentation, etiologic differential diagnosis, and "clinical clues" are discussed. CONCLUSION: This review provides a clinically focused, practical approach to truncal movement disorders, which will be helpful for physicians in everyday practice.

Juventudes migrantes institucionalizadas: una mirada desde la Terapia Ocupacional del Sur / Juventude migrante institucionalizada: uma visão a partir da Terapia Ocupacional do Sul / Institutionalized migrant youth: a view from the Southern Occupational Therapy

Resumen Introducción El proceso migratorio implica una serie de desafíos ocupacionales, sociales y culturales, sin embargo, cuando este proceso se trata de jóvenes no acompañados que se institucionalizan, cambia radicalmente todo su desempeño e identidad ocupacional. Objetivo Analizar el impacto ocupacional de jóvenes no acompañados institucionalizados en un servicio de protección y emergencia en Cataluña, España. Método Estudio etnográfico que utilizó como técnica de recogida de información: las observaciones de campo, entrevistas semi estructuradas y conversaciones informales, las cuales fueron transcritas y codificadas a través de un proceso de análisis del contenido. Resultados Arrojaron tres grandes temas que explican el fenómeno a) El contexto precario del país de origen: la construcción del deseo migratorio, b) Racismo institucional: producción cultural de discriminación social y c) Privación ocupacional: como limitación para la autonomía y la inserción cultural. Conclusión Se evidencia la influencia de la institucionalización como un factor estructural que limita la elección y participación ocupacional de los jóvenes. Esta problemática se refugia en un imperativo jurídico de "protección" que termina reproduciendo un sistema de discriminación colonial, racial y asistencial que viola los derechos humanos de los jóvenes migrantes.

Resumo Introdução O processo de migração envolve uma série de desafios ocupacionais, sociais e culturais, porém, quando esse processo envolve jovens desacompanhados que se institucionalizam, muda radicalmente todo o seu desempenho e identidade ocupacional. Objetivo Analisar o impacto ocupacional de jovens desacompanhados institucionalizados em um serviço de proteção e emergência na Catalunha, Espanha. Método Estudo etnográfico que utilizou como técnica de coleta de informações: observações de campo, entrevistas semiestruturadas e conversas informais, as quais foram transcritas e codificadas por meio de um processo de análise de conteúdo. Resultados Três eixos temáticos foram escolhidos que explicam o fenômeno a) O contexto precário do país de origem: a construção do desejo migratório, b) Racismo institucional: produção cultural da discriminação social e c) Privação ocupacional: como limitação para autonomia e inserção cultural. Conclusão A influência da institucionalização é evidenciada como um fator estrutural que limita a escolha e a participação ocupacional dos jovens. Esse problema se refugia em um imperativo legal de "proteção" que acaba reproduzindo um sistema de discriminação colonial, racial e previdenciária que viola os direitos humanos dos jovens migrantes.

Abstract Introduction The migration process involves a series of occupational, social, and cultural challenges; however, when this process involves unaccompanied youth who become institutionalized, it radically changes their entire performance and occupational identity. Objective To analyze the occupational impact of unaccompanied youth institutionalized in a protection and emergency service in Catalonia, Spain. Method Ethnographic study that used as an information-gathering technique: field observations, semi-structured interviews, and informal conversations, which were transcribed and coded through a content analysis process. Results They brought up three main themes that explain the phenomenon a) The precarious context of the country of origin: the construction of the migratory desire, b) Institutional racism: cultural production of social discrimination and c) Occupational deprivation: as a limitation for autonomy and cultural insertion. Conclusion The influence of institutionalization is evidenced as a structural factor that limits the choice and occupational participation of young people. This problem takes refuge in a legal imperative of "protection" that ends up reproducing a system of colonial, racial, and welfare discrimination that violates the human rights of young migrants.

Vitamin B6 Deficiency in Patients With Parkinson Disease Treated With Levodopa/Carbidopa.

OBJECTIVE: The aim of the study was to investigate the role of L-DOPA/carbidopa (CD) therapy on vitamin B6 levels in patients with Parkinson disease (PD). METHODS: This is a cross-sectional retrospective study of vitamin B6 plasma levels in 24 patients with PD treated with L-DOPA/CD for 3 or more years, orally or intraduodenally. Vitamin B6 levels in plasma were measured by ELISA. RESULTS: All patients treated with intraduodenal L-DOPA/CD (6 of 6) and 13 of 18 patients receiving L-DOPA/CD orally had low plasma levels of vitamin B6. Eight of the 19 patients with low vitamin B6 levels had symptoms of hypovitaminosis B6. Patients with low vitamin B6 had been treated with larger doses of L-DOPA/CD, although the differences did not have statistical significance. Patients treated with intraduodenal L-DOPA/CD have vitamin B6 levels significantly lower than those treated with oral L-DOPA/CD. The variables that most correlated with vitamin B6 levels were the cumulative annual doses of CD (r = -0.36) and L-DOPA (r = -0.33) during the year preceding the study and the time to develop dyskinesias or fluctuations (r = +0.43). CONCLUSIONS: Vitamin B6 could play an important role in PD and its levels seem to be influenced by L-DOPA/CD. Plasma vitamin B6 levels should be monitored in patients receiving high L-DOPA/CD doses, especially those treated with intraduodenal infusion.

"Grandes respondedores y recuperación". Tratamiento con clozapina asociado a factor estimulante de colonias de granulocitos / "Great responders and recovery." Treatment with clozapine associated with granulocyte colony stimulating factor

No disponible