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Toward European harmonization of national myasthenia gravis registries: modified Delphi procedure-based expert consensus on collectable data.
BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder. Several new treatment concepts have emerged in recent years, but access to these treatments varies due to differing national reimbursement regulations, leading to disparities across Europe. This highlights the need for high-quality data collection by stakeholders to establish MG registries. A European MG registry could help bridge the treatment access gap across different countries, offering critical data to support regulatory decisions, foster international collaborations, and enhance clinical and epidemiological research. Several national MG registries already exist or are in development. To avoid duplication and ensure harmonization in data collection, a modified Delphi procedure was implemented to identify essential data elements for inclusion in national registries. RESULTS: Following a literature review, consultations with patient associations and pharmaceutical companies, and input from multiple European MG experts, 100 data elements were identified. Of these, 62 reached consensus for inclusion and classification, while only 1 item was agreed for exclusion. 30 items failed to reach the ≥ 80% agreement threshold and were excluded. Among the 62 accepted items, 21 were classified as mandatory data elements, 32 optional, and 9 items pertained to the informed consent form. CONCLUSIONS: Through a modified Delphi procedure, consensus was successfully achieved. This consensus-based approach represents a crucial step toward harmonizing MG registries across Europe. The resulting dataset will facilitate the sharing of knowledge and enhance European collaborations. Furthermore, the harmonized data may assist in regulatory or reimbursement decisions regarding novel therapies, as well as address treatment access disparities between European countries.
LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization
Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years of follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Data were from the Parkinson's Progression Markers Initiative, a multicentre prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient-reported outcome assessments were administered. Biomarkers included dopamine transporter scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels and serum neurofilament light chain. Linear mixed-effects (LMMs) models examined differences in trajectory in CSF-negative and CSF-positive groups. A total of 148 LRRK2 parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay, were included. At baseline, the negative group was older than the positive group [median (inter-quartile range) 69.1 (65.2-72.3) versus 61.5 (55.6-66.9) years, P < 0.001] and a greater proportion were female [28 (61%) versus 43 (42%), P = 0.035]. Despite being older, the negative group had similar duration since diagnosis and similar motor rating scale [16 (11-23) versus 16 (10-22), P = 0.480] though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared with 75 (77%) of the positive group. The negative group, compared with the positive group, had higher per cent-expected putamenal dopamine transporter binding for their age and sex [0.36 (0.29-0.45) versus 0.26 (0.22-0.37), P < 0.001]. Serum neurofilament light chain was higher in the negative group compared with the positive group [17.10 (13.60-22.10) versus 10.50 (8.43-14.70) pg/mL; age-adjusted P-value = 0.013]. In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (P = 0.037), but no other differences in trajectory were found. Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline. The underlying biology in LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.
Carbene-activated stannylenes to access selective C(sp3)–H bond scission at the steric limit
The ubiquity of N-heterocyclic carbenes (NHCs) in diverse areas of chemical research typically arises from their potent stabilising capabilities and role as innocent spectators to stabilise otherwise non-bottleable compounds and complexes. This has, until now, been particularly true for NHC-stabilised stannylenes, with no exceptions reported thus far. Herein, we demonstrate that the combination of heteroleptic terphenyl-/amido-based stannylenes and tetra-alkyl substituted NHCs renders the corresponding NHC-ligated stannylenes highly reactive, yet isolable. In solution, this induces sterically controlled inter- and intramolecular C(sp3)–H bond scissions, resulting in the selective formation of stannylene metallocycles that depend on both the NHC source and the meta-terphenyl ligand coordinated to tin.
Flash Communication: Cyanophosphide Transfer Reactions
Cyanophosphides of the general form [RPCN]− can be viewed as cyanide adducts of phosphinidenes and are phosphorus species in the (+1)-oxidation state. We have recently reported on the stable cyanophosphide [DippTerPCN]K (DippTer = 2,6-Dipp2C6H3, Dipp = 2,6-iPrC6H3) and now investigate its reactions with ECln (E = Ge, n = 2; E = P, As, n = 3) in either salt metathesis or base-assisted dehydrohalogenation reactions. In the case of GeCl2, salt metathesis with [DippTerPCN]K afforded the dimer of a chlorogermylene [DippTerP(CN)GeCl]2. When only 0.5 equiv of GeCl2 was used, the diphosphanylgermylene [DippTerP(CN)]2Ge was generated in solution. With ECl3 (E = P, As), facile cyanophosphide transfer was achieved from DippTerP(H)CN in NEt3-assisted dehydrohalogenation, giving diphosphanes or arsaphosphanes of the type DippTerP(CN)ECl2 (E = P, As), respectively.
Communication Between Anaesthesia Providers for Clinical and Professional Purposes: A Scoping Review
Background: Anaesthesia providers in all contexts need to be able to communicate with colleagues to meet a variety of clinical and professional needs, including physical help, advice and support as well as learning, supervision and mentorship. Such communication can be regarded as a ‘social resource’ which underpins anaesthesia providers’ practice, but which has not itself been extensively studied. The objective of this scoping review is to provide an overview of the literature related to communication among anaesthesia providers to meet clinical and professional goals, focusing on the modalities, contexts and purposes or outcomes of such communication, as well as which providers are involved.Methods: We conducted a scoping review using the JBI methodology to examine the current literature available, searching the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL and Google Scholar. Papers were eligible for inclusion where they primarily addressed the subject of communication between trained anaesthesia providers for any clinical or professional purpose (excluding purely social interactions). Data were charted for the location and cadre of providers represented, means of communication and the situation, purposes and outcomes of communication.Results: 3872 records were identified for screening, and 225 papers were ultimately included. Communication was reported both as a variable influencing a wide range of clinical and nonclinical outcomes and as an outcome in itself which might be modified by other factors. It was also considered in a smaller group of studies as a resource with varying availability to anaesthesia providers. Physician providers were well represented in included documents, but nurse anaesthetists, clinical officers and other nonphysician, nonnurse anaesthetists were far less commonly included. The majority of identified studies on communication between anaesthesia providers originated from and related to high‐income countries.Conclusion: Communication between anaesthesia providers affects all aspects of their practice and has implications for both patient outcomes and workforce capacity. More research is necessary to understand how the availability of communication as a resource affects patient care and health worker well‐being, particularly in low‐ and middle‐income contexts and among nonphysician anaesthesia providers.
The Clinical Trial Landscape in Autoimmune Encephalitis: Challenges and Opportunities.
Autoimmune encephalitis (AE) is an important cause of neurologic morbidity and mortality. Treatment algorithms are primarily based on observational studies, retrospective series, and expert opinion. Despite clinical improvement with empiric therapy, recovery is often incomplete with a substantial burden of residual neurologic deficits and recurring symptoms. There is a pressing need for higher quality evidence-based therapies. However, designing and conducting clinical trials for patients with rare diseases such as AE has specific challenges, including slow recruitment, suboptimal outcome measures, and inclusivity vs exclusivity of the various disease subtypes. The anticipated knowledge gained from AE clinical trials emphasizes the need to overcome these challenges and support the development of the next generation of clinical trials. Yet, given these challenges, alternative approaches may be required. In this article, we review past and present clinical trials in AE with a focus on studies enrolling patients with neural surface antibodies. We discuss the potential challenges and opportunities inherent to clinical trials in rare diseases and provide an outlook for the field.
Asymmetry in amyotrophic lateral sclerosis: clinical, neuroimaging and histological observations.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralised onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.
Understanding disrupted motivation in Parkinson's disease through a value-based decision-making lens
Neurobehavioural disturbances such as loss of motivation have profound effects on the lives of many people living with Parkinson's disease (PD), as well as other brain disorders. The field of decision-making neuroscience, underpinned by a plethora of work across species, provides an important framework within which to investigate apathy in clinical populations. Here we review how changes in a number of different processes underlying value-based decision making may lead to the common phenotype of apathy in PD. The application of computational models to probe both behaviour and neurophysiology show promise in elucidating these cognitive processes crucial for motivated behaviour. However, observations from the clinical management of PD demand an expanded view of this relationship, which we aim to delineate. Ultimately, effective treatment of apathy may depend on identifying the pattern in which decision making and related mechanisms have been disrupted in individuals living with PD.
Research priorities for the study of atrial fibrillation during acute and critical illness: recommendations from the Symposium on Atrial Fibrillation in Acute and Critical Care
AbstractAtrial fibrillation (AF) is a common arrhythmia encountered in acute and critical illness and is associated with poor short and long-term outcomes. Given the consequences of developing AF, research into prevention, prediction and treatment of this arrhythmia in the critically ill are of great potential benefit, however, study of AF in critically ill patients faces unique challenges, leading to a sparse evidence base to guide management in this population. Major obstacles to the study of AF in acute and critical illness include absence of a common definition, challenges in designing studies that capture complex etiology and assess causality, lack of a clear outcome set, difficulites in recruitment in acute environments with respect to timing, consent, and workflow, and failure to embed studies into clinical care platforms and capitalize on emerging technologies. Collaborative effort by researchers, clinicians, and stakeholders should be undertaken to address these challenges, both through interdisciplinary cooperation for the optimization of research efficiency and advocacy to advance the understanding of this common and complex arrhythmia, resulting in improved patient care and outcomes. The Symposium on Atrial Fibrillation in Acute and Critical Care was convened to address some of these challenges and propose potential solutions.