1 Oct

Real-world effectiveness of cladribine as an escalation strategy for MS: Insights from the Czech nationwide ReMuS registry

Background: Cladribine, a selective immune reconstitution therapy, is approved for the treatment of adult patients with highly active multiple sclerosis (MS).

Objectives: Provide experience with cladribine therapy in a real-world setting.

Methods: This is a registry-based retrospective observational cohort study. First, using data from the Czech nationwide registry ReMuS, we analysed patients who initiated cladribine from September 1, 2018 to December 31, 2021. Second, we analysed a subgroup of patients who initiated cladribine between September 1, 2018 to June 30, 2020, thus possessing a follow-up period of at least 2 years. We evaluated demographic and MS characteristics including disease-modifying therapies (DMTs) before and after cladribine administration, relapses, Expanded Disability Status Scale (EDSS), and adherence.

Results: In total, 617 patients (335 with follow-up of at least 2 years) started cladribine therapy in the study period (mean age 37.0, mean disease duration 8.4 years, 74.1% females). In most cases, cladribine was administered as a second-line drug, a total of 80.7% had been escalated from a platform DMT. During 2 years before cladribine initiation, the average annualised relapse rate (ARR) was .67. 

1 Oct

Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

1 Oct

Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients

Background: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far.

Objective: We aimed to deliver pilot data on the genetic landscape of ALS in our country.

Methods: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22).

Results: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72).

1 Oct

A closed 3D printed microfluidic device for automated growth and differentiation of cerebral organoids from single-cell suspension

The development of 3D organoids has provided a valuable tool for studying human tissue and organ development in vitro. Cerebral organoids, in particular, offer a unique platform for investigating neural diseases. However, current methods for generating cerebral organoids suffer from limitations such as labor-intensive protocols and high heterogeneity among organoids. To address these challenges, we present a microfluidic device designed to automate and streamline the formation and differentiation of cerebral organoids. The device utilizes microwells with two different shapes to promote the formation of a single aggregate per well and incorporates continuous medium flow for optimal nutrient exchange. In silico simulations supported the effectiveness of the microfluidic chip in replicating cellular microenvironments. Our results demonstrate that the microfluidic chip enables uniform growth of cerebral organoids, significantly reducing the hands-on time required for maintenance. Importantly, the performance of the microfluidic system is comparable to the standard 96-well plate format even when using half the amount of culture medium, and the resulting organoids exhibit substantially developed neuroepithelial buds and cortical structures. This study highlights the potential of custom-designed microfluidic technology in improving the efficiency of cerebral organoid culture.

1 Oct

Virtual Waiting Room: The New Narrative of Waiting in Oncology Care

This conceptual study introduces the "virtual waiting room," an innovative, interactive, web-based platform designed to enhance the waiting experience in oncology by providing personalized, educational, and supportive content. Central to our study is the implementation of the circular entry model, which allows for non-linear navigation of health information, empowering patients to access content based on their immediate needs and interests. This approach respects the individual journeys of patients, acknowledging the diverse pathways through which they seek understanding and manage their health. The virtual waiting room is designed not only to support patients but also to facilitate stronger communication and shared understanding between patients, caregivers, and families. By providing a shared digital space, the platform enables caregivers and family members to access the same information and resources, thereby promoting transparency and collective knowledge. This shared access is crucial in managing the emotional complexities of oncology care, where effective communication can significantly impact treatment outcomes and patient well-being. Furthermore, the study explores how the circular entry model within the virtual waiting room can enhance patient autonomy and engagement by offering customized interactions based on user feedback and preferences.

13 Sep

REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Objective: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH.

Methods: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated.

6 Sep

Assessment of lumbar paraspinal muscle morphology using mDixon Quant magnetic resonance imaging (MRI): a cross-sectional study in healthy subjects

Background: Lumbar paraspinal muscles (LPM) are a part of the deep spinal stabilisation system and play an important role in stabilising the lumbar spine and trunk. Inadequate function of these muscles is thought to be an essential aetiological factor in low back pain, and several neuromuscular diseases are characterised by dysfunction of LPM. The main aims of our study were to develop a methodology for LPM assessment using advanced magnetic resonance imaging (MRI) methods, including a manual segmentation process, to confirm the measurement reliability, to evaluate the LPM morphological parameters [fat fraction (FF), total muscle volume (TMV) and functional muscle volume (FMV)] in a healthy population, to study the influence of physiological factors on muscle morphology, and to build equations to predict LPM morphological parameters in a healthy population.

Methods: This prospective cross-sectional observational comparative single-centre study was conducted at the University Hospital in Brno, enrolling healthy volunteers from April 2021 to March 2023. MRI of the lumbar spine and LPM (erector spinae muscle and multifidus muscle) were performed using a 6-point Dixon gradient echo sequence. The segmentation of the LPM and the control muscle (psoas muscle) was done manually to obtain FF and TMV in a range from Th12/L1 to L5/S1. 

6 Sep

The moderating effect of perceived hope in the relationship between anxiety and posttraumatic growth during the Russian-Ukrainian war

Introduction: This study examines the relationships between perceived hope, posttraumatic growth, well-being, anxiety, and perceived threat of the Russian-Ukrainian War (RUW) in the Czech adult population. Drawing on the evidence of posttraumatic growth (PTG) amidst crisis, we hypothesized that perceived hope moderates the effects of perceived threat of war and anxiety on PTG.

Methods: Data were obtained from 1,000 Czech respondents via an online questionnaire ten months post-invasion. The form included measures of posttraumatic growth, perceived hope, well-being, anxiety and depression, and perceived threat of war.

Results: Our findings reveal that perceived hope acted as a moderator enhancing the positive effects of perceived threat and anxiety on PTG. However, perceived hope did not significantly moderate the direct effects of perceived threats and anxiety on well-being.

Discussion: This study highlights the significant role of hope amidst adversity and underscores its potential as a target for interventions aiming to foster PTG in populations who navigate traumatic experiences.