Nanoscale octopus guiding telomere entanglement: An innovative strategy for inducing apoptosis in cancer cells.

Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.

Comparative evaluation of single and multiple exposure to PM2.5 in respirable air on cardiac physiology, structure and function in a Wistar rat model.

Many studies have shown the negative relationship between long term exposure to PM2.5 and cardiac dysfunction. Recently, studies have shown that even a single exposure of PM2.5 from air sample in permissible range can induce very mild cardiac pathological changes. In the present study, we revisited the toxic effect of PM2.5 on rat heart by adopting single and multiple exposure durations. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m3 daily for 3 hr for single (1 day) and multiple (7, 14, 21 days) durations. The major pathological changes noted in 21 days exposed myocardium comprised of an elevated ST segment (the segment between the S wave and the T wave), development of cardiac fibrosis, hypertrophy, cardiac injury, tissue inflammation and declined cardiac function. With 14 days exposed heart, the electrocardiograms (ECG),data showed insignificantly declined heart rate and an increased QT (the time from the start of the Q wave to the end of the T wave) interval along with mild fibrosis, hypertrophy and lesser number of TUNEL positive cells. On the other hand, single- and 7-days exposure to PM2.5 did not impart any significant changes in the myocardium. To determine the reversibility potential of PM2.5 induced cardiotoxicity, a washout period of 24 hours was adopted and all observed changes in the myocardium were reversed till day 7, but not in 14- and 21-days exposed samples. Based on the above findings we concluded that PM2.5 associated cardiac dysfunction is the cumulative outcome of ineffective cardiac adaptive and repair process that accumulate additively over the time due to prolonged exposure durations.

Multiple sclerosis treatments a review of current biomedical engineering approaches.

Multiple Sclerosis (MS) is an autoimmune condition targeting the central nervous system (CNS) characterized by focal demyelination with inflammation, causing neurodegeneration and gliosis. This is accompanied by a refractory period in relapsing MS or chronic progression in primary progressive MS. Current MS treatments target disease relapses and aim to reduce further demyelination and disability. These include the treatment of acute exacerbations through global immunomodulation upon corticosteroid administration, which are accompanied by adverse reactions. Disease modifying therapies (DMTs) which provide targeted immunosuppression of T and B cells, and sequestration of leukocytes out of CNS, have led to further improvements in demyelination prevention and disease burden reduction. Despite their efficacy, DMTs are ineffective in remyelination, pathology reversal and have minimal effects in progressive MS. The advent of modern biomedical engineering approaches in combination with a better understanding of MS pathology, has led to the development of novel, regenerative approaches to treatment. Such treatments utilize neural stem cells (NSCs) and can reduce disease relapses and reverse damage caused by the disease through localized tissue regeneration. While at initial stages, pre-clinical and clinical studies utilizing NSCs and immune modulation have shown promising outcomes in tissue regeneration, creating a potential new era in MS therapy.

Targeting GPRC5D for multiple myeloma therapy.

Given its nearly ubiquitous expression on plasma cells and limited expression on essential normal tissue, the G protein-coupled receptor class C group 5 member D (GPRC5D) presents a promising opportunity for utilization as an immunotherapy target in multiple myeloma (MM). The therapeutic strategies targeting GPRC5D, such as bispecific antibodies (BsAbs), chimeric antigen receptor (CAR) T cells, and antibody-drug conjugates (ADCs), have been prominently emphasized in relapsed/refractory MM (R/R MM) in recent years. Further clinical trials are necessary to confirm the long-term efficacy of GPRC5D-targeting immunotherapies alone, explore their potentials co-targeting with other specific antigens, or investigate their combinations with existing treatments to overcome MM resistance. This review provides an overview of current research progress in GPRC5D, encompassing its biological characteristics and translational journey from laboratory to clinical application.

Sleep and cognitive outcomes in multiple sclerosis; a systematic review.

BACKGROUND: Multiple sclerosis (MS) is a disabling disease of the central nervous system. People living with MS often have co-existing sleep disorders and cognitive dysfunction. The objective of this study was to scrutinize the relationship between cognitive outcomes and sleep conditions in MS. METHODS: This study followed the Joanna Briggs Institute's (JBI) and PRISMA guidelines. PubMed, Scopus, Embase, and Web of Science databases were searched and original studies delineating the relationship between sleep status and cognitive findings in MS patients| were included. The risk of bias was assessed using the JBI critical appraisal tools. RESULTS: In the final review, out of 1635 screened records, 35 studies with 5321 participants were included. Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and polysomnography were the most common assessment tools for evaluation of sleep condition, and cognitive evaluations were conducted using the tests including Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test (BVMT). Assessing the quality of studies showed no significant bias in most of the included articles. A link between sleep condition and cognitive abilities was suggested in the literature, especially with objective measurement of sleep condition; however, current evidence did not support a substantial association between self-reported sleep quality and processing speed and working memory in patients with MS. DISCUSSION: Evidence proposes sleep is an independent factor associated with cognitive outcomes in MS. Given the limitations of the evidence such as the lack of well-designed prospective studies, these findings need to be interpreted with caution.

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Integrating palliative care into multiple myeloma management : Optimizing quality of life across the disease continuum.

BACKGROUND: Multiple myeloma (MM) poses significant challenges due to its complex symptomatology and evolving treatment landscape. While therapeutic advances have improved survival outcomes, holistic management of MM requires addressing the numerous physical and psychosocial needs of patients. Palliative care (PC) offers a comprehensive approach to symptom management and supportive care on a physical, psychosocial and spiritual level; however, its role in MM remains underexplored. METHODS: This retrospective single-center study examines the outcome of 22 MM patients admitted to the Division of Palliative Medicine at the Medical University of Vienna. We investigated reasons for admission, symptom severity, functional status, length of stay and overall survival. RESULTS: Most common reasons for palliative care unit (PCU) admission were nutritional problems (82%), fatigue (77%) and pain (68%). Median ECOG score at PCU admission was 3. The timepoint within the timeline of myeloma disease at which hospitalization took place varied greatly. Some patients were hospitalized shortly after diagnosis, other patients after many years of active disease and therapy. Median time from MM initial diagnosis to first PCU stay was 4.3 years (range 0.6-23.8 years). The median length of hospital (PCU) stay was 11 days (range 1-127days) and 45% of patients died during PCU hospitalization. The reduction in symptom burden as a result of the inpatient stay in the PCU is reflected in the PERS2ON score, which was measured on the day of admission (median 23 days, range 6-32 days) and on the day of discharge (median 16 days, range 7-20 days). CONCLUSION: PC interventions effectively addressed the complex symptom burden experienced by patients with MM. Multidimensional approaches encompassing physical, psychological and social domains proved instrumental in optimizing quality of life. Integrating PC principles into MM management paradigms is essential to prioritize patient-centered care across the disease continuum.

Whole-genome sequencing reveals cellular origin of concomitant chronic lymphocytic leukemia and multiple myeloma: a case report.

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are hematological disorders affecting B cells. The clonal relationship between CLL and MM has not always been clarified, although this information is critical to understanding its pathogenesis. Here, we present a rare clinical case of synchronous CLL and MM. Whole-genome sequencing (WGS) was performed using malignant lymph node (LN) and bone marrow (BM) tissues. Based on the high consistency of single nucleotide variants (SNVs), significantly mutated genes (SMGs), copy number variations (CNVs), different B cell receptor (BCR) IGH rearrangement features in LN and BM, and the different light-chain expression patterns in CLL and MM cells, we concluded that CLL and MM cells from this patient originated from the same hematopoietic stem cell/progenitors, different pro-B cells and suffered oncogenic mutations at different B cell differentiation stages. Depth analysis of genome features using WGS provides a new method to explore the process of malignant B cell genesis.

The correlation between serum bone metabolism indexes and bone disease and survival in newly diagnosed multiple myeloma patients.

Objective Myeloma-related bone disease (MBD) is one of the most common complications of multiple myeloma (MM). This study aims to investigate the correlation between serum bone metabolism indexes (BMIs), the clinical characteristics and prognosis of newly diagnosed MM (NDMM) patients. METHODS: The serum BMIs of 148 patients with NDMM in a single hematological disease treatment center from April 2014 to December 2019 were analyzed retrospectively, including type I collagen amino terminal elongation peptide (PINP), ß-C-terminal telopeptide of type I collagen (ß-CTX) and N-terminal osteocalcin (N-MID). Other clinical indexes were simultaneously collected and the degree of bone damage in patients was evaluated. We explored the effect of serum BMIs on the prognosis and identified independent prognostic factors. Another 77 NDMM patients from April 2018 to February 2021 served as the validation cohort. RESULTS: The area under the curve (AUC) predicted by ß-C-terminal telopeptide of type I collagen (ß-CTX), type I collagen amino terminal elongation peptide (PINP), and N-terminal osteocalcin (N-MID) for overall survival (OS) were 0.708, 0.613, and 0.538, respectively. Patients with high serum levels had shorter OS (p < .001, p = .004, p = .027, respectively). Cox multivariate analysis indicated that serum ß- CTX、lactic dehydrogenase、hemoglobin and the degree of bone injury were independent prognostic factors. A COX regression model was established with a C-index of 0.782 and validated with a C-index of 0.711. CONCLUSION: The serum BMIs are correlated with the patients' OS, and ß- CTX can be an independent prognostic factor.

Stepwise One-Shot Borylation Reactions for Intersecting DABNA Substructures Exhibiting Bright Yellow‒Green Electroluminescence with EQE Beyond 40% and Mild Roll-Off.

Boron/nitrogen (B/N)-doped polycyclic aromatic hydrocarbons (PAHs) with the multiple resonance (MR) effect are promising for organic light-emitting diodes (OLEDs) because of their narrowband emission and thermally activated delayed fluorescence (TADF) characteristics. Nevertheless, exploring the variety of such emitters is challenging because of the tricky and limited synthetic protocols. Herein, we designed a novel B/N-doped PAH, L-DABNA-1, whose backbone (L-DABNA) could not be achieved via conventional routes (e.g., one-pot borylation or one-shot borylation). We successfully synthesized it through stepwise one-shot borylations with precisely introducing decorations. The unique MR backbone with intersecting DABNA substructures sharing an aniline group, avoiding any para-N-π-B motif, allows L-DABNA-1 to maintain narrowband TADF emission while significantly redshifting to the yellow-green region with a reverse intersystem crossing rate (kRISC) of 1.28 × 105 s-1. An L-DABNA-1-based OLED device achieved a maximum external quantum efficiency (EQE) of over 40% and maintained a high EQE of 36.3% at 1000 cd m-2, with a current efficiency reaching ~170 cd A-1. This work not only demonstrated the great potential of stepwise borylations in synthesizing B/N-doped PAH backbones, expanding their chemical space, but also provided a promising pathway for exploring MR-TADF emitters at longer wavelengths.

AB026. A rare case report: multiple hemangioblastoma.

BACKGROUND: Hemangioblastomas (HBLs) are uncommon tumors of the central nervous system (CNS), corresponding to 1% to 2.5% of all intracranial tumors. They can present sporadically or in patients with von Hippel-Lindau (VHL) disease along with a variety of benign and malignant tumors, and are most often located in the cerebellum, brainstem, and spinal cord. Although surgical resection is currently considered the main therapeutic option for symptomatic lesions, evidence supporting the application of microsurgery has not been systematically assessed. However, post-operative outcomes can vary depending on factors including disease location, number of lesions, and tumor characteristics that make complete resections difficult. The objective of this case report is to document a rare case of multiple HBL in a 45-year-old man, highlighting the need for further research, the absence of a standardized treatment protocol for appropriate management strategies. CASE DESCRIPTION: A 45-year-old man presented to the outpatient neurology department with a chief complaint of gradual weakness of the left side of his body, walking unsteadily, and seizure. Neurological examination revealed a positive dysmetria sign. According to his medical records, he was diagnosed with multiple HBL since August 2022 and subsequently underwent two times partial tumor resections, and a ventriculoperitoneal (VP)-shunt due to hydrocephalus. The latest magnetic resonance imaging examination shows improvement in the original tumor. He is currently receiving symptomatic therapy with complaints have improved. CONCLUSIONS: This case report highlights a rare occurrence of multiple HBL in a 45-year-old man. Surgical management of HBL was the most common modality and was suggested as an effective and optimal treatment, but the recurrence possibility of the cystic wall tumor must also be considered in the choice of treatment.

AB051. Multiple meningiomas developed outside the radiation field after cranial irradiation: a case report.

BACKGROUND: Cranial irradiation has well-known long-term side effects, including radiation-induced neoplasms and vasculopathy. This report describes a case of aggressive and rapid-growing multiple meningiomas developed outside the radiation field after the treatment of medulloblastoma. CASE DESCRIPTION: A 6-year-old boy underwent surgery (gross total resection) and radiotherapy (19.8 Gy for posterior fossa only) against medulloblastoma in the 4th ventricle. The patient could not receive further craniospinal irradiation because of ventriculoperitoneal shunt-related complications. Eighteen years after the radiotherapy, the first meningioma developed in the right temporal convexity, without recurrence of medulloblastoma. It was left untreated because it was asymptomatic. Three years later, the meningioma grew from 0.6 to 6.3 cm3 in volume and another large meningioma (22.1 cm3) developed in the left temporal convexity with additional small meningioma in the right frontal convexity. The left large temporal meningioma showed aggressive nature invading the adjacent temporal bone and temporalis muscle. It was completely resected and the histology revealed as transitional meningioma with 2% of Ki-67. Another new meningioma was identified on the right cerebellar convexity three years post-craniotomy. Subsequent follow-up indicated a progressive increase in the tumor size and gamma knife radiosurgery was performed with right frontal convexity small meningioma. The patient is currently under ongoing surveillance through follow-up assessments. CONCLUSIONS: For patients who received radiotherapy at a young age, clinicians should consider the possibility of secondary neoplasm development even outside the radiation field. Careful imaging follow-up and surgical management are warranted because of the aggressive nature of secondary tumors even though benign in histology.

Clinical utility of brief screening measures during neuropsychological consultation for pediatric onset multiple sclerosis.

OBJECTIVE: Pediatric-onset multiple sclerosis (POMS) accounts for approximately 2 to 5% of all individuals with MS and is associated with an increased risk for cognitive impairment. In recent years, neuropsychological screening questionnaires have been increasingly utilized for pediatric populations in multidisciplinary settings. This study examines the clinical utility of the Colorado Learning Difficulties Questionnaire (CLDQ) and Pediatric Perceived Cognitive Functioning (Peds PCF) screening measures for identifying cognitive impairment in persons with POMS during a target neuropsychological evaluation. METHOD: Retrospective data was gathered from electronic medical records at a single pediatric hospital. RESULTS: Forty-nine participants were included (69% female; 43% Hispanic/Latinx; mean age = 16.1 years old, range = 9.9 to 20.6 years old). Correlation analyses demonstrated strong interrelatedness between caregiver ratings on screening measures and performance on traditional neuropsychological measures. Effect sizes were medium across comparisons (CLDQ: Spearman's rho = -.321 to -.563; PedsPCF: Spearman's rho = .308 to .444). Exploratory cut-points using receiver operating characteristic analysis and Youden indices are also discussed. CONCLUSIONS: Comparison of scores across caregiver rating questionnaires and on a targeted neuropsychological battery suggests that the screening surveys alone may not be sensitive enough to identify children with cognitive impairments, but ratings may provide qualitatively meaningful information along with neuropsychological testing. This study illustrates how pediatric neuropsychologists can leverage screening tools to focus consultative interviews and effectively triage referrals for evaluation within an academic medical setting.

Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles.

The functionality of the central nervous system (CNS) relies on the connection, integration, and the exchange of information among neural cells. The crosstalk among glial cells and neurons is pivotal for a series of neural functions, such as development of the nervous system, electric conduction, synaptic transmission, neural circuit establishment, and brain homeostasis. Glial cells are crucial players in the maintenance of brain functionality in physiological and disease conditions. Neuroinflammation is a common pathological process in various brain disorders, such as neurodegenerative diseases, and infections. Glial cells, including astrocytes, microglia, and oligodendrocytes, are the main mediators of neuroinflammation, as they can sense and respond to brain insults by releasing pro-inflammatory or anti-inflammatory factors. Recent evidence indicates that extracellular vesicles (EVs) are pivotal players in the intercellular communication that underlies physiological and pathological processes. In particular, glia-derived EVs play relevant roles in modulating neuroinflammation, either by promoting or inhibiting the activation of glial cells and neurons, or by facilitating the clearance or propagation of pathogenic proteins. The involvement of EVs in neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Multiple Sclerosis (MS)- which share hallmarks such as neuroinflammation and oxidative stress to DNA damage, alterations in neurotrophin levels, mitochondrial impairment, and altered protein dynamics- will be dissected, showing how EVs act as pivotal cell-cell mediators of toxic stimuli, thereby propagating degeneration and cell death signaling. Thus, this review focuses on the EVs secreted by microglia, astrocytes, oligodendrocytes and in neuroinflammatory conditions, emphasizing on their effects on neurons and on central nervous system functions, considering both their beneficial and detrimental effects.

Lipid levels and multiple myeloma risk: insights from Meta-analysis and mendelian randomization.

BACKGROUND: Lipid levels have been suggset to be correlated with multiple myeloma (MM) risk, though causality remains unconfirmed. To explore this further, a detailed study combining meta-analysis and Mendelian randomization (MR) was conducted. METHODS: Literature searches were performed on PubMed and Embase; summary data for plasma lipid traits were extracted from the IEU and MM data from the FinnGen database. Meta-analysis and MR were utilized to analyze the link of lipids with MM risk, including mediator MR to identify potential mediators. The study was conducted in accordance with PRISMA and STROBE-MR guidelines. RESULTS: Observational studies analyzed through meta-analysis showed that elevated levels of LDL, HDL, total cholesterol (TC), and triglycerides correlate with a lower risk of MM, with HRs of 0.73, 0.59, 0.60, and 0.84, respectively. MR analysis confirmed a potential causal link of triglyceride with a reduced MM risk (OR: 0.67, 95% CI: 0.46-0.98), independent of BMI. Mediation analysis pointed to X-11,423-O-sulfo-L-tyrosine and neuropilin-2 as potential mediators. CONCLUSIONS: The findings suggest that higher lipid levels (LDL, HDL, TC, and triglycerides) are linked with a reduced MM risk, and higher triglyceride levels are causally associated with a reduced MM risk. This suggests new avenues for therapeutic interventions targeting MM.

Ulnar lengthening for children with forearm deformity from hereditary multiple exostoses: a retrospective study from a tertiary medical center.

BACKGROUND: Patients with hereditary multiple exostosis (HME) usually present with forearm deformity with or without radial head dislocation. Ulna lengthening has been proposed to address this condition. Exostosis resection plus ulna lengthening has been adopted in our hospital since 2008, and patients with this condition were retrospectively reviewed. Herein, we aimed to investigate the optimal timing and clinical outcomes of this surgical approach. METHODS: In all, thirty-five patients (40 forearms), including 22 boys and 13 girls, were enrolled in our study from July 2014 to September 2020. We divided the patients into 4 groups based on the age when they received surgery and the status of the radial head. Pronation and supination of the forearm, flexion and extension of the elbow, wrist ulnar deviation and wrist radial deviation, and radiological parameters including ulnar length (UL), ulnar variance (UV), the percentage of radial bowing (RB/RL), radio articular angle (RAA) and carpal slip (CS), were assessed and recorded. RESULTS: The mean UL was significantly improved after surgery in four Groups (P<0.05). In patients with radial head dislocation, we found significant improvement in forearm, wrist function and elbow flexion (p < 0.05). For the patients with radial head dislocation, the juniors demonstrated better improvement in % RB and RAA (p<0.05, p = 0.003 and 0.031). CONCLUSION: Exostosis resection and ulna lengthening with unilateral external fixation can effectively improve the function and radiological parameters of forearm deformity in HME children. For patients with radial head dislocation, early surgery can achieve better results. For patients not associated with radial head dislocation, we recommend regular follow-up and surgical treatment after 10 years of age.

Effectiveness of a digital lifestyle management intervention (levidex) to improve quality of life in people with multiple sclerosis: results of a randomized controlled trial.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease with diverse symptomatology, significantly impacting patients' quality of life (QoL). While pharmacological therapies focus primarily on reducing inflammation and relapse rates, non-pharmacological interventions, including digital health applications, have shown promise in improving QoL among persons with MS (PwMS). Pilot studies had shown the feasibility and acceptability of levidex, a digital health application based on cognitive behavioral therapy (CBT) principles, a broad set of behavior change techniques, and relevant lifestyle-change advice. This randomized controlled trial aimed to examine the effects of levidex on MS-related QoL over 6 months. METHODS: Participants who were diagnosed with MS for at least one year were recruited via the internet in Germany, using a secure survey software platform, and were randomly assigned to the intervention group (IG), in which they received standard care + levidex, or an active control group (CG), in which they received standard care and were offered web-adapted material on the topic of lifestyle change from the German Multiple Sclerosis Society (DMSG). The primary outcome was MS-related QoL after 6 months, measured by the Hamburg Quality of Life Questionnaire in MS (HAQUAMS); secondary outcomes included QoL subscales, sick days, and health behavior, among others. Analyses of Covariance (ANCOVA) were used to examine intervention effects at 6 months. Participants were recruited between November 2020 and February 2022. RESULTS: A total of 421 adult participants (mean age: 47.5, 78.1% women) were included and randomized (IG, n = 195, CG, n = 226). After 6 months, the IG exhibited significantly higher MS-related QoL, compared to the CG (total score HAQUAMS, adjusted group mean difference = -0.14, 95% CI: [-0.22, -0.06], p = 0.001; Cohen's d = 0.23), with significant effects also observed on the cognitive and mood subscales. At 6 months, IG participants also reported significantly fewer sick days (median = 2 days in IG vs. 6 days in CG; W = 3939, p = 0.012) and significantly higher levels of daily activities, as measured by the Frenchay Activity Index, adjusted group mean difference = 1.37, 95% CI = [0.33, 2.40], p = 0.010; Cohen's d = 0.16. Safety analyses showed no adverse events and good satisfaction. CONCLUSIONS: Compared to the control group, levidex facilitated clinically relevant improvements in MS-related QoL, reduced sick days, and enhanced activity in PwMS over 6 months. These findings suggest that levidex can serve as an effective non-pharmacological adjunctive treatment element to standard care and could help improve QoL among PwMS. TRIAL REGISTRATION: Registered on 22.09.2020 at the German Clinical Trials Register DRKS00023023.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

Prebiotic inulin controls Th17 cells mediated central nervous system autoimmunity through modulating the gut microbiota and short chain fatty acids.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination occurring in the central nervous system (CNS). Inulin is a common prebiotic that can improve metabolic disorders by modulating the gut microbiota. However, its capacity to affect CNS autoimmunity is poorly recognized. Experimental autoimmune encephalomyelitis (EAE) is a classical mouse model of MS. Herein, we found that oral administration of inulin ameliorated the severity EAE in mice, accompanied by reductions in inflammatory cell infiltration and demyelination in the CNS. These reductions were associated with decreased proportion and numbers of Th17 cells in brain and spleen. Consistent with the findings, the serum concentrations of IL-17, IL-6, and TNF-α were reduced in inulin treated EAE mice. Moreover, the proliferation of auto-reactive lymphocytes, against MOG35-55 antigen, was attenuated ex vivo. Mechanistically, inulin treatment altered the composition of gut microbiota. It increased Lactobacillus and Dubosiella whereas decreased g_Prevotellaceae_NK3B31_group at the genus level, alongside with elevated concentration of butyric acid in fecal content and serum. In vitro, butyrate, but not inulin, could inhibit the activation of MOG35-55 stimulated lymphocytes. Furthermore, fecal microbiota transplantation assay confirmed that fecal contents of inulin-treated normal mice had an ameliorative effect on EAE mice. In contrast, antibiotic cocktail (ABX) treatment diminished the therapeutic effect of inulin in EAE mice as well as the reduction of Th17 cells, while supplementation with Lactobacillus reuteri restored the amelioration effect. These results confirmed that the attenuation of inulin on Th17 cells and inflammatory demyelination in EAE mice was dependent on its modulation on gut microbiota and metabolites. Our findings provide a potential therapeutic regimen for prebiotic inulin supplementation in patients with multiple sclerosis.

Implementing changing behaviour towards aerobic and strength exercise: Results of a randomised, phase I study determining the safety, feasibility, and consumer-evaluation of an online exercise program in persons with multiple sclerosis.

BACKGROUND: Many people with MS do not meet the recommended exercise regime to elicit health benefits. This study aimed to determine the feasibility, safety, acceptability, and appropriateness of an exercise intervention delivered online to persons with MS that meets current exercise recommendations and behaviour change principles. METHODS: Seventy-two participants (age: 43.3 ± 13.3 years) with mild to moderate MS were stratified according to previous exercise behaviour and block-randomised into one of three groups: Control (CON; n = 24), General Exercise (GE; n = 24) who at screening did not meet current exercise recommendations, and Advanced Exercise, (AE; n = 24) who at screening met the current exercise recommendations. GE and AE groups received a four-month online-supervised, behaviour change theory-based exercise program and were assessed at baseline, four-months, five-months, and eleven-months for physical activity participation. The feasibility of process, resources, management, and scientific outcomes was assessed. RESULTS: Of 198 potential participants, 143 met the eligibility criteria (72 %), and 72 were randomised. Fifty-three participants completed the intervention (74 % immediate retention), and 44 were retained at the six-month follow-up (61 %). Personnel time was 369 h, and total per-participant cost was Au$1036.20. Adherence rate to ≥70 % of exercise sessions was 73 % (GE) and 38 % (AE). The GE group observed a small magnitude of improvement in physical activity (d = -0.23). CONCLUSIONS: An online exercise program embedded with behaviour interventions for either GE or AE appears feasible, acceptable, appropriate and safe and may show long-term efficacy in increased exercise behaviours for persons with mild to moderate MS. TRIAL REGISTRATION: ANZCRT number ACTRN12619000228189p.