BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair.

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.

Differential Role of Factor XIII in Acute Myocardial Infarction and Ischemic Stroke.

Factor XIII is a transglutaminase enzyme that plays a crucial role in hemostasis and wound healing. It crosslinks fibrin strands, stabilizing clots and promoting clot resistance to fibrinolysis. Additionally, Factor XIII has been found to have multiple other functions that extend beyond coagulation, including the regulation of inflammation and tissue repair processes. Emerging evidence suggests that Factor XIII may also have differential roles in acute myocardial infarction and ischemic stroke, two common cardiovascular events with significant morbidity and mortality. In acute myocardial infarction, Factor XIII has been implicated in promoting clot stability and reducing the risk of re-occlusion. In ischemic stroke, Factor XIII may also contribute to the pathogenesis of cerebral ischemia by promoting clot formation and exacerbating neuronal damage. Several studies have investigated the association between Factor XIII and these cardiovascular events, using various approaches such as genetic polymorphism analysis, animal models, and clinical data analysis. These studies have provided important insights into the role of Factor XIII in acute myocardial infarction and ischemic stroke, highlighting its potential as a therapeutic target for interventions aimed at improving outcomes in these conditions. In this review, we will summarize the current understanding of Factor XIII's role in acute myocardial infarction and ischemic stroke.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Efficacy and safety results after >3.5 years of treatment with the Bruton's tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study.

BACKGROUND: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. OBJECTIVE: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. METHODS: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. RESULTS: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population (Z-scores); T1 gadolinium-enhancing lesion numbers remained low. No new safety signals were identified. In the OLE, evobrutinib was detected in the CSF of all sub-study patients. CONCLUSION: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma.

Patient Reported Outcome Measurement (PROM) under real-life conditions of non-curable cancer outpatients with the Integrated Palliative Outcome Scale (IPOS) and NCCN-Distress Thermometer - A mixed methods study.

Objective: Prospective cohort study to test the real-life feasibility of longitudinal patient-reported outcome measurement PROM (Integrated Palliative Outcome Scale IPOS, and NCCN Distress Thermometer DT) required for outpatients with non-curable lung or prostate cancer in comprehensive cancer centers. Methods: Assessment with paper-based IPOS and DT was observed for 15 months. We analyzed response to patients' distress (requests for supportive and palliative services) following PROM. Focus groups to comprehensively explore the user experience of patients, informal caregivers and health care professionals (HCP) supplemented the analysis. Results: Ninety-seven percent (125/129) of the patients received a questionnaire once, but quarterly assessment as recommended by certification committees was achieved only in 50% and 31% of prostate and lung cancer patients. Although both instruments were well accepted, only IPOS showed a high content validity, because some patients had difficulties in understanding the DT. Patients felt comfortable with completing the PROM, and HCP found PROM helped to structure the patient encounter. Due to organizational deficiencies in the handling of the instruments and operationalization of reactions to identified distress, the referrals to supportive and palliative services were rare. Conclusion: To facilitate consequences from PROM it should be a standardized intervention rather than assessment alone. Innovation: The patient perspective improves the implementation of PROM under real-life clinical conditions.

Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.

Toward identifying key mechanisms of progression in multiple sclerosis.

A major therapeutic goal in the treatment of multiple sclerosis (MS) is to prevent the accumulation of disability over an often decades-long disease course. Disability progression can result from acute relapses as well as from CNS intrinsic parenchymal disintegration without de novo CNS lesion formation. Research focus has shifted to progression not associated with acute inflammation, as it is not sufficiently controlled by currently available treatments. This review outlines how recent advances in the understanding of the pathogenesis of progressive MS have been facilitated by the development of more precise, less static pathogenetic concepts of progressive MS, as well as by new techniques for the analysis of region-specific proteomic and transcriptomic signatures in the human CNS. We highlight key drivers of MS disease progression and potential targets in its treatment.

Serum neurofilament light chains in progressive multiple sclerosis patients treated with repeated cycles of high-dose intravenous steroids.

Background and objectives: In progressive multiple sclerosis (MS) patients, CNS inflammation trapped behind a closed blood brain barrier drives continuous neuroaxonal degeneration, thus leading to deterioration of neurological function. Therapeutics in progressive MS are limited. High-dose intravenous glucocorticosteroids (HDCS) can cross the blood-brain barrier and may reduce inflammation within the CNS. However, the treatment efficacy of HDCS in progressive MS remains controversial. Serum neurofilament light chains (sNfL) are an established biomarker of neuroaxonal degeneration and are used to monitor treatment responses. We aimed to investigate whether repeated cycles of intravenous HDCS reduce the level of sNfL in progressive MS patients. Methods: We performed a monocentric observational study of 25 patients recruited during ongoing clinical routine care who were treated with repeated cycles of intravenous HDCS as long-term therapy for their progressive MS. sNfL were measured in 103 repeated blood samples (median time interval from baseline 28 weeks, range 2-55 weeks) with the Single Molecular Array (SiMoA) technology. The Expanded Disability Status Score (EDSS) was documented at baseline and follow-up. Results: The median age of patients was 55 years (range 46-77 years) with a median disease duration of 26 years (range 11-42 years). sNfL baseline levels at study inclusion were significantly higher in progressive MS patients compared to age-matched healthy controls (median 16.7 pg/ml vs 11.5 pg/ml, p=0.002). sNfL levels showed a positive correlation with patient age (r=0.2, p=0.003). The majority of patients (72%, 16/23) showed reduced sNfL levels ≥20 weeks after HDCS compared to baseline (median 13.3 pg/ml, p=0.03). sNfL levels correlated negatively with the time interval from baseline HDCS therapy (r=-0.2, p=0.03). This association was also evident after correction for treatment with disease-modifying drugs (adjusted R2=0.10, p=0.001). The EDSS remained stable (median 6.5) within a median treatment duration of 26 weeks (range 13-51 weeks). Conclusion: Although larger studies are needed to confirm our findings, we were able to demonstrate that HDCS treatment reduces sNfL levels and therefore may slow down neuroaxonal damage in a subgroup of patients with progressive MS. Moreover, a stable EDSS was observed during therapy. Findings suggest that HDCS may be beneficial for the treatment of progressive MS.

Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release.

Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identifies microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We find that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally-anchored array to facilitate efficient cytokine trafficking and release. We identify cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescues tau and amyloid fibril-induced morphology changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses.

Touch localization after nerve repair in the hand: insights from a new measurement tool.

Errors of touch localization after hand nerve injuries are common, and their measurement is important for evaluating functional recovery. Available empirical accounts have significant methodological limitations, however, and a quantitatively rigorous and detailed description of touch localization in nerve injury is lacking. Here, we develop a new method of measuring touch localization and evaluate its value for use in nerve injury. Eighteen patients with transection injuries to the median/ulnar nerves and 33 healthy controls were examined. The hand was blocked from the participant's view and points were marked on the volar surface using an ultraviolet (UV) pen. These points served as targets for touch stimulation. Two photographs were taken, one with and one without UV lighting, rendering targets seen and unseen, respectively. The experimenter used the photograph with visible targets to register their locations, and participants reported the felt position of each stimulation on the photograph with unseen targets. The error of localization and its directional components were measured, separate from misreferrals-errors made across digits, or from a digit to the palm. Nerve injury was found to significantly increase the error of localization. These effects were specific to the territory of the repaired nerve and showed considerable variability at the individual level, with some patients showing no evidence of impairment. A few patients also made abnormally high numbers of misreferrals, and the pattern of misreferrals in patients differed from that observed in healthy controls.NEW & NOTEWORTHY We provide a more rigorous and comprehensive account of touch localization in nerve injury than previously available. Our results show that touch localization is significantly impaired following median/ulnar nerve transection injuries and that these impairments are specific to the territory of the repaired nerve(s), vary considerably between patients, and can involve frequent errors spanning between digits.

Prevalence, Predictive Factors, and Clinical Manifestations of Fungal Esophagitis in Children.

OBJECTIVES: Fungal esophagitis (FE) is the most common cause of esophageal infection and its prevalence in immunocompetent adults is rising. However, there is minimal data on FE in children without human immunodeficiency virus. Therefore, the objective of this study was to determine the prevalence, symptoms, endoscopic appearances, and predictive factors of FE in children, regardless of immune status. METHODS: A 2010-2020 retrospective case-control study was conducted on 1823 children presenting to Sydney Children's Hospital for elective endoscopy with esophageal biopsy. Histopathology reports were reviewed to identify FE cases and determine prevalence rates. Thirty-two patients with FE were age- and sex-matched (1:2) to 64 controls. Significant symptoms and risk factors of FE were identified via univariate and multivariate logistic regression analysis. RESULTS: The prevalence of FE in children was 1.76%. Common symptoms included dysphagia (25%), heartburn (25%), poor oral intake (21.9%), vomiting (18.8%), cough (15.6%), nausea (12.5%), and weight loss (9.4%). No significant differences in symptoms were found between cases and controls. On endoscopy, although white plaques were associated with FE ( P < 0.001), visually normal findings were reported in 28.1% of cases. Topical swallowed corticosteroids were a significant independent risk factor for FE (adjusted odds ratio = 10.740, 95% confidence interval: 1.213-95.101, P = 0.033). CONCLUSIONS: The prevalence of FE in this pediatric cohort reflects rates among immunocompetent adults. Given that many of these children presented with a wide range of gastrointestinal symptoms, esophageal biopsy is required to accurately diagnose FE. Pediatricians should consider the risk of FE when prescribing topical swallowed corticosteroids.

Integrating maternal, newborn, child health and non-communicable disease care in the sustainable development goal era.

Noncommunicable diseases (NCDs) and maternal newborn and child health (MNCH) are two deeply intertwined health areas that have been artificially separated by global health policies, resource allocations and programming. Optimal MNCH care can provide a unique opportunity to screen for, prevent and manage early signs of NCDs developing in both the woman and the neonate. This paper considers how NCDs, NCD modifiable risk factors, and NCD metabolic risk factors impact MNCH. We argue that integrated management is essential, but this faces challenges that manifest across all levels of domestic health systems. Progress toward Sustainable Development targets requires joined-up action.

Bruton's tyrosine kinase as a promising therapeutic target for multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). Although there are several disease-modifying therapies that can effectively manage MS relapses, the treatment of chronic progressive MS remains a difficult task. CNS-compartmentalized inflammation plays a primary role in progressive MS, especially by activated microglia. In this context, Bruton's tyrosine kinase (BTK) inhibition may be a promising therapeutic approach, as the enzyme is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. AREAS COVERED: This paper discusses a novel and promising approach for MS treatment. We discuss the factors assumed to promote progression in MS and how this process could be counteracted by BTK inhibition, as well as summarize all available clinical data on the usefulness of this therapeutic approach for halting MS progression. EXPERT OPINION: Current therapeutic approaches in MS are effective for treating relapses but fail to halt progression of the disease. This reflects the emerging concept that the underlying pathophysiology of chronic progressive MS differs from that of relapsing-remitting MS. Understanding the CNS intrinsic process in more detail provides novel therapeutic targets, and one of these may be the inhibition of the enzyme BTK.

Comment on "Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice".

We highlight potential issues with a Western blot assay using mouse anti-caspase-1 antibody to detect cleaved caspase-1 p20 subunit in mouse brain tissue lysates.

Unnecessary hospitalisations and polypharmacy practices in Romania: A health system evaluation for strengthening primary health care.

Background: Children and pregnant women usually have multiple contacts with the health care system. While most conditions can be managed by primary health care (PHC) providers, hospitalisations are nevertheless common and often unjustified. The number of hospitalizations decreased in Romania at the start of the COVID-19 pandemic. While this is likely due to the disruption of health services and public health measures established to limit the spread of COVID-19, it also suggests that a proportion of hospitalisations prior to the pandemic were unnecessary. This healthcare system evaluation in Romania quantified unnecessary and unnecessarily prolonged hospitalisations in children, pregnant women and women hospitalised for delivery, and assessed antibiotic and polypharmacy practices in these groups. Methods: We conducted the healthcare system evaluation in 10 hospitals across the country. We extracted data from medical records of patients hospitalized between 2019 and 2020. In each hospital, we randomly selected 40 medical records for each of the following groups: children 2-59 months of age, pregnant women, and women hospitalised for delivery. Clinical data were compared against WHO standards indicating a need for inpatient treatment or antibiotic therapy. Results: Among 209 children and 349 pregnant women, unnecessary hospitalisations accounted for 57.9% and 56.2% of hospitalisations, respectively. Among necessary hospitalisations, a large proportion was unnecessarily prolonged, including 44.4% (n = 32/72) in children, 23.3% (n = 34/146) in pregnant women, and 45.8% (n = 110/240) in women after delivery. The proportion of unnecessary and unnecessarily prolonged hospitalisations did not differ between the pre-pandemic, the lockdown, and the post-lockdown periods. Antibiotics were prescribed to 53.1% (n = 43/81) of children with diarrhoea, while 50.8% (n = 61/120) of women with caesarean section received an unjustified prolonged course of antibiotics. Children and women were commonly prescribed unnecessary medications. Conclusions: Findings of this evaluation should inform evidence-based decisions and actions for strengthening PHC and the healthcare system structure and improving the management of common diseases in mothers, newborns, and children. The evaluation should be repeated periodically to monitor progress.

Natalizumab Promotes Activation of Peripheral Monocytes in Patients With Multiple Sclerosis.

OBJECTIVES: Natalizumab (NTZ), a monoclonal antibody against very late antigen-4 (VLA-4), is one of the most efficient therapies to prevent acute relapses in multiple sclerosis (MS). VLA-4 is the key adhesion molecule for peripheral immune cells, especially lymphocytes to enter the CNS. While its blockade thus virtually abrogates CNS infiltration of these cells, long-term exposure to natalizumab may also affect immune cell function. METHODS: In this study, we report that in patients with MS, NTZ treatment is associated with an enhanced activation status of peripheral monocytes. RESULTS: Expression of 2 independent activation markers, CD69 and CD150, was significantly higher on blood monocytes from NTZ-treated patients when compared with those from matched untreated patients with MS, while other properties such as cytokine production remained unchanged. DISCUSSION: These findings consolidate the concept that peripheral immune cells remain fully competent on NTZ treatment, an excellent asset rare among MS treatments. However, they also suggest that NTZ may exert nondesirable effects on the progressive aspect of MS, where myeloid cells and their chronic activation are attributed a prominent pathophysiologic role.