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BACKGROUND: Relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS) have distinct clinical courses, but underlying pathophysiological differences remain unclear. We compared pathological components between RRMS, PPMS, and other inflammatory and neurodegenerative disorders, leveraging soluble biomarkers and post-mortem pathology. METHODS: Serum and cerebrospinal fluid (CSF) of people diagnosed with (pw) PPMS (n = 104), RRMS (n = 38), Alzheimers disease (AD, n = 22), neuromyelitis optica spectrum disorder (NMOSD, n = 10), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD, n = 10) were collected. B-cell maturation antigen (BCMA), soluble CD27 (sCD27), osteopontin (OPN), chitinase-3-like-1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and synaptosomal-associated protein-25 (SNAP25) were measured. Lymphocytes (CD20+, CD138+, CD3+) and pyramidal-tract axonal density in RR-onset (n = 86) and PPMS (n = 45) post-mortem brain tissue were quantified. RESULTS: Soluble and post-mortem tissue biomarkers did not differ between pwRRMS and pwPPMS. Compared to AD, MS had higher CSF sCD27 (p

BACKGROUND: Intraocular pressure (IOP) monitoring in glaucoma management is evolving with novel devices. We investigated the reproducibility of 24 hour profiles on two consecutive days and after 30 days of self-measurements via telemetric IOP monitoring. METHODS: Seven primary patients with open-angle glaucoma previously implanted with a telemetric IOP sensor in one eye underwent automatic measurements throughout 24 hours on two consecutive days (day 1 and day 2). Patients wore an antenna adjacent to the study eye connected to a reader device to record IOP every 5 min. Also, self-measurements in six of seven patients were collected for a period of 30 days. Analysis included calculation of hourly averages to correlate time-pairs of day 1 versus day 2 and the self-measurements vers day 2. RESULTS: The number of IOP measurements per patient ranged between 151 and 268 on day 1, 175 and 268 on day 2 and 19 and 1236 during 30 days of self-measurements. IOP time-pairs of automatic measurements on day 1 and day 2 were significantly correlated at the group level (R=0.83, p

Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes with fundamental roles in the development and function of peripheral nerves. Over the past 10 years, significant advances in identifying molecular disease mechanisms underlying axonal and myelin degeneration, acquired from cellular biology studies and transgenic fly and rodent models, have facilitated the development of promising treatment strategies. However, no clinical treatment has emerged to date. This lack of treatment highlights the urgent need for more biologically and clinically relevant models recapitulating IPNs. For both neurodevelopmental and neurodegenerative diseases, patient-specific induced pluripotent stem cells (iPSCs) are a particularly powerful platform for disease modeling and preclinical studies. In this review, we provide an update on different in vitro human cellular IPN models, including traditional two-dimensional monoculture iPSC derivatives, and recent advances in more complex human iPSC-based systems using microfluidic chips, organoids, and assembloids.

Abstract Background In SELECT-AXIS 2, upadacitinib improved the signs and symptoms of active non-radiographic axial spondyloarthritis (nr-axSpA) through 52 weeks versus placebo and was well tolerated. Here, we evaluated the efficacy and safety of upadacitinib through 2 years. Methods The study enrolled eligible adult patients with a clinical diagnosis of nr-axSpA who met the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria and had objective signs of active inflammation on magnetic resonance imaging (MRI) of sacroiliac joints and/or high-sensitivity C-reactive protein. Patients were randomized 1:1 to receive double-blinded treatment with upadacitinib 15 mg once daily (QD) or placebo for 52 weeks, after which all patients received open-label treatment with upadacitinib 15 mg QD. Efficacy results over 104 weeks were reported as observed (AO) and either AO with non-responder imputation (AO-NRI; binary endpoints) or AO with mixed-effect model for repeated measures (continuous endpoints). Treatment-emergent adverse events (TEAEs) were summarized through week 104. Results Of 313 patients randomized and treated, 224 (continuous upadacitinib n = 117; placebo/upadacitinib n = 107) completed 104 weeks of treatment. In patients who received continuous upadacitinib, sustained improvement was observed through 2 years of treatment across efficacy endpoints including disease activity, pain, function, enthesitis, quality of life, and MRI measures of inflammation. At week 104, 57.1%, 59.0%, and 31.4% of patients achieved ASAS40 response, and low disease activity and inactive disease (as defined by Axial Spondyloarthritis Disease Activity Score), respectively (AO-NRI); week 104 outcomes were generally similar in patients who initially received placebo and were switched to upadacitinib at week 52. In total, 286 patients were exposed to ≥ 1 dose of upadacitinib, comprising 378.3 patient-years (PY) of exposure. Upadacitinib was generally well tolerated, with exposure-adjusted event rates (EAERs) for TEAEs, serious adverse events (AEs), and AEs leading to study drug discontinuation of 207.5, 8.7, and 5.3 events/100 PY, respectively. EAERs of TEAEs of special interest were broadly consistent with those reported through week 52. Conclusions Treatment with upadacitinib demonstrated consistent improvement and maintenance of treatment effect across efficacy endpoints through 2 years; no new safety signals were identified with additional exposure. Trial registration NCT04169373.

Abstract The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G4C2 repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.

Intergovernmental Organisations (IGOs) have been playing a prominent role in the Open Educational Resources (OER) movement in advocating for and supporting the development of governmental OER policies. Research shows that IGOs perform multiple roles in influencing national and global education policy processes and possess multiple policy instruments with which they can assert their influence. We adopted the conceptual framework of policy instruments to understand the types of policy instruments applied by the selected IGOs. We carried out semi-structured interviews with representatives from four important IGOs. Results show that the selected IGOs collectively used discursive dissemination, funding, technical assistance, standard-setting and coordinative functions OER policy instruments to influence the development of governmental OER policies. We report on the perceived and observed successes of these IGOs OER policy instruments and the related challenges. We discuss relevant findings and their implications for further research and activities of IGOs.

Abstract Anthropogenic climate change is altering patterns of extreme weather events across the planet, with far-ranging consequences for biodiversity. Increases in the frequency, duration, and severity of droughts are anticipated to substantially impact natural ecosystems. Here, we predicted the extent to which 1221 terrestrial vertebrates in the contiguous United States will be increasingly exposed to annual (12-month) and prolonged (36-month) drought, under three global climate models and two representative concentration pathways. On average, a 377% increase in annual drought exposure and a 579% increase in prolonged drought exposure are anticipated for the study area by 2050–2080, compared to 1950–2005. Species in the southwestern USA could see the largest increases in drought exposure, while this area also has the highest vertebrate diversity and an abundance of drought-threatened species. Our results aid in identifying vertebrates and ecoregions anticipated to see large increases in drought exposure, which can inform conservation strategies aimed at mitigating vertebrate extinction risks.

Abstract Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA+ ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP R191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.

BACKGROUND: Patients with glaucoma on topical glaucoma medication are often affected by dry eye symptoms and thus likely to rub or squeeze their eyelids. Here, we telemetrically measure peak intraocular pressure (IOP) during eyelid manoeuvres and eyelid rubbing. METHODS: Eleven patients with primary open-angle glaucoma (POAG) previously implanted with a telemetric IOP sensor (Eyemate-IO) were instructed to look straight ahead for 1 min as a baseline measurement. Next, 6 repeats of blinking on instruction with 10 s intervals in between were performed. In addition, 5 repeats of eyelid closure (n=9), eyelid squeezing and eyelid rubbing (n=7) were performed with 15 s intervals in between. IOP was recorded via an external antenna placed around the study eye. Average peak IOP increases from baseline were analysed and tested against zero (no change) with one-sample t-tests. RESULTS: For eyelid rubbing, the average peak ∆ IOP increase (mean±SEM) was 59.1±9.6 mm Hg (p

Objective:. VASCERN (https://vascern.eu/) is the European Reference Network for Rare Multisystemic Vascular Diseases. VASCERN-VASCA is the working group within VASCERN that focuses on the study of vascular anomalies. One of the objectives of this group is to establish patient pathways to guide physicians toward efficient diagnostic and management measures. The patient pathway presented here is focused on capillary malformations (CMs). Methods:. The Nominal Group Technique, a structured variation of small group discussion was used. Two facilitators were identified: one to propose initial discussion points and draw the pathway and another to chair the discussion. A dermatologist (E. Baselga) was chosen as the first facilitator due to her specific clinical and research expertise. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and biannual face-to-face meetings. Results:. The pathway starts from the clinical recognition of a vascular red stain, describing clinical characteristics and location. Depending on the clinical features, a subsequent workup for associated manifestations or complications is suggested. These steps should enable the establishment of 6 subtypes of CMs: (1) nevus simplex; (2) isolated CM, syndromic or nonsyndromic; (3) CM of microcephaly CM syndrome; (4) CM of CM–arteriovenous malformation syndromes; (5) “pseudo” CM of arteriovenous malformation; (6) cutis marmorata telangiectatica congenita. Management according to the recognized phenotype is detailed in subsequent pages of the pathway. A color code is used to differentiate (1) clinical evaluations, (2) investigations, (3) associated genes, and (4) treatments. Actions relevant to all types are marked in separate boxes, for example, when to perform specific imaging. Conclusion:. The collaborative efforts of VASCERN-VASCA, a European network of the 14 Expert Centers for Vascular Anomalies, have led to a consensus pathway for CMs. This pathway may help clinicians to guide in the diagnosis and management of CMs, as well as to emphasize the crucial role of multidisciplinary expert centers in the management of these patients. This pathway is available on the VASCERN website (http://vascern.eu/).

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.

Introduction Preterm infants born before 32 weeks of gestation are generally admitted to a neonatal intensive care unit (NICU) to receive life-saving treatment, resulting in early exposure to stressful events. Yet, NICU admission is not only stressful for the infant but can also have a long-lasting negative impact on parental mental health, who may worry about their child. Parental mental health problems might affect child development through parental behaviour and the parent–infant relationship. Simultaneously, adverse child development after preterm birth can (further) elevate parental stress and mental health problems, straining parental behaviour, the parent–infant relationship and child development. This systematic review and meta-analysis aims to examine the association between preterm-born children’s development (

Background. Baseline lung allograft dysfunction (BLAD) after lung transplant is associated with an increased risk of dying, but the association with health-related quality of life (HRQL) and exercise capacity is not known. We hypothesized that BLAD would be associated with reduced HRQL and 6-min walk distance (6MWD) at 1 y post–lung transplant. Methods. We analyzed patients who underwent lung transplants in our program from 2004 to 2018 who completed 1-y 36-item Short Form (SF-36) questionnaire and 6MWD testing. We secondarily analyzed the Beck Depression Inventory and Borg dyspnea scores in patients using the available data. We defined BLAD as a failure of both forced expiratory volume in 1 s and forced vital capacity to reach ≥80% predicted of a healthy reference population’s lung function on 2 consecutive tests ≥3 wk apart at any time point posttransplant. We tested the relationship between BLAD status and SF-36 physical component summaries and 6MWD using least squares regression, adjusting for age at transplant, sex at birth, and primary lung disease. Results. Two hundred sixty-four patients were included, 96 (36%) of whom met the criteria for BLAD. Patients with interstitial lung disease as an indication for transplant and those who received older, female, and heavy smoking donors were at increased risk of BLAD. SF-36 physical component summary scores were lower in patients with BLAD (75 versus 85; P = 0.0076), as were 6MWD values (528 versus 572 m; P = 0.0053). BLAD was associated with lower SF-36 scores (P = 0.0025) and 6MWD (P = 0.0008) in adjusted regression models at 1 y posttransplant. We did not observe differences in Beck Depression Inventory or Borg scores. Conclusions. BLAD was associated with reduced HRQL and 6MWD scores at 1 y posttransplant in adjusted models. This suggests that poor posttransplant lung function could contribute to lower HRQL and exercise capacity in lung recipients and is worthy of further exploration in terms of causes, prevention, and treatment.

Objective Upadacitinib improved the signs and symptoms of non‐radiographic axial spondyloarthritis (nr‐axSpA) versus placebo over 14 weeks in the primary analysis of the SELECT‐AXIS 2 nr‐axSpA study. Here, we evaluated the efficacy and safety of upadacitinib through 1 year in patients with nr‐axSpA in SELECT‐AXIS 2. Methods Patients aged at least 18 years diagnosed with nr‐axSpA who fulfilled the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria and were receiving stable background therapy were randomized to upadacitinib 15 mg once daily or placebo for the 52‐week double‐blind period. Efficacy was assessed using non‐responder imputation incorporating multiple imputation (NRI‐MI) and as‐observed analyses for binary endpoints, and mixed‐effects model repeated measures for continuous endpoints. Results Of 314 randomized patients, 259 (upadacitinib, n = 129; placebo, n = 130) completed 52 weeks of treatment. More patients receiving upadacitinib versus placebo achieved ≥40% improvement in ASAS at week 52 (63% vs 43%, NRI‐MI; nominal P < 0.001). Similar treatment effects were observed for the achievement of axSpA Disease Activity Score inactive disease (33% v 11%, NRI‐MI; nominal P < 0.001). Overall, patients receiving upadacitinib versus placebo showed greater improvement in disease activity, inflammation, pain, function, enthesitis, and quality of life through 52 weeks. Adverse events were generally comparable between the treatment groups. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, inflammatory bowel disease, or deaths were reported in those receiving upadacitinib. Conclusion Treatment with upadacitinib showed sustained efficacy versus placebo with no new safety findings identified through 1 year. These results support the continued favorable benefit–risk profile of upadacitinib treatment for nr‐axSpA.