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The rapid, human-induced changes in the Earth system during the Anthropocene present humanity with critical sustainability challenges. Social-ecological systems (SES) research provides multiple approaches for understanding the complex interactions between humans, social systems, and environments and how we might direct them towards healthier and more resilient futures. However, general theories of SES change have yet to be fully developed. Formal evolutionary theory has been applied as a dynamic theory of change of complex phenomena in biology and the social sciences, but rarely in SES research. In this paper, we explore the connections between both fields, hoping to foster collaboration. After sketching out the distinct intellectual traditions of SES research and evolutionary theory, we map some of their terminological and theoretical connections. We then provide examples of how evolutionary theory might be incorporated into SES research through the use of systems mapping to identify evolutionary processes in SES, the application of concepts from evolutionary developmental biology to understand the connections between systems changes and evolutionary changes, and how evolutionary thinking may help design interventions for beneficial change. Integrating evolutionary theory and SES research can lead to a better understanding of SES changes and positive interventions for a more sustainable Anthropocene. This article is part of the theme issue Evolution and sustainability: gathering the strands for an Anthropocene synthesis.

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In this paper, the challenge is to increasing of the heat exchanger performance by placing different size balls inside the tubes. the development of previous studies to enhance relatively bad case of heat transfer where the inserting (a large ball and then a small ball) to collide the water molecules in the ball and generate turbulent flow (Reynolds number range from 50,000 to 350,000) and thus increase the thermal performance due to collision of particles with the inner casing of the tube and reduce the stagnation near the wall. The usefulness of small ball, after the big ball, is Reduce of gets wake flow. A simulation was made when changing the diameter ratio of big to small ball (Dr = 3, 4, 5). Also, the distance between the big ball and the small ball was changed (X = 2, 3, 5) mm. It was concluded that the best ball diameter ratio and best Distance is (Dr= D_b/D_sb = 5), (X = 3 mm), respectively. The pressure drop acts as a side effect of enhancement. Therefore, the method of equal pumping was adopted. The average thermal performance factor (TPF=1.178) of tube with insert the balls enhanced by 17.8% at (x=3mm) and (Dr=5) when compared with smooth tube.

Background and Purpose: Paramagnetic rim lesions (PRLs) are chronic active lesions associated with a severe disease course in multiple sclerosis (MS). This study was undertaken to investigate an association between retinal layer thinning (annualized loss of peripapillary retinal nerve fiber layer [aLpRNFL] and ganglion cell-inner plexiform layer [aLGCIPL]) and PRLs in patients with MS (pwMS)., Methods: In this study, pwMS with brain magnetic resonance imaging and ≥2 optical coherence tomography scans were included. Cox proportional hazard regression models were performed using progression independent of relapse activity (PIRA) as the dependent variable, and aLpRNFL, aLGCIPL, or the number of PRLs as independent variables, adjusted for covariates., Results: We analyzed data from 97 pwMS (mean age = 35.2 years [SD = 9.9], 71.1% female, median disease duration = 2.3 years [interquartile range = 0.9-9.0]). The number of PRLs was associated with aLpRNFL and aLGCIPL. PIRA was observed in 18 (18.6%) pwMS, with aLpRNFL (hazard ratio [HR] = 1.44 per %/year), aLGCIPL (HR = 1.61 per %/year), and the number of PRLs (HR = 1.24 per PRL) being associated with increased risk of PIRA., Conclusions: The number of PRLs is associated with inner retinal layer thinning and increased risk of PIRA. A combination of PRLs and retinal layer thinning could serve as a surrogate for pwMS at highest risk of disability progression., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side effects, highlighting the importance of adjusted treatment considerations. MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immunopathological and MRI aspects of ageing in the CNS in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome., Methods: Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses., Results: A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%., Discussion: In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred., Classification of Evidence: This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Background : Intracardiac thrombosis is common in transthyretin amyloid cardiomyopathy (ATTR-CM), and patients are at risk for thromboembolic events. However, silent cerebral infarcts and the extent of cerebral small vessel disease in patients with cardiac amyloidosis are unknown. Methods : Thirty-two consecutively selected ATTR-CM patients were prospectively studied by cerebral magnetic resonance imaging (cMRI) and compared with 43 CHA 2 DS 2 -VASc-matched controls (Co). Structural clinical standard cMRI sequences and features of cerebral vessel involvement were included and quantified by two board certified neuroradiologists in consensus blinded to clinical status. Group differences were estimated using generalized (logistic) linear regression models adjusting for vascular risk factors based on the CHA 2 DS 2 -VASc score. Results : The median CHA 2 DS 2 -VASc score was 4 for ATTR-CM and Co ( p = 0.905). There were no differences between groups in the frequency of current or former smokers ( p = 0.755), body-mass-index > 30 ( p = 0.106), and hyperlipidemia ( p = 0.869). The number of territorial infarcts (4 vs. 0, p = 0.018) was higher in ATTR-CM compared to Co, as was the mean number of cerebral microbleeds (1.4 vs. 0.3, p ≤ 0.001) and the number of Virchow-Robin spaces (43.8 vs. 20.6, p ≤ 0.001). Lacunar lesion presence was higher in ATTR-CM (6 vs. 2, p = 0.054). CHA 2 DS 2 -VASc score, atrial fibrillation, anticoagulation, and the interaction term of CHA 2 DS 2 -VASc score and atrial fibrillation did not affect the probability of a territorial ischemic lesion or lacunar lesion in logistic regression modeling. Conclusions : In patients with ATTR-CM free from clinically apparent neurological symptoms, cMRI revealed unreported significant small cerebral vessel disease and territorial ischemia. Our findings may support low thresholds for anticoagulation and cMRI in patients with ATTR-CM.

Background: In multiple sclerosis (MS), both lesion accrual and brain atrophy predict clinical outcomes. However, it is unclear whether these prognostic features are equally relevant throughout the course of MS. Among 103 participants recruited following a clinically isolated syndrome (CIS) and followed up over 30 years, we explored (1) whether white matter lesions were prognostically more relevant earlier and brain atrophy later in the disease course towards development of secondary progressive (SP) disease; (2) if so, when the balance in prognostic contribution shifts and (3) whether optimised prognostic models predicting SP disease should include different features dependent on disease duration., Methods: Binary logistic regression models were built using age, gender, brain lesion counts and locations, and linear atrophy measures (third ventricular width and medullary width) at each time point up to 20 years, using either single time point data alone or adjusted for baseline measures., Results: By 30 years, 27 participants remained CIS while 60 had MS (26 SPMS and 16 MS-related death). Lesions counts were prognostically significant from baseline and at all later time points while linear atrophy measure models reached significance from 5 years. When adjusted for baseline, in combined MRI models including lesion count and linear atrophy measures, only lesion counts were significant predictors. In combined models including relapse measures, Expanded Disability Status Scale scores and MRI measures, only infratentorial lesions were significant predictors throughout., Conclusions: While SPMS progression is associated with brain atrophy, in predictive models only infratentorial lesions were consistently prognostically significant., Competing Interests: Competing interests: PA is a clinical research fellow funded by an MS Society grant (Ref: 141) and was previously in a post supported by Merck (supervised by DTC and SAT). He also works as a medical advisor for Mara Health. NS is a clinical research fellow funded by an MRC grant (Ref: MR/W019906/1) and previously in a post support by Merck (supervised by DTC and SAT). KC has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck. She has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris. LH has no disclosures. FP receives funding from National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH). FP received a Guarantors of Brain fellowship 2017–2020. SAT has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and cosupervises a clinical fellowship supported by Merck. OC is a member of independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. FB is supported by the NIHR biomedical research centre at UCLH. Steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena. Consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD. CT has received a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by 'la Caixa' Foundation (ID 100010434), the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche, Novartis, Bristol Myers Squibb and Merck and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs. DTC is a consultant for Hoffmann-La Roche. In the last 3 years, he has been a consultant for Biogen, has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, the Medical Research Council and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and a speaker’s honorarium from Novartis. He cosupervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Children with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity., Methods: A retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI., Results: Patients' age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage., Conclusions: Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic CP. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hedrich, Patel, Haider, Taylor, Lau, Hook, Dorfer, Roessler, Stepien, Lippolis, Schned, Koeller, Mayr, Azizi, Peyrl, Lopez, Lassaletta, Bennett, Gojo and Bartels.)

Objective: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations., Methods: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41., Results: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM&#95;001008212.2: c.1078&#95;1079del; p.Lys360ValfsTer18)., Interpretation: OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: • Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. • The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. • Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: Recently, the 7 Tesla (7 T) Epilepsy Task Force published recommendations for 7 T magnetic resonance imaging (MRI) in patients with pharmaco-resistant focal epilepsy in pre-surgical evaluation. The objective of this study was to implement and evaluate this consensus protocol with respect to both its practicability and its diagnostic value/potential lesion delineation surplus effect over 3 T MRI in the pre-surgical work-up of patients with pharmaco-resistant focal onset epilepsy., Methods: The 7 T MRI protocol consisted of T1-weighted, T2-weighted, high-resolution-coronal T2-weighted, fluid-suppressed, fluid-and-white-matter-suppressed, and susceptibility-weighted imaging, with an overall duration of 50 min. Two neuroradiologists independently evaluated the ability of lesion identification, the detection confidence for these identified lesions, and the lesion border delineation at 7 T compared to 3 T MRI., Results: Of 41 recruited patients > 12 years of age, 38 were successfully measured and analyzed. Mean detection confidence scores were non-significantly higher at 7 T (1.95 ± 0.84 out of 3 versus 1.64 ± 1.19 out of 3 at 3 T, p = 0.050). In 50% of epilepsy patients measured at 7 T, additional findings compared to 3 T MRI were observed. Furthermore, we found improved border delineation at 7 T in 88% of patients with 3 T-visible lesions. In 19% of 3 T MR-negative cases a new potential epileptogenic lesion was detected at 7 T., Conclusions: The diagnostic yield was beneficial, but with 19% new 7 T over 3 T findings, not major. Our evaluation revealed epilepsy outcomes worse than ILAE Class 1 in two out of the four operated cases with new 7 T findings., (© 2023. The Author(s).)

Objective: In the era of flow diversion, there is an increasing demand to train neurosurgeons outside the operating room in safely performing clipping of unruptured intracranial aneurysms. This study introduces a clip training simulation platform for residents and aspiring cerebrovascular neurosurgeons, with the aim to visualize peri-aneurysm anatomy and train virtual clipping applications on the matching physical aneurysm cases., Methods: Novel, cost-efficient techniques allow the fabrication of realistic aneurysm phantom models and the additional integration of holographic augmented reality (AR) simulations. Specialists preselected suitable and unsuitable clips for each of the 5 patient-specific models, which were then used in a standardized protocol involving 9 resident participants. Participants underwent four sessions of clip applications on the models, receiving no interim training (control), a video review session (video), or a video review session and holographic clip simulation training (video + AR) between sessions 2 and 3. The study evaluated objective microsurgical skills, which included clip selection, number of clip applications, active simulation time, wrist tremor analysis during simulations, and occlusion efficacy. Aneurysm occlusions of the reference sessions were assessed by indocyanine green videoangiography, as well as conventional and photon-counting CT scans., Results: A total of 180 clipping procedures were performed without technical complications. The measurements of the active simulation times showed a 39% improvement for all participants. A median of 2 clip application attempts per case was required during the final session, with significant improvement observed in experienced residents (postgraduate year 5 or 6). Wrist tremor improved by 29% overall. The objectively assessed aneurysm occlusion rate (Raymond-Roy class 1) improved from 76% to 80% overall, even reaching 93% in the extensively trained cohort (video + AR) (p = 0.046)., Conclusions: The authors introduce a newly developed simulator training platform combining physical and holographic aneurysm clipping simulators. The development of exchangeable, aneurysm-comprising housings allows objective radio-anatomical evaluation through conventional and photon-counting CT scans. Measurable performance metrics serve to objectively document improvements in microsurgical skills and surgical confidence. Moreover, the different training levels enable a training program tailored to the cerebrovascular trainees' levels of experience and needs.

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501 -positive ( n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10 -3 ], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10 -3 ] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501 -negative patients ( n = 35). PVRL2 -positive patients ( n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10 -3 ], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2 -negative patients ( n = 18). In contrast, IRX1 -positive ( n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10 -3 ], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10 -3 ] than IRX1 -negative patients ( n = 30). In multiple sclerosis cases, IRX1 -positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis., Competing Interests: N.S. has been a clinical research fellow in a post supported by Merck (supervised by S.A.T. and D.C.) and subsequently by MRC (MR/W019906/1). K.C has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck; she has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris. F.P.C. received a Guarantors of Brain fellowship 2017–2020. F.P.C. and B.K. are supported by the National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH). A.J.T. reports personal fees paid to his institution from Eisai Ltd; is an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for MS Journal receiving an honorarium from SAGE Publications; receives support for travel as member, Clinical Trials Committee, International PPMS Alliance, and from the National MS Society (NMSS) (USA) as member, NMSS Research Programs Advisory Committee. S.A.T. receives support from the UCLH Biomedical Research Centre; has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. W.B. has received speaker honoraria for educational activities and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Viatris. O.C. is a member of independent data and safety monitoring board for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. C.T. is currently being funded by a Junior Leader La Caixa Fellowship (The project that gave rise to these results received the support of a fellowship from ‘la Caixa’ Foundation (ID 100010434); fellowship code is LCF/BQ/PI20/117600080; She has also received the 2021 Merck’s Award for the Investigation in MS (Spain) and a grant from Instituto de Salud Carlos III (ISCIII), Spain (grant ID: PI21/01860); In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK Multiple Sclerosis Society (grant number 77); She has also received speaker honoraria from Roche and Novartis; She serves on the Editorial Board of Neurology and Multiple Sclerosis Journal. F.B. is supported by the UCLH biomedical research centre; He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena; He is a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics; He has research agreements with Merck, Biogen, GE Healthcare, Roche; He is co-founder and shareholder of Queen Square Analytics LTD. D.C. is a consultant for Hoffmann-La Roche; In the last three years he has been a consultant for Biogen, received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Multiple Sclerosis Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and speaker’s honorarium from Novartis; He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. The remaining authors, L.H., R.S., C.A.M.G.W.K. and H.H.: nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Therapeutic plasma exchange (TPE) is commonly performed using membrane-based TPE (mTPE) and is prone to filter failure., Design, Setting, Participants, & Measurements: We report on 46 patients, with a total of 321 mTPE treatments using the NxStage machine. This was a retrospective study with an aim to evaluate the effect of heparin, pre-filter saline dilution and the impact of total plasma volume exchanged (< 3 L vs. ≥3 L) on the rate of filter failure. Primary outcome was the overall rate of filter failure. Secondary outcomes included factors that may have indirectly influenced the rate of filter failure, including hematocrit, platelet count, replacement fluid (Fresh Frozen Plasma vs. albumin), and access type., Results: We found that treatments that received both pre-filter heparin and saline had a statistically significant decrease in filter failure rate as compared to those that received neither (28.6% vs. 5.3%, P = .001), and compared to the treatments that received pre-filter heparin alone (14.2% vs. 5.3%, P = .015). In treatments that received both pre-filter heparin and saline predilution, we noted a significantly higher filter failure rate when the plasma volume exchanged was ≥3 L as compared to those that had <3 L exchanged (12.2% vs. 0.9%, P = .001)., Conclusions: Rate of filter failure in mTPE can be reduced by implementing several therapeutic interventions including pre-filter heparin and pre-filter saline solution. These interventions were not associated with any clinically significant adverse events. Despite the above-mentioned interventions, large plasma volume exchanges of ≥3 L can negatively impact filter life., (© 2023 Wiley Periodicals LLC.)

The Gulf of Oman is becoming increasingly polluted with plastics, hence bioplastics have been considered 'a substitute', although their biodegradability in marine environments has not been well investigated. Most research has been performed on cellulose-based bioplastics, whereas starch-based bioplastics have proven to be a suitable, but less researched, alternative. This study is the first of its kind designed to investigate the degradability of two different types of starch-based bioplastic bags, available in the market and labeled as "biodegradable", in the pelagic and benthic zones of one of the warmest marine environment in the world. Fourier-Transform Infrared Spectroscopy (FTIR) showed a clear reduction in the presence of OH, CH, and CO in the bioplastic bags after 5 weeks of immersion. Thermo-Gravimetric Analysis (TGA) indicated degradation of glycerol, starch, and polyethylene. The biofouling bacterial communities on bioplastic surfaces showed distinct grouping based on the immersion zone. Candidaatus saccharibacteria, Verrucomicrobiae, Acidimicrobiia and Planctomycetia sequences were only detectable on bioplastics in the pelagic zone, whereas Actinomyces, Pseudomonas, Sphingobium and Acinetobacter related sequences were only found on bioplastics in the benthic layer. We conclude that starch-based bioplastics are more readily degradable in the Gulf of Oman than conventional plastics, hence could serve as a better environmentally friendly alternative., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Paramagnetic rim lesions (PRLs) are an imaging biomarker in multiple sclerosis (MS), associated with a more severe disease., Objectives: To determine quantitative magnetic resonance imaging (MRI) metrics of PRLs, lesions with diffuse susceptibility-weighted imaging (SWI)-hypointense signal (DSHLs) and SWI-isointense lesions (SILs), their surrounding periplaque area (PPA) and the normal-appearing white matter (NAWM)., Methods: In a cross-sectional study, quantitative MRI metrics were measured in people with multiple sclerosis (pwMS) using the multi-dynamic multi-echo (MDME) sequence post-processing software "SyMRI.", Results: In 30 pwMS, 59 PRLs, 74 DSHLs, and 107 SILs were identified. Beside longer T1 relaxation times of PRLs compared to DSHLs and SILs (2030.5 (1519-2540) vs 1615.8 (1403.3-1953.5) vs 1199.5 (1089.6-1334.6), both p  < 0.001), longer T1 relaxation times were observed in the PRL PPA compared to the SIL PPA and the NAWM but not the DSHL PPA. Patients with secondary progressive multiple sclerosis (SPMS) had longer T1 relaxation times in PRLs compared to patients with late relapsing multiple sclerosis (lRMS) (2394.5 (2030.5-3040) vs 1869.3 (1491.4-2451.3), p  = 0.015) and also in the PRL PPA compared to patients with early relapsing multiple sclerosis (eRMS) (982 (927-1093.5) vs 904.3 (793.3-958.5), p  = 0.013)., Conclusion: PRLs are more destructive than SILs, leading to diffuse periplaque white matter (WM) damage. The quantitative MRI-based evaluation of the PRL PPA could be a marker for silent progression in pwMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.K. has participated in meetings sponsored by, received speaker honoraria or travel funding from Alexion, BMS/Celgene, Janssen-Cilag, Merck, Novartis, Roche, and Sanofi-Genzyme and held a grant for a Multiple Sclerosis Clinical Training Fellowship Programme from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). V.S. has nothing to disclose. J.L. has nothing to disclose. L.H. has nothing to disclose. G.B. has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi-Genzyme, and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis. G.K. has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, and received honoraria for consulting from Biogen. F.L. has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene/BMS, Janssen, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. B.K. has received honoraria for speaking and for consulting from Biogen, BMS-Celgene, Johnson & Johnson, Merck, Novartis, Roche, Teva, and Sanofi-Genzyme outside of the submitted work. No conflict of interest with respect to this study. P.S.R. has received honoraria for consultancy/speaking from AbbVie, Almirall, Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, and Teva and has received research grants from Amicus, Biogen, Merck, and Roche. T.B. has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, BMS/Celgene, GSK, GW/Jazz Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi-Genzyme, Teva, and UCB. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Bayer, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, Teva and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva). H.L. has received honoraria for lectures from Novartis, Biogen, ROCHE, Merck, and Sanofi-Aventis. A.D.-B.’s position as junior group leader for Translational Morphology in Neuroscience is supported by a research grant from Biogen. She has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene (BMS), Merck, Novartis, Roche, and Sanofi, and has received an unrestricted grant from Merck GmbH, an affiliate of Merck KGaA. S.H. has participated in meetings sponsored by or received speaker honoraria or travel funding from Biogen and Sanofi-Aventis.

Background: The relation of sarcopenia and disability in MS is unknown., Objective: To investigate the relation of temporal muscle thickness (TMT) and disability., Methods: A cohort of 132 people who presented with a clinically isolated syndrome (CIS) suggestive of MS at a mean age of 30.0 years, were prospectively followed clinically and with MRI over 30-years. TMT and expanded disability status scale (EDSS) were assessed at baseline, one- five- ten- fourteen- twenty- and thirty-year follow-up., Results: At 30-years, 27 participants remained classified as having had a CIS, 34 converted to relapsing remitting MS, 26 to secondary progressive MS, and 16 had died due to MS. Using linear mixed effect models with subject nested in time, greater annualized TMT-thinning was seen in individuals who developed MS (-0.04 mm/a, 95%CI: -0.07 to -0.01, p = 0.023). In those who converted to MS, a thinner TMT was reached at 14- (p = 0.008), 20- (p = 0.002) and 30-years (p< 0.001). TMT was negatively correlated with EDSS at 20-years (R=-0.18, p = 0.032) and 30-years (R-0.244, p = 0.005). Longitudinally, TMT at earlier timepoints was not predictive for 30-year clinical outcomes., Conclusion: TMT thinning is accelerated in MS and correlated with disability in later disease stages, but is not predictive of future disability., Competing Interests: Declaration of Competing Interest LH has no conflicts of interest relevant to this study. KC has received honoraria for speaking at meetings, advisory work or support to attend meetings from Merck, Biogen Idec, Sanofi Genzyme and Roche. SM has no conflicts of interest relevant to this study. JF has no conflicts of interest relevant to this study. OC has served as a consultant for Novartis and has received a speaker honorarium from Merck. She has obtained funding from NIHR, UCLH NIHR BRC, National and UK MS Society, PMSA, and MRC. DC is a consultant Hoffmann-La Roche. In the last three years he has been a consultant for Biogen, has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and a speaker's honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. FB is a consultant for Biogen, Bayer, Merck, Roche, Novartis, IXICO and Combinostics; has received funding from European Commission Horizon (2020), UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre and GE healthcare; and serves on the editorial boards of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal, and Neurology., (Copyright © 2023. Published by Elsevier B.V.)