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BACKGROUND: Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. OBJECTIVE: To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. METHODS: The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). RESULTS: We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). CONCLUSIONS: While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

Collagen XII-related disease (COL12 -RD), also classified as myopathic Ehlers-Danlos syndrome (EDS), is a congenital onset disorder with overlapping connective tissue and muscle involvement. Biallelic loss-of-function (LoF), as well as dominantly acting monoallelic variants in COL12A1 , have been recognized to cause COL12 -RD. While there have been additional reports of patients with dominant COL12A1 variants, fewer cases of the presumed more severe recessive COL12 -RD have been documented. We present clinical, immunocytochemical, and imaging data on eight additional patients from seven families, with biallelic variants in COL12A1. All patients presented with a consistent constellation of symptoms including congenital onset disease characterized by hypotonia, dysmorphic features including most notably gingival hypertrophy, prominent distal joint hyperlaxity with co-occurring contractures of large joints, and muscle involvement of variable degrees, evident both clinically and on muscle imaging. Five patients presented with a severe congenital phenotype manifesting with profound weakness, significantly delayed or minimal attainment of motor milestones, respiratory insufficiency, and feeding difficulties. Three patients presented with milder disease manifesting with mild to moderate muscle weakness and delayed milestones but were able to achieve independent ambulation. Patients were found to have biallelic LoF COL12A1 variants, except for one family with compound heterozygosity for a missense variant (p.I1393Ffs*11/ p.A1110D). Consistent with the variable clinical spectrum, in vitro collagen XII immunocytochemistry analysis in fibroblasts ranged from complete absence of collagen XII expression in a patient with severe disease, to a mild reduction in a patient with milder disease. This series aids to further establish COL12A1 as a recessive myopathic EDS gene and to expand the clinical spectrum to include a milder EDS phenotype. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is a significant clinical outcome for muscular dystrophy. Echocardiography (echo) is a versatile measure of cardiac function that is available in most muscular dystrophy centers and, therefore, has high utility for clinical care and multicenter clinical trials. Echo outcomes for treatment trials in muscular dystrophy have traditionally measured ejection fraction (EF). However, this measure can be challenging to obtain with more advanced disease due to chest wall deformities and difficulty with positioning for testing. This study was performed to pilot prospective measures of echo outcomes at 5 centers of the Cooperative International Neuromuscular Research Group (CINRG) using a central sonography protocol and 2 central readers. Forty-eight participants 8–18years old with genetically confirmed Duchenne muscular dystrophy, Becker muscular dystrophy or limb girdle muscular dystrophy underwent electrocardiogram, echo and B-type natriuretic peptide testing. Notably, the echo quality was insufficient to read EF for 23 studies by one reader and for 5 studies by the other reader. In contrast, myocardial performance index (MPI) measured by Doppler could be read by both readers in 46 studies. Furthermore, the agreement of cardiac measures between the 2 independent readers and between one reader performing 2 different reads was greater for MPI than for EF. In 35% of studies, an abnormal MPI while EF remained normal suggested early cardiac dysfunction. This finding suggests that MPI may demonstrate increased sensitivity to detect cardiomyopathy when compared to EF. In subsequent analyses to explore echo measures of even greater sensitivity to detect cardiac dysfunction, speckle tracking was performed to measure longitudinal and circumferential strain. The results suggest that MPI and strain measures are sensitive and amenable to central reading for muscular dystrophy clinical trials. [Copyright &y& Elsevier]

Background and Objectives: This survey study aimed to (1) identify patient/family research priorities in pediatric-onset multiple sclerosis (POMS), and (2) delineate optimized methods for research study/clinical trials design, engagement, and implementation., Methods: Participants were as follows: (1) parents of a child (<18 years) with POMS enrolled in a national registry, (2) adolescents (13-17 years) with POMS in the registry, and (3) adults (18-40 years) with POMS receiving care at a registry affiliated clinic. Of 293 eligible participants, 192 completed surveys., Results: Experiences with health care and medications were generally positive but there remain areas of priority improvement. Incentives to participate in clinical trials included medications previously tested and in pill form, bloodwork/study visits required ⩾ every 3 months, cognitive testing ⩽1 hour, compensation for travel and time, ability to continue current multiple sclerosis (MS) medication, option to take study medication if on placebo, and individualized study feedback. Priorities for clinical research were (1) psychosocial impact, (2) cognitive/academic impact, (3) environmental risk, and (4) nutrition., Conclusions: Results highlighted the importance of a holistic approach to study design and a focus on the impact of disease on daily life to best engage patients and families in POMS clinical trials and research., 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: T.C. has received compensation for consulting from Banner Life Sciences*, Biogen, Bristol Myers Squibb, Janssen, Genentech, Novartis Pharmaceuticals, Octave Bioscience, Sandoz, Siemens, TG Therapeutics*, UCB Biopharma, and Vida Ventures*. He has received compensation for speaking engagements from Prime Education, LLC*. He has received research support from the National Institutes of Health, National MS Society, US Department of Defense, Sumaira Foundation, Brainstorm Cell Therapeutics, Bristol Myers Squibb, Genentech, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Massachusetts Life Sciences Center, Novartis Pharmaceuticals, Octave Bioscience, Sanofi Genzyme, Tiziana Life Sciences, and Wesley Clover International. All activities and funding have occurred within the past 24 months (*relationship has since ended), and disclosures do not conflict with the work being presented.

Background: Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials., Objective: To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age., Methods: MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18., Results: Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 - 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 - 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38-1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04-0.21) and none developed new T2 lesions., Conclusion: This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab., Competing Interests: Declaration of competing interest ZN, TC, MW, AV, TL, NSH, TCH, MR, JT, TSCH, SM, MR, AA had no disclosures. MG has received research funding from Roche and Pfizer. LB received funding from NIH, Harvard Medical School Shore grant, ROHHAD Fight, Inc. She received honoraria from Novartis. She participated in clinical trials with Biogen, Alexion and Genentech/Roche. She is a consultant to the national Vaccine Injury Compensation Program and Massachusetts Department of Public Health. L Krupp has received advisory board/consulting fees, travel and meal allowances, and/or research funding from Sanofi-Aventis, Biogen, Novartis, Eisai, Roche, Gerson Lehrman, Janssen, Cambridge Medical Technologies and Medergy Marketing over the last three years. She is also a non-compensated consultant and/or advisory board member with Novartis and Celgene. Dr. Krupp receives royalties for use of the Fatigue Severity Scale by various biopharmaceutical entities. J Rose has current research funding from NMSS, Biogen, VA, and NIH. S Guye, C Liu and C Manlius are employee of F. Hoffmann-la Roche Ltd. E Waubant has participated in multicenter clinical trials funded by Genentech, Alexion and Biogen. She has current support from the NIH, NMSS, PCORI, CMSC, Department of Defense and Race to Erase MS. This study was Sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Network funding provided by National MS Society (SI-1808–32,326)., (Copyright © 2024. Published by Elsevier B.V.)

Background: Understanding nutrition's role in multiple sclerosis (MS) can guide recommendations and intervention-based studies., Objective: Evaluate the association between nutrition and pediatric-onset MS outcomes., Methods: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase., Results: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07-1.86), and risk of T2 progression by 40% (1.40, 1.12-1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60-0.95), 45% (0.55, 0.32-0.96), and 15% (0.84, 0.74-0.96), respectively. No associations were found with EDSS., Conclusion: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS., Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs)., Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p  < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction ( p  < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction ( p  = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58)., Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk., Methods: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02)., Results: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors., Conclusions: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may., Competing Interests: Declaration of Competing Interest There is no conflict of interest related to this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Patient-powered research networks (PPRNs) for autoimmune disease are widely used in the adult population to recruit patients and drive patient-centered research, but few have included pediatric patients. We aimed to characterize viewpoints regarding research needs and participation in pediatric-onset multiple sclerosis (POMS) via a PPRN-disseminated survey., Methods: This is an exploratory, cross-sectional study. The study period was February 1, 2022, to February 9, 2023. Three questionnaires were disseminated to (1) patients with POMS (PwPOMS), (2) caregivers of PwPOMS (C-PwPOMS), and (3) health care providers/researchers in POMS (HR-POMS)., Results: A total of 88 participants were included for analysis; 44% (n = 39) were PwPOMS, 42% (n = 37) were C-PwPOMS, and 14% (n = 12) were HR-POMS. Some PwPOMS (18%) and C-PwPOMS (9%) expressed research hesitancy, but more, 69% of PwPOMS and 68% of C-PwPOMS, were interested in research participation. Nevertheless, less than half of PwPOMS (38%) and C-PwPOMS (38%) reported previous research involvement. HR-POMS reported difficulties in funding (100%) and recruiting participants (58%). PwPOMS (67%), C-PwPOMS (62%), and HR-POMS (67%) were open to future involvement in PPRNs., Conclusions: Participants with POMS in this study expressed strong interest in research involvement but also expressed participation hesitancy, which may contribute to recruiting challenges expressed by researchers. Although the exploratory design limits generalizability to the larger POMS population, this study shows PPRNs are well-suited to soliciting attitudes and opinions of key stakeholders in POMS. Future studies utilizing PPRNs for POMS should prioritize diverse, representative cohorts and focus on understanding and mitigating issues hindering research participation., Competing Interests: Declaration of Competing Interest T.S. receives grant funding from the National MS Society. She participates in research funded by Roche. She has received speakers’ compensation from Roche and Cycle Pharma. T.C.C. receives research funding from Hoffmann-La Roche and National MS Society. M.P.G. has received institutional funding for POMS clinical trials from Biogen and Roche/Genentech and institutional funding for research unrelated to POMS from Pfizer. The other authors have nothing to disclose. The views presented in this publication are solely the responsibility of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors, or its Methodology Committee., (Copyright © 2023 Elsevier Inc. All rights reserved.)

ADEM is an inflammatory disease, with new onset polyfocal neurologic symptoms, encephalopathy and multifocal demyelination, typically in childhood. Initial diagnosis of ADEM is challenging and up to 20 % of children with MS or NMOSD are initially diagnosed with ADEM. We describe characteristics of patients with monophasic ADEM vs. recurrent demyelinating syndromes at onset and identify features consistent with monophasic course. This is a multicenter observational study of children with demyelinating disease, followed at 12 regional pediatric MS centers. Descriptive statistics were used to report patient characteristics, clinical/imaging features and outcomes. Logistic regression was used to predict features associated with monophasic course. As of July 2019, 837 children with final diagnosis of ADEM (n = 79), MS (n = 646) or NMOSD (n = 112) were identified. The mean follow-up was 5·7 +/- 3·2 years. ADEM patients were youngest with mean age at first event 5·2 +/- 3·8 years (p < 0.001) and male predominant (66 %) (p < 0·001). After 2 years of follow-up, 83 % of patients initially diagnosed with monophasic ADEM retained this diagnosis. In multivariable analysis, older age (OR 1·16 [95 % CI 1·02 - 1·33] for 1-year increase, p = 0·02), presenting with optic neuritis (OR 8.18 [95 % CI 1.88 - 35.64], p = 0·005) and presence of gadolinium enhancement (OR 4.08 [95 % CI 1.38 - 12.08], p = 0·011) were associated with reclassification of ADEM to MS, NMOSD or DDNOS within 2 years. Children with monophasic ADEM vs. those reclassified as other demyelinating disorders are younger at onset, and less likely to have optic neuritis or gadolinium-enhancing lesions at onset., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC)., Methods: This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC., Results: One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs., Conclusions: Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population., Competing Interests: Declaration of competing interest No conflicts of interest noted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM&#95;152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

Background: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis., Methods: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090)., Results: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes., Conclusions: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis., Competing Interests: Competing interests: EW has current support from the NIH, NMSS, PCORI, CMSC and Race to Erase MS., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions., Objective: Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs)., Methods: POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken., Results: Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy ( p  = 0.016)., Conclusions: B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.