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BACKGROUND: The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC). METHODS: Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics. RESULTS: The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%). CONCLUSIONS: Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.

Background and objectivesNeuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab.MethodsWe recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%).ResultsThe Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps.DiscussionAn established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

Background: Preschool is a crucial period for developing motor skills. Objective: This study evaluated factors associated with motor competence in preschoolers from a Brazilian urban area. Methods: A total of 211 preschoolers (51.2% girls and 48.8% boys) were evaluated. Body mass index was calculated; the Brazilian Economic Research Criterion, the Mini-Mental Scale (MMC) and the Early Childhood Environment Rating Scale®, Revised (ECERS-R™) were applied; the Habitual Physical Activity time was recorded; the Test of Gross Motor Development (TGMD-2) was performed. Univariate analysis was performed using simple linear regression for the independent variables, considering the motor test subscales as dependent variables. Variables with p < 0.20 in the univariate analysis were considered for the multiple linear regression model and were entered into the stepwise method. Results: The independent variables remaining in the Standard Score Locomotor model were BMI, presence of park at school, and MMC (R[superscript 2] = 0.16). The independent variables remaining in the Standard Object Control score were MMC and gender (R[superscript 2] = 0.03). The variables associated with the highest scores of Gross Motor Quotient were MMC, body mass index, and presence of a park at school, respectively (R[superscript 2] = 0.11). Conclusions: Male eutrophic preschoolers who are physically active and attend schools with parks or courtyards in a Brazilian urban area have the highest scores for global cognitive function and motor competence.

BackgroundPatients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort.Method197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site.ResultsNo significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere.ConclusionThe results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.

BACKGROUND AND OBJECTIVES: To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts. METHODS: The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG-seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA). RESULTS: Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (-22.7 μm) after the first ON was higher than after the next (-3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC. DISCUSSION: Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.

PurposeOptical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD.ParticipantsThe current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices.Findings to dateThe cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline.Future plansWe are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.

Aim: To investigate the effects of high‐intensity interval training (HIIT) on periodontitis (PD) progression and behavioural outcomes. Materials and Methods: Forty‐eight Wistar rats were divided into four groups: non‐trained (NT); non‐trained with PD; HIIT with PD; and HIIT. The HIIT protocol, involving daily treadmill sessions, spanned 8 weeks, with PD induced by ligature after the 6th week. Behavioural tests were conducted to assess anxiety and memory. Post euthanasia, we evaluated the systemic inflammatory profile and oxidative stress markers in the hippocampus and amygdala. A morphological evaluation and elemental composition analysis of the mandibular alveolar bone were performed. Results: PD exacerbated alveolar bone level, bone surface damage and alterations in calcium and phosphorus percentages on the bone surface (p <.05), while HIIT attenuated these changes (p <.05). HIIT improved systemic inflammatory markers altered by PD (tumour necrosis factor [TNF]‐α, interleukin [IL]‐10, TNF‐α/IL‐10 and IL‐1β/IL‐10 ratios, p <.05). PD animals exhibited lower total antioxidant capacity and levels of thiobarbituric acid reactive substances in the amygdala and hippocampus, respectively (p <.05). HIIT maintained these parameters at levels similar to those in NT animals. HIIT improved anxiety and memory outcomes altered by PD (p <.05). Conclusions: HIIT attenuates systemic inflammation, anxiety and memory outcomes promoted by PD. [ABSTRACT FROM AUTHOR]

Genomic selection and doubled haploids hold significant potential to enhance genetic gains and shorten breeding cycles across various crops. Here, we utilized stochastic simulations to investigate the best strategies for optimize a sweet corn breeding program. We assessed the effects of incorporating varying proportions of old and new parents into the crossing block (3:1, 1:1, 1:3, and 0:1 ratio, representing different degrees of parental substitution), as well as the implementation of genomic selection in two distinct pipelines: one calibrated using the phenotypes of testcross parents (GSTC scenario) and another using F1 individuals (GSF1). Additionally, we examined scenarios with doubled haploids, both with (DH) and without (DHGS) genomic selection. Across 20 years of simulated breeding, we evaluated scenarios considering traits with varying heritabilities, the presence or absence of genotype-by-environment effects, and two program sizes (50 vs 200 crosses per generation). We also assessed parameters such as parental genetic mean, average genetic variance, hybrid mean, and implementation costs for each scenario. Results indicated that within a conventional selection program, a 1:3 parental substitution ratio (replacing 75% of parents each generation with new lines) yielded the highest performance. Furthermore, the GSTC model outperformed the GSF1 model in enhancing genetic gain. The DHGS model emerged as the most effective, reducing cycle time from 5 to 4 years and enhancing hybrid gains despite increased costs. In conclusion, our findings strongly advocate for the integration of genomic selection and doubled haploids into sweet corn breeding programs, offering accelerated genetic gains and efficiency improvements. [ABSTRACT FROM AUTHOR]

Multiple short daily bouts of HIIT are more effective than single daily sessions in improving cardiometabolic and cellular adaptations in rats. We hypothesize that a short period of detraining is sufficient to abolish the superior adaptive responses to multiple versus single daily sessions of HIIT in rats. Male rats were divided into untrained, 1xHIIT, and 3xHIIT groups. Over eight weeks, the 1xHIIT group performed 115 min single daily sessions of HIIT, while the 3xHIIT group performed three 5 min sessions with 4 h intervals. After training, both groups remained sedentary for four weeks (detraining). Resting oxygen consumption (VO2), body composition, glucose/insulin tolerance, and blood pressure were recorded. After euthanasia, cardiac function/histology and gastrocnemius mitochondrial density were analyzed. After training, both 1xHIIT and 3xHIIT protocols induced similar improvements in VO2, maximal oxygen uptake (VO2max), cardiac function/hypertrophy, and gastrocnemius mitochondrial density. These effects were maintained even after detraining. Only the 3xHIIT protocol improved insulin sensitivity. After detraining, this effect was abolished. After training, both 1xHIIT and 3xHIIT protocols reduced adiposity. After detraining, the adiposity increased in both groups, with a more pronounced increase in the 3xHIIT rats. A four-week detraining period abolishes the superior adaptive responses to multiple versus single daily HIIT sessions in rats. [ABSTRACT FROM AUTHOR]

Species of the genus Cynodon are among the most cultivated forage crops in the world due to their high yield and nutritional quality, and its use in cattle feeding has been associated with gains in animal weight and increased milk production. The objective of this study was to model covariance structures in Cynodon spp. clones and study the changes in ranking of the selected genotypes, since it is believed that affects the ranking of genotypes. A total of 202 genotypes were evaluated in an experiment conducted in an augmented block design with four replications and four harvests. The genotypes were assessed for plant height, green weight, percentage of dry matter, and plant vigor. Nineteen repeated measures models with different covariance structures were tested. The best-fitted model adopts the CORH covariance structure for the genetic effects. Correct modeling of the covariance structure affected the ranking of genotypes in all variables evaluated. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.

Neuromyelitis optica spectrum disorder (NMO/SD) and its clinical variants have at their core the loss of immune tolerance to aquaporin-4 and perhaps other autoantigens. The characteristic phenotype is disruption of astrocyte function and demyelination of spinal cord, optic nerves, and particular brain regions. In this second of a 2-part article, we present further perspectives regarding the pathogenesis of NMO/SD and how this disease might be amenable to emerging technologies aimed at restoring immune tolerance to disease-implicated self-antigens. NMO/SD appears to be particularly well-suited for these strategies since aquaporin-4 has already been identified as the dominant autoantigen. The recent technical advances in reintroducing immune tolerance in experimental models of disease as well as in humans should encourage quantum leaps in this area that may prove productive for novel therapy. In this part of the article series, the potential for regulatory T and B cells is brought into focus, as are new approaches to oral tolerization. Finally, a roadmap is provided to help identify potential issues in clinical development and guide applications in tolerization therapy to solving NMO/SD through the use of emerging technologies. Each of these perspectives is intended to shine new light on potential cures for NMO/SD and other autoimmune diseases, while sparing normal host defense mechanisms.