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Background We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability. Methods From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured. Results Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p  = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p  = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions ( p  = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm 3 vs. 85 mm 3 , p  < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients ( p  < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores ( p  < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients ( p  = 0.03 and p  = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration ( p  = 0.046, p  = 0.01, p  = 0.005, and p  = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV ( p  = 0.001), particularly for thalamic volume ( p  = 0.001), with disease duration compared with Caucasian patients. Conclusions Gray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients.

Although shared behavioral and neural mechanisms between working memory (WM) and motor sequence learning (MSL) have been suggested, the additive and interactive effects of training have not been studied. This study aimed at investigating changes in brain functional connectivity (FC) induced by sequential (WM + MSL and MSL + WM) and combined (WM × MSL) training programs. 54 healthy subjects (27 women; mean age: 30.2 ± 8.6 years) allocated to three training groups underwent twenty-four 40-min training sessions over 6 weeks and four cognitive assessments including functional MRI. A double-baseline approach was applied to account for practice effects. Test performances were compared using linear mixed-effects models and t-tests. Resting state fMRI data were analysed using FSL. Processing speed, verbal WM and manual dexterity increased following training in all groups. MSL + WM training led to additive effects in processing speed and verbal WM. Increased FC was found after training in a network including the right angular gyrus, left superior temporal sulcus, right superior parietal gyrus, bilateral middle temporal gyri and left precentral gyrus. No difference in FC was found between double baselines. Results indicate distinct patterns of resting state FC modulation related to sequential and combined WM and MSL training suggesting a relevance of the order of training performance. These observations could provide new insight for the planning of effective training/rehabilitation.

There is a limited correlation between white matter (WM) lesion load as determined by magnetic resonance imaging and disability in multiple sclerosis (MS). The reasons for this so-called clinico-radiological paradox are diverse and may, at least partly, relate to the fact that not just the overall lesion burden, but also the exact anatomical location of lesions predict the severity and type of disability. We aimed at studying the relationship between lesion distribution and disability using a voxel-based lesion probability mapping approach in a very large dataset of MS patients. T2-weighted lesion masks of 2348 relapsing-remitting MS patients were spatially normalized to standard stereotaxic space by non-linear registration. Relations between supratentorial WM lesion locations and disability measures were assessed using a non-parametric ANCOVA (Expanded Disability Status Scale [EDSS]; Multiple Sclerosis Functional Composite, and subscores; Modified Fatigue Impact Scale) or multinomial ordinal logistic regression (EDSS functional subscores). Data from 1907 (81%) patients were included in the analysis because of successful registration. The lesion mapping showed similar areas to be associated with the different disability scales: periventricular regions in temporal, frontal, and limbic lobes were predictive, mainly affecting the posterior thalamic radiation, the anterior, posterior, and superior parts of the corona radiata. In summary, significant associations between lesion location and clinical scores were found in periventricular areas. Such lesion clusters appear to be associated with impairment of different physical and cognitive abilities, probably because they affect commissural and long projection fibers, which are relevant WM pathways supporting many different brain functions.

Background Lesion location is a prognostic factor of disease progression and disability accrual. Objective To investigate lesion formation in 11 brain regions, assess correlation between lesion location and physical and cognitive disability measures and investigate treatment effects by region. Methods In 2355 relapsing–remitting multiple sclerosis patients from the FREEDOMS and FREEDOMS II studies, we extracted T2-weighted lesion number, volume and density for each brain region; we investigated the (Spearman) correlation in lesion formation between brain regions, studied association between location and disability (at baseline and change over 2 years) using linear/logistic regression and assessed the regional effects of fingolimod versus placebo in negative binomial models. Results At baseline, the majority of lesions were found in the supratentorial brain. New and enlarging lesions over 24 months developed mainly in the frontal and sublobar regions and were substantially correlated to pre-existing lesions at baseline in the supratentorial brain (p = 0.37–0.52), less so infratentorially (p = −0.04–0.23). High sublobar lesion density was consistently and significantly associated with most disability measures at baseline and worsening of physical disability over 24 months. The treatment effect of fingolimod 0.5 mg was consistent across the investigated areas and tracts. Conclusion These results highlight the role of sublobar lesions for the accrual of disability in relapsing–remitting multiple sclerosis.

Subcortical T2-weighted (T2w) lesions are very common in older adults and have been associated with dementia. However, little is known about the strategic lesion distribution and how lesion patterns relate to vascular risk factors and cognitive impairment. The aim of this study was to analyze the association between T2w lesion load and location, vascular risk factors, and cognitive impairment in a large cohort of older adults. 1017 patients participating in a large prospective cohort study (INtervention project on cerebroVAscular disease and Dementia in the district of Ebersberg, INVADE II) were analyzed. Cerebral T2w white matter and deep grey matter lesions, the so-called white matter hyperintensities (WMHs), were outlined semi-automatically on fluid attenuated inversion recovery images and normalized to standard stereotaxic space (MNI152) by non-linear registration. Patients were assigned to either a low-risk or a high-risk group. The risk assessment considered ankle brachial index, intima media thickness, carotid artery stenosis, atrial fibrillation, previous cerebro-/cardiovascular events and peripheral artery disease as well as a score based on cholesterol levels, blood pressure and smoking. Separate lesion distributions were obtained for the two risk groups and compared using voxel-based lesion-symptom mapping. Moreover, we assessed the relation between lesion location and cognitive impairment (demographically adjusted z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery Plus, CERAD-NAB Plus) using voxel-based statistics (α = 0.05). A total of 878 out of 1017 subjects (86%) had evaluable MRI data and were included in the analyses (mean age: 68.2 ± 7.6 years, female: 515). Patients in the high-risk group were characterized by a significantly higher age, a higher proportion of men, a higher lesion load (p < 0.001), and a worse performance in some of the cognitive subdomain scores (p < 0.05). Voxels with significant associations to the subjects' cerebrovascular risk profiles were mainly found at locations of the corpus callosum, superior corona radiata, superior longitudinal fasciculus, internal and external capsule, and putamen. While several cognitive domains have shown significant associations with the participants’ total lesion burden (p < 0.05), no focal WMH locations were found to be associated with cognitive impairment. Age, gender, several cognitive scores, and WMH lesion load were shown to be significantly associated with vascular risk factors in a population of older, but cognitively preserved adults. Vascular risk factors seem to promote lesion formation most severely at well-defined locations. While lesion load showed weak associations to some cognitive scores, no focal locations causing specific cognitive disturbances were identified in this large cohort of older adults. •Study of association between T2w lesion load and location, vascular risk factors, cognition.•Increased vascular risk reflected in higher age, proportion of men, lesion load, cognitive disturbances.•Periventricular lesions significantly associated with vascular risk factors.•Total lesion burden but not focal locations partially explain cognitive disturbances.

ObjectiveTo validate the precision and accuracy of the semi-automated cord image analyser (Cordial) for lumbar spinal cord (SC) volumetry in 3D T1w MRI data of healthy controls (HC).Materials and methods40 3D T1w images of 10 HC (w/m: 6/4; age range: 18–41 years) were acquired at one 3T-scanner in two MRI sessions (time interval 14.9±6.1 days). Each subject was scanned twice per session, allowing determination of test-retest reliability both in back-to-back (intra-session) and scan-rescan images (inter-session). Cordial was applied for lumbar cord segmentation twice per image by two raters, allowing for assessment of intra- and inter-rater reliability, and compared to a manual gold standard.ResultsWhile manually segmented volumes were larger (mean: 2028±245 mm3 vs. Cordial: 1636±300 mm3, p<0.001), accuracy assessments between manually and semi-automatically segmented images showed a mean Dice-coefficient of 0.88±0.05. Calculation of within-subject coefficients of variation (COV) demonstrated high intra-session (1.22–1.86%), inter-session (1.26–1.84%), as well as intra-rater (1.73–1.83%) reproducibility. No significant difference was shown between intra- and inter-session reproducibility or between intra-rater reliabilities. Although inter-rater reproducibility (COV: 2.87%) was slightly lower compared to all other reproducibility measures, between rater consistency was very strong (intraclass correlation coefficient: 0.974).ConclusionWhile under-estimating the lumbar SCV, Cordial still provides excellent inter- and intra-session reproducibility showing high potential for application in longitudinal trials.Key Points• Lumbar spinal cord segmentation using the semi-automated cord image analyser (Cordial) is feasible.• Lumbar spinal cord is 40-mm cord segment 60 mm above conus medullaris.• Cordial provides excellent inter- and intra-session reproducibility in lumbar spinal cord region.• Cordial shows high potential for application in longitudinal trials.

Background Although multidisciplinary rehabilitation programs are commonly used in clinical practice for patients with multiple sclerosis (MS), they are currently underexamined. Objective This study aims to investigate the efficacy and underlying brain mechanisms of an inpatient multidisciplinary rehabilitation. Methods Twenty-four patients with relapse-onset MS underwent a 4-week personalized inpatient multidisciplinary rehabilitation and three assessment sessions including MRI, clinical, cognitive and motor function evaluation. Twenty-four healthy controls underwent two assessment sessions 4 weeks apart. Test performances were compared using repeated measures ANOVA, Tukey and t tests. A motor sequence learning (MSL) task was presented during fMRI and data were analysed using FSL. Results Patients had less perceived fatigue, improved walking speed and quality of life following the rehabilitation, which could be maintained at follow-up 4 weeks after rehabilitation. After rehabilitation, differences in accuracy of the MSL task between groups diminished, indicating an improved performance in patients. Improved accuracy went along with changes of brain activity in the left cerebellum and right frontal lobe post-rehabilitation, which could be maintained at follow-up. No changes between sessions were observed in controls. Conclusion Multidisciplinary rehabilitation may improve highly impacting symptoms through more efficient recruitment of brain regions and therefore positively influence MS patients’ quality of life.

Whilst public health measures were effective in reducing COVID-19 transmission, unintended negative consequences may have occurred. This study aims to assess changes alcohol consumption and the heavy episodic drinking (HED) during the pandemic. Data were from the Optimise Study, a longitudinal cohort of Australian adults September 2020-August 2022 that over-sampled priority populations at higher risk of contracting COVID-19, developing severe COVID-19 or experiencing adverse consequences of lockdowns. Frequency of alcohol consumption (mean number of days per week) and past-week HED were self-reported. Generalised linear models estimated the association between time and (1) the frequency of alcohol consumption and (2) heavy episodic drinking. Data from 688 participants (mean age: 44.7 years, SD:17.0; 72.7% female) and 10,957 surveys were included. Mean days of alcohol consumption per week decreased from 1.92 (SD: 1.92) in 2020 to 1.54 (SD:1.94) in 2022. The proportion of participants reporting HED decreased from 25.4% in 2020 to 13.1% in 2022. During two lockdown periods, known as \"lockdown five\", (OR:0.65, 95%CI [0.47,0.90]) and \"lockdown six\" (OR:0.76, 95%CI [0.67,0.87]), participants were less likely to report HED. Participants alcohol drinking frequency and HED decreased during the pandemic. This study provides a strong description of alcohol consumption during the pandemic and suggests that lockdowns did not have the unintended consequences of increased alcohol consumption.

Background Longitudinal studies are critical to informing evolving responses to COVID-19 but can be hampered by attrition bias, which undermines their reliability for guiding policy and practice. We describe recruitment and retention in the Optimise Study, a longitudinal cohort and social networks study that aimed to inform public health and policy responses to COVID-19. Methods Optimise recruited adults residing in Victoria, Australia September 01 2020–September 30 2021. High-frequency follow-up data collection included nominating social networks for study participation and completing a follow-up survey and four follow-up diaries each month, plus additional surveys if they tested positive for COVID-19 or were a close contact. This study compared number recruited to a-priori targets as of September 302,021, retention as of December 31 2021, comparing participants retained and not retained, and follow-up survey and diary completion October 2020–December 2021. Retained participants completed a follow-up survey or diary in each of the final three-months of their follow-up time. Attrition was defined by the number of participants not retained, divided by the number who completed a baseline survey by September 302,021. Survey completion was calculated as the proportion of follow-up surveys or diaries sent to participants that were completed between October 2020–December 2021. Results At September 302,021, 663 participants were recruited and at December 312,021, 563 were retained giving an overall attrition of 15% ( n  = 100/663). Among the 563 retained, survey completion was 90% ( n  = 19,354/21,524) for follow-up diaries and 89% ( n  = 4936/5560) for monthly follow-up surveys. Compared to participants not retained, those retained were older (t-test, p  <  0.001), and more likely to be female (χ 2 , p  = 0.001), and tertiary educated (χ 2 , p =  0.018). Conclusion High levels of study retention and survey completion demonstrate a willingness to participate in a complex, longitudinal cohort study with high participant burden during a global pandemic. We believe comprehensive follow-up strategies, frequent dissemination of study findings to participants, and unique data collection systems have contributed to high levels of study retention.

β-Thalassemia is a genetic anemia caused by partial or complete loss of β-globin synthesis, leading to ineffective erythropoiesis and RBCs with a short life span. Currently, there is no efficacious oral medication modifying anemia for patients with β-thalassemia. The inappropriately low levels of the iron regulatory hormone hepcidin enable excessive iron absorption by ferroportin, the unique cellular iron exporter in mammals, leading to organ iron overload and associated morbidities. Correction of unbalanced iron absorption and recycling by induction of hepcidin synthesis or treatment with hepcidin mimetics ameliorates β-thalassemia. However, hepcidin modulation or replacement strategies currently in clinical development all require parenteral drug administration. We identified oral ferroportin inhibitors by screening a library of small molecular weight compounds for modulators of ferroportin internalization. Restricting iron availability by VIT-2763, the first clinical stage oral ferroportin inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia intermedia. VIT-2763 not only improved erythropoiesis but also corrected the proportions of myeloid precursors in spleens of Hbbth3/+ mice. VIT-2763 is currently being developed as an oral drug targeting ferroportin for the treatment of β-thalassemia.