Discovery of NSD2-Degraders from Novel and Selective DEL Hits.

NSD2 is a histone methyltransferase predominantly catalyzing di-methylation of histone H3 on lysine K36. Increased NSD2 activity due to mutations or fusion-events affecting the gene encoding NSD2 is considered an oncogenic event and a driver in various cancers, including multiple myelomas carrying t(4;14) chromosomal translocations and acute lymphoblastic leukemia's expressing the hyperactive NSD2 mutant E1099 K. Using DNA-encoded libraries, we have identified small molecule ligands that selectively and potently bind to the PWWP1 domain of NSD2, inhibit NSD2 binding to H3K36me2-bearing nucleosomes, but do not inhibit the methyltransferase activity. The ligands were subsequently converted to selective VHL1-recruiting NSD2 degraders and by using one of the most efficacious degraders in cell lines, we show that it leads to NSD2 degradation, decrease in K3 K36me2 levels and inhibition of cell proliferation.

Linking lesions in sensorimotor cortex to contralateral hand function in multiple sclerosis: a 7†T MRI study.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially.

"11 for Health" in the Faroe Islands: Popularity in schoolchildren aged 10-12 and the effect on well-being and health knowledge.

BACKGROUND: We aimed to investigate the popularity of the "11 for Health program for Europe" for 10-12-year-old Faroese children and the effects on well-being and health knowledge. METHODS: We applied a cluster-randomized controlled trial, including a total of 19 school clusters, randomized into intervention schools (IG, n = 12) and control schools (CG, n = 7). A total of 261 children (137 boys and 124 girls) participated. IG completed the 11-week program, consisting of 2 × 45 min weekly sessions with football drills, small-sided games, and health education. CG continued their regular education. Pre- and post-intervention, the participants completed a shortened version of the multidimensional well-being questionnaire KIDSCREEN-27 and a 34-item multiple-choice health knowledge questionnaire. RESULTS: Between-group differences (p < 0.05) were observed in change scores for physical well-being and overall peers and social support in favor of IG compared with CG, as well as for physical well-being in IG girls compared with CG girls. Between-group differences in change score for overall health knowledge (11.8%, p < 0.001, ES: 0.82) were observed in favor of IG, as well as for playing football (8.9%, p = 0.039, ES: 0.24), be active (8.1%, p = 0.017, ES: 0.32), control your weight (18.5%, p < 0.001, ES: 0.52), wash your hands (19.5%, p < 0.001, ES: 0.59), eat a balanced diet (19.3%, p < 0.001, ES: 0.64), get fit (12.1%, p = 0.007, ES: 0.34), and think positive (5.5%, p = 0.039, ES: 0.22). The program was reported as enjoyable with equal moderate-to-high scores for girls (3.68 ± 1.23; ±SD) and boys (3.84 ± 1.17) on a 1-5 Likert Scale. CONCLUSION: The "11 for Health program for Europe" improved physical well-being, peers, and social support and broad-spectrum health knowledge in 10-12-year-old Faroese schoolchildren and was rated popular.

Motivational predictors of children's involvement in out-of-school activities: An application of a football program.

The "11 for Health in Denmark" in-school educational football program has shown to have numerous positive physiological and psychological effects in 10- to 12-year-old schoolchildren. A key part of the successful application of the program, however, has not yet been examined, namely the motivational processes underlying participation and behavioral changes. This study examined such motivational processes (i.e., autonomous motivation, beliefs, and intentions) using the trans-contextual model (TCM) and investigated if the 11 for Health in Denmark program increased intentions to participate in physical activity (PA) outside of school in 10- to 12-year-old schoolchildren. Using a web-based questionnaire, Danish-speaking schoolchildren (N = 276 [boys, 50.4%]; Mage  = 10.44, SD = 0.35) from three schools and seven classes completed TCM-based questionnaires at three time-points (weeks 0, 1, and 5) while participating in the 11 for Health in Denmark program. Single-indicator structural equation modeling was performed to examine goodness-of-fit and parameter estimates. A path analysis using maximum likelihood estimation was used to test the direct and indirect effects of the TCM model. The results partly supported a mediation sequence, as we found significant direct effects in eight of 13 motivational variables (ß = -0.25-0.83, p < 0.05), indirect effects in one of nine variables (ß = 0.15, p < 0.01), but no effects with regard to PA behavior. Findings provide evidence for a motivational link between Danish-speaking schoolchildren's autonomous and controlled motivation from in school to out of school, and may inform future interventions promoting motivation and participation in out of school PA.

The Danish "11 for Health" program raises health knowledge, well-being, and fitness in ethnic minority 10- to 12-year-olds.

OBJECTIVES: This study investigated the effects of the health promotion intervention "11 for Health in Denmark" program on 10- to 12-year-old ethnic minority schoolchildren's enjoyment, health knowledge, well-being, and fitness. METHODS: 1122 Danish 5th grade schoolchildren with ethnic minority background from 154 schools were randomized (5:1) to an intervention group (IG, n = 944) or a control group (CG, n = 178). The IG and CG were also divided into subgroups of children active in a sports club (IGPA: n = 644; CGPA: n = 122) and not active in a sports club (IGPI: n = 300, CGPI: n = 56). IG participated in the "11 for Health in Denmark" 11-week program, consisting of 2 × 45 min per week of football drills, small-sided games, and health education, whereas CG continued their regular activities. Pre-post physical testing and questionnaires were applied (short version of the multidimensional well-being questionnaire KIDSCREEN-27, and a 34-item health knowledge questionnaire). RESULTS: The "11 for Health in Denmark" program was rated moderate-to-high on a 1-5 scale for enjoyment by girls (3.57) and boys (3.65). The intervention had positive between-group effect on health knowledge in relation to hygiene (IG vs GC: 10.6% points (CI95%: 6.9:14.3), p < 0.05), nutrition (9.6% point (CI95%: 7.4:11.8), p < 0.01) and physical activity 4.4% points (CI95%: 2.2:6.6) as well as overall health knowledge (5.7% points, (CI95%: 4.3;7.1), p < 0.05), with similar effects for girls and boys. The IGPI subgroup showed a positive effect on well-being (p = 0.04, school and learning) and also fitness effects on performance and VO2  max (p = 0.02: p = 0.01). The IGPA subgroup showed a positive effect on fitness scores (p = 0.02, BMI). CONCLUSION: The intervention program was enjoyable and had a positive impact on health knowledge of ethnic minority background schoolchildren. In addition, the intervention program had the strongest positive effects on well-being and fitness scores for the non-sports club-active children.

Implementation facilitation of the "11 for Health in Denmark": A case study in a Danish 5th grade class.

The "11 for Health in Denmark" concept aims to enhance 10-12-year-old schoolchildren's physical activity levels and health knowledge through an 11-week football intervention and has been shown to induce positive effects in numerous areas. However, little is known about the implementation facilitation of this concept in schools. This case study therefore aims to gain a deeper understanding of the implementation facilitation of "11 for Health" in a Danish 5th grade class comprising 22 schoolchildren (12 boys and 10 girls, Mage 11.86±) and one teacher. Data were derived from multiple school situations using photographs and videos, observations, and informal interviews. Five themes were identified: (1) environmental and organizational factors impacting on the implementation; (2) familiarization with the concept for the teacher and schoolchildren; (3) previous clique formation; (4) the central role of the teacher; and (5) the importance of how praise partners are allocated. We found high adherence to the "11 for Health" concept, in which the teacher played a key role by applying an autonomy-supportive style of teaching and using the praise partner concept in a suitable manner. A clique of football-playing boys was a resource, as their praising of classmates encouraged adherence. However, familiarization with the "11 for Health" concept was a challenge and the clique's competitive nature occasionally built barriers to other schoolchildren without football experience, potentially leading to a more controlled form of motivation. Based on the results, we encourage teachers to apply autonomy-supportive teaching when applying the "11 for Health" concept.

Well-Being, Physical Fitness, and Health Profile of 2,203 Danish Girls Aged 10-12 in Relation to Leisure-time Sports Club Activity-With Special Emphasis on the Five Most Popular Sports.

ABSTRACT: Madsen, M, Larsen, MN, Cyril, R, Møller, TK, Madsen, EE, Ørntoft, C, Lind, RR, Ryom, K, Christiansen, SR, Wikman, J, Elbe, AM, and Krustrup, P. Well-being, physical fitness, and health profile of 2,203 Danish girls aged 10-12 in relation to leisure-time sports club activity-with special emphasis on the five most popular sports. J Strength Cond Res 36(8): 2283-2290, 2022-This study investigated the relationship between leisure-time sports club activities and well-being as well as physical health parameters in 10-12-year-old Danish girls. Two thousand two hundred three girls took part in the study, which included questionnaires on participation in leisure-time sports clubs, well-being, Yo-Yo intermittent recovery level 1 children's test, long jump, balance tests, body composition, blood pressure (BP), and resting heart rate (RHR). Data were analyzed according to whether the girls participated in leisure-time sport and according to the 5 most frequently reported sports. Girls enrolled in leisure-time sports had higher physical well-being (49.3 ± 8.6 vs. 45.2 ± 8.3), psychological well-being (50.4 ± 9.0 vs. 49.4 ± 9.8), experienced more peer and social support (50.2 ± 10.0 vs. 48.9 ± 10.7), and perceived a more positive school environment (52.5 ± 8.0 vs. 50.5 ± 9.3), as well as showing higher Yo-Yo (+39%), long jump (+10%), and balance performance (+15%) than girls not involved in sport clubs. The girls active in sports clubs had higher relative muscle mass (+5%), lower fat percentage (-11%), body mass index (-5%), RHR (-3.4 b·min -1 ), and diastolic BP (-1.4 mm Hg) compared with girls not involved in sport ( p < 0.05). Girls who played soccer showed higher aerobic fitness compared with inactive girls (+67%), dancers (+39%), swimmers (+38%), and gymnasts (+16%). Gymnasts had a lower fat percentage than inactive girls (-19%), team handballers (-10%), swimmers (-12%), and soccer players (-4%). Girls participating in club-based leisure-time sports showed higher well-being and better fitness and health profiles than girls not involved in any sports club activities. Girls involved in soccer had better aerobic fitness and gymnasts a lower fat percentage.

An 11-week school-based 'health education through football programme' improves health knowledge related to hygiene, nutrition, physical activity and well-being-and it's fun! A scaled-up, cluster-RCT with over 3000 Danish school children aged 10-12 years old.

ObjectivesOur large-scale cluster randomised controlled trial aimed to investigate the effects on health knowledge and enjoyment of an 11 week 'health education through football' programme for children aged 10-12 years old. Methods 3127 Danish school children (49% girls) aged 10-12 years from a total of 154 schools located in 63% of the Danish municipalities (69 of 98) took part in the analysis. A 5:1 cluster randomisation was performed at school level for the intervention group (IG) or the control group (CG). The twice-weekly 45 min intervention was the '11 for Health in Denmark' programme, which includes health education, football drills and small-sided games. The health education element focused on hygiene, nutrition, physical activity and well-being. Outcomes: The participants completed a 34-item multiple-choice computer-based health knowledge questionnaire preintervention and postintervention. IG also evaluated whether the programme was enjoyable. Results Between-group differences (p<0.05) were observed in overall health knowledge in favour of IG (+7.2% points, 95% CI 6.1% to 8.4%, effect size, ES:0.59), with similar effects for girls (+7.4% points, 95% CI 5.9% to 9.0%, ES:0.57) and for boys (+7.0% points, 95% CI 5.3% to 8.7%, p<0.05, ES:0.51). Marked between-group differences were observed in favour of IG, for health knowledge related to hygiene (IG vs CG:+13.9% points, 95% CI 11.1% to 16.7%, ES:0.53), nutrition (+10.3% points, 95% CI 8.5% to 12.1%, ES:0.53), physical activity (+5.9% points, 95% CI 4.1% to 7.7%, ES:0.36) and well-being (+4.4% points, 95% CI 2.7% to 6.1%, ES:0.28). Both girls and boys gave the programme moderate to high scores for enjoyment (3.6±1.0 and 3.7±1.1, respectively). Conclusion Health education through sport, using the '11 for Health' model, was enjoyable for girls and boys aged 10-12 years old, and improved health knowledge related to hygiene, nutrition, physical activity and well-being.

The "11 for Health in Denmark" intervention in 10- to 12-year-old Danish girls and boys and its effects on well-being-A large-scale cluster RCT.

BACKGROUND: The present study investigates the well-being effects for 10- to 12-year-old children  who participated in the school-based intervention "11 for Health in Denmark," which comprises physical activity (PA) and health education. Subgroup analyses were carried out for boys and girls. METHOD: Three thousand sixty-one children were randomly assigned to an intervention group (IG) or a control group (CG) by 5:1 cluster randomization by school. 2533 children (mean age 11.5 ± 0.4; 49.7% boys) were assigned to IG and 528 children (mean age 11.4 ± 0.5; 50.8% boys) were assigned to CG. IG participated in the "11 for Health in Denmark" 11-week program, consisting of 2 × 45 min per week of football drills, small-sided games, and health education. CG did not participate in any intervention and continued with their regular education. Before and after the intervention period, both groups answered a shortened version of the multidimensional well-being questionnaire KIDSCREEN-27. RESULTS: The "11 for Health in Denmark" intervention program had a positive effect on physical well-being in girls (IG: 48.6 ± 8.5 to 50.2 ± 9.3), whereas the improvement was not significant in boys. The program also had a positive impact on well-being scores for peers and social support (IG: 50.2 ± 10.2 to 50.8 ± 10.1), though when analyzed separately in the subgroups of boys and girls the changes were not significant. No between-group differences were found for psychological well-being or school environment. CONCLUSION: The intervention program had a positive between-group effect on physical well-being in girls, whereas the change was not significant in boys. The overall scores for peers and social support improved during the intervention period, but no subgroup differences were found.

Cardiovascular adaptations after 10 months of intense school-based physical training for 8- to 10-year-old children.

This study examined cardiovascular adaptations in 8- to 10-year-old schoolchildren after 10 months (a full school year) of 3 × 40 minute per week of small-sided ball games (SSG, including football, basketball, and/or floorball) or circuit strength training (CST). The study involved 291 Danish schoolchildren, 8-10 years old, cluster-randomized to SSG (n = 93, 4 schools, 5 classes), CST (n = 83, 4 schools, 4 classes), or a control group (CON, n = 115, 2 schools, 5 classes). Before and after the 10-month intervention, resting heart rate and blood pressure measurements were performed as well as comprehensive transthoracic echocardiography and peripheral arterial tonometry (PAT). Analysis of baseline-to-10-months changes showed between-group differences (P < 0.05) after both training interventions in diastolic blood pressure (delta scores: SSG -2.1 ± 6.0 mm Hg; CST -3.0 ± 7.1 mm Hg; CON 0.2 ± 5.3 mm Hg). Moreover, there were between-group differences in delta scores (P < 0.05) in interventricular septum thickness (SSG 0.17 ± 0.87 mm; CST 0.30 ± 0.94 mm; CON -0.15 ± 0.68 mm), left-atrial volume index (SSG 0.32 ± 5.13 mL/m2 ; CON 2.60 ± 5.94 mL/m2 ), and tricuspid annular plane systolic excursion (SSG -0.4 ± 3.3 mm; CON: 0.1 ± 3.6 mm). No significant between-group differences were observed for the PAT-derived reactive hyperemia index. In conclusion, 10 months of 3 × 40 minutes per week of SSG and CST in 8- to 10-year-old children decreased diastolic blood pressure and elicited discrete cardiac adaptations, suggesting that intense physical exercise in school classes can have effects on cardiovascular health in children.

Positive effects on bone mineralisation and muscular fitness after 10†months of intense school-based physical training for children aged 8-10†years: the FIT FIRST randomised controlled trial.

OBJECTIVES: We investigated whether musculoskeletal fitness of school children aged 8-10 years was affected by frequent intense PE sessions. DESIGN AND PARTICIPANTS: 295 Danish school children aged 8-10 years were cluster randomised to a small-sided ball game group (SSG) (n=96, four schools, five classes), a circuit strength training group (CST) (n=83, four schools, four classes) or a control group (CON, n=116, two schools, five classes). INTERVENTION: SSG or CST was performed 3×40 min/week over 10 months. Whole-body dual-energy X-ray absorptiometry (DXA) scans were used to determine areal bone mineral density (aBMD), bone mineral content (BMC) and lean body mass (LBM). Flamingo balance, standing long jump and 20-m sprint tests were used to determine muscular fitness. RESULTS: Analysis of baseline-to-10 months change scores showed between-group differences in favour of the interventions in whole-body aBMD (SSG vs CON: 8 mg/cm2, 95% CI 3 to 13; CST vs CON: 7 mg/cm2, 95% CI 2 to 13, p<0.05) and leg BMC (SSG vs CON: 11 g, 95% CI 4 to 18; CST vs CON: 11 g, 95% CI 3 to 18, p<0.05). SSG had higher change scores in leg aBMD compared with CON and CST (SSG vs CON: 19 mg/cm2, 95% CI 11 to 39, p<0.05; SSG vs CST: 12 mg/cm2, 95% CI 3 to 21, p<0.05), and CST had higher change scores in whole-body BMC compared with CON (CST vs CON: 25 g, 95% CI 10 to 39, p<0.05). Both training types resulted in higher change scores in postural balance (SSG vs CON: 2.4 fewer falls/min, 95% CI 0.3 to 4.5, CST vs CON: 3.6 fewer falls/min, 95% CI 1.3 to 5.9, p<0.05) and jump length (SSG vs CON: 10%, 95% CI 5 to 16%; CST vs CON: 9%, 95% CI 3 to 15%, p<0.05). No between-group differences were observed for sprint performance or LBM (p>0.05). CONCLUSIONS: In conclusion, 3×40 min/week with SSG or CST over a full school year improves bone mineralisation and several aspects of muscular fitness of children aged 8-10 years, suggesting that well-organised intense physical education classes can contribute positively to develop musculoskeletal health in young children. TRIAL REGISTRATION NUMBER: NCT02000492, post results.

Quantification of fluorescence angiography in a porcine model.

PURPOSE: There is no consensus on how to quantify indocyanine green (ICG) fluorescence angiography. The aim of the present study was to establish and gather validity evidence for a method of quantifying fluorescence angiography, to assess organ perfusion. METHODS: Laparotomy was performed on seven pigs, with two regions of interest (ROIs) marked. ICG and neutron-activated microspheres were administered and the stomach was illuminated in the near-infrared range, parallel to continuous recording of fluorescence signal. Tissue samples from the ROIs were sent for quantification of microspheres to calculate the regional blood flow. A software system was developed to assess the fluorescent recordings quantitatively, and each quantitative parameter was compared with the regional blood flow. The parameter with the strongest correlation was then compared with results from an independently developed algorithm, to evaluate reproducibility. RESULTS: A strong correlation was found between regional blood flow and the slope of the fluorescence curves (ROI I: Pearson r = 0.97, p < 0.001; ROI II: 0.96, p < 0.001) as the normalized slope (ROI I: Pearson r = 0.92, p = 0.004; ROI II: r = 0.96, p = 0.001). There was acceptable correlation of the slope of the curve between two independently developed algorithms (ROI I+II: Pearson r = 0.83, p < 0.001), and good resemblance was found with the Bland-Altman method, with no proportional bias. CONCLUSIONS: Perfusion assessment with quantitative indocyanine green fluorescence angiography is not only feasible but easy to perform with commercially available equipment and readily accessible software.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. METHODS: In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. RESULTS: Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). DISCUSSION: Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Transcranial magnetic stimulation of primary motor cortex elicits an immediate transcranial evoked potential.

BACKGROUND: Transcranial evoked potentials (TEPs) measured via electroencephalography (EEG) are widely used to study the cortical responses to transcranial magnetic stimulation (TMS). Immediate transcranial evoked potentials (i-TEPs) have been obscured by pulse and muscular artifacts. Thus, the TEP peaks that are commonly reported have latencies that are too long to be caused by direct excitation of cortical neurons. METHODS: In 25 healthy individuals, we recorded i-TEPs evoked by a single biphasic TMS pulse targeting the primary motor hand area (M1HAND) or parietal or midline control sites. Sampling EEG at 50 kHz enabled us to reduce the duration of the TMS pulse artifact to a few milliseconds, while minor adjustments of the TMS coil tilt or position enabled us to avoid cranial muscular twitches during the experiment. RESULTS: We observed an early positive EEG deflection starting after approx. 2 ms followed by a series of superimposed peaks with an inter-peak interval of ∼1.1-1.4 ms in multiple electrodes surrounding the stimulated sensorimotor region. This multi-peak i-TEP response was only evoked by TMS of the M1HAND region and was modified by changes in stimulation intensity and current direction. DISCUSSION: Single-pulse TMS of the M1HAND evokes an immediate local multi-peak response at the cortical site of stimulation. Our results suggest that the observed i-TEP patterns are genuine cortical responses evoked by TMS caused by synchronized excitation of pyramidal neurons in the targeted precentral cortex. This notion needs to be corroborated in future studies, including further investigations into the potential contribution of instrumental or physiological artifacts.

Performance and robustness of small molecule retention time prediction with molecular graph neural networks in industrial drug discovery campaigns.

This study explores how machine-learning can be used to predict chromatographic retention times (RT) for the analysis of small molecules, with the objective of identifying a machine-learning framework with the robustness required to support a chemical synthesis production platform. We used internally generated data from high-throughput parallel synthesis in context of pharmaceutical drug discovery projects. We tested machine-learning models from the following frameworks: XGBoost, ChemProp, and DeepChem, using a dataset of 7552 small molecules. Our findings show that two specific models, AttentiveFP and ChemProp, performed better than XGBoost and a regular neural network in predicting RT accurately. We also assessed how well these models performed over time and found that molecular graph neural networks consistently gave accurate predictions for new chemical series. In addition, when we applied ChemProp on the publicly available METLIN SMRT dataset, it performed impressively with an average error of 38.70 s. These results highlight the efficacy of molecular graph neural networks, especially ChemProp, in diverse RT prediction scenarios, thereby enhancing the efficiency of chromatographic analysis.

Creatine kinase response to high-intensity aerobic exercise in adult-onset muscular dystrophy.

INTRODUCTION: We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies. METHODS: Fourteen patients with Becker (BMD), facioscapulohumeral (FSHD), or limb-girdle type 2 (LGMD2) muscular dystrophy, and 8 healthy subjects performed 5 cycling tests: an incremental max test, and tests at 65%, 75%, 85%, and 95% of maximal oxygen uptake (VO2max ). Heart rate and oxygen consumption were measured during the tests, and plasma CK was measured before, immediately after, and 24 hours after exercise. RESULTS: All subjects were able to perform high-intensity exercise at the different levels. In patients with LGMD2 and FSHD, CK normalized 24 hours after exercise compared with the pre-exercise value, whereas those with BMD and healthy controls had elevated CK values 24 hours after exercise. CONCLUSIONS: The findings suggest that high-intensity exercise is generally well tolerated in patients with LGMD2 and FSHD, whereas those with BMD may be more prone to exercise-induced damage.

Patient-tailored transcranial direct current stimulation to improve stroke rehabilitation: study protocol of a randomized sham-controlled trial.

BACKGROUND: Many patients do not fully regain motor function after ischemic stroke. Transcranial direct current stimulation (TDCS) targeting the motor cortex may improve motor outcome as an add-on intervention to physical rehabilitation. However, beneficial effects on motor function vary largely among patients within and across TDCS trials. In addition to a large heterogeneity of study designs, this variability may be caused by the fact that TDCS was given as a one-size-fits-all protocol without accounting for anatomical differences between subjects. The efficacy and consistency of TDCS might be improved by a patient-tailored design that ensures precise targeting of a physiologically relevant area with an appropriate current strength. METHODS: In a randomized, double-blinded, sham-controlled trial, patients with subacute ischemic stroke and residual upper-extremity paresis will receive two times 20 min of focal TDCS of ipsilesional primary motor hand area (M1-HAND) during supervised rehabilitation training three times weekly for 4 weeks. Anticipated 60 patients will be randomly assigned to active or sham TDCS of ipsilesional M1-HAND, using a central anode and four equidistant cathodes. The placement of the electrode grid on the scalp and current strength at each cathode will be personalized based on individual electrical field models to induce an electrical current of 0.2 V/m in the cortical target region resulting in current strengths between 1 and 4 mA. Primary endpoint will be the difference in change of Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score between active TDCS and sham at the end of the intervention. Exploratory endpoints will include UE-FMA at 12 weeks. Effects of TDCS on motor network connectivity and interhemispheric inhibition will be assessed with functional MRI and transcranial magnetic stimulation. DISCUSSION: The study will show the feasibility and test the efficacy of personalized, multi-electrode anodal TDCS of M1-HAND in patients with subacute stroke patients with upper-extremity paresis. Concurrent multimodal brain mapping will shed light into the mechanisms of action of therapeutic personalized TDCS of M1-HAND. Together, the results from this trial may inform future personalized TDCS studies in patients with focal neurological deficits after stroke.

Asymmetries in Ground Reaction Forces During Turns by Elite Slalom Alpine Skiers Are Not Related to Asymmetries in Muscular Strength.

The ground reaction forces (GRF) associated with competitive alpine skiing, which are relatively large, might be asymmetric during left and right turns due to asymmetries in the strength of the legs and torso and the present investigation was designed to evaluate this possibility. While skiing a symmetrical, 20-gate slalom course, the asymmetries of 9 elite alpine skiers were calculated on the basis of measurements provided by inertial motion units (IMU), a Global Navigation Satellite System and pressure insoles. In addition, specialized dynamometers were utilized to assess potential asymmetry in the strength of their legs and torso in the laboratory. In total, seven variables related to GRF were assessed on-snow and eight related to strength of the legs and torso in the laboratory. The asymmetries in these parameters between left and right turns on snow were expressed in terms of the symmetry (SI) and Jaccard indices (JI), while the asymmetries between the left and right sides of the body in the case of the laboratory measurements were expressed as the SIs. The three hypotheses to be tested were examined using multivariable regression models. Our findings resulted in rejection of all three hypotheses: The asymmetries in total GRF (H1), as well as in the GRF acting on the inside and outside legs (H2) and on the rear- and forefeet GRF (H3) during left and right turns were not associated with asymmetries in parameters related to muscular strength. Nevertheless, this group of elite slalom skiers exhibited significant asymmetry between their right and left legs with respect to MVC during ankle flexion (0.53 ± 0.06 versus 0.60 ± 0.07 Nm/kg, respectively) and hip extension (2.68 ± 0.39 versus 2.17 ± 0.26 Nm/kg), as well as with respect to the GRFs on the inside leg while skiing (66.8 ± 7.39 versus 76.0 ± 10.0 %BW). As indicated by the JI values, there were also large asymmetries related to GRF as measured by pressure insoles (range: 42.7-56.0%). In conclusion, inter-limb asymmetries in GRFs during elite alpine skiing are not related to corresponding asymmetries in muscular strength. Although our elite athletes exhibited relatively small inter-limb asymmetries in strength, their asymmetries in GRF on-snow were relatively large.

Imaging cortical multiple sclerosis lesions with ultra-high field MRI.

BACKGROUND: Cortical lesions are abundant in multiple sclerosis (MS), yet difficult to visualize in vivo. Ultra-high field (UHF) MRI at 7 T and above provides technological advances suited to optimize the detection of cortical lesions in MS. PURPOSE: To provide a narrative and quantitative systematic review of the literature on UHF MRI of cortical lesions in MS. METHODS: A systematic search of all literature on UHF MRI of cortical lesions in MS published before September 2020. Quantitative outcome measures included cortical lesion numbers reported using 3 T and 7 T MRI and between 7 T MRI sequences, along with sensitivity of UHF MRI towards cortical lesions verified by histopathology. RESULTS: 7 T MRI detected on average 52 ± 26% (mean ± 95% confidence interval) more cortical lesions than the best performing image contrast at 3 T, with the largest increase in type II-IV intracortical lesion detection. Across all studies, the mean cortical lesion number was 17 ± 6 per patient. In progressive MS cohorts, approximately four times more cortical lesions were reported than in CIS/early RRMS, and RRMS. Yet, there was no difference in lesion type ratio between these MS subtypes. Furthermore, superiority of one MRI sequence over another could not be established from available data. Post-mortem lesion detection with UHF MRI agreed only modestly with pathological examinations. Mean pro- and retrospective sensitivity was 33 ± 6% and 71 ± 10%, respectively, with the highest sensitivity towards type I and type IV lesions. CONCLUSION: UHF MRI improves cortical lesion detection in MS considerably compared to 3 T MRI, particularly for type II-IV lesions. Despite modest sensitivity, 7 T MRI is still capable of visualizing all aspects of cortical lesion pathology and could potentially aid clinicians in diagnosing and monitoring MS, and progressive MS in particular. However, standardization of acquisition and segmentation protocols is needed.

Real-time predictions of seabird distribution improve oil spill risk assessments.

Current knowledge of the distribution of sensitive seabirds is inadequate to safeguard seabird populations from impacts of oil spills in the Arctic. This gap is mainly driven by the fact that statistical models applied to survey data are coarse-scale and static with limited documentation of the distributional dynamics and patchiness of seabirds relevant to risk assessments related to oil spills. This paper describes a dynamic modelling framework solution for prediction of fine-scale densities and movements of seabirds in close-to-real time using fully integrated 3-D hydrodynamic models, dynamic habitat suitability models and agent-based models. The modelling framework has been developed and validated for the swimming migration of Brünnich's Guillemot Uria lomvia in the Barents Sea. The results document that the distributional dynamics of Brünnich's Guillemot and other seabird species to a large degree can be simulated with in-situ state variables and patterns reflecting the physical meteorology and oceanography and habitat suitability.