Tensor electrical impedance myography identifies bulbardisease progression in amyotrophic lateral sclerosis

Objective Electrical impedance myography (EIM) is a promising biomarker for amyotrophic lateral sclerosis (ALS). A key issue is how best to utilise the complex high dimensional, multi-frequency data output by EIM to fully characterise the progression of disease. Methods Muscle volume conduction properties were obtained from EIM recordings of the tongue across three electrode configurations and 14 input frequencies (76 Hz–625 kHz). Analyses of individual frequencies, averaged EIM spectra and non-negative tensor factorisation were undertaken. Longitudinal data were collected from 28 patients and 17 healthy volunteers at 3-monthly intervals for a maximum of 9 months. EIM was evaluated against the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) bulbar sub-score, tongue strength and an overall bulbar disease burden score. Results Longitudinal changes to individual patient EIM spectra demonstrated complex shifts in the spectral shape. At a group level, a clear pattern emerged over time, characterised by an increase in centre frequency and general shift to the right of the spectral shape. Tensor factorisation reduced the spectral data from a total of 168 data points per participant per recording to a single value which captured the complexity of the longitudinal data and which we call tensor EIM (T-EIM). The absolute change in tensor EIM significantly increased within 3 months and continued to do so over the 9-month study duration. In a hypothetical clinical trial scenario tensor EIM required fewer participants (n = 64 at 50% treatment effect), than single frequency measures (n range 87–802) or ALSFRS-R bulbar subscore (n = 298). Conclusions Changes to tongue EIM spectra over time in ALS are complex. Tensor EIM captured and quantified disease progression and was more sensitive to changes than single frequency EIM measures and other biomarkers of bulbar disease. Significance Objective biomarkers for the assessment of bulbar disease in ALS are lacking. Tensor EIM enhances the biomarker potential of EIM data and can improve bulbar symptom monitoring in clinical trials

Tensor electrical impedance myography identifies clinically relevant features in amyotrophic lateral sclerosis

Objective. Electrical impedance myography (EIM) shows promise as an effective biomarker in amyotrophic lateral sclerosis (ALS). EIM applies multiple input frequencies to characterise muscle properties, often via multiple electrode configurations. Herein, we assess if non-negative tensor factorisation (NTF) can provide a framework for identifying clinically relevant features within a high dimensional EIM dataset. Approach. EIM data were recorded from the tongue of healthy and ALS diseased individuals. Resistivity and reactivity measurements were made for 14 frequencies, in three electrode configurations. This gives 84 (2 × 14 × 3) distinct data points per participant. NTF was applied to the dataset for dimensionality reduction, termed tensor EIM. Significance tests, symptom correlation and classification approaches were explored to compare NTF to using all raw data and feature selection. Main Results. Tensor EIM provides highly significant differentiation between healthy and ALS patients (p < 0.001, AUROC = 0.78). Similarly tensor EIM differentiates between mild and severe disease states (p < 0.001, AUROC = 0.75) and significantly correlates with symptoms (ρ = 0.7, p < 0.001). A trend of centre frequency shifting to the right was identified in diseased spectra, which is in line with the electrical changes expected following muscle atrophy. Significance. Tensor EIM provides clinically relevant metrics for identifying ALS-related muscle disease. This procedure has the advantage of using the whole spectral dataset, with reduced risk of overfitting. The process identifies spectral shapes specific to disease allowing for a deeper clinical interpretation

Multi-dimensional electrical impedance myography of the tongue as a potential biomarker for amyotrophic lateral sclerosis

Objective In amyotrophic lateral sclerosis (ALS) bulbar disease biomarkers are lacking. We evaluated a novel tongue electrical impedance myography (EIM) system, utilising both 2D and 3D electrode configurations for detection of tongue pathology. Methods Longitudinal multi-frequency phase angle spectra were recorded from 41 patients with ALS (baseline, 3 and 6 months) and 30 healthy volunteers (baseline and 6 months). ALS functional rating scale-revised (ALSFRS-R) data and quantitative tongue strength measurements were collected. EIM data were analysed for reliability (intra-class correlation coefficient; ICC) and differences between patients and volunteers ascertained using both univariate (Mann-Whitney U test) and multivariate techniques (feature selection and L2 norm). Results The device produced highly reliable data (pooled ICC: 0.836). Significant EIM differences were apparent between ALS patients and healthy volunteers (P<0.001). EIM data demonstrated a significant relationship to tongue strength and bulbar ALSFRS-R scores (P<0.015). The EIM recordings revealed a group level longitudinal change over 6 months and consistently identified patients in whom symptoms or tongue strength changed. Conclusions The novel EIM tongue system produces reliable data and can differentiate between healthy muscle and ALS-related disease. Significance Tongue EIM utilising multiple frequencies and electrode configurations has potential as a bulbar disease biomarker in ALS

Genetic variability among sorghum accessions for seed starch and stalk total sugar content

Sorghum (Sorghum bicolor (L.) Moench) is a staple food grain in many semi-arid and tropical areas of the world, notably in sub-Saharan Africa because of its adaptation to harsh environments. Among important biochemical components for sorghum for processors are the levels of starch (amylose and amylopectin) and total sugar contents. The aim of this study was to determine the genetic variation for total starch in the seed, its components and total sugar in the stalks of the sorghum accessions from Ethiopia and South Africa. Samples of 22 sorghum accessions were evaluated. Significant variations were observed in total starch (31.01 to 64.88 %), amylose (14.05 to 18.91 %), the amylose/amylopectin ratio (0.31 to 0.73) and total stalk sugar content (9.36 to 16.84 %). Multivariate analysis showed a wide genetic variation within and among germplasm accessions which could be used in the selection of parental lines for the improvement of traits of interest through breeding. The variation found among the sorghum accessions shows that an improved total starch and starch components and stalk sugar contents can be achieved through crossing these selected genotypes

Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

High-efficiency chlorine dioxide delignification. Summary of progress, April 1--June 30, 1998

The authors have been pursuing strategies for improving the efficiency of utilization and environmental performance of ClO{sub 2} in the delignification of kraft pulps. These strategies combine a pretreatment followed by ClO{sub 2} treatment under conditions selected to result in high efficiency, and a suitably altered alkaline extraction stage. In addition, a series of experiments was completed in which the authors compared the response to conventional D(EO) delignification of conventional kraft pulps and pulps from a laboratory simulation of Ahlstrom`s Lo-Solids{reg_sign} extended delignification (modified) process. These experiments were conducted over a range of kappa numbers for both pulping processes, and at high and low kappa factors. The results showed that the modified pulps were slightly easier to bleach in the conventional process, an observation which parallels the corresponding observation made earlier, when the same pulps were bleached with the Rapid D{sub 0} short-retention process. In other experiments, two sets of hardwood pulps of varied unbleached kappa number were subjected to determinations of their hexeneuronic acid contents. Pulps representing both conventional batch and extended (RDH) kraft pulping processes were included. Residual lignin and effluent structural analyses by NMR and gel permeation chromatography are continuing to generate data for the development of structure-bleachability relationships. Analysis of this data is in progress

Bien plus que des bananes: les reseaux de responsabilite sociale et les relations de travail dans l'industrie de la banane de la region colombienne d'Uraba

Cet article entend cerner la dynamique du changement intervenu dans les relations de travail et des mouvements sociaux qui l?accompagnent dans l?industrie de la banane en Colombie, et, plus particulièrement, dans la première nproductrice d?Urabá