A machine learning analysis of a "normal-like" IDH-WT diffuse glioma transcriptomic subgroup associated with prolonged survival reveals novel immune and neurotransmitter-related actionable targets.

BACKGROUND: Classification of primary central nervous system tumors according to the World Health Organization guidelines follows the integration of histologic interpretation with molecular information and aims at providing the most precise prognosis and optimal patient management. According to the cIMPACT-NOW update 3, diffuse isocitrate dehydrogenase-wild type (IDH-WT) gliomas should be graded as grade IV glioblastomas (GBM) if they possess one or more of the following molecular markers that predict aggressive clinical course: EGFR amplification, TERT promoter mutation, and whole-chromosome 7 gain combined with chromosome 10 loss. METHODS: The Cancer Genome Atlas (TCGA) glioma expression datasets were reanalyzed in order to identify novel tumor subcategories which would be considered as GBM-equivalents with the current diagnostic algorithm. Unsupervised clustering allowed the identification of previously unrecognized transcriptomic subcategories. A supervised machine learning algorithm (k-nearest neighbor model) was also used to identify gene signatures specific to some of these subcategories. RESULTS: We identified 14 IDH-WT infiltrating gliomas displaying a "normal-like" (NL) transcriptomic profile associated with a longer survival. Genes such as C5AR1 (complement receptor), SLC32A1 (vesicular gamma-aminobutyric acid transporter), MSR1 (or CD204, scavenger receptor A), and SYT5 (synaptotagmin 5) were differentially expressed and comprised in gene signatures specific to NL IDH-WT gliomas which were validated further using the Chinese Glioma Genome Atlas datasets. These gene signatures showed high discriminative power and correlation with survival. CONCLUSION: NL IDH-WT gliomas represent an infiltrating glioma subcategory with a superior prognosis which can only be detected using genome-wide analysis. Differential expression of genes potentially involved in immune checkpoint and amino acid signaling pathways is providing insight into mechanisms of gliomagenesis and could pave the way to novel treatment targets for infiltrating gliomas.

Acute lumbosacral nerve stimulation does not affect anorectal motor function in a rodent model.

BACKGROUND: Sacral nerve stimulation has become a first line treatment for fecal incontinence, however, its effect on the motor function of the anorectum is uncertain. The aim of this study was to apply acute lumbosacral nerve stimulation in an animal model and to determine its effect on the external and internal anal sphincter forces, the rectoanal inhibitory and excitatory reflexes, and the slow wave frequency of the internal anal sphincter. METHODS: Lumbosacral nerve stimulation was applied to 16 nulliparous female rats. A novel in vivo preparation was designed to allow simultaneous monitoring of external and internal anal sphincter forces. The effect of rectal distension on the two anal sphincters was also studied. KEY RESULTS: Lumbosacral nerve stimulation delivered at either S1 or L6 in rodents did not affect sphincter forces, rectoanal reflexes or slow wave frequency of anal canal smooth muscle. CONCLUSIONS & INFERENCES: The absence of effect on the motor pathways of continence suggests that the mechanism of action is predominantly on sensory feedback mechanisms from the anorectum, thereby increasing cortical awareness of the pelvic floor.

Pilot study trialling a new ambulatory method for the clinical assessment of regional gastrointestinal transit using multiple electromagnetic capsules.

BACKGROUND: Gastrointestinal (GI) motor disorders often involve several regions of the GI tract. Therefore, easy and safe assessment of whole gut and regional motility is valuable for more precise diagnosis. 3D-Transit is a novel method for ambulatory evaluation of total and regional gastrointestinal transit times (GITT) based on the anatomical localization of ingestible electromagnetic capsules. The main purpose of this study was to test the performance of the 3D-Transit system. METHODS: Twenty healthy volunteers each ingested three electromagnetic capsules over a period of two consecutive days. Standard radio-opaque markers (ROM) were also ingested to assess the agreement between total GITT obtained with both methods. KEY RESULTS: Investigations were well-tolerated and three capsules could be tracked simultaneously with minimal data loss (Capsule 1: median: 0.2% of time (range 0-25.3%). Region specific contraction patterns were identified and used for computation of total and regional GITT in all subjects. Inter-observer agreement was 100% for total GITT (median variation 0%) but less for regional GITT. Day-to-day and diurnal variations were significant for total and regional GITT. Total GITT assessed by 3D-Transit capsules were moderately well-correlated to those assessed with standard ROM (Spearman's rho = 0.7). CONCLUSIONS & INFERENCES: 3D-transit is a well-tolerated and minimal invasive ambulatory method for assessment of GI motility. By providing both total and regional transit times, the 3D-Transit system holds great promise for future clinical studies of GI function in health and disease.

Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.

BACKGROUND: Disorders of gastrointestinal (GI) transit and motility are common, and cause either delayed or accelerated transit through the stomach, small intestine or colon, and affect one or more regions. Assessment of regional and/or whole gut transit times can provide direct measurements and diagnostic information to explain the cause of symptoms, and plan therapy. PURPOSE: Recently, several newer diagnostic tools have become available. The American and European Neurogastroenterology and Motility Societies undertook this review to provide guidelines on the indications and optimal methods for the use of transit measurements in clinical practice. This was based on evidence of validation including performance characteristics, clinical significance, and strengths of various techniques. The tests include measurements of: gastric emptying with scintigraphy, wireless motility capsule, and (13)C breath tests; small bowel transit with breath tests, scintigraphy, and wireless motility capsule; and colonic transit with radioopaque markers, wireless motility capsule, and scintigraphy. Based on the evidence, consensus recommendations are provided for each technique and for the evaluations of regional and whole gut transit. In summary, tests of gastrointestinal transit are available and useful in the evaluation of patients with symptoms suggestive of gastrointestinal dysmotility, since they can provide objective diagnosis and a rational approach to patient management.

Predicting the subcellular localization of viral proteins within a mammalian host cell.

BACKGROUND: The bioinformatic prediction of protein subcellular localization has been extensively studied for prokaryotic and eukaryotic organisms. However, this is not the case for viruses whose proteins are often involved in extensive interactions at various subcellular localizations with host proteins. RESULTS: Here, we investigate the extent of utilization of human cellular localization mechanisms by viral proteins and we demonstrate that appropriate eukaryotic subcellular localization predictors can be used to predict viral protein localization within the host cell. CONCLUSION: Such predictions provide a method to rapidly annotate viral proteomes with subcellular localization information. They are likely to have widespread applications both in the study of the functions of viral proteins in the host cell and in the design of antiviral drugs.

Perceptions and practices of registered nurses regarding pastoral care and the spiritual need of hospital patients.

Reports the findings of a questionnaire survey designed to examine the impact of pastoral care on patient care and job satisfaction of registered nurses (N-280) employed in a metropolitan hospital. Suggests that educational strategies be explored as a way of broadening the perspectives of nurses regarding reasons for consulting pastoral care departments.

Isometric exercise training lowers resting blood pressure.

Both rhythmic and "resistive" (weight lifting) exercise training can produce modest decreases in resting blood pressure. The next logical point along an exercise continuum consisting of different proportions of rhythmic and isometric efforts is a strictly isometric effort. The purpose of these studies was to assess the effects of isometric, handgrip exercise training on resting blood pressure. To avoid the extreme pressor responses elicited by fatiguing isometric efforts, the isometric exercise training used in this study consisted of brief handgrip contractions separated by rest periods. Modest repeated rises in systolic and diastolic pressures therefore served as the putative stimuli for training adaptations in resting blood pressures. Human subjects in study 1 trained with four, 2-min isometric handgrip contractions with 3-min rests between contractions. The intensity of the contractions was equal to 30% of their maximal effort for each day. The bouts of isometric exercise were performed three times per week for 8 wk. Study 2 training consisted of four contractions of 50% of maximum effort held for a duration of 45 s with 1-min rests. These were performed 5 d.wk-1 for 5 wk. In Study 1, all eight trained subjects had a significant decline in both systolic and diastolic resting blood pressures, with group averages of 12.5 and 14.9 mm Hg, respectively. Seven matched control subjects who did not train had no change in resting pressures. In study 2, subjects were trained in their home or workplace and experienced significant mean declines in resting systolic and diastolic pressures of 9.5 and 8.9 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Group differences and individual classification accuracy associated with letter/word oddity problems.

The ability of 27 pairs of mildly mentally retarded and normally achieving 6- through 8-year-old students to apply an oddity rule to an experimental set of letter and word oddity problems was assessed. The mildly retarded group evidenced a markedly lower level of performance on all five experimental oddity problems, but they did evidence successful generalization to oddity arrays that visually were very different from those used in training. High levels (greater than 90%) of sensitivity, specificity, positive predictive accuracy, and negative predictive accuracy were observed using only six cards. Only slightly lower (greater than or equal to 85%) values were obtained when using a cut-off score. This subset of six cards is, therefore, an excellent candidate for inclusion in a cognitive preschool screening test being developed for the early detection of children with mild mental retardation.

Classification of normally achieving and mildly mentally retarded students on the basis of their oddity transfer performance.

Forty mildly retarded, 6- through 9-year-old children selected from educable mentally retarded (EMR) classes and 40 normally achieving students of the same age were pretrained on the oddity solution and then given eight different, six-trial oddity transfer problems. A higher level of transfer was associated with the older (8- and 9-year-olds) and with the normally achieving students. The students' performance on the oddity transfer trials was used to classify them into their two respective groups. High levels of classification accuracy were observed in the discriminant function analyses. On both the group comparison and the individual student classifications, all eight oddity types were sensitive to differences between the normally achieving and mildly retarded grade school students.

Perceptual and conceptual variants of the oddity task as a predictor of learning disability.

This paper compares LD and non-LD peers on eight variants of the oddity task. This study is part of a larger programmatic research effort aimed at the development of a screening test to detect preschool children who currently pass existing screening tests but, nonetheless, subsequently experience school failure. The theoretical orientation of this approach is to assess active, ongoing cognitive processing ability. The oddity task, which can be structured to assess such processing ability, was evaluated in the present study as a potential component of this screening test. Consistent with a priori predictions, the data resulted in strong group and developmental differences. Oddity performance increased over age, with the non-LD children performing consistently better than their LD peers at each age. Perceptual and conceptual factors were manipulated across the oddity variations, and both factors contributed to group differences. These results were discussed in relationship to early diagnosis and prognosis for learning disabilities that might result from deficiencies in abstract processing ability.