Robust Machine Learning-Based Correction on Automatic Segmentation of the Cerebellum and Brainstem.

Automated segmentation is a useful method for studying large brain structures such as the cerebellum and brainstem. However, automated segmentation may lead to inaccuracy and/or undesirable boundary. The goal of the present study was to investigate whether SegAdapter, a machine learning-based method, is useful for automatically correcting large segmentation errors and disagreement in anatomical definition. We further assessed the robustness of the method in handling size of training set, differences in head coil usage, and amount of brain atrophy. High resolution T1-weighted images were acquired from 30 healthy controls scanned with either an 8-channel or 32-channel head coil. Ten patients, who suffered from brain atrophy because of fragile X-associated tremor/ataxia syndrome, were scanned using the 32-channel head coil. The initial segmentations of the cerebellum and brainstem were generated automatically using Freesurfer. Subsequently, Freesurfer's segmentations were both manually corrected to serve as the gold standard and automatically corrected by SegAdapter. Using only 5 scans in the training set, spatial overlap with manual segmentation in Dice coefficient improved significantly from 0.956 (for Freesurfer segmentation) to 0.978 (for SegAdapter-corrected segmentation) for the cerebellum and from 0.821 to 0.954 for the brainstem. Reducing the training set size to 2 scans only decreased the Dice coefficient ≤0.002 for the cerebellum and ≤ 0.005 for the brainstem compared to the use of training set size of 5 scans in corrective learning. The method was also robust in handling differences between the training set and the test set in head coil usage and the amount of brain atrophy, which reduced spatial overlap only by <0.01. These results suggest that the combination of automated segmentation and corrective learning provides a valuable method for accurate and efficient segmentation of the cerebellum and brainstem, particularly in large-scale neuroimaging studies, and potentially for segmenting other neural regions as well

Clinical and molecular correlates in fragile X premutation females.

The prevalence of the fragile X premutation (55-200 CGG repeats) among the general population is relatively high, but there remains a lack of clear understanding of the links between molecular biomarkers and clinical outcomes. In this study we investigated the correlations between molecular measures (CGG repeat size, FMR1 mRNA, FMRP expression levels, and methylation status at the promoter region and in FREE2 site) and clinical phenotypes (anxiety, obsessive compulsive symptoms, depression and executive function deficits) in 36 adult premutation female carriers and compared to 24 normal control subjects. Premutation carriers reported higher levels of obsessive compulsive symptoms, depression, and anxiety, but demonstrated no significant deficits in global cognitive functions or executive function compared to the control group. Increased age in carriers was significantly associated with increased anxiety levels. As expected, FMR1 mRNA expression was significantly correlated with CGG repeat number. However, no significant correlations were observed between molecular (including epigenetic) measures and clinical phenotypes in this sample. Our study, albeit limited by the sample size, establishes the complexity of the mechanisms that link the FMR1 locus to the clinical phenotypes commonly observed in female carriers suggesting that other factors, including environment or additional genetic changes, may have an impact on the clinical phenotypes. However, it continues to emphasize the need for assessment and treatment of psychiatric problems in female premutation carriers

Core flexibility of a truncated metazoan mitochondrial tRNA

Secondary and tertiary structures of tRNAs are remarkably preserved from bacteria to humans, the notable exception being the mitochondrial (m) tRNAs of metazoans, which often deviate substantially from the canonical cloverleaf (secondary) or ‘L’-shaped (tertiary) structure. Many metazoan mtRNAs lack either the TψC (T) or dihydrouridine (D) loops of the canonical cloverleaf, which are known to confer structural rigidity to the folded structure. Thus, the absence of canonical TψC–D interactions likely results in greater dispersion of anticodon-acceptor interstem angle than for canonical tRNAs. To test this hypothesis, we have assessed the dispersion of the anticodon-acceptor angle for bovine mtRNASer(AGY), which lacks the canonical D arm and is thus incapable of forming stabilizing interarm interactions. Using the method of transient electric birefringence (TEB), and by changing the helical torsion angle between a core mtRNA bend and a second bend of known angle/rigidity, we have demonstrated that the core of mtRNASer(AGY) has substantially greater flexibility than its well-characterized canonical counterpart, yeast cytoplasmic tRNAPhe. These results suggest that increased flexibility, in addition to a more open interstem angle, would allow both noncanonical and canonical mtRNAs to utilize the same protein synthetic apparatus

Rapid Effective Trace-Back Capability Value in Reducing the Cost of a Foot and Mouth Disease Event

This study evaluates how the availability of animal tracing affects the cost of a hypothetical Foot and Mouth Disease (FMD) outbreak in the Texas High Plains using alternative tracing scenarios. To accomplish this objective, the AusSpread epidemic disease spread model (Ward et al., 2006) is used to simulate a High Plains FMD outbreak under different animal tracing possibilities. A simple economic costing module (Elbakidze, 2008) is used to determine the savings in terms of animal disease mitigation costs from rapid, effective trace-back. The savings from increased traceability are then be compared to the cost of a functional National Animal Identification System (NAIS). Initial results indicate that rapid, effective tracing reduces the overall cost of disease outbreaks and that the benefits per animal in terms of reduced cost of an outbreak more than outweigh the annualized cost per animal of implementing a NAIS. A value of time related to controlling an outbreak is estimated to have increased benefits from an identification system that incorporates a rapid response capability. We also find the level of benefits vary depending on the location of initial infection and whether or not welfare slaughter occurs.Traceability, Foot and Mouth Disease, Economics, Agricultural and Food Policy, Livestock Production/Industries,

Fragile X Premutation

Whereas full mutation CGG-repeat expansions (>200 repeats) of the fragile X gene (FMR1) give rise to the neurodevelopmental disorder, fragile X syndrome (FXS); smaller, ‘premutation’ expansions (55 to 200 repeats) are now gaining increasing recognition as the basis for a spectrum of clinical involvement, from neurodevelopmental problems; to mid-adult disorders, such as primary ovarian insufficiency and mood and psychiatric disorders; to the late-adult-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The premutation disorders are thought to arise through a molecular mechanism involving toxicity of the elevated levels of expanded CGG-repeat mRNA (‘RNA toxicity’), a process that is entirely distinct from the FMR1 protein-deficiency that gives rise to FXS. However, despite the importance of the spectrum of clinical disorders associated with the premutation, and a high prevalence rate (1 in 130 to 250 females and 1 in 250 to 810 males), relatively little attention has been paid to these disorders and there is a general lack of awareness among clinicians as to the distinction between the premutation disorders and FXS. To address this lack of awareness, an international conference on the premutation was held in Perugia, Italy, in June 2013. The conference covered the expanding range of clinical involvement, refinements of the assessments and tools for characterizing such involvement, and the rapidly expanding understanding of the pathogenic molecular and cellular mechanisms that give rise to the spectrum of involvement among premutation carriers. All of these advances support ongoing efforts to develop new targeted treatments for the premutation disorders. As an outgrowth of the meeting, papers were solicited from the conference attendees such that groups of scientists and clinicians would develop works that broadly covered the topics of the meeting. The following papers represent that effort

Effects of mavoglurant on visual attention and pupil reactivity while viewing photographs of faces in Fragile X Syndrome.

BackgroundNumerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). However multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder.MethodsWe evaluated social gaze behavior-a key phenotypic feature of the disorder-and sympathetic nervous system influence on pupil size using a previously-validated eye tracking paradigm as a biobehavioral probe, in 57 adolescent or adult patients with FXS at baseline and following three months of blinded treatment with one of three doses of mavoglurant or placebo, within the context of the AFQ056 RCTs.ResultsPatients with FXS treated with mavoglurant demonstrated increased total absolute looking time and number of fixations to the eye region while viewing human faces relative to baseline, and compared to those treated with placebo. In addition, patients had greater pupil reactivity to faces relative to baseline following mavoglurant treatment compared to placebo.DiscussionThe study shows that negative modulation of mGluR5 activity improves eye gaze behavior and alters sympathetically-driven reactivity to faces in patients with FXS, providing preliminary evidence of this drug's impact on behavior in humans with the disorder

Low efficacy of the combination artesunate plus amodiaquine for uncomplicated falciparum malaria among children under 5 years in Kailahun, Sierra Leone.

OBJECTIVE: In 2004, Sierra Leone adopted artesunate plus amodiaquine as first-line antimalarial treatment. We evaluated the efficacy of this combination in Kailahun, where a previous study had shown 70.2% efficacy of amodiaquine in monotherapy. METHODS: Method and outcome classification of the study complied with WHO guidelines. Children 6-59 months with uncomplicated malaria were followed-up for 28 days. PCR genotyping was used to distinguish recrudescence from reinfection. Reinfections were reclassified as cured. RESULTS: Of 172 children who were referred to the study clinic, 126 satisfied inclusion criteria and were enrolled. No early treatment failures were reported. The day 14, efficacy was 98.2% (95% CI: 93.8-99.8). Of 65 recurrent parasitaemias analysed by PCR, 17 were recrudescences. The PCR-adjusted day 28 efficacy was 84.5% (95% CI: 76.4-90.7). All true failures occurred in the last 8 days of follow-up. Of 110 children who completed the 28-day follow-up, 54 (49.1%) experienced a novel infection. CONCLUSION: The efficacy of this combination was disappointing. The high reinfection rate suggested little prophylactic effect. In Kailahun a more efficacious combination might be necessary in the future. The efficacy of AS + AQ needs to be monitored in Kailahun and in the other regions of Sierra Leone