Uncertainty Estimation in Classification of MGNT Using Radiogenomics for Glioblastoma Patients

Glioblastoma Multiforme (GBM) is one of the most malignant brain tumors among all high-grade brain cancers. Temozolomide (TMZ) is the first-line chemotherapeutic regimen for glioblastoma patients. The methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) gene is a prognostic biomarker for tumor sensitivity to TMZ chemotherapy. However, the standardized procedure for assessing the methylation status of MGMT is an invasive surgical biopsy, and accuracy is susceptible to resection sample and heterogeneity of the tumor. Recently, radio-genomics which associates radiological image phenotype with genetic or molecular mutations has shown promise in the non-invasive assessment of radiotherapeutic treatment. This study proposes a machine-learning framework for MGMT classification with uncertainty analysis utilizing imaging features extracted from multimodal magnetic resonance imaging (mMRI). The imaging features include conventional texture, volumetric, and sophisticated fractal, and multi-resolution fractal texture features. The proposed method is evaluated with publicly available BraTS-TCIA-GBM pre-operative scans and TCGA datasets with 114 patients. The experiment with 10-fold cross-validation suggests that the fractal and multi-resolution fractal texture features offer an improved prediction of MGMT status. The uncertainty analysis using an ensemble of Stochastic Gradient Langevin Boosting models along with multi-resolution fractal features offers an accuracy of 71.74% and area under the curve of 0.76. Finally, analysis shows that our proposed method with uncertainty analysis offers improved predictive performance when compared with different well-known methods in the literature

Automatic detection of cognitive impairment with virtual reality

Cognitive impairment features in neuropsychiatric conditions and when undiagnosed can have a severe impact on the affected individual's safety and ability to perform daily tasks. Virtual Reality (VR) systems are increasingly being explored for the recognition, diagnosis and treatment of cognitive impairment. In this paper, we describe novel VR-derived measures of cognitive performance and show their correspondence with clinically-validated cognitive performance measures. We use an immersive VR environment called VStore where participants complete a simulated supermarket shopping task. People with psychosis (k=26) and non-patient controls (k=128) participated in the study, spanning ages 20-79 years. The individuals were split into two cohorts, a homogeneous non-patient cohort (k=99 non-patient participants) and a heterogeneous cohort (k=26 patients, k=29 non-patient participants). Participants' spatio-temporal behaviour in VStore is used to extract four features, namely, route optimality score, proportional distance score, execution error score, and hesitation score using the Traveling Salesman Problem and explore-exploit decision mathematics. These extracted features are mapped to seven validated cognitive performance scores, via linear regression models. The most statistically important feature is found to be the hesitation score. When combined with the remaining extracted features, the multiple linear regression model resulted in statistically significant results with R2 = 0.369, F-Stat = 7.158, p(F-Stat) = 0.000128

Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK)

BACKGROUND: Numerous studies have implicated spinal extracellular signal-regulated kinases (ERKs) as mediators of nociceptive plasticity. These studies have utilized pharmacological inhibition of MEK to demonstrate a role for ERK signaling in pain, but this approach cannot distinguish between effects of ERK in neuronal and non-neuronal cells. The present studies were undertaken to test the specific role of neuronal ERK in formalin-induced inflammatory pain. Dominant negative MEK (DN MEK) mutant mice in which MEK function is suppressed exclusively in neurons were tested in the formalin model of inflammatory pain. RESULTS: Formalin-induced second phase spontaneous pain behaviors as well as thermal hyperalgesia measured 1 – 3 hours post-formalin were significantly reduced in the DN MEK mice when compared to their wild type littermate controls. In addition, spinal ERK phosphorylation following formalin injection was significantly reduced in the DN MEK mice. This was not due to a reduction of the number of unmyelinated fibers in the periphery, since these were almost double the number observed in wild type controls. Further examination of the effects of suppression of MEK function on a downstream target of ERK phosphorylation, the A-type potassium channel, showed that the ERK-dependent modulation of the A-type currents is significantly reduced in neurons from DN MEK mice compared to littermate wild type controls. CONCLUSION: Our results demonstrate that the neuronal MEK-ERK pathway is indeed an important intracellular cascade that is associated with formalin-induced inflammatory pain and thermal hyperalgesia

Genetic Targeting of ERK1 Suggests a Predominant Role for ERK2 in Murine Pain Models

The extracellular signal-regulated kinase (ERK) isoforms, ERK1 and ERK2, are believed to be key signaling molecules in nociception and nociceptive sensitization. Studies utilizing inhibitors targeting the shared ERK1/2 upstream activator, mitogen-activated protein kinase kinase (MEK), and transgenic mice expressing a dominant negative form of MEK have established the importance of ERK1/2 signaling. However, these techniques do not discriminate between ERK1 and ERK2. To dissect the function of each isoform in pain, we utilized mice with a targeted genetic deletion of ERK1 (ERK1 KO) to test the hypothesis that ERK1 is required for behavioral sensitization in rodent pain models. Despite activation (phosphorylation) of ERK1 following acute noxious stimulation and in models of chronic pain, we found that ERK1 was not required for formalin-induced spontaneous behaviors, complete Freund’s adjuvant-induced heat and mechanical hypersensitivity, and spared nerve injury-induced mechanical hypersensitivity. However, ERK1 deletion did delay formalin-induced long-term heat hypersensitivity, without affecting formalin-induced mechanical hypersensitivity, suggesting that ERK1 partially shapes long-term responses to formalin. Interestingly, ERK1 deletion resulted in elevated basal ERK2 phosphorylation. However, this did not appear to influence nociceptive processing, since inflammation-induced ERK2 phosphorylation and pERK1/2 immunoreactivity in spinal cord were not elevated in ERK1 KO mice. Additionally, systemic MEK inhibition with SL327 attenuated formalin-induced spontaneous behaviors similarly in WT and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1. Taken together, these results suggest that ERK1 plays a limited role in nociceptive sensitization and supports a predominant role for ERK2 in these processes

N-acetyl-B-D-glucosaminidase and inflammatory response after cardiopulmonary bypass

OBJECTIVE: To determine the changes in activity of plasma N-acetyl-beta-D-glucosaminidase, a marker for inflammation as well as renal, pulmonary and cardiac damage and proinflammatory cytokines in patients undergoing coronary artery bypass grafting and find out the relationship between their plasma levels with clinical outcome of patients. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: The Aga Khan University, Karachi, from January to June 2003. PATIENTS AND METHODS: N-acetyl-beta-D-glucosaminidase (NAG) activity and concentrations of tumor necrosis factor-alpha of (TNFalpha), interleukin 6 (IL-6), interleukin 8 (IL8) and granulocyte-macrophage colony stimulating factor (GM-CSF) were monitored in plasma samples of 12 angina patients undergoing coronary artery bypass grafting (CABG), before, immediately after and 5 days post-surgical procedure. Serum glucose concentrations were also monitored in those patients. Patient\u27s clinical condition was monitored during this time period. RESULTS: No significant increase was observed in plasma NAG activity (a marker of inflammation) or in plasma levels of TNFalpha, IL-6, IL-8 and GM-CSF immediately after surgery, indicating that cardiopulmonary bypass itself does not produce any significant amount of inflammation immediately after CABG. However, 5 days post surgery, there was a significant increase in plasma NAG activity (p=0.001), TNFalpha (p=0.047) and GM-CSF (p=0.045). There was no relationship between plasma NAG activity and clinical outcome because various parameters of renal, cardiac and pulmonary functions, though slightly affected, remained within the normal limits. CONCLUSION: Increased levels of NAG and TNFalpha did not affect clinical outcome. However, data suggest that NAG can be a potential marker for inflammation and end organ damage following CABG. An increase in GM-CSF on day 5 following CABG indicates enhanced body\u27s defense mechanism against infection

Factors associated with glycaemic control among type 2 diabetes mellitus patients

Background: Type 2 diabetes mellitus has become one of the most serious global health problems recently. The Malaysian National Diabetes Registry has reported that 76.2% of the population have poor glycaemic control (HbA1c ≥6.5%). Thus, the objective of this study is to determine the association between sociodemographic and medical profiles with glycaemic control among type 2 diabetes mellitus patients in five health clinics in the Tampin district. Materials and Methods: A cross sectional study was conducted in five health clinics in the Tampin district, Negeri Sembilan, Malaysia. Three hundred and twenty four type 2 diabetes mellitus patients participated in this study. A face-to face interview was conducted with each respondent using validated questionnaire. Descriptive analyses, such as the chi square test, were performed using the Statistical Packages for Social Sciences version 22 software. Results: The response rate was 90%. The percentage of poor glycaemic control was 66.4%. They were associated with age (χ²=10.405, p 0.006), marital status (χ ²=5.718, p 0.017), and education status (χ²=7.312, p 0.026). In addition, types of medication intake (χ²=18.058, p=<0.001), family history (χ²=7.234, p 0.007), and co-morbidities (χ²=5.718, p 0.017) are also associated with the percentage. Conclusion: The majority of the respondents of this study had poor glycaemic control. The factors that contribute to the poor glycaemic control are among respondents who are: of older age (≥65 years); single/widowed/separated/divorced; of non-formal education; on insulin alone / combination of oral agent and insulin; no family history; and do not experience co-morbidities. For the future wellbeing of all type 2 diabetes mellitus patients, a good glycaemic control is important. Therefore, plans with appropriate significance on early preventive measures to diabetic treatment need to be strengthened in order to boost quality of life among type 2 diabetes mellitus patients

The appendage role of insect disco genes and possible implications on the evolution of the maggot larval form

AbstractThough initially identified as necessary for neural migration, Disconnected and its partially redundant paralog, Disco-related, are required for proper head segment identity during Drosophila embryogenesis. Here, we present evidence that these genes are also required for proper ventral appendage development during development of the adult fly, where they specify medial to distal appendage development. Cells lacking the disco genes cannot contribute to the medial and distal portions of ventral appendages. Further, ectopic disco transforms dorsal appendages toward ventral fates; in wing discs, the medial and distal leg development pathways are activated. Interestingly, this appendage role is conserved in the red flour beetle, Tribolium (where legs develop during embryogenesis), yet in the beetle we found no evidence for a head segmentation role. The lack of an embryonic head specification role in Tribolium could be interpreted as a loss of the head segmentation function in Tribolium or gain of this function during evolution of flies. However, we suggest an alternative explanation. We propose that the disco genes always function as appendage factors, but their appendage nature is masked during Drosophila embryogenesis due to the reduction of limb fields in the maggot style Drosophila larva