Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol.

BACKGROUND: There is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum. METHODS/DESIGN: The study is an randomised open trial with two parallel groups to assess whether, for children undergoing intensive care in the UK aged <or= 16 years who are ventilated, have an arterial line in-situ and are receiving vasoactive support following injury, major surgery or in association with critical illness in whom it is anticipated such treatment will be required to continue for at least 12 hours, tight control will increase the numbers of days alive and free of mechanical ventilation at 30 days, and lead to improvement in a range of complications associated with intensive care treatment and be cost effective. Children in the tight control group will receive insulin by intravenous infusion titrated to maintain BG between 4 and 7.0 mmol/l. Children in the control group will be treated according to a standard current approach to BG management. Children will be followed up to determine vital status and healthcare resources usage between discharge and 12 months post-randomisation. Information regarding overall health status, global neurological outcome, attention and behavioural status will be sought from a subgroup with traumatic brain injury (TBI). A difference of 2 days in the number of ventilator-free days within the first 30 days post-randomisation is considered clinically important. Conservatively assuming a standard deviation of a week across both trial arms, a type I error of 1% (2-sided test), and allowing for non-compliance, a total sample size of 1000 patients would have 90% power to detect this difference. To detect effect differences between cardiac and non-cardiac patients, a target sample size of 1500 is required. An economic evaluation will assess whether the costs of achieving tight BG control are justified by subsequent reductions in hospitalisation costs. DISCUSSION: The relevance of tight glycaemic control in this population needs to be assessed formally before being accepted into standard practice

A feature selection method for classification within functional genomics experiments based on the proportional overlapping score

Background: Microarray technology, as well as other functional genomics experiments, allow simultaneous measurements of thousands of genes within each sample. Both the prediction accuracy and interpretability of a classifier could be enhanced by performing the classification based only on selected discriminative genes. We propose a statistical method for selecting genes based on overlapping analysis of expression data across classes. This method results in a novel measure, called proportional overlapping score (POS), of a feature's relevance to a classification task.Results: We apply POS, along-with four widely used gene selection methods, to several benchmark gene expression datasets. The experimental results of classification error rates computed using the Random Forest, k Nearest Neighbor and Support Vector Machine classifiers show that POS achieves a better performance.Conclusions: A novel gene selection method, POS, is proposed. POS analyzes the expressions overlap across classes taking into account the proportions of overlapping samples. It robustly defines a mask for each gene that allows it to minimize the effect of expression outliers. The constructed masks along-with a novel gene score are exploited to produce the selected subset of genes

Novel roles for class II Phosphoinositide 3-Kinase C2 beta in signalling pathways involved in prostate cancer cell invasion

Phosphoinositide 3-kinases (PI3Ks) regulate several cellular functions such as proliferation, growth, survival and migration. The eight PI3K isoforms are grouped into three classes and the three enzymes belonging to the class II subfamily (PI3K-C2a, ß and ?) are the least investigated amongst all PI3Ks. Interest on these isoforms has been recently fuelled by the identification of specific physiological roles for class II PI3Ks and by accumulating evidence indicating their involvement in human diseases. While it is now established that these isoforms can regulate distinct cellular functions compared to other PI3Ks, there is still a limited understanding of the signalling pathways that can be specifically regulated by class II PI3Ks. Here we show that PI3K-C2ß regulates mitogen-activated protein kinase kinase (MEK1/2) and extracellular signal-regulated kinase (ERK1/2) activation in prostate cancer (PCa) cells. We further demonstrate that MEK/ERK and PI3K-C2ß are required for PCa cell invasion but not proliferation. In addition we show that PI3K-C2ß but not MEK/ERK regulates PCa cell migration as well as expression of the transcription factor Slug. These data identify novel signalling pathways specifically regulated by PI3K-C2ß and they further identify this enzyme as a key regulator of PCa cell migration and invasion

Geochemistry in the modern soil survey program

Elemental analysis has played an important role in the characterization of soils since inception of the soil survey in the US. Recent efforts in analysis of trace and major elements (geochemistry) have provided necessary data to soil survey users in a variety of areas. The first part of this paper provides a brief overview of elemental sources, forms, mobility, and bioavailability; critical aspects important to users of soil survey geochemical data for appropriate use and interpretations. Examples are provided based on data gathered as part of the US soil survey program. The second part addresses the organization of sample collection in soil survey and how soil surveys are ideally suited as a sampling strategy for soil geochemical studies. Geochemistry is functional in characterization of soil types, determining soil processes, ecological evaluation, or issues related to soil quality and health, such as evaluating suitability of soils for urban or agricultural land use. Applications of geochemistry are on-going across the US and are documented herein. This analytical direction of soil survey complements historic efforts of the National Cooperative Soil Survey Program and addresses the increasing need of soil survey users for data that assists in understanding the influence of human activities on soil properties

Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review.

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases

Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations

A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93–07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP-ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL

Functional Cohesion of Gene Sets Determined by Latent Semantic Indexing of PubMed Abstracts

High-throughput genomic technologies enable researchers to identify genes that are co-regulated with respect to specific experimental conditions. Numerous statistical approaches have been developed to identify differentially expressed genes. Because each approach can produce distinct gene sets, it is difficult for biologists to determine which statistical approach yields biologically relevant gene sets and is appropriate for their study. To address this issue, we implemented Latent Semantic Indexing (LSI) to determine the functional coherence of gene sets. An LSI model was built using over 1 million Medline abstracts for over 20,000 mouse and human genes annotated in Entrez Gene. The gene-to-gene LSI-derived similarities were used to calculate a literature cohesion p-value (LPv) for a given gene set using a Fisher's exact test. We tested this method against genes in more than 6,000 functional pathways annotated in Gene Ontology (GO) and found that approximately 75% of gene sets in GO biological process category and 90% of the gene sets in GO molecular function and cellular component categories were functionally cohesive (LPv<0.05). These results indicate that the LPv methodology is both robust and accurate. Application of this method to previously published microarray datasets demonstrated that LPv can be helpful in selecting the appropriate feature extraction methods. To enable real-time calculation of LPv for mouse or human gene sets, we developed a web tool called Gene-set Cohesion Analysis Tool (GCAT). GCAT can complement other gene set enrichment approaches by determining the overall functional cohesion of data sets, taking into account both explicit and implicit gene interactions reported in the biomedical literature

Comparative study of laparoscopic ventral mesh rectopexy versus perineal stapler resection for external full-thickness rectal prolapse in elderly patients: enhanced outcomes and reduced recurrence rates—a retrospective cohort study

Background: In elderly patients with external full-thickness rectal prolapse (EFTRP), the exact differences in postoperative recurrence and functional outcomes between laparoscopic ventral mesh rectopexy (LVMR) and perineal stapler resection (PSR) have not yet been investigated. Methods: We conducted a retrospective multicenter study on 330 elderly patients divided into LVMR group (n = 250) and PSR (n = 80) from April 2012 to April 2019. Patients were evaluated before and after surgery by Wexner incontinence scale, Altomare constipation scale, and patient satisfaction questionnaire. The primary outcomes were incidence and risk factors for EFTRP recurrence. Secondary outcomes were postoperative incontinence, constipation, and patient satisfaction. Results: LVMR was associated with fewer postoperative complications (p &lt; 0.001), lower prolapse recurrence (p &lt; 0.001), lower Wexner incontinence score (p = 0.03), and lower Altomare’s score (p = 0.047). Furthermore, LVMR demonstrated a significantly higher surgery–recurrence interval (p &lt; 0.001), incontinence improvement (p = 0.019), and patient satisfaction (p &lt; 0.001) than PSR. Three and 13 patients developed new symptoms in LVMR and PSR, respectively. The predictors for prolapse recurrence were LVMR (associated with 93% risk reduction of recurrence, OR 0.067, 95% CI 0.03–0.347, p = 0.001), symptom duration (prolonged duration was associated with an increased risk of recurrence, OR 1.131, 95% CI 1.036–1.236, p = 0.006), and length of prolapse (increased length was associated with a high recurrence risk (OR = 1.407, 95% CI = 1.197–1.655, p &lt; 0.001). Conclusions: LVMR is safe for EFTRP treatment in elderly patients with low recurrence, and improved postoperative functional outcomes

Outcomes of allogeneic stem cell transplant in adult Philadelphia negative acute lymphoblastic leukemia patients treated with the pediatric-inspired GIMEMA 1913 protocol. A Campus ALL study

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the best consolidative treatment for high-risk acute lymphoblastic leukemia (ALL). The Campus ALL study group analyzed the clinical outcomes of patients treated in the real-life with the pediatric-inspired and minimal/measurable residual disease (MRD)-oriented GIMEMA LAL1913 protocol who underwent alloHSCT. Key factors impacting on outcomes were MRD and remission status (1st complete remission vs 2nd complete remission) at transplant. MRD positivity was associated with poorer outcomes, with 3-year overall survival (OS) and disease-free survival (DFS) of 47% and 41% in MRD-positive patients compared to 80% and 70% in MRD-negative patients. Additionally, MRD negativity was associated with improved outcomes also for patients in 2nd complete remission with 3-year OS and DFS rates of 60% and 56%, respectively, compared to only 13% for both outcomes in MRD-positive cases. Patients older than 55 years showed survival rates comparable to younger patients, despite having a slightly higher non-relapse mortality, which remained below 20% at 3 years. These findings underscore the crucial role of alloHSCT in high-risk ALL and emphasize the importance of an early accurate disease risk allocation. The adverse outcome observed with MRD positivity advocates for early pre-transplant intervention with immunotherapy, whenever possible