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The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis as well as transcriptome data across 763 primary tumors. Characterization of CD271+ and CD271- cells by RNA sequencing revealed that these two subpopulations are molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling is upregulated in the CD271+ population and inhibiting this pathway reduced CD271 levels, stem/progenitor cell proliferation and cell survival as well as cell migration in vitro. Importantly, the MEK inhibitor selumetinib extends survival and reduces CD271 levels in vivo. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.
Introduction: Patients with chronic diseases are known to benefit from exercise. Such patients often visit the emergency department (ED). There are few studies examining prescribing exercise in the ED. We wished to study if exercise prescription in the ED is feasible and effective. Methods: In this pilot prospective block randomized trial, patients in the control group received routine care, whereas the intervention group received a combined written and verbal prescription for moderate exercise (150 minutes/week). Both groups were followed up by phone at 2 months. The primary outcome was achieving 150 min of exercise per week. Secondary outcomes included change in exercise, and differences in reported median weekly exercise. Comparisons were made by Mann-Whitney and Fishers tests (GraphPad). Results: Follow-up was completed for 22 patients (11 Control; 11 Intervention). Baseline reported median (with IQR) weekly exercise was similar between groups; Control 0(0-0)min; Intervention 0(0-45)min. There was no difference between groups for the primary outcome of 150 min/week at 2 months (Control 3/11; Intervention 4/11, RR 1.33 (95%CI 0.38-4.6;p=1.0). There was a significant increase in median exercise from baseline in both groups, but no difference between the groups (Control 75(10-225)min; Intervention 120(52.5-150)min;NS). 3 control patients actually received exercise prescription as part of routine care. A post-hoc comparison of patients receiving intervention vs. no intervention, revealed an increase in patients meeting the primary target of 150min/week (No intervention 0/8; Intervention 7/14, RR 2.0 (95%CI 1.2-3.4);p=0.023). Conclusion: Recruitment was feasible, however our study was underpowered to quantify an estimated effect size. As a significant proportion of the control group received the intervention (as part of standard care), any potential measurable effect was diluted. The improvement seen in patients receiving intervention and the increase in reported exercise in both groups (possible Hawthorne effect) suggests that exercise prescription for ED patients may be beneficial.
The morphology of englacial drainage networks and their temporal evolution are poorly characterised, particularly within cold ice masses. At present, direct observations of englacial channels are restricted in both spatial and temporal resolution. Through novel use of a terrestrial laser scanning (TLS) system, the interior geometry of an englacial channel in Austre Brøggerbreen, Svalbard, was reconstructed and mapped. Twenty-eight laser scan surveys were conducted in March 2016, capturing the glacier surface around a moulin entrance and the uppermost 122 m reach of the adjoining conduit. The resulting point clouds provide detailed 3-D visualisation of the channel with point accuracy of 6.54 mm, despite low (<60%) overall laser returns as a result of the physical and optical properties of the clean ice, snow, hoar frost and sediment surfaces forming the conduit interior. These point clouds are used to map the conduit morphology, enabling extraction of millimetre-to-centimetre scale geometric measurements. The conduit meanders at a depth of 48 m, with a sinuosity of 2.7, exhibiting teardrop shaped cross-section morphology. This improvement upon traditional surveying techniques demonstrates the potential of TLS as an investigative tool to elucidate the nature of glacier hydrological networks, through reconstruction of channel geometry and wall composition.
The principal method adopted for the soil phosphate analysis for the Shaugh Moor project was a slightly modified version of that published by Dick and Tabatabai (1977). This method involves extraction of soil phosphate by alkaline oxidation with Sodium hypobromite (NaOBr-NaOh). It has been calculated that this process extracts about 60-70% of total phosphate from soils such as those on Shaugh Moor (Ralph, pers comm). This was considered satisfactory foe the purposes of this project.
It is thought that this method has not been used before in archaeological survey work but it is suggested that the simplicity of the technique and the relatively high level of phosphate extraction might prove of value in future work.
One of the cornerstones in the development of a new feed rationing system for dairy cows must involve a reappraisal of both the concepts and ‘numbers’ adopted in defining the energy requirements for dairy cows. This is particularly important in the present scenario where increasingly high levels of animal output are being achieved from very different animal genotypes to those used in UK dairying 20 - 30 years ago. One of the tasks within the Feed Into Milk (FIM) project was to develop a new system to predict the energy requirements of todays dairy cow. The objective of the present study was to collate all available energy metabolism data with dairy cows in the UK and to develop relationships for describing metabolisable energy (ME) requirement for maintenance (MEm) and efficiency of ME use for lactation (kl) using both existing and new methodologies.
San Pietro and Rittenberg (1953) reported that urea appeared to meet all the requirements of a satisfactory tracer. Urea is non toxic, not foreign to the body and it shows an even and rapid distribution throughout the total body water without any physiological effect. For these reasons in addition to its easy and accurate measurement, urea is an ideal candidate tracer to estimate empty body water in vivo. Total body water volume (urea space) can be estimated by dividing the total amount of urea infused by the increase in plasma urea concentration from prior to infusion until 12 or 30 minutes after mean infusion time. Kock and Preston (1973) reported significant relationships between urea space measurements and percentage of empty body fat and water in cattle. However, Andrew et al. (1995) using 21 Holstein cows showed that prediction of empty body water using the urea space technique only explained 31 % of the variation. The objective of this experiment was to use the urea dilution technique to estimate the body composition of lactating dairy cows and produce relationships between urea space and body fat and protein content.
The Feed into Milk (FIM) project in the United Kingdom has developed a Mitscherlich equation from calorimetric data for energy rationing of dairy cattle (Agnew et al., 2004). The objective of the present study was to evaluate this equation using independent data sets obtained in both calorimetric and production studies.
The current energy (E) feeding standards (AFRC, 1993) have the objective of providing accurate feeding of dairy cows when there is either zero tissue E retention or a given tissue E change. Such approaches are of limited practical value in the real world in which we must be able to predict optimum feeding levels and strategies for animals of differing milk yield potential producing in a range of physical and economic environments. In the latter context the key economic factor is how the animal responds to additional increments of feed. This is primarily driven by how the animal partitions that additional E between milk output and body tissue gain. The objective of this experiment was to use calorimetric techniques to explore the impact of level of metabolisable E (ME) intake (MEI) on milk E output (E1) and tissue E gain (Eg) and hence partitioning of increments of MEI between milk and tissues.
The immune system’s remarkable ability to protect the body from invasion by foreign pathogens stems from its capacity to distinguish biologic “self” from “nonself.” An aberration in this normally well-regulated process leads to so-called autoimmunity, in which immune effector cells are directed against “self” tissues. Persistent abnormal immunologic activation results in autoimmune disease, each type characterized by a typical pattern of clinical signs and symptoms and confirmed by the presence of immune effector cells, usually autoantibodies. In some autoimmune conditions, serologically detected autoantibodies play an active role in tissue damage, while in others they serve only to confirm the existence of an autoimmune process. The pathophysiology leading to autoimmunity likely involves a failure of complex regulatory mechanisms, which normally control activation and deactivation of the immune system. Recent investigations suggest that full expression of autoimmune disease depends on a combination of environmental, genetic, and host factors.
Introduction: Data regarding adverse events (AEs) (unintended harm to the patient from health care provided) among children seen in the emergency department (ED) are scarce despite the high risk setting and population. The objective of our study was to estimate the risk and type of AEs, and their preventability and severity, among children treated in pediatric EDs. Methods: Our prospective cohort study enrolled children <18 years of age presenting for care during 21 randomized 8 hr-shifts at 9 pediatric EDs from Nov 2014 to October 2015. Exclusion criteria included unavailability for follow-up or insurmountable language barrier. RAs collected demographic, medical history, ED course, and systems level data. At day 7, 14, and 21 a RA administered a structured telephone interview to all patients to identify flagged outcomes (e.g. repeat ED visits, worsening/new symptoms, etc). A validated trigger tool was used to screen admitted patients’ health records. For any patients with a flagged outcome or trigger, 3 ED physicians independently determined if an AE occurred. Primary outcome was the proportion of patients with an AE related to ED care within 3 weeks of their ED visit. Results: We enrolled 6377 (72.0%) of 8855 eligible patients; 545 (8.5%) were lost to follow-up. Median age was 4.4 years (range 3 months to 17.9 yrs). Eight hundred and seventy seven (13.8%) were triaged as CTAS 1 or 2, 2638 (41.4%) as CTAS 3, and 2839 (44.7%) as CTAS 4 or 5. Top entrance complaints were fever (11.2%) and cough (8.8%). Flagged outcomes/triggers were identified for 2047 (32.1%) patients. While 252 (4.0%) patients suffered at least one AE within 3 weeks of ED visit, 163 (2.6%) suffered an AE related to ED care. In total, patients suffered 286 AEs, most (67.9%) being preventable. The most common AE types were management issues (32.5%) and procedural complications (21.9%). The need for a medical intervention (33.9%) and another ED visit (33.9%) were the most frequent clinical consequences. In univariate analysis, older age, chronic conditions, hospital admission, initial location in high acuity area of the ED, having >1 ED MD or a consultant involved in care, (all p<0.001) and longer length of stay (p<0.01) were associated with AEs. Conclusion: While our multicentre study found a lower risk of AEs among pediatric ED patients than reported among pediatric inpatients and adult ED patients, a high proportion of these AEs were preventable.
Introduction: The positive health outcomes of exercise have been well-studied, and exercise prescription has been shown to reduce morbidity in several chronic health conditions. However, patient attitudes around the prescription of exercise in the emergency department (ED) have not been explored. The aim of our pilot study is to explore patients’ willingness and perceptions of exercise being discussed and prescribed in the ED. Methods: This study is a survey of patients who had been previously selected for exercise prescription in a pilot study conducted at a tertiary care ED. This intervention group were given a standardized provincial written prescription to perform moderate exercise for 150 minutes per week. Participants answered a discharge questionnaire and were followed up by a telephone interview 2 months later. A structured interview of opinions around exercise prescription was conducted. Questions included a combination of non-closed style interview questions and Likert scale. Patients rated prescription detail, helpfulness and likelihood on a Likert scale from 1-5 (1 being strongly disagree and 5 being strongly agree). Median values (+/-IQRs) are presented, along with dominant themes. Results: 17 people consented to exercise prescription and follow up surveys. 2 were excluded due to hospital admission. 15 participants were enrolled and completed the discharge survey. Two-month follow up survey response rate was 80%. Patients rated the detail given in their prescription as 5 (+/-1). Helpfulness of prescription was rated as 4 (+/-2). Likelihood to continue exercising based on the prescription was rated as 4 (+/-2). 11/12 participants felt that exercise should be discussed in the Emergency Department either routinely or on a case-by-case basis.1 participant felt it should not be discussed at all. Conclusion: Our study demonstrates that most patients are open to exercise being discussed during their Emergency Department visit, and that the prescription format was well-received by study participants.
Introduction: Point-of-care-ultrasound is an established tool in the early diagnosis of abdominal aortic aneurysm (AAA), with a reported pooled sensitivity of 97.5% and pooled specificity 98.9%. Despite these impressive numbers, body habitus and bowel gas often render emergency department (ED) PoCUS for AAA inconclusive. We devised a manual aid “the modified peace sign technique” to improve visualization of the aorta, consisting of placing the divided fingers of the free hand of the sonographer around the probe to increase gas dispersion and improve the view of the obscured aorta. We tested the technique on volunteers during a training course when the initial scan was indeterminate due to inability to view the aorta from sub-xiphoid to bifurcation. Methods: In our pilot study, 7 physicians were asked to make a best attempt to perform an aortic scan. If they were unable to visualize the aorta, they were asked to use the modified peace sign technique. Participants recorded the number of times which they used the technique and the frequency that the technique allowed for a complete aortic scan, previously unobtainable. All scans were supervised by certified PoCUS physicians. Results: The technique was used a total of 25 times. Following failure to complete an aortic scan using their best attempt, participants were subsequently able to obtain a complete aortic scan 70% (95% CI 48 to 83%) of the time using the modified peace sign technique. Conclusion: In our pilot study, the modified peace sign technique had an estimated effect size of 70% improvement for visualization of the aorta in volunteers. Further studies are required to validate the technique in clinical practice.
The anticipated release of EnlistTM cotton, corn, and soybean cultivars likely will increase the use of 2,4-D, raising concerns over potential injury to susceptible cotton. An experiment was conducted at 12 locations over 2013 and 2014 to determine the impact of 2,4-D at rates simulating drift (2 g ae ha−1) and tank contamination (40 g ae ha−1) on cotton during six different growth stages. Growth stages at application included four leaf (4-lf), nine leaf (9-lf), first bloom (FB), FB + 2 wk, FB + 4 wk, and FB + 6 wk. Locations were grouped according to percent yield loss compared to the nontreated check (NTC), with group I having the least yield loss and group III having the most. Epinasty from 2,4-D was more pronounced with applications during vegetative growth stages. Importantly, yield loss did not correlate with visual symptomology, but more closely followed effects on boll number. The contamination rate at 9-lf, FB, or FB + 2 wk had the greatest effect across locations, reducing the number of bolls per plant when compared to the NTC, with no effect when applied at FB + 4 wk or later. A reduction of boll number was not detectable with the drift rate except in group III when applied at the FB stage. Yield was influenced by 2,4-D rate and stage of cotton growth. Over all locations, loss in yield of greater than 20% occurred at 5 of 12 locations when the drift rate was applied between 4-lf and FB + 2 wk (highest impact at FB). For the contamination rate, yield loss was observed at all 12 locations; averaged over these locations yield loss ranged from 7 to 66% across all growth stages. Results suggest the greatest yield impact from 2,4-D occurs between 9-lf and FB + 2 wk, and the level of impact is influenced by 2,4-D rate, crop growth stage, and environmental conditions.
The valley of the Baxie River, situated in the western region of the Loess Plateau in central China, contains a loess profile 15 m thick, which can be considered representative of loess-paleosol sequences formed over the last 17 ka. Both thermoluminescence (TL) determinations on fine-grained sediment (4–11 μm) and 14C determinations on various organic fractions of paleosols from the profile have provided an extremely useful chronological framework for these sequences. These sequences indicate a weakened summer monsoon during the last glacial maximum followed by a strengthening of the summer monsoon, beginning ca. 13 ka cal bp. An abrupt change to a weakened summer monsoon regime lasted from ca. 10.9 to 10.2 ka cal bp. The Asian summer monsoon circulation, recording the Holocene optimum, then increased and lasted from ca. 10.2 to 6 ka cal bp. The organic component of samples taken down the profile has δ13C values ranging from −21 to −24‰ with respect to the PDB standard. The more positive δ13C values suggest that the proportion of C4-type plants in river valleys of the Loess Plateau increased as Asian summer monsoon influence weakened, and C3-type vegetation increased as the summer monsoon influence strengthened. Magnetic susceptibility and organic content were low during loess deposition, also reflecting weakening of summer monsoon. Two 14C determinations on the humin fraction of the organic component near the top of the lower paleosol and the base of the upper paleosol complex gave ages of 10.2 and 10.9 ka cal BP, respectively. These ages mark the beginning and termination of a brief event involving increased dust influx under weakened summer monsoon conditions.
Introduction: Multiples barriers to appropriate analgesia are reported in the paediatric emergency department (PED), including limited accessibility to effective strategies. Our objective: was to evaluate the improvement in the accessibility of pain and anxiety management strategies in Canadian PEDs, after the creation of a national pediatric pain Quality Improvement Collaborative (QIC), through Pediatric Emergency Research Canada (PERC). Methods: In 2013, the TRAPPED 1 survey was administered to Canadian PEDs, in order to evaluate what resources were in place for pain and anxiety management. A pain QIC was then created to stimulate the implementation of new strategies, through information sharing between PEDs. In 2015, the TRAPPED 2 cross sectional survey was administered. Its focus was to evaluate the improvement in the accessibility of specific strategies reported by each centre, after participating in this QIC, and working to implement change within their own PEDs. Results: All 15/15 Canadian PEDs responded to the TRAPPED 1 survey in 2013 and 11 agreed to participate in the national pain QIC. In-person, phone meetings, follow up surveys and email communications were employed for information sharing. Strategies identified by the QIC to be newly introduced in individual centres were educational initiatives, distraction options, nurse-initiated protocols and intranasal (IN) medications. All 15 PEDs completed the TRAPPED 2 survey. Compared to 2013, an increased number of PEDs used face-based pain scales (14/15 vs 6/15) and behavioural scales (5/15 vs 1/15) for pain assessment in 2015. Use of reminder posters on pain management at triage increased from 4/15 to 6/15 PEDs. Availability of tablets for distraction increased from 4/15 to 10/15 PEDs. Nurse-initiated protocols for topical anesthetic and oral sucrose (for needle procedures) increased from 10/15 to 12/15 sites and from 12/15 to 14/15 sites respectively. Availability of IN medications increased; fentanyl from 9/15 to 14/15 sites and midazolam from 8/15 to 10/15 sites. Ten of the 11 PEDs involved in the QIC strategy reported the implementation of at least one of their own identified strategies. Conclusion: This study suggests that the use of a QIC may improve the introduction of new strategies to reduce pain and anxiety in EDs. QICs may also be helpful to other centres when introducing new strategies.
Impaired neuropsychological functioning is a feature of major depression. Previous studies have suggested that at least some aspects of neuropsychological functioning improve with successful treatment of major depression. The extent to which medications may affect the degree of normalization of these functions is unclear. The aim of the current study was to examine the course of neuropsychological functioning during treatment of major depression with cognitive–behaviour therapy (CBT) or schema therapy (ST).
A total of 69 out-patients with a primary diagnosis of major depression and 58 healthy controls completed mood ratings, neuropsychological measures, and measures of emotional processing at baseline and after 16 weeks. Participants were randomized after baseline assessment to a year-long course of CBT or ST. Patients reassessed at 16 weeks were medication-free throughout the study.
Significant neuropsychological impairment was evident at baseline in depressed participants compared with healthy controls. After 16 weeks of psychotherapy, mean depression rating scores fell more than 50%. However, no neuropsychological measures showed convincing evidence of significant improvement and emotional processing did not change.
Persisting impairment in neuropsychological functioning after the first 16 weeks of CBT or ST suggests a need to modify psychological treatments to include components targeting cognitive functioning.