Search

Background: The overall level of physical and psychological symptom burden of advanced cancer patients (ACP) in an outpatient setting is notoriously difficult to assess. Therefore, more efficient and objective assessment is needed to accomplish this important task. Objectives: The aim of this study was to compare the physical and psychological symptom burden rated by palliative care nurse (PCN) versus patient?s self-rating. Design: This retrospective German cohort study analyzed symptom burden using an electronic patient-reported outcome measure (ePROM). After referral to an outpatient specialized palliative care team, a PCN assessed the patient?s symptoms both up to three months before initial presentation (IP) and at IP. Group differences were identified using analyses of variance (ANOVA). Further descriptive analysis of patient characteristics was used. Subjects: The study enrolled 164 ACP who were referred to a specialized palliative care (SPC) team. Mean age was 62 (? 12.6) years. Gastrointestinal (n = 46; 28.0%), lung (n = 32; 19.5%), and breast cancer (n = 34; 20.7%) were the most common entities. Results: Most frequent reasons for referral were pain (n = 55; 33.5%) and social care problems (n = 36; 22.0%). Patients reported significantly higher grades on depression (n = 144; Z = ?2.8, p = 0.005), anxiety (n = 144; Z = ?2.376, p = 0.018), and worsened general condition (n = 139; Z = ?7.005, p < 0.001). Conclusion: ACP in an outpatient setting were more frequently referred to SPC for pain management and assistance with social problems with regard to the cancer and its limitations. Psychological distress was underrated by the PCN in comparison with patient self-reporting through ePROM. This underlines the importance of self-reported outcome measurement.

Objectives Most children with uncomplicated urinary tract infections (UTI) can be managed with oral antibiotics. However, identifying those likely to fail oral and need intravenous antibiotics due to complicating features at presentation is challenging. We aimed to derive, validate and test a score to guide initial antibiotic route.Design This cohort study enrolled children both prospectively and retrospectively. Patients were divided into two groups based on whether they received intravenous or oral antibiotics after 24 hours, including those who switched between routes. Children diagnosed with confirmed UTI were used to derive then validate the score, comparing complicating clinical features between the two groups. Combinations of significantly differentiating features generated receiver operating characteristic curves and the optimal cut-off for intravenous antibiotic use was selected.Setting The emergency department of a tertiary paediatric hospital.Participants All children aged 3 months–17 years with suspected UTI were eligible, and were included if they fulfilled the diagnostic criteria for UTI.Outcome measures The effectiveness of the derived clinical score to differentiate patients at presentation who had complicated UTI requiring ongoing intravenous antibiotics.Results There were 1240 patients, of whom 167 children aged 12 months–11 years with confirmed UTI comprised the derivation cohort. The combination of features that performed optimally (area under curve 0.85, 95% CI 0.79 to 0.91) were: rigors, urological abnormality, pyrexia (≥38°C), emesis, recurrent (≥3) UTI, tachycardia: the RUPERT score (1 point each, maximum 6). A score ≥3 accurately classified route of antibiotics after 24 hours for 80% patients (sensitivity 77%, specificity 81%). For the 168 patients in the validation cohort, the score accurately classified 76% (sensitivity 67%, specificity 78%). The score tested well in ‘probable’ UTI and adolescents, and less well in infants.Conclusion The Melbourne RUPERT score provides the first standardised, easy-to-use score to aid clinicians in deciding route of antibiotics for more complicated UTI in children. It now needs prospective validation.

Abstract Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthases in which its production of NO is crucial for cardiac function. However, non‐canonical roles of BH4 have been discovered recently and the cell‐specific role of cardiomyocyte BH4 in cardiac function and metabolism remains to be elucidated. Therefore, we developed a novel mouse model of cardiomyocyte BH4 deficiency, by cardiomyocyte‐specific deletion of Gch1, which encodes guanosine triphosphate cyclohydrolase I, a required enzyme for de novo BH4 synthesis. Cardiomyocyte (cm)Gch1 mRNA expression and BH4 levels from cmGch1 KO mice were significantly reduced compared to Gch1flox/flox (WT) littermates. Transcriptomic analyses and protein assays revealed downregulation of genes involved in fatty acid oxidation in cmGch1 KO hearts compared with WT, accompanied by increased triacylglycerol concentration within the myocardium. Deletion of cardiomyocyte BH4 did not alter basal cardiac function. However, the recovery of left ventricle function was improved in cmGch1 KO hearts when subjected to ex vivo ischaemia–reperfusion (IR) injury, with reduced infarct size compared to WT hearts. Metabolomic analyses of cardiac tissue after IR revealed that long‐chain fatty acids were increased in cmGch1 KO hearts compared to WT, whereas at 5 min reperfusion (post‐35 min ischaemia) fatty acid metabolite levels were higher in WT compared to cmGch1 KO hearts. These results indicate a new role for BH4 in cardiomyocyte fatty acid metabolism, such that reduction of cardiomyocyte BH4 confers a protective effect in response to cardiac IR injury. Manipulating cardiac metabolism via BH4 could play a therapeutic role in limiting IR injury.

Introduced Phragmites (Phragmites australis australis (Cav.) Trin. Ex Steud.) is one of the most invasive plants in North America. To supplement existing management tools, a classical biological control program began in Canada in 2019 using two host-specific stem-boring moths, Archanara neurica (Hübner) and Lenisa geminipuncta (Haworth) (Lepidoptera: Noctuidae). In this article, we summarize the first three years of monitoring data for L. geminipuncta and A. neurica as biological control agents for introduced Phragmites. First, we assess agent presence and activity in the initial years post-release based on feeding damage from long-term monitoring data across 30 release sites initiated between 2019 and 2023. Second, we investigate the within-site distribution of agent feeding damage to improve future monitoring and agent collection from nurse sites. Third, we report the results of an experiment to determine optimal release densities of A. neurica larvae. We found agent feeding damage at 92% of initial release sites in the first year and agent activity persisted at all of these sites into years two and three post-release. Patterns of agent feeding damage suggest that the agents disperse quickly through the patch following release, favouring the interior area over the edges of introduced Phragmites stands. Finally, releasing intermediate densities of 40 A. neurica larvae per release point was more efficient than releasing either units of 20 or 80 larvae. The results of the first three years of monitoring are highly encouraging for the introduced Phragmites biological control program. Insights from these early monitoring results will be used to refine optimal release strategies, improve our ability to locate egg-bearing stems at nurse sites to facilitate the collection and redistribution of agents to new release locations, and inform protocols for longer-term monitoring of impacts on the target weed once agents are established.

Field releases of the stem-boring moths Archanara neurica and Lenisa geminipuncta (Lepidoptera: Noctuidae) as classical biological control agents for introduced Phragmites australis australis (Cav.) Trin. ex Steud. began in Canada during 2019. Since then, we have developed and tested release methods for eggs and larvae of both agents. Experiments here include comparisons of: (1) egg survival from exposed “egg card” and protected “egg cup” release methods to assess the risk of agent predation and test mitigation strategies; (2) performance of egg cups overwintered at the release site and those placed shortly before emergence in spring to test for any potential phenological asynchrony between biological control agents and the target weed; and (3) effectiveness of egg cup and larval-inoculated stem releases at a large geographic scale across 15 field sites in southern Ontario. Egg card releases experienced high egg loss likely due to predation (∼90 % of eggs), but egg cups were successful at reducing these losses to near zero. Releasing eggs in cups during the spring made it easier to place releases near phenologically synchronized microsites, minimized the risk of damage to the egg cups, and avoided a 16 % reduction in egg hatch likely associated with desiccation. Both larval-inoculated stems and egg cups produced highly encouraging feeding damage in the first season of release, with 7.7-fold higher damage from stem larvae compared to egg cups. Overall, we recommend a combination of larval-inoculated stems and spring egg cups for the primary release strategies of A. neurica and L. geminipuncta as biological control agents of introduced Phragmites. Both methods offer protection from predation and varying degrees of control over phenological mismatches. The release of larval-inoculated stems is a more labour-intensive but highly effective method in terms of initial feeding damage whereas egg cups are a more efficient mass-release method than stems with a lower amount of initial feeding damage per agent released.

The box tree moth Cydalima perspectalis (Walker) (Lepidoptera: Crambidae) (BTM) is a native moth throughout eastern Asia, having recently become invasive in Europe (2007) where it feeds on boxwood (= box tree), Buxus spp. The moth rapidly spread across Europe and the Caucasus causing damage to both ornamental and wild Buxus. In 2018, C. perspectalis was found in Toronto, ON, Canada, and has since spread south into the US. To better predict where the moth will establish and have significant impact on ornamental trade in North America, we used most recent scientific literature and distribution points to update the temperature and diapause indices of an existing ecoclimatic CLIMEX model. The model parameters provided a good fit for the potential distribution of BTM compared to its known distribution across eastern Asia and in Europe. Interestingly, our results suggest that the current native distribution in Asia is incomplete and that further expansion is also possible in its introduced range, especially in northern Europe, along the Mediterranean coast of Africa, and eastward to central Russia. In North America, the model predicts that most of North America should be climatically suitable for the moth's establishment, with the exception of Alaska and the northern territories of Canada, as well as higher elevations in the Rocky Mountains and southern hot and dry areas. Our study highlights the importance of the CLIMEX model to assess the risk of BTM spreading in its newly invaded areas, especially North America, and its use to help make decisions in terms of regulatory dispersal restrictions and choice of management options.

ABSTRACT Streptococcus pneumoniae (Sp) frequently causes secondary pneumonia after influenza A virus (IAV) infection, leading to high morbidity and mortality worldwide. Concomitant pneumococcal and influenza vaccination improves protection against coinfection but does not always yield complete protection. Impaired innate and adaptive immune responses have been associated with attenuated bacterial clearance in influenza virus-infected hosts. In this study, we showed that preceding low-dose IAV infection caused persistent Sp infection and suppression of bacteria-specific T-helper type 17 (Th17) responses in mice. Prior Sp infection protected against subsequent IAV/Sp coinfection by improving bacterial clearance and rescuing bacteria-specific Th17 responses in the lungs. Furthermore, blockade of IL-17A by anti-IL-17A antibodies abrogated the protective effect of Sp preinfection. Importantly, memory Th17 responses induced by Sp preinfection overcame viral-driven Th17 inhibition and provided cross-protection against different Sp serotypes following coinfection with IAV. These results indicate that bacteria-specific Th17 memory cells play a key role in providing protection against IAV/Sp coinfection in a serotype-independent manner and suggest that a Th17-based vaccine would have excellent potential to mitigate disease caused by coinfection. IMPORTANCE Streptococcus pneumoniae (Sp) frequently causes secondary bacterial pneumonia after influenza A virus (IAV) infection, leading to increased morbidity and mortality worldwide. Current pneumococcal vaccines induce highly strain-specific antibody responses and provide limited protection against IAV/Sp coinfection. Th17 responses are broadly protective against Sp single infection, but whether the Th17 response, which is dramatically impaired by IAV infection in naïve mice, might be effective in immunization-induced protection against pneumonia caused by coinfection is not known. In this study, we have revealed that Sp-specific memory Th17 cells rescue IAV-driven inhibition and provide cross-protection against subsequent lethal coinfection with IAV and different Sp serotypes. These results indicate that a Th17-based vaccine would have excellent potential to mitigate disease caused by IAV/Sp coinfection.

BackgroundHypoxia plays a critical role in the tumor microenvironment by affecting cellular proliferation, metabolism, apoptosis, DNA repair, and chemoresistance. Since hypoxia provokes a distinct shift of microRNA, it is important to illustrate the relative contribution of each hypoxamiR to cancer progression.AimsThe present study aims to shed light on the hypoxamiRs that are involved in pancreatic and breast cancer progression to highlight novel targets for the development of new therapies.MethodsFor 20 cycles, MCF7 breast cancer cells and PANC-1 pancreatic cancer cells were subjected to chronic cyclic hypoxia, which consisted of 72 hours of hypoxia followed by 24 hours of reoxygenation. After 10 and 20 cycles of hypoxia, miRNA expression alterations were profiled using RT-PCR array and further analyzed using a visual analytics platform. The MTT cell proliferation assay was used to determine hypoxic cells’ chemoresistance to doxorubicin.ResultsUnder chronic cyclic hypoxia, hypoxic PANC-1 cells have a comparable doubling time with their normoxic counterparts, whereas hypoxic MCF7 cells show a massive increase in doubling time when compared to their normoxic counterparts. Both hypoxic cell lines developed EMT-like phenotypes as well as doxorubicin resistance. According to the findings of miRNet, 6 and 10 miRNAs were shown to play an important role in enriching six hallmarks of pancreatic cancer in the 10th and 20th cycles of hypoxia, respectively, while 7 and 11 miRNAs were shown to play an important role in enriching the four hallmarks of breast cancer in the 10th and 20th cycles of hypoxia, respectively.ConclusionsmiR-221, miR-21, miR-155, and miR-34 were found to be involved in the potentiation of hypoxic PANC-1 hallmarks at both the 10th and 20th cycles, while miR-93, miR-20a, miR-15, and miR-17 were found to be involved in the potentiation of hypoxic MCF7 hallmarks at both the 10th and 20th cycles. This variation in miRNA expression was also connected to the emergence of an EMT-like phenotype, alterations in proliferation rates, and doxorubicin resistance. The chemosensitivity results revealed that chronic cyclic hypoxia is critical in the formation of chemoresistant phenotypes in pancreatic and breast cancer cells. miR-181a and let-7e expression disparities in PANC1, as well as miR-93, miR-34, and miR-27 expression disparities in MCF7, may be associated with the formation of chemoresistant MCF7 and PANC-1 cells following 20 cycles of chronic cyclic hypoxia. Indeed, further research is needed since the particular mechanisms that govern these processes are unknown.

Abstract Objective Currently there is no parent administered scale for facial nerve function in children. We set out to assess the agreement between a newly developed parent‐administered modified version of the House‐Brackmann (HB) scale and the standard clinician‐administered HB scale in children with Bell's palsy. Study Design Secondary analysis of a triple‐blind, randomized, placebo‐controlled trial of corticosteroids to treat idiopathic facial paralysis (Bell's palsy) in children (6 months to

Declining tree health status due to pollutant impacts and nutrient imbalance is widespread in urban forests; however, chemical fertilizer use is increasingly avoided to reduce eutrophication impacts. Biochar (pyrolyzed organic waste) has been advocated as an alternative soil amendment, but biochar alone generally reduces plant N availability. The combination of biochar and either organic forms of N or Plant Growth Promoting Microbes (PGPMs) as biofertilizers may address these challenges. We examined the effects of two wood biochar types with Bacillus velezensis and an inactivated yeast (IY) biofertilizer in a three-month factorial greenhouse experiment with Acer saccharinum L. (silver maple) saplings grown in a representative urban soil. All treatments combining biochars with biofertilizers significantly increased sapling growth, with up to a 91% increase in biomass relative to controls. Growth and physiological responses were closely related to nutrient uptake patterns, with nutrient vector analyses indicating that combined biochar and biofertilizer treatments effectively addressed nutrient limitations of both macronutrients (N, P, K, Mg, Ca), and micronutrients (B, Fe, Mn, Mo, Na, S, and Zn). Biochar-biofertilizer treatments also reduced foliar concentrations of Cu, suggesting potential to mitigate toxic metal impacts common in urban forestry. We conclude that selected combinations of biochar and biofertilizers have substantial promise to address common soil limitations to tree performance in urban settings.

Abstract Background Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Methods With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. Results We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo. Conclusions These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

Measurement(s) earthworm communities • Abundance • organic material • Diversity • environmental properties Technology Type(s) digital curation Factor Type(s) location Sample Characteristic - Organism Lumbricina Sample Characteristic - Environment soil Sample Characteristic - Location global Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.13399118

ABSTRACT: Hemoplasmas are bacteria able to adhere themselves loosely to the plasma membrane of erythrocytes and may parasitize several species of mammals. There are three known species of hemoplasmas that parasitize domestic and wild cats: Mycoplasma haemofelis, ‘Candidatus Mycoplasma haemominutum’ and ‘Candidatus Mycoplasma turicensis’. Dogs are infected by at least two species of hemoplasmas: ‘Candidatus Mycoplasma haematoparvum’ and Mycoplasma haemocanis. The hemoplasmoses are very important in veterinary clinics, either because of its worldwide distribution and severity of clinical signs, depending on parasite species and host immune competence, or due to its zoonotic potential and capability of infecting endangered species. This study set out to investigate which hemoplasmas species parasitize different captive wild carnivores in order to clarify the epidemiology of hemoplasmoses in wild animals. Furthermore, the research intended to characterize the hematological changes caused by different species of hemotropic mycoplasmas infection in order to establish their clinical importance to wild species and the capacity of these species to become a reservoir of studied agents. Samples of 33 wild felids and 18 wild canids were investigated using polymerase chain reaction (PCR) to detect hemoplasmas DNA and it was observed that the occurrence of infection in these species is 45.5% and 83.3%, respectively. Factors such as age, gender or anaemia are not more frequent in animals positive for the infection. Therefore, it is concluded that infection caused by hemoplasmas in wild carnivores has high prevalence, and either agent pathogenicity is low, or chronic stage is more frequent, resulting in a low rate of diagnosis.

Abstract 1. Pre‐release testing for biological control agents is focused primarily on assessment of host‐range specificity and safety of potential agents. Agent impact is considered pre‐release; however, the ultimate assessment of an agent must occur following release in the field under the target population levels and conditions of the invaded ecosystems. The invasive Eurasian vine, Vincetoxicum rossicum, has spread aggressively through its invaded range of eastern North America since its initial introduction in the late 1800s. In laboratory tests, the Eurasian moth Hypena opulenta has shown great promise as a potential control agent for V. rossicum. 2. We were interested in the defoliating ability of H. opulenta and its subsequent effect on the seed production of V. rossicum under field conditions. To examine this, we established a field site near Kirkfield, Ontario, that consisted of meadow and forest understory plots, both of which were highly invaded by V. rossicum. 3. We report highly significant feeding by H. opulenta in both light conditions. Unexpectedly, we observed a significant increase in seed production following folivory in shade conditions. We observed no significant effect of larval folivory on seed production under sun conditions, where V. rossicum seed production is greater by a factor of 10 as compared to shade conditions. 4. It is unclear how continuous exposure to folivory by H. opulenta will affect mature V. rossicum stands, although it might be expected that such populations would invest in defenses to herbivory, possibly at the expense of reproductive output. In order to better understand if V. rossicum populations in either light condition could exhibit longer‐term compensatory growth in response to folivory, further experimental work is needed that examines inter‐annual variability in V. rossicum reproduction at variable H. opulenta densities.

In this paper, we investigate the links between prospective elementary teachers' (PTs') ability to notice student mathematical thinking, their mathematical knowledge for teaching (MKT) and their ability to decompose learning goals into component conceptual parts (Morris et al., 2009). Previously, researchers have proposed theoretical connections between MKT and teachers' professional noticing, but empirical support for these relationships has been limited. Results of this mixed-methods study indicate that PTs who scored higher on an MKT assessment outperformed their peers in terms of attending to student thinking but had similar performance in terms of interpreting that thinking. However, PTs who were able to conceptually unpack a learning goal into subconstructs performed higher-quality interpretations of student thinking. We hypothesize that the skill of decomposing learning goals may allow PTs to apply their mathematics knowledge to successfully interpret student work. These results have implications for understanding how noticing and MKT may develop in relation with each other.

Background: Companion animals may reduce depression and loneliness in socially isolated homebound older adults. However, whether owning a cat or dog is more beneficial in this population remains unknown. Materials and Methods: Pet attachment and the levels of depressive symptoms and loneliness were examined in 39 homebound older adults who exclusively owned a cat(s) or a dog(s). Cat owners (n = 12) and dog owners (n=27) were assessed for depressive symptoms (Geriatric Depression Scale-Short Form), loneliness (R-UCLA Loneliness Scale), and attachment to pets (Likert scale). Results: Cat owners reported significantly lower levels of depressive symptoms than dog owners (t= 2.12; p = 0.04). There were no significant differences between cat owners and dog owners in regards to levels of loneliness (t = -0.83; p = 0.41). Both cat owners and dog owners reported a high level of attachment to pets (Median=10 of 10). Conclusions: Although this study provides preliminary evidence that owning a cat to which one is attached is associated with lower levels of depressive symptoms than owning a dog to which one is attached in homebound older adults, the findings should be replicated with longitudinal studies. Findings from such studies may assist homebound older adults in selecting either a cat or dog as a companion pet.

In pathogens that produce lipooligosaccharide (LOS), sugar residues within the surface-exposed LOS outer core mediate interactions with components of the host immune system, promoting bacterial infection. Many LOS structures are controlled by phase variation mediated by random slipped-strand base mispairing, which can reversibly switch gene expression on or off. Phase variation diversifies the LOS, however its adaptive role is not well-understood. Nontypeable Haemophilus influenzae (NTHi) is an important pathogen that causes a range of illnesses in the upper and lower respiratory tract. In NTHi a phase variable galactosyltransferase encoded by lic2A initiates galactose chain extension of the LOS outer core. The donor substrate for Lic2A, UDP-galactose, is generated from UDP-glucose by UDP-galactose epimerase encoded by galE. Our previous fitness profiling of H. influenzae mutants in a murine lung model showed that the galE mutant had a severe survival defect, while the lic2A mutant's defect was modest, leading us to postulate that unidentified factors act as suppressors of potential defects in a lic2A mutant. Herein we conducted a genome-wide genetic interaction screen to identify genes epistatic on lic2A for survival in the murine lung. An unexpected finding was that galE mutants exhibited restored virulence properties in a lic2A mutant background. We identified an alternative antibody epitope generated by Lic2A in the galE mutant that increased sensitivity to classical complement mediated killing in human serum. Deletion of lic2A or restoration of UDP-galactose synthesis alleviated the galE mutant's virulence defects. These studies indicate that when deprived of its galactosyl substrate, Lic2A acquires an alternative activity leading to increased recognition of NTHi by IgM and decreased survival in the lung model. Biofilm formation was increased by deletion of galE and by increased availability of UDP-GlcNAc precursors that can compete with UDP-galactose production. NTHi's ability to reversibly inactivate lic2A by phase-variation may influence survival in niches of infection in which UDP-Galactose levels are limiting.

Essential muscular organ that provides the whole body with oxygen and nutrients, the heart is the first organ to function during embryonic development. Cardiovascular diseases, including acquired and congenital heart defects, are the leading cause of mortality in industrialized countries. Fibroblast Growth Factors (FGFs) are involved in a variety of cellular responses including proliferation, differentiation, and migration. Among the 22 human/mouse FGFs, the secreted FGF10 ligand through the binding of its specific receptors (FGFR1b and FGFR2b) and subsequent activation of downstream signaling is known to play essential role in cardiac development, homeostasis and disease. FGF10 is one of the major marker of the early cardiac progenitor cells and a crucial regulator of differentiated cardiomyocyte proliferation in the developing embryo. Increasing evidence support the hypothesis that a detailed understanding of developmental processes is essential to identify targets for cardiac repair and regeneration. Indeed the activation of resident cardiomyocyte proliferation together with the injection of cardiac progenitors represent the most promising therapeutical strategies for cardiac regenerative medicine. The recent findings showing that FGF10 promotes adult cardiomyocyte cell cycle reentry and directs stem cell differentiation and cell reprogramming toward the cardiogenic lineage provide new insights into therapeutical strategies for cardiac regeneration and repair.

Introduction Intranasal fentanyl and nitrous oxide (N2O) can be combined to create a non-parenteral procedural sedation regimen for children in the paediatric emergency department. This combination of intranasal fentanyl and N2O provides effective pain relief for more painful procedures, but is associated with a higher incidence of vomiting than N2O alone. Our aim is to assess whether ondansetron used preventatively reduces the incidence of vomiting associated with intranasal fentanyl and N2O for procedural sedation compared with placebo.Methods and analysis This study is a double blind, randomised placebo-controlled superiority trial. This is a single-centre trial of 442 children aged 3–18 years presenting to a tertiary care Paediatric Emergency Department at the Royal Children’s Hospital (RCH), Melbourne, Australia, requiring procedural sedation with intranasal fentanyl and N2O. After written consent, eligible participants are randomised to receive ondansetron or placebo along with intranasal fentanyl, 30–60 min prior to N2O administration. The primary outcome is vomiting during or up to 1 hour after procedural sedation. Secondary outcomes include: number of vomits and retching during procedural sedation, vomiting 1–24 hours after procedural sedation, procedural sedation duration and associated adverse events, procedure abandonment, parental satisfaction and the value parents place on the prevention of vomiting. This trial will allow refinement of a non-parenteral sedation regimen for children requiring painful procedures.Ethics and dissemination This study has ethics approval at the RCH, Melbourne, protocol number 36174. The results from this trial will be submitted to conferences and published in a peer-reviewed journal.Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12616001213437).

Human exposure to green space and vegetation is widely recognized to result in physical and mental health benefits; however, to date, the specific effects of tree cover, diversity, and species composition on student academic performance have not been investigated. We compiled standardized performance scores in Grades 3 and 6 for the collective student body in 387 schools across the Toronto District School Board (TDSB), and examined variation in relation to tree cover, tree diversity, and tree species composition based on comprehensive inventories of trees on school properties combined with aerial-photo-based assessments of tree cover. Analyses accounted for variation due to socioeconomic factors using the learning opportunity index (LOI), a regional composite index of external challenges to learning that incorporates income and other factors, such as students with English as a second language. As expected, LOI had the greatest influence on student academic performance; however, the proportion of tree cover, as distinct from other types of "green space" such as grass, was found to be a significant positive predictor of student performance, accounting for 13% of the variance explained in a statistical model predicting mean student performance assessments. The effects of tree cover and species composition were most pronounced in schools that showed the highest level of external challenges, suggesting the importance of urban forestry investments in these schools.

Streptococcus pneumoniae is among the top causes of bacterial endophthalmitis, an infectious disease of the intraocular fluids. The mechanisms by which S. pneumoniae grows and thrives in the intraocular cavity are not well understood. We used a bacterial genome-wide assessment tool (transposon insertion site sequencing) to determine genes essential for S. pneumoniae growth in vitreous humor. The results indicated that an ascorbic acid (AA) transport system subunit was important for growth. We created an isogenic gene deletion mutant of the AA transcriptional activator, ulaR2, in 2 strains of S. pneumoniae. Growth curve analysis indicated that ulaR2 deletion caused attenuated growth in vitro for both strains. However, in vivo vitreous humor infection in rabbits with either strain determined that ulaR2 was necessary for growth in one strain but not the other. These results demonstrate that ulaR2 may be important for fitness during S. pneumoniae endophthalmitis depending on the background of the strain.

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

Mesozoic bird fossils from the Pacific Coast of North America are rare, but small numbers are known from the Late Cretaceous aged sediments of Hornby Island, British Columbia. Most are unassociated fragments that offer little information, but additional preparation of a large coracoid has revealed more details of its structure, as well as three associated wing bones. Phylogenetic analysis suggests that Maaqwi cascadensis, gen. et sp. nov. represents a derived crown or near-crown member of Ornithurae, and specifically suggests affinities with Vegaviidae. M. cascadensis is characterized by large size, and regressions based on dimensions of the coracoid suggest a large bird, with an estimated body mass of approximately 1.5 kilograms. The bones are robust, with thick walls, suggesting that M. cascadensis was a bird adapted for diving, similar to modern loons and grebes. The wings are short, while the coracoid is unusually short and broad, similar to modern loons. Along with the Ichthyornithes and Hesperornithes, M. cascadensis and Vegaviidae appear to represent a third clade of bird that evolved to exploit marine habitats in the Late Cretaceous, one specialized for foot-propelled diving and rapid cruising flight over water.

Nontypeable Haemophilus influenzae (NTHi) cause a range of illnesses including otitis media, sinusitis, and exacerbation of chronic obstructive pulmonary disease, infections that contribute to the problem of antibiotic resistance and are themselves often intractable to standard antibiotic treatment regimens. We investigated a strategy to exploit binding of the complement inhibitor Factor H (FH) to NTHi as a functional target for an immunotherapeutic containing the NTHi binding domain of FH fused to the Fc domain of IgG1. Chimeric proteins containing the regions that most FH-binding bacteria use to engage human FH, domains 6 and 7 (FH6,7/Fc) and/or 18 through 20 (FH18-20/Fc), were evaluated for binding to NTHi. FH6,7/Fc bound strongly to each of seven NTHi clinical isolates tested and efficiently promoted complement-mediated killing by normal human serum. FH18-20/Fc bound weakly to three of the strains but did not promote complement dependent killing. Outer-membrane protein P5 has been implicated in FH binding by NTHi, and FH6,7/Fc binding was greatly diminished in five of seven P5 deficient isogenic mutant strains tested, implicating an alternative FH binding protein in some strains. Binding of FH18-20/Fc was decreased in the P5 mutant of one strain. A murine model was used to evaluate potential therapeutic application of FH6,7/Fc. FH6,7/Fc efficiently promoted binding of C3 to NTHi exposed to mouse serum, and intranasal delivery of FH6,7/Fc resulted in significantly enhanced clearance of NTHi from the lung. Moreover, a P5 deficient mutant was attenuated for survival in the lung model, suggesting that escape mutants lacking P5 would be less likely to replace strains susceptible to FH6,7/Fc. These results provide evidence for the potential utility of FH6,7/Fc as a therapeutic against NTHi lung infection. FH binding is a common property of many respiratory tract pathogens and FH/Fc chimeras may represent promising alternative or adjunctive therapeutics against such infections, which are often polymicrobial.

Nutritional enhancement of crops using genetic engineering can potentially affect herbivorous pests. Recently, oilseed crops have been genetically engineered to produce the long-chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at levels similar to that found in fish oil; to provide a more sustainable source of these compounds than is currently available from wild fish capture. We examined some of the growth and development impacts of adding EPA and DHA to an artificial diet of Pieris rapae, a common pest of Brassicaceae plants. We replaced 1% canola oil with EPA: DHA (11:7 ratio) in larval diets, and examined morphological traits and growth of larvae and ensuing adults across 5 dietary treatments. Diets containing increasing amounts of EPA and DHA did not affect developmental phenology, larval or pupal weight, food consumption, nor larval mortality. However, the addition of EPA and DHA in larval diets resulted in progressively heavier adults (F 4, 108 = 6.78; p = 0.011), with smaller wings (p < 0.05) and a higher frequency of wing deformities (R = 0.988; p = 0.001). We conclude that the presence of EPA and DHA in diets of larval P. rapae may alter adult mass and wing morphology; therefore, further research on the environmental impacts of EPA and DHA production on terrestrial biota is advisable.

Dietary supplementation with the peroxisome proliferator-activated receptor α (PPARα) ligand WY 14,643 gave rise to a 4- to 5-fold increase in the expression of mRNA for the ATP binding cassette transporter A1 (ABCA1) in the intestine of normal mice. There was no effect in the intestine of PPARα-null mice. Consumption of a high-cholesterol diet also increased intestinal ABCA1 expression. The effects of WY 14,643 and the high-cholesterol diet were not additive. WY 14,643 feeding reduced intestinal absorption of cholesterol in the normal mice, irrespective of the dietary cholesterol concentration, and this resulted in lower diet-derived cholesterol and cholesteryl ester concentrations in plasma and liver. At each concentration of dietary cholesterol, there was a similar significant inverse correlation between intestinal ABCA1 mRNA content and the amount of cholesterol absorbed. The fibrate-induced changes in the intestines of the normal mice were accompanied by an increased concentration of the mRNA encoding the sterol-regulatory element binding protein-1c gene (SREBP-1c), a known target gene for the oxysterol receptor liver X receptor α (LXRα). There was a correlation between intestinal ABCA1 mRNA and SREBP-1c mRNA contents, but not between SREBP-1c mRNA content and cholesterol absorption.These results suggest that PPARα influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXRα.

Peroxisome proliferator-activated receptor α (PPARα)-null mice were used to investigate the nature of the relationship between the normal circadian rhythm of hepatic PPARα expression and the expression of the lipogenic and cholesterogenic sterol regulatory element-binding protein (SREBP)-regulated genes, acetyl-CoA carboxylase, fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR). The expression of FAS and HMG-CoAR varied rhythmically over the diurnal cycle in the normal mice, with patterns that were the opposite of that of PPARα. The diurnal variation of lipogenic and cholesterogenic gene expression was attenuated or abolished in the PPARα-null mice. This resulted in decreased expression compared with normal mice, but only during the dark phase of the cycle, when food intake was high. The diurnal variation in hepatic fatty acid and cholesterol synthesis was also abolished in the PPARα-null animals and the variations in the concentration of plasma triacylglycerol, nonesterified fatty acids, and cholesterol were all attenuated. The failure of HMG-CoAR expression to increase during the feeding period in the PPARα-null mice was associated with a decrease in hepatic nonesterified cholesterol content and an increase in cholesteryl ester compared with normal mice. There was no defect in the downregulation of hepatic HMG-CoAR mRNA in response to dietary cholesterol in the PPARα-null mice. Under these conditions, hepatic PPARγ expression increased in both the control and PPARα-deficient mice. The results suggest that PPARα-deficiency disturbs the normal circadian regulation of certain SREBP-sensitive genes in the liver, but does not affect their response to dietary cholesterol. —Patel, D. D., B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons. Disturbances in the normal regulation of SREBP-sensitive genes in PPARα-deficient mice.

The integration of lipid metabolism in the splanchnic bed and in subcutaneous adipose tissue before and after ingestion of a 75 g glucose load was studied by Fick's principle in seven healthy subjects. Six additional subjects were studied during a hyperinsulinemic euglycemic clamp. Release of non-esterified fatty acids (NEFA) from adipose tissue and splanchnic NEFA extraction followed a similar time-course after oral glucose, and there was a highly significant relationship between adipose tissue NEFA release and splanchnic NEFA uptake. There was no immediate inhibition of splanchnic very low density lipoprotein (VLDL)-triacylglycerol (TAG) output when plasma insulin levels increased after glucose. Adipose tissue extraction of VLDL-TAG tended to vary in time in a manner similar to splanchnic VLDL-TAG output and the two were significantly related. The area-under-curves (AUC) for splanchnic extraction of NEFA was significantly lower than that for output of VLDL, implying depletion of hepatic TAG stores during the experiment. In the hyperinsulinemic clamp experiments, there was on average suppression of splanchnic VLDL-TAG output although between-person variability was marked. This suppression could be explained by a very low supply of NEFA during the clamp. We conclude that there is an integrated pattern of metabolism in splanchnic and adipose tissues in the postabsorptive and post-glucose states. Flux of NEFA from adipose tissue drives splanchnic NEFA uptake. Splanchnic VLDL-TAG secretion appears to be regulated by a number of factors and in turn controls TAG extraction in adipose tissue. Insulin does not seem to play a key role in the acute regulation of hepatic VLDL metabolism under these particular conditions in vivo.—Bülow, J., L. Simonsen, D. Wiggins, S. M. Humphreys, K. N. Frayn, D. Powell, and G. F. Gibbons. Co-ordination of hepatic and adipose tissue lipid metabolism after oral glucose. J. Lipid Res. 1999. 40: 2034–2043.

Lipoprotein lipase (LPL) is synthesized in tissues involved in fatty acid metabolism such as muscle and adipose tissue. LPL is also found in the circulation, but is mostly lipolytically inactive. The proportion of active circulating LPL increases after a fatty meal. We investigated the release of active and inactive LPL from adipose tissue and muscle in the fasting and postprandial states. Arteriovenous concentration gradients of LPL across adipose tissue and forearm muscle were measured in male subjects before and after a fat-rich meal (n = 7) and before and during infusion of a triacylglycerol emulsion (Intralipid) (n = 6). Plasma LPL activity rose after the meal and more so during Intralipid infusion. Plasma LPL mass (>95% inactive LPL) increased after the meal but decreased after Intralipid infusion. In the fasting state (n = 13) muscle efflux of LPL activity was 0.263 ± 0.098 mU/min per 100 ml of muscle tissue whereas there was an influx of LPL activity to adipose tissue of 0.085 ± 0.100 mU/min per 100 g of adipose tissue (P < 0.02 muscle vs. adipose tissue). Similarly in the postprandial state only muscle released LPL activity. Both tissues released LPL mass. In the fasting state efflux was 17.8 ± 8.8 ng/min per 100 ml muscle and 55.2 ± 21.3 ng/min per 100 g of adipose tissue (P < 0.05 muscle vs. adipose tissue). Release of LPL, either active or inactive, was not correlated with levels of non-esterified fatty acids or plasma triacylglycerol. In conclusion, there is a substantial release of LPL from adipose tissue and muscle, most of which is inactive. A small proportion of active LPL seems to be redistributed from muscle to adipose tissue.—Karpe, F., T. Olivecrona, G. Olivecrona, J. S. Samra, L. K. M. Summers, S. M. Humphreys, and K. N. Frayn. Lipoprotein lipase transport in plasma: role of muscle and adipose tissues in regulation of plasma lipoprotein lipase concentrations. J. Lipid Res. 1998. 39: 2387–2393.

To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro , an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction.

The combination of biochar (BC) with compost has been suggested to be a promising strategy to promote plant growth and performance, but although “synergistic” effects have been stated to occur, full-factorial experiments are few, and explicit tests for synergism are lacking. We tested the hypothesis that a combination of BC and spent mushroom substrate (SMS) has a positive synergistic effect on plant growth and physiological performance in a nutrient-limited growing media. A greenhouse experiment with a full factorial design was conducted using mixed-wood BC (3.0 kg·m−2) and SMS (1.5 kg·m−2) (the combination was not co-composted) as organic soil amendments for the annual Abutilon theophrasti and the perennial Salix purpurea. Several measurements related to plant growth and physiological performance were taken throughout the experiment. Contrary to the hypothesis, we found that the combination of BC + SMS had neutral or antagonistic interactive effects on many plant growth traits. Antagonistic effects were found on maximum leaf area, above- and belowground biomass, reproductive allocation, maximum plant height, chlorophyll fluorescence, and stomatal conductance of A. theophrasti. The effect on S. purpurea was mostly neutral. We conclude that the generalization that BC and compost have synergistic effects on plant performance is not supported.

Metabolic substrate utilization of the human failing heart is an area of controversy. The purpose of this study is to directly quantify myocardial substrate utilization in moderately severe heart failure, type 2 diabetes and healthy controls using simultaneous coronary sinus and arterial blood sampling. Patients with heart failure (n = 9, mean NYHA 2.7+/-0.5), with type 2 diabetes (n = 5) and with normal heart function (n = 10) were studied after an overnight fast in connection with electrophysiological investigations/treatments.A systemic infusion of [(2)H(2)]palmitate allowed for the calculation of absolute palmitate extraction across the heart. Blood samples were analysed for non-esterified fatty acids, triacylglycerol, glycerol, glucose, pyruvate, lactate, 3-hydroxybutyrate, and blood gases after simultaneous sampling of arterial and coronary sinus blood. Arterio-coronary sinus metabolite concentration differences and fractional extractions for all substrates were similar between the groups. The absolute NEFA uptakes assessed by [(2)H(2)]palmitate extraction were also similar between the groups. Using direct measurements of metabolic substrate uptake by arterio-venous difference technique, the compensated human failing heart does not appear to have reduced myocardial fatty acid uptake.

A problem-based online learning (PBe-L) teaching sequence was designed for calculating the shelf life (expiration date) of an on-site solution of refrigerated drug as part of activities of a Pharmaceutical Physical Chemistry course of Pharmacy major at FES Cuautitlán UNAM in Mexico. The teacher presents students the problem, a group collaborative activity is carried out to search for information in PBL cycles. Students are then shown a virtual experiment that includes experimental results. Another group collaborative activity is carried out for the search of information, for the procedural analysis of the results. Applying knowledge and understanding of the topics of chemical kinetics, temperature effect on the rate of chemical reactions and drug degradation reactions, etc., students solve the problem. Hake's factor was determined for the conceptual gain. A Likert-type satisfaction survey was conducted and compared to the results of a group that was applied to the PBL strategy in person. At the end of the sequence students achieved recognition, comprehension and application learnings and conceptual gain was high. Allowing an integration of its cognitive framework of kinetics topics.

The fluorescent pigment tracking technique was used to identify features of microhabitats preferred by Peromyscus maniculatus (Deer mouse) and to examine the ecological significance of such preferences in the Canadian boreal forest. Data were also analyzed by sex. Mice spent most of their travel time in areas lacking plant cover, or in areas associated with low shrubs, herbaceous dicots, leaf litter, and woody debris. They preferred deciduous trees as canopy cover, logs 5-10 cm in diameter as understory cover, and leaf litter as a substrate. Grass and bare soil were avoided as understory cover and substrate, respectively. Males showed no preference for low shrubs and avoided herbaceous dicots, whereas females showed no preference for herbaceous dicots and avoided low shrubs. Males showed no preference for sand and avoided rocks, whereas females preferred sand and showed no preference for rocks.

Physical principles and laws determine the set of possible organismal phenotypes. Constraints arising from development, the environment, and evolutionary history then yield workable, integrated phenotypes. We propose a theoretical and practical framework that considers the role of changing environments. This 'ecomechanical approach' integrates functional organismal traits with the ecological variables. This approach informs our ability to predict species shifts in survival and distribution and provides critical insights into phenotypic diversity. We outline how to use the ecomechanical paradigm using drag-induced bending in trees as an example. Our approach can be incorporated into existing research and help build interdisciplinary bridges. Finally, we identify key factors needed for mass data collection, analysis, and the dissemination of models relevant to this framework.

Pissodes strobi Peck ataca plantaciones jóvenes de Pinus banksiana en el norte de Ontario, Canadá. Este estudio se realizó con los objetivos de 1) evaluar la mortalidad de P. strobi causada por predación por mamíferos, aves, e insectos en rodales plantados y sembrados, y 2) examinar la selección de microhabitat por Sorex cinereus (Insectivora, Soricidae), predador de P. strobi, para elaborar recomendaciones tendientes á incrementar su abundancia. La mortalidad total de adultos de P. strobi durante el invierno fue mayor en el rodal plantado (92%) que en el sembrado (78%). No hubo diferencia significativa en la mortalidad causada por otros factores entre rodales sembrados y plantados. La mortalidad de P. strobi debida a predación por mamíferos fue 12 %. Las aves predaron 8% de las larvas tardías y pupas, mientras que los insectos predadores parasitoides (mortalidad densodependiente inversa) y el apiñamiento (mortalidad densodependiente directa) produjeron una mortalidad de 48%. Sorex cinereus seleccionó microhabitats con alta cobertura de dicotiledóneas herbáceas, arbustos bajos y broza rica en hojas secas. Un manejo apropiado del bosque para incrementar la mortalidad de P. strobi debería considerar 1) dejar rodales maduros alrededor de aquellos recientes para incrementar los sitios de nidificación disponibles para las aves que anidan en cavidades; 2) dejar troncos caídos y en pie durante el proceso de preparación del sitio para la reforestación, para mejorar la calidad de microhabitat para mamíferos predadores; 3) reducir la aplicación de herbicidas; y 4) destruir los sitios de hibernación de la plaga.

The fossil otolith-based sciaenid genus Equetulus is known almost exclusively from South America, the Caribbean, and Central America, with the various species ranging in age from the late Oligocene to late Miocene. The only exception to this geographical distribution is the isolated occurrence of Equetulus silverdalensis n. comb. in the Belgrade Formation (latest Oligocene–early Miocene) in the Atlantic Coastal Plain of the USA (North Carolina) and a mention of its occurrence in the Chickasawhay Limestone (late Oligocene) in the Gulf Coastal Plain of the USA (Mississippi). However, sampling of the Paynes Hammock Sand (late Oligocene, Chattian) near Millry, Alabama, USA, resulted in the discovery of an otolith representing the first occurrence of E. silverdalensis in Alabama and the first systematic description of the species from the Gulf Coastal Plain of the USA. These occurrences suggest a potential distribution of this fossil species from Atlantic Coastal Plain of North Carolina to the central Gulf Coastal Plain of Alabama and possibly Mississippi.