Anesthesia environmental sustainability programs-a survey of Canadian department chiefs and residency program directors.

INTRODUCTION: Anesthesia-related activities contribute to operating room waste impacting climate change. The aim of this study was to ascertain 1) the current existence and scope of department and education programs concerned with anesthesia "green" practice; and 2) perceived barriers to environmental sustainability efforts among Canadian anesthesia department chiefs and residency program directors. METHODS: Association of Canadian University Departments of Anesthesia-affiliated anesthesiology department chiefs (n = 113) were invited to complete an online survey ascertaining current efforts in, and barriers to, environmentally sustainable anesthesia practice. Similarly, Canadian anesthesiology residency program directors (n = 17) were invited to complete an online survey delineating current educational programs on environmental sustainability and identifying interest in, and barriers to, developing a Canada-wide curriculum. RESULTS: The response rates for department chiefs and program directors were 23% (26/113) and 41% (7/17), respectively. Department chiefs indicated that their departments participate in sustainability efforts such as donating medical equipment (65%) and recycling (58%). Despite interest in environmental sustainability, department chiefs identified inadequate funding (72%), lack of a mandate (64%), and inadequate knowledge (60%) as barriers to implementing environmentally sustainable practices. Only 29% of responding Canadian anesthesiology programs include environmental sustainability in their curriculum. Responding residency program directors believe residents would benefit from more teaching on the topic (86%) but identified barriers including a lack of faculty expertise (100%) and time constraints (71%). Respondents (71%) also indicated an interest in developing a Canadian curriculum on the topic. CONCLUSION: Our results highlight current attitudes, gaps, and barriers to environmentally sustainable anesthesiology practice among departmental and educational leadership. Furthermore, this study identifies potential opportunities to develop cross-Canada collaborative educational programs in this field.

RéSUMé: INTRODUCTION: Les activités liées à l'anesthésie contribuent aux déchets de salle d'opération qui ont un impact sur les changements climatiques. L'objectif de cette étude était d'établir 1) l'existence et la portée des programmes départementaux et de formation s'intéressant à une pratique écoresponsable de l'anesthésie; et 2) les obstacles perçus aux efforts en matière de durabilité environnementale parmi les chefs de départements et les directeurs de programmes de résidence en anesthésie canadiens. MéTHODE: Les chefs des départements d'anesthésiologie affiliés à l'Association canadienne universitaire des départements d'anesthésie (ACUDA) (n = 113) ont été invités à remplir un sondage en ligne afin de déterminer les efforts actuels et les obstacles à une pratique durable de l'anesthésie. Les directeurs de programmes de résidence en anesthésiologie canadiens (n = 17) ont également été invités à remplir un sondage en ligne décrivant les programmes de formation actuels portant sur la durabilité environnementale et identifiant l'intérêt pour et les obstacles à la création d'un cursus s'appliquant à tout le Canada. RéSULTATS: Les taux de réponse des chefs de département et des directeurs de programme étaient de 23 % (26/113) et 41 % (7/17), respectivement. Les chefs de département ont indiqué que leurs départements prenaient part aux efforts de durabilité en faisant don des équipements médicaux (65 %) et en recyclant (58 %). Malgré un intérêt pour la durabilité environnementale, les chefs de département ont fait mention d'un financement inadapté (72 %), de l'absence de mandat (64 %), et d'un manque de connaissances (60 %) en tant qu'obstacles à la mise en place de pratiques durables. Seuls 29 % des programmes d'anesthésiologie canadiens ayant répondu comportaient un volet sur la durabilité environnementale dans leur programme. Les directeurs de programmes de résidence ayant répondu étaient d'avis que les résidents bénéficieraient d'une augmentation de l'enseignement à ce sujet (86 %) mais ont identifié divers obstacles, notamment un manque d'expertise du corps enseignant (100 %) et des contraintes de temps (71 %). Les répondants (71 %) ont également indiqué leur intérêt pour la création d'un cursus canadien à ce sujet. CONCLUSION: Nos résultats résument les attitudes, écueils et obstacles actuels à une pratique durable de l'anesthésiologie parmi les directions des départements et des programmes de formation. En outre, cette étude identifie des occasions potentielles de création de programmes éducatifs collaboratifs pancanadiens dans ce domaine.

Moonlighting Proteins and Cardiopathy in the Spatial Response of MCF-7 Breast Cancer Cells to Tamoxifen.

BACKGROUND: The purpose of this study is to apply quantitative high-throughput proteomics methods to investigate dynamic aspects of protein changes in nucleocytoplasmic distribution of proteins and of total protein abundance for MCF-7 cells exposed to tamoxifen (Tam) in order to reveal the agonistic and antagonistic roles of the drug. EXPERIMENTAL DESIGN: The MS-based global quantitative proteomics with the analysis of fractions enriched in target subcellular locations is applied to measure the changes in total abundance and in the compartmental abundance/distribution between the nucleus and cytoplasm for several thousand proteins differentially expressed in MCF-7 cells in response to Tam stimulation. RESULTS: The response of MCF-7 cells to the Tam treatment shows significant changes in subcellular abundance rather than in their total abundance. The bioinformatics study reveals the relevance of moonlighting proteins and numerous pathways involved in Tam response of MCF-7 including some of which may explain the agonistic and antagonistic roles of the drug. CONCLUSIONS: The results indicate possible protective role of Tam against cardiovascular diseases as well as its involvement in G-protein coupled receptors pathways that enhance breast tissue proliferation.

Soil amendments with ethylene precursor alleviate negative impacts of salinity on soil microbial properties and productivity.

Some microbes enhance stress tolerance in plants by minimizing plant ethylene levels via degradation of its immediate precursor, 1-aminocyclopropane-1-carboxylate (ACC), in the rhizosphere. In return, ACC is used by these microbes as a source of nitrogen. This mutualistic relationship between plants and microbes may be used to promote soil properties in stressful environments. In this study, we tested the hypothesis that amendments of ACC in soils reshape the structure of soil microbiome and alleviate the negative impacts of salinity on soil properties. We treated non-saline and artificially-developed saline soils with ACC in different concentrations for 14 days. The structure of soil microbiome, soil microbial properties and productivity were examined. Our results revealed that microbial composition of bacteria, archaea and fungi in saline soils was affected by ACC amendments; whereas community composition in non-saline soils was not affected. The amendments of ACC could not fully counteract the negative effects of salinity on soil microbial activities and productivity, but increased the abundance of ACC deaminase-encoding gene (acdS), enhanced soil microbial respiration, enzymatic activity, nitrogen and carbon cycling potentials and Arabidopsis biomass in saline soils. Collectively, our study indicates that ACC amendments in soils could efficiently ameliorate salinity impacts on soil properties and plant biomass production.

Hospital admission on weekends for patients who have surgery and 30-day mortality in Ontario, Canada: A matched cohort study.

BACKGROUND: Healthcare interventions on weekends have been associated with increased mortality and adverse clinical outcomes, but these findings are inconsistent. We hypothesized that patients admitted to hospital on weekends who have surgery have an increased risk of death compared with patients who are admitted and have surgery on weekdays. METHODS AND FINDINGS: This matched cohort study included 318,202 adult patients from Ontario health administrative and demographic databases, admitted to acute care hospitals from 1 January 2005 to 31 December 2015. A total of 159,101 patients who were admitted on weekends and underwent noncardiac surgery were classified by day of surgery (weekend versus weekday) and matched 1:1 to patients who both were admitted and had surgery on a weekday (Tuesday to Thursday); matching was based on age (in years), anesthesia basic unit value for the surgical procedure, median neighborhood household income quintile, resource utilization band (a ranking system of overall morbidity), rurality of home location, year of admission, and urgency of admission. Of weekend admissions, 16.2% (25,872) were elective and 53.9% (85,744) had surgery on the weekend of admission. The primary outcome was all-cause mortality within 30 days of the date of hospital admission. The 30-day all-cause mortality for patients admitted on weekends who had noncardiac surgery was 2.6% (4,211/159,101) versus 2.5% (3,901/159,101) for those who were admitted and had surgery on weekdays (adjusted odds ratio [OR] 1.05; 95% CI 1.00 to 1.11; P = 0.03). However, there was significant heterogeneity in the increased odds of death according to the urgency of admission and when surgery was performed (weekend versus weekday). For urgent admissions on weekends (n = 133,229), there was no significant increase in odds of mortality when surgery was performed on the weekend (adjusted OR 1.02; 95% CI 0.95 to 1.09; P = 0.7) or on a subsequent weekday (adjusted OR 1.05; 95% CI 0.98 to 1.12; P = 0.2) compared to urgent admissions on weekdays. Elective admissions on weekends (n = 25,782) had increased risk of death both when surgery was performed on the weekend (adjusted OR 3.30; 95% CI 1.98 to 5.49; P < 0.001) and when surgery was performed on a subsequent weekday (adjusted OR 2.70; 95% CI 1.81 to 4.03; P < 0.001). The main limitations of this study were the lack of data regarding reason for admission and cause of increased time interval from admission to surgery for some cases, the small number of deaths in some subgroups (i.e., elective surgery), and the possibility of residual unmeasured confounding from increased illness severity for weekend admissions. CONCLUSIONS: When patients have surgery during their hospitalization, admission on weekends in Ontario, Canada, was associated with a small but significant proportional increase in 30-day all-cause mortality, but there was significant heterogeneity in outcomes depending on the urgency of admission and when surgery was performed. An increased risk of death was found only for elective admissions on weekends; whether this is a function of patient-level factors or represents a true weekend effect needs to be further elucidated. These findings have potential implications for resource allocation in hospitals and the redistribution of elective surgery to weekends.

Influence of Surgical Procedures and General Anesthesia on Child Development Before Primary School Entry Among Matched Sibling Pairs.

Importance: Substantial preclinical evidence suggests that the developing brain is susceptible to injury from anesthetic drugs. Findings from clinical studies of the neurotoxic effects of anesthesia are mixed, but these effects can be influenced by unmeasured confounding from biological and environmental risk and protective factors on child development. Objective: To examine the association between surgical procedures that require general anesthesia before primary school entry and child development in biological siblings. Design, Setting, and Participants: This retrospective sibling-matched cohort study included sibling pairs aged 5 to 6 years with the same birth mother who had Early Development Instrument (EDI) data completed. The EDI is a population-based measure of child development that assesses children's readiness to learn in 5 major domains (physical health and well-being, social knowledge and competence, emotional health and maturity, language and cognitive development, and communication skills and general knowledge). All eligible children in public and Catholic schools in Ontario, Canada, from 2004 through 2012 were included. Data were analyzed from December 13, 2017, through July 27, 2018. Exposures: Surgical procedures that require general anesthesia from the date of birth to EDI completion. Main Outcomes and Measures: Early developmental vulnerability, defined as any major domain of the EDI in the lowest 10th percentile of the Ontario population. Results: Of the 187 226 eligible children for whom the EDI was completed, a total of 10 897 sibling pairs (21 794 children; 53.8% female; mean [SD] age, 5.7 [0.3] years) were subsequently identified, including 2346 with only 1 child exposed to surgery. No significant differences were found between exposed and unexposed children in early developmental vulnerability (697 of 3080 [22.6%] vs 3739 of 18 714 [20.0%]; adjusted odds ratio [aOR], 1.03; 95% CI, 0.98-1.14; P = .58) or for each of the 5 major EDI domains (aOR for language and cognitive development, 0.96 [95% CI, 0.80-1.14]; aOR for physical health and well-being, 1.09 [95% CI, 0.96-1.24]; aOR for social knowledge and competence, 0.98 [95% CI, 0.84-1.14]; aOR for emotional health and maturity, 0.98 [95% CI, 0.84-1.14]; and aOR for communication skills and general knowledge, 0.90 [95% CI, 0.77-1.05]), after adjusting for confounding factors (age at EDI completion, sex, mother's age at birth, and eldest sibling status). Conclusions and Relevance: In this provincial cohort study, children who had surgical procedures that require general anesthesia before primary school entry were not found to be at increased risk of adverse child development outcomes compared with their biological siblings who did not have surgery. These findings further support that anesthesia exposure in early childhood is not associated with detectable adverse child development outcomes.

A national survey on attitudes and barriers on recycling and environmental sustainability efforts among Canadian anesthesiologists: an opportunity for knowledge translation.

BACKGROUND: Anesthesia-related activities produce 25% of all operating room (OR) waste and contribute to environmental pollution and climate change. The aim of this study was to document Canadian anesthesiologists' current practice, attitudes towards, and perceived barriers regarding recycling of OR waste and environmental sustainability efforts. METHODS: With Research Ethics Board approval, members of the Canadian Anesthesiologists' Society (CAS) completed an online survey consisting of 25 questions assessing current environmentally sustainable practices in anesthesiology and gaps, barriers, and interest in gaining further knowledge on this topic. RESULTS: Four hundred and twenty-six of 2,695 (16%) CAS members responded to the questionnaire. Despite a willingness to recycle at work among most anesthesiologists (393/403, 97.5%), only 122/403 (30.2%) did so. Other sustainability efforts in Canadian ORs included donating unused medical equipment and supplies to medical missions (198/400, 49.5%) and evening shut-off of anesthesia machines and other OR equipment (185/400, 46.3%). Reported barriers to recycling in the OR included a lack of support from hospital/OR leadership (254/400, 63.5%) and inadequate information/education (251/400, 62.8%). Only 122/389 (31.4%) of respondents were aware of any efforts to expand sustainability programs at their institutions but 273/395 (69.1%) of respondents indicated an interest in obtaining further education on the topic. CONCLUSION: Canadian anesthesiologists appear ready to incorporate environmental sustainability in their practice but indicate that significant barriers exist. Our study highlights the need for further educational programs and implementation strategies.

RéSUMé: CONTEXTE: Les activités liées à l'anesthésie produisent 25 % de tous les déchets en salle d'opération et contribuent à la pollution de l'environnement et au changement climatique. Le but de cette étude était de documenter les pratiques actuelles des anesthésiologistes canadiens, leurs attitudes envers le recyclage des déchets de salle d'opération et les efforts pour la protection de l'environnement, ainsi que les obstacles perçus comme s'y opposant. MéTHODES: Après approbation d'un Comité d'éthique de la recherche, les membres de la Société canadienne des anesthésiologistes (SCA) ont pu remplir une enquête en ligne comportant 25 questions évaluant les pratiques actuelles en anesthésiologie pour un environnement durable ses obstacles, ses lacunes, ainsi que l'intérêt à en savoir plus sur ce sujet. RéSULTATS: Quatre cent vingt-six des 2695 membres (16 %) de la SCA ont répondu au questionnaire. Malgré un désir de recyclage dans le cadre du travail chez la plupart des anesthésiologistes (393/403, 97,5 %), seulement 122/403 (30,2 %) le faisaient. D'autres efforts des salles d'opération canadiennes en faveur de la durabilité incluaient le don de l'équipement médical et des fournitures non utilisés à des missions médicales (198/400, 49,5 %) et la fermeture des appareils d'anesthésie et des autres équipements de la salle d'opération le soir (185/400, 46,3 %). Les obstacles au recyclage en salle d'opération qui ont été mentionnés incluaient une absence de soutien de la part du leadership de l'hôpital/de la salle d'opération (254/400, 63,5 %) et une information/éducation insuffisante sur le sujet (251/400, 62,8 %). Seulement 122 des 389 répondants (31,4 %) étaient au courant d'efforts d'extension des programmes en faveur de l'environnement, mais 273/395 (69,1 %) répondants ont manifesté de l'intérêt à obtenir plus de formation sur le sujet. CONCLUSION: Les anesthésiologistes canadiens semblent prêts à incorporer la protection de l'environnement dans leurs pratiques, mais indiquent qu'il existe des obstacles significatifs. Notre étude souligne le besoin de poursuivre les programmes éducatifs et les stratégies de mise en œuvre.

Cirrhotic Human Liver Extracellular Matrix 3D Scaffolds Promote Smad-Dependent TGF-ß1 Epithelial Mesenchymal Transition.

An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFß signaling. This was also supported by the presence and release of higher concentration of endogenous TGFß1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFß1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFß1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFß-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development.

Asymmetric Vinylogous Aza-Darzens Approach to Vinyl Aziridines.

A new asymmetric approach to assemble cis-vinyl aziridines is reported. A reaction of strategically substituted dienolates, decorated with a γ-leaving group, with chiral sulfinimines afforded chiral vinyl aziridine products in good to excellent yields. This is the first systematic study toward the realization of a useful asymmetric vinylogous aza-Darzens reaction. The reaction is initiated by a syn-selective addition, affording cis-vinyl aziridine products after displacement of bromide. The low syn-diastereoselectivity is attributed to competing retro-Mannich pathways.

Use of Serratus Plane Block for Repair of Coarctation of Aorta: A Report of 3 Cases.

OBJECTIVES: The practice of regional anesthesia techniques (thoracic, epidural, paravertebral) in pediatric cardiac surgery enhances perioperative outcomes such as improved perioperative analgesia, decreased stress response, early extubation, and shortened hospital stay. However, these blocks can be technically challenging and can be associated with unacceptable failure rate and complications in infants. For these reasons, regional anesthesia is sometimes avoided in pediatric cardiac surgery. We describe the simple and effective serratus plane block for thoracotomy analgesia in 2 neonates and a child. CASE REPORT: We present 3 pediatric patients, each of whom was having coarctation repair and received an ultrasound-guided serratus plane block for thoracotomy analgesia. The patients were 3 days, 14 days, and 4 years old, weighing from 1.9 to 16 kg. The serratus plane block was performed prior to surgical incision. The block was technically simple compared with thoracic epidural or paravertebral block. All patients were extubated immediately after completion of surgery. Apart from the induction dose of fentanyl (2 µg/kg), no further opioids were required intraoperatively. Postoperative opioid requirements as well as duration of intensive care and hospital stay were lower than recent averages (for the same demographic and procedure) in our hospital. CONCLUSIONS: We propose that the serratus plane block is a simple procedure that provides good perioperative analgesia for infant thoracotomy, potentially facilitating early extubation and a shorter hospital stay.

Inhalational Anesthetics Induce Neuronal Protein Aggregation and Affect ER Trafficking.

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.

Strategic tillage in conservation agricultural systems of north-eastern Australia: why, where, when and how?

Farmers often resort to an occasional tillage (strategic tillage (ST)) operation to combat constraints of no-tillage (NT) farming systems. There are conflicting reports regarding impacts of ST and a lack of knowledge around when, where and how ST is implemented to maximise its benefits without impacting negatively on soil and environment. We established 14 experiments during 2012-2015 on farms with long-term history of continuous NT to (i) quantify the associated risks and benefits to crop productivity, soil and environmental health and (ii) explore key factors that need to be considered in decisions to implement ST in an otherwise NT system. Results showed that introduction of ST reduced weed populations and improved crop productivity and profitability in the first year after tillage, with no impact in subsequent 4 years. Soil properties were not impacted in Vertosols; however, Sodosols and Dermosols suffered short-term negative soil health impacts (e.g. increased bulk density). A Sodosol and a Dermosol also posed higher risks of runoff and associated loss of nutrients and sediment during intense rainfall after ST. The ST reduced plant available water in the short term, which could result in unreliable sowing opportunities for the following crop especially in semi-arid climate that prevails in north-eastern Australia. The results show that generally, there were no significant differences in crop productivity and soil health between tillage implements and tillage frequencies between ST and NT. The study suggests that ST can be a viable strategy to manage constraints of NT systems, with few short-term soil and environmental costs and some benefits such as short-term farm productivity and profitability and reduced reliance on herbicides.

Incidence of non-physiologically complex surgical procedures performed in children: an Ontario population-based study of health administrative data.

PURPOSE: Quantification of surgical procedures undertaken by hospitals is necessary for informing resource allocation and modelling healthcare services. Our objective was to quantify the incidence, similarity, and diversity of non-physiologically complex surgical procedures performed at pediatric specialist hospitals and other hospitals performing pediatric surgery. METHODS: We conducted a population-based cohort study of children aged 28 days to 18 yr who underwent surgery in the province of Ontario from 2007 to 2015 using healthcare administrative databases. We estimated the incidence of non-physiologically complex procedures (i.e., ≤ 7 basic units in the 2015 Ontario Health Insurance Plan Schedule of Benefits) performed in pediatric specialist hospitals and other hospitals performing pediatric surgery. We used Yue and Clayton's index and the effective number of common procedures (1/Herfindahl index) to quantify the similarity and diversity of pediatric surgical procedures performed in these hospital types. RESULTS: Overall, 830,830 pediatric surgical procedures were performed in 158 Ontario hospitals during the eight-year study period. Most surgical procedures performed at hospitals performing pediatric surgery were non-physiologically complex (vs 50%, P < 0.001). The incidence of non-physiologically complex procedures increased progressively each year at pediatric specialist hospitals and was associated with a reciprocal decline among the other hospitals. Comparing pediatric specialist hospitals with the other hospitals, the mean similarity index for non-physiologically complex procedures was less than moderate (0.52; 95% confidence interval [CI], 0.51 to 0.54). The mean effective number of common non-physiologically complex procedures (i.e., the diversity) among the pediatric specialist hospitals was greater than at the other 154 hospitals performing pediatric surgery (65.3 vs 21.8 procedures, respectively; mean difference, 43.5; 95% CI, 42.2 to 44.8; P < 0.001). CONCLUSIONS: Non-physiologically complex procedures have progressively migrated to pediatric specialist hospitals from other hospitals in Ontario. Specialty pediatric hospitals are principally dissimilar from other hospitals performing pediatric surgery based not on physiological complexity, but on their diversity. These findings suggest that some types of surgical procedures may be redistributed from specialist pediatric hospitals to other hospitals performing pediatric surgery. TRIAL REGISTRATION: www.clinicaltrials.gov , number NCT03144544. Registered 2 May 2016.

Unique signalling connectivity of FGFR3-TACC3 oncoprotein revealed by quantitative phosphoproteomics and differential network analysis.

The FGFR3-TACC3 fusion is an oncogenic driver in diverse malignancies, including bladder cancer, characterized by upregulated tyrosine kinase activity. To gain insights into distinct properties of FGFR3-TACC3 down-stream signalling, we utilised telomerase-immortalised normal human urothelial cell lines expressing either the fusion or wild-type FGFR3 (isoform IIIb) for subsequent quantitative proteomics and network analysis. Cellular lysates were chemically labelled with isobaric tandem mass tag reagents and, after phosphopeptide enrichment, liquid chromatography-high mass accuracy tandem mass spectrometry (LC-MS/MS) was used for peptide identification and quantification. Comparison of data from the two cell lines under non-stimulated and FGF1 stimulated conditions and of data representing physiological stimulation of FGFR3 identified about 200 regulated phosphosites. The identified phosphoproteins and quantified phosphosites were further analysed in the context of functional biological networks by inferring kinase-substrate interactions, mapping these to a comprehensive human signalling interaction network, filtering based on tissue-expression profiles and applying disease module detection and pathway enrichment methods. Analysis of our phosphoproteomics data using these bioinformatics methods combined into a new protocol-Disease Relevant Analysis of Genes On Networks (DRAGON)-allowed us to tease apart pathways differentially involved in FGFR3-TACC3 signalling in comparison to wild-type FGFR3 and to investigate their local phospho-signalling context. We highlight 9 pathways significantly regulated only in the cell line expressing FGFR3-TACC3 fusion and 5 pathways regulated only by stimulation of the wild-type FGFR3. Pathways differentially linked to FGFR3-TACC3 fusion include those related to chaperone activation and stress response and to regulation of TP53 expression and degradation that could contribute to development and maintenance of the cancer phenotype.

Dexamethasone as an adjuvant to peripheral nerve block.

BACKGROUND: Peripheral nerve block (infiltration of local anaesthetic around a nerve) is used for anaesthesia or analgesia. A limitation to its use for postoperative analgesia is that the analgesic effect lasts only a few hours, after which moderate to severe pain at the surgical site may result in the need for alternative analgesic therapy. Several adjuvants have been used to prolong the analgesic duration of peripheral nerve block, including perineural or intravenous dexamethasone. OBJECTIVES: To evaluate the comparative efficacy and safety of perineural dexamethasone versus placebo, intravenous dexamethasone versus placebo, and perineural dexamethasone versus intravenous dexamethasone when added to peripheral nerve block for postoperative pain control in people undergoing surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, DARE, Web of Science and Scopus from inception to 25 April 2017. We also searched trial registry databases, Google Scholar and meeting abstracts from the American Society of Anesthesiologists, the Canadian Anesthesiologists' Society, the American Society of Regional Anesthesia, and the European Society of Regional Anaesthesia. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) comparing perineural dexamethasone with placebo, intravenous dexamethasone with placebo, or perineural dexamethasone with intravenous dexamethasone in participants receiving peripheral nerve block for upper or lower limb surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 35 trials of 2702 participants aged 15 to 78 years; 33 studies enrolled participants undergoing upper limb surgery and two undergoing lower limb surgery. Risk of bias was low in 13 studies and high/unclear in 22. Perineural dexamethasone versus placeboDuration of sensory block was significantly longer in the perineural dexamethasone group compared with placebo (mean difference (MD) 6.70 hours, 95% confidence interval (CI) 5.54 to 7.85; participants1625; studies 27). Postoperative pain intensity at 12 and 24 hours was significantly lower in the perineural dexamethasone group compared with control (MD -2.08, 95% CI -2.63 to -1.53; participants 257; studies 5) and (MD -1.63, 95% CI -2.34 to -0.93; participants 469; studies 9), respectively. There was no significant difference at 48 hours (MD -0.61, 95% CI -1.24 to 0.03; participants 296; studies 4). The quality of evidence is very low for postoperative pain intensity at 12 hours and low for the remaining outcomes. Cumulative 24-hour postoperative opioid consumption was significantly lower in the perineural dexamethasone group compared with placebo (MD 19.25 mg, 95% CI 5.99 to 32.51; participants 380; studies 6). Intravenous dexamethasone versus placeboDuration of sensory block was significantly longer in the intravenous dexamethasone group compared with placebo (MD 6.21, 95% CI 3.53 to 8.88; participants 499; studies 8). Postoperative pain intensity at 12 and 24 hours was significantly lower in the intravenous dexamethasone group compared with placebo (MD -1.24, 95% CI -2.44 to -0.04; participants 162; studies 3) and (MD -1.26, 95% CI -2.23 to -0.29; participants 257; studies 5), respectively. There was no significant difference at 48 hours (MD -0.21, 95% CI -0.83 to 0.41; participants 172; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. Cumulative 24-hour postoperative opioid consumption was significantly lower in the intravenous dexamethasone group compared with placebo (MD -6.58 mg, 95% CI -10.56 to -2.60; participants 287; studies 5). Perinerual versus intravenous dexamethasoneDuration of sensory block was significantly longer in the perineural dexamethasone group compared with intravenous by three hours (MD 3.14 hours, 95% CI 1.68 to 4.59; participants 720; studies 9). We found that postoperative pain intensity at 12 hours and 24 hours was significantly lower in the perineural dexamethasone group compared with intravenous, however, the MD did not surpass our pre-determined minimally important difference of 1.2 on the Visual Analgue Scale/Numerical Rating Scale, therefore the results are not clinically significant (MD -1.01, 95% CI -1.51 to -0.50; participants 217; studies 3) and (MD -0.77, 95% CI -1.47 to -0.08; participants 309; studies 5), respectively. There was no significant difference in severity of postoperative pain at 48 hours (MD 0.13, 95% CI -0.35 to 0.61; participants 227; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. There was no difference in cumulative postoperative 24-hour opioid consumption (MD -3.87 mg, 95% CI -9.93 to 2.19; participants 242; studies 4). Incidence of severe adverse eventsFive serious adverse events were reported. One block-related event (pneumothorax) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. Four non-block-related events occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the placebo group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed Complex Regional Pain Syndrome Type I and one in the intravenous dexamethasone group developed pneumonia. The quality of evidence is very low due to the sparse number of events. AUTHORS' CONCLUSIONS: Low- to moderate-quality evidence suggests that when used as an adjuvant to peripheral nerve block in upper limb surgery, both perineural and intravenous dexamethasone may prolong duration of sensory block and are effective in reducing postoperative pain intensity and opioid consumption. There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not apply to participants at risk of dexamethasone-related adverse events for whom clinical trials would probably be unsafe.There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not be apply to participants who at risk of dexamethasone-related adverse events for whom clinical trials would probably be unsafe. The nine ongoing trials registered at ClinicalTrials.gov may change the results of this review.

New Class of Anion-Accelerated Amino-Cope Rearrangements as Gateway to Diverse Chiral Structures.

We report useful new lithium-assisted asymmetric anion-accelerated amino-Cope rearrangement cascades. A strategic nitrogen atom chiral auxiliary serves three critical roles, by (1) enabling in situ assembly of the chiral 3-amino-1,5-diene precursor, (2) facilitating the rearrangement via a lithium enolate chelate, and (3) imparting its influence on consecutive inter- or intramolecular C-C or C-X bond-forming events via resulting chiral enamide intermediates or imine products. The mechanism of the amino-Cope rearrangement was explored with density functional theory. A stepwise dissociation-recombination mechanism was found to be favored. The stereochemistry of the chiral auxiliary determines the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot.

Minimally Important Differences in Patient or Proxy-Reported Outcome Studies Relevant to Children: A Systematic Review.

CONTEXT: No study has characterized and appraised all anchor-based minimally important differences (MIDs) associated with patient-reported outcome (PRO) instruments in pediatric studies. OBJECTIVE: To complete a comprehensive systematic survey and appraisal of published anchor-based MIDs associated with PRO instruments used in children. DATA SOURCES: Medline, Embase, and PsycINFO (1989 to February 11, 2015). STUDY SELECTION: Studies reporting empirical ascertainment of anchor-based MIDs among PROs used in pediatric care. DATA EXTRACTION: All pertinent data items related to the characteristics of PRO instruments, anchors, and MIDs. RESULTS: Of 4179 unique citations, 30 studies (including 32 cohorts) proved eligible and reported on 28 unique PROs (8 generic, 13 disease-specific, 5 symptoms-specific, 2 function-specific), with 9 (32%) classified as patient-reported, 11 (39%) proxy-reported, and 8 (29%) both patient- and proxy-reported. Of the 30 studies, we rated 14 (44%) as providing highly credible estimates of the MID. Most cohorts (n = 20, 62%) recorded patients' direct response to the target PRO and the use of an independent standard of comparison (n = 25, 78%). Most, however, failed to effectively report measurement properties of the anchor (n = 24, 75%). LIMITATIONS: We have not yet addressed the measurement properties of instrument to measure credibility; our search was restricted to 3 electronic sources, and we used a single data abstractor. CONCLUSIONS: Our study found 28 PROs that have been developed for children, with fewer than half providing credible estimates. Clinicians, clinical trialists, systematic reviewers, and guideline developers seeking to effectively summarize and interpret results of studies addressing PROs in child health are likely to find our comprehensive compendium of MIDs of use, both in providing best estimates of MIDs and identifying credible estimates.

Inner Plant Values: Diversity, Colonization and Benefits from Endophytic Bacteria.

One of the most exciting scientific advances in recent decades has been the realization that the diverse and immensely active microbial communities are not only 'passengers' with plants, but instead play an important role in plant growth, development and resistance to biotic and abiotic stresses. A picture is emerging where plant roots act as 'gatekeepers' to screen soil bacteria from the rhizosphere and rhizoplane. This typically results in root endophytic microbiome dominated by Proteobacteria, Actinobacteria and to a lesser extent Bacteroidetes and Firmicutes, but Acidobacteria and Gemmatimonadetes being almost depleted. A synthesis of available data suggest that motility, plant cell-wall degradation ability and reactive oxygen species scavenging seem to be crucial traits for successful endophytic colonization and establishment of bacteria. Recent studies provide solid evidence that these bacteria serve host functions such as improving of plant nutrients through acquisition of nutrients from soil and nitrogen fixation in leaves. Additionally, some endophytes can engage 'priming' plants which elicit a faster and stronger plant defense once pathogens attack. Due to these plant growth-promoting effects, endophytic bacteria are being widely explored for their use in the improvement of crop performance. Updating the insights into the mechanism of endophytic bacterial colonization and interactions with plants is an important step in potentially manipulating endophytic bacteria/microbiome for viable strategies to improve agricultural production.