Cascade oxime formation, cyclization to a nitrone, and intermolecular dipolar cycloaddition.

Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine

Results of vascular resections during pancreatectomy from two European centres: an analysis of survival and disease-free survival explicative factors

AbstractObjectives. The object of our study was to report on the experience with vascular resections at pancreatectomy in two European specialist hepatopancreatobiliary centres and evaluate outcome and prognostic factors. Patients and methods. From 1989 to 2002, 45 patients (21 men, 24 women) underwent pancreatectomy for a pancreatic mass: Whipple's procedure (n= 33), total pancreatectomy (n= 10) or left splenopancreatectomy (n= 2), along with a vascular resection, i.e. venous (n= 39), arterial (n= 1) or venous + arterial (n= 5). Results. Operative mortality was nil, postoperative mortality was 2.2% (n= 1); 34 patients had an uneventful postoperative course. Reoperations were performed for portal vein thromobosis (n= 1), pancreatic leak (n= 1), gastric outlet syndrome (n= 1) and gastrointestinal bleeding (n= 1). In all, 43 patients had cancer on pathology examination, with retropancreatic invasion in 72% and lymph node extension in 62.8%. Resection was R0 in 21 cases. Vessel wall invasion was present in 13 cases and 19 had perivascular invasion. Disease-free survival (DFS) at 1, 2 and 3 years was 36.0%, 15.0% and 12.0%, respectively. Median DFS length was 8.7 months (95% CI: 7.2; 10.2). Overall survival rates were 56.6%, 28.9% and 19.2%, respectively. Median survival length was 14.2 months (95% CI: 9.8; 18.6). A multivariate analysis of prognostic variables identified tumour location (other than head of pancreas), neoadjuvant chemotherapy and advanced disease stage as adverse factors for DFS. Conclusion. Survival and DFS rates of these patients are comparable to those without vascular resection. Tumour localization, tumour stage, neoadjuvant treatment and tumour recurrence are explanatory variables of survival. Tumour localization, tumour stage and neoadjuvant treatment were explanatory variables for DFS. However, the type and extent of vascular resections as well as vessel wall invasion does not affect survival and DFS

Shared goals for mental health research: what, why and when for the 2020s

Mental health problems bring substantial individual, community and societal costs and the need for innovation to promote good mental health and to prevent and treat mental health problems has never been greater. However, we know that research findings can take up to 20 years to implement. One way to push the pace is to focus researchers and funders on shared, specific goals and targets. We describe a consultation process organised by the Department of Health and Social Care and convened by the Chief Medical Officer to consider high level goals for future research efforts and to begin to identify UK-specific targets to measure research impact. The process took account of new scientific methods and evidence, the UK context with a universal health care system (the NHS) and the embedded research support from the National Institute for Health Research Clinical Research Network, as well as the views of individual service users and service user organisations. The result of the consultation is a set of four overarching goals with the potential to be measured at intervals of three, five or ten years

Highly diastereoselective synthesis of substituted pyrrolidines using a sequence of azomethine ylide cycloaddition and nucleophilic cyclization

Abstract: Although cycloadditions of azomethine ylides usually give mixtures of endo/exo adducts, we successfully tuned the mechanistic path of a new reaction cascade to afford substituted pyrrolidines in high yields and diastereomeric purity. This was achieved by forcing the demetalation of tin- or silicon-substituted iminium ions, followed by azomethine ylide cycloaddition and nucleophilic cyclization. Structural complexity is thus built rapidly in a fully controlled one-pot reaction cascade

Feasibility of implementation of CARD™ for school-based immunizations in Calgary, Alberta: a cluster trial

Background: Negative experiences with school-based immunizations can contribute to vaccine hesitancy in youth and adulthood. We developed an evidence-based, multifaceted and customizable intervention to improve the immunization experience at school called the CARD™ (C-Comfort, A-Ask, R-Relax, D-Distract) system. We evaluated the feasibility of CARD™ implementation for school-based immunizations in Calgary, Canada. Methods: In a mixed methods study, two Community Health Centres providing immunization services, including 5 schools each with grade 9 students (aged approximately 14 years), were randomized to CARD™ or control (usual care). In the CARD™ group, public health staff and students were educated about coping strategies prior to immunization clinics. Clinics were organized to reduce fear and to support student’s choices for coping strategies. Public health staff in the CARD™ group participated in a focus group discussion afterwards. We sought a recruitment rate of 80% for eligible schools, an external stakeholder focus group (e.g., school staff) with 6 or more individuals, 85% of individual injection-related data acquisition (student and immunizer surveys), and 80% absolute agreement between raters for a subset of data that were double-coded. Across focus groups, we examined perceptions of acceptability, appropriateness, feasibility and fidelity of CARD™. Results: Nine (90%) of eligible schools participated. Of 219 students immunized, injection-related student and immunizer data forms were acquired for 195 (89.0%) and 196 (89.5%), respectively. Reliability of data collection was high. Fifteen public health and 5 school staff participated in separate focus groups. Overall, attitudes towards CARD™ were positive and compliance with individual components of CARD™ was high. Public health staff expressed skepticism regarding the value of student participation in the CARD™ system. Suggestions were made regarding processes to refine implementation. Conclusion: While most outcome criteria were satisfied and overall perceptions of implementation outcomes were positive, some important challenges and opportunities were identified. Feedback is being used to inform a large cluster trial that will evaluate the impact of CARD™ during school-based immunizations. Trial registration: The trial is registered at ClinicalTrials.gov (NCT03948633); Submitted April 24, 2019