Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids

Abstract A unified strategy for enantioselective total synthesis of all stereoisomers of the [2+2] family of quadrigemine alkaloids is reported. In this approach, two enantioselective intramolecular Heck reactions are carried out at the same time on precursors fashioned in four steps from either meso- or (+)-chimonanthine to form the two critical quaternary carbons of the peripheral cyclotryptamine rings of these products. Useful levels of catalyst control are realized in either desymmetrizing a meso precursor or controlling diastereoselectivity in elaborating C2-symmetric intermediates. None of the synthetic quadrigemines are identical with alkaloids isolated previously and referred to as quadrigemines A and E. In addition, we report improvements in our previous total syntheses of (+)- or (-)-quadrigemine C that shortened the synthetic sequence to 10 steps and provided these products in 2.2% overall yield from tryptamine

An examination of chemistry and transport processes in the tropical lower stratosphere using observations of long-lived and short-lived compounds obtained during STRAT and POLARIS

A suite of compounds with a wide range of photochemical lifetimes (3 months to several decades) was measured in the tropical and midlatitude upper troposphere and lower stratosphere during the Stratospheric Tracers of Atmospheric Transport (STRAT) experiment (fall 1995 and winter, summer, and fall 1996) and the Photochemistry of Ozone Loss in the Arctic Region in Summer (POLARIS) deployment in late summer 1997. These species include various chlorofluorocarbons, hydrocarbons, halocarbons, and halons measured in whole air samples and CO measured in situ by tunable diode laser spectroscopy. Mixing ratio profiles of long-lived species in the tropical lower stratosphere are examined using a one-dimensional (1-D) photochemical model that includes entrainment from the extratropical stratosphere and is constrained by measured concentrations of OH. Profiles of tracers found using the 1-D model agree well with all the observed tropical profiles for an entrainment time scale of 8.5-4+6 months, independent of altitude between potential temperatures of 370 and 500 K. The tropical profile of CO is used to show that the annually averaged ascent rate profile, on the basis of a set of radiative heating calculations, is accurate to approximately ±44%, a smaller uncertainty than found by considering the uncertainties in the radiative model and its inputs. Tropical profiles of ethane and C2Cl4 reveal that the concentration of Cl is higher than expected on the basis of photochemical model simulations using standard gas phase kinetics and established relationships between total inorganic chlorine and CFC-11. Our observations suggest that short-lived organic chlorinated compounds and HCl carried across the tropical tropopause may provide an important source of inorganic chlorine to the tropical lower stratosphere that has been largely unappreciated in previous studies. The entrainment timescale found here is considerably less than the value found by a similar study that focused on observations obtained in the lower stratosphere during 1994. Several possible explanations for this difference are discussed. Copyright 1999 by the American Geophysical Union

Retrospective cohort study evaluating clinical, biochemical and pharmacological prognostic factors for prostate cancer progression using primary care data

This is the final version. Available on open access from BMJ Publishing group via the DOI in this recordObjectives – To confirm the association of previously reported prognostic factors with future progression of localised prostate cancer using primary care data and identify new potential prognostic factors for further assessment in prognostic model development and validation. Design – Retrospective cohort study, employing Cox proportional hazards regression controlling for age, PSA, and Gleason score, stratified by diagnostic stage. Setting – Primary care in England Participants – Males with localised prostate cancer diagnosed between 01/01/1987 and 31/12/2016 within the Clinical Practice Research Datalink database, with linked data from the National Cancer Registration and Analysis Service and Office for National Statistics. Primary and Secondary outcomes – Primary outcome measure was prostate cancer mortality. Secondary outcomes measures were all-cause mortality and commencing systematic therapy. Up13 staging after diagnosis was not used as a secondary outcome owing to significant missing data. Results 10,901 males (mean age 74.38 +/- 9.03 years) with localised prostate cancer were followed up for a mean of 14.12 (+/- 6.36) years. 2,331 (21.38%) men underwent systemic therapy and 3,250 (31.65%) died, including 1,250 (11.47%) from prostate cancer. Factors associated with an increased risk of prostate cancer mortality included age; high PSA; current or ex-smoker; ischaemic heart disease; high C-Reactive Protein; high ferritin; low haemoglobin; high blood glucose; and low albumin. Conclusions This study identified several new potential prognostic factors for prostate cancer progression, as well as confirming some known prognostic factors, in an independent primary care data set. Further research is needed to develop and validate a prognostic model for prostate cancer progression.Can Test Collaborative/CRU

Differences in access and patient outcomes across antiretroviral treatment clinics in the Free State province: A prospective cohort study

Objective. To assess differences in access to antiretroviral treatment (ART) and patient outcomes across public sector treatment facilities in the Free State province, South Africa. Design. Prospective cohort study with retrospective database linkage. We analysed data on patients enrolled in the treatment programme across 36 facilities between May 2004 and December 2007, and assessed percentage initiating ART and percentage dead at 1 year after enrolment. Multivariable logistic regression was used to estimate associations of facility-level and patient-level characteristics with both mortality and treatment status. Results. Of 44 866 patients enrolled, 15 219 initiated treatment within 1 year; 8 778 died within 1 year, 7 286 before accessing ART. Outcomes at 1 year varied greatly across facilities and more variability was explained by facility-level factors than by patient-level factors. The odds of starting treatment within 1 year improved over calendar time. Patients enrolled in facilities with treatment initiation available on site had higher odds of starting treatment and lower odds of death at 1 year compared with those enrolled in facilities that did not offer treatment initiation. Patients were less likely to start treatment if they were male, severely immunosuppressed (CD4 count ≤50 cells/μl), or underweight

Process evaluation for complex interventions in primary care: understanding trials using the normalization process model

Background: the Normalization Process Model is a conceptual tool intended to assist in understanding the factors that affect implementation processes in clinical trials and other evaluations of complex interventions. It focuses on the ways that the implementation of complex interventions is shaped by problems of workability and integration.Method: in this paper the model is applied to two different complex trials: (i) the delivery of problem solving therapies for psychosocial distress, and (ii) the delivery of nurse-led clinics for heart failure treatment in primary care.Results: application of the model shows how process evaluations need to focus on more than the immediate contexts in which trial outcomes are generated. Problems relating to intervention workability and integration also need to be understood. The model may be used effectively to explain the implementation process in trials of complex interventions.Conclusion: the model invites evaluators to attend equally to considering how a complex intervention interacts with existing patterns of service organization, professional practice, and professional-patient interaction. The justification for this may be found in the abundance of reports of clinical effectiveness for interventions that have little hope of being implemented in real healthcare setting

Neuromodulation of innate immunity by remote ischaemic conditioning in humans: Experimental cross-over study.

Experimental animal studies on the mechanisms of remote ischaemic conditioning (RIC)-induced cardioprotection against ischaemia/reperfusion injury demonstrate involvement of both neuronal and humoral pathways. Autonomic parasympathetic (vagal) pathways confer organ protection through both direct innervation and/or immunomodulation, but evidence in humans is lacking. During acute inflammation, vagal release of acetylcholine suppresses CD11b expression, a critical β2-integrin regulating neutrophil adhesion to the endothelium and transmigration to sites of injury. Here, we tested the hypothesis that RIC recruits vagal activity in humans and has an anti-inflammatory effect by reducing neutrophil CD11b expression. Participants (age:50 ​± ​19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 3 ​× ​8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate, heart rate variability (HRV)) before, and 10 ​min after, the last cycle of RIC. RR-interval increased after RIC (reduced heart rate) by 40 ​ms (95% confidence intervals (95%CI):13-66; n ​= ​17 subjects; P ​= ​0.003). RR-interval did not change after brachial plexus blockade (mean difference: 20 ​ms (95%CI:-11 to 50); P ​= ​0.19). The high-frequency component of HRV was reduced after RICblock, but remained unchanged after RIC (P ​< ​0.001), indicating that RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression in whole blood (measured by flow cytometry) was reduced by RIC (3615 median fluorescence units (95%CI:475-6754); P = 0.026), compared with 2331 units (95%CI:-3921 to 8582); P = 0.726) after RICblock. These data suggest that in humans RIC recruits vagal cardiac and anti-inflammatory mechanisms via ischaemia/reperfusion-induced activation of sensory nerve fibres that innervate the organ undergoing RIC

Bird collisions in a railway crossing a wetland of international importance (Sado estuary, Portugal)

L. Borda-de-Água et al. (eds.), Railway Ecology, chapter 7, p. 103-115Many studies have evaluated bird mortality in relation to roads and other human structures, but little is known about the potential impacts of railways. In particular, it is uncertain whether railways are an important mortality source when crossing wetlands heavily used by aquatic birds. Here we analyze bird collisions in a railway that crosses the Nature Reserve of the Sado Estuary (Portugal) over an annual cycle, documenting bird mortality and the flight behaviour of aquatic birds in relation to a bowstring bridge. During monthly surveys conducted on 16.3 km of railway, we found 5.8 dead birds/km/10 survey days in the section crossing wetland habitats (6.3 km), while <0.5 dead birds/km/10 survey days were found in two sections crossing only forested habitats. Most birds recorded were small songbirds (Passeriformes), while there was only a small number of aquatic birds (common moorhen, mallard, flamingo, great cormorant, gulls) and other non-passerines associated with wetlands (white stork). During nearly 400 h of observations, we recorded 27,000 movements of aquatic birds across the Sado bridge, particularly in autumn and winter. However, only <1% of movements were within the area of collision risk with trains, while about 91% were above the collision risk area, and 8% were below the bridge. Overall, our case study suggests that bird collisions may be far more numerous in railways crossing wetland habitats than elsewhere, although the risk to aquatic birds may be relatively low. Information from additional study systems would be required to evaluate whether our conclusions apply to other wetlands and railway linesinfo:eu-repo/semantics/publishedVersio

Using the theory of planned behaviour as a process evaluation tool in randomised trials of knowledge translation strategies : A case study from UK primary care

Peer reviewedPublisher PD

The functional response of a generalist predator

Peer reviewedPublisher PD

Beyond the limits of clinical governance? The case of mental health in English primary care

Background: Little research attention has been given to attempts to implement organisational initiatives to improve quality of care for mental health care, where there is a high level of indeterminacy and clinical judgements are often contestable. This paper explores recent efforts made at an organisational level in England to improve the quality of primary care for people with mental health problems through the new institutional processes of 'clinical governance'. Methods: Framework analysis, based on the Normalisation Process Model (NPM), of attempts over a five year period to develop clinical governance for primary mental health services in Primary Care Trusts (PCTs). The data come from a longitudinal qualitative multiple case-study approach in a purposive sample of 12 PCTs, chosen to reflect a maximum variety of organisational contexts for mental health care provision. Results: The constant change within the English NHS provided a difficult context in which to attempt to implement 'clinical governance' or, indeed, to reconstruct primary mental health care. In the absence of clear evidence or direct guidance about what 'primary mental health care' should be, and a lack of actors with the power or skills to set about realising it, the actors in 'clinical governance' had little shared knowledge or understanding of their role in improving the quality of mental health care. There was a lack of ownership of 'mental health' as an integral, normalised part of primary care. Conclusion: Despite some achievements in regard to monitoring and standardisation of prescribing practice, mental health care in primary care seems to have so far largely eluded the gaze of 'clinical governance'. Clinical governance in English primary mental health care has not yet become normalised. We make some policy recommendations which we consider would assist in the process normalisation and suggest other contexts to which our findings might apply