Novel textbook outcomes following emergency laparotomy: Delphi exercise

Background Textbook outcomes are composite outcome measures that reflect the ideal overall experience for patients. There are many of these in the elective surgery literature but no textbook outcomes have been proposed for patients following emergency laparotomy. The aim was to achieve international consensus amongst experts and patients for the best Textbook Outcomes for non-trauma and trauma emergency laparotomy. Methods A modified Delphi exercise was undertaken with three planned rounds to achieve consensus regarding the best Textbook Outcomes based on the category, number and importance (Likert scale of 1–5) of individual outcome measures. There were separate questions for non-trauma and trauma. A patient engagement exercise was undertaken after round 2 to inform the final round. Results A total of 337 participants from 53 countries participated in all three rounds of the exercise. The final Textbook Outcomes were divided into ‘early’ and ‘longer-term’. For non-trauma patients the proposed early Textbook Outcome was ‘Discharged from hospital without serious postoperative complications (Clavien–Dindo ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation or death). For trauma patients it was ‘Discharged from hospital without unexpected transfusion after haemostasis, and no serious postoperative complications (adapted Clavien–Dindo for trauma ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation on or death)’. The longer-term Textbook Outcome for both non-trauma and trauma was ‘Achieved the early Textbook Outcome, and restoration of baseline quality of life at 1 year’. Conclusion Early and longer-term Textbook Outcomes have been agreed by an international consensus of experts for non-trauma and trauma emergency laparotomy. These now require clinical validation with patient data

Oriented Synchrotron Radiation Circular Dichroism and Linear Dichroism Spectroscopy of Peptides in Model Membranes

The orientation of membrane-associated alpha-helical peptides was investigated using novel methodologies of oriented Synchrotron Radiation Circular Dichroism (SRCD) and linear dichroism (SRLD) spectroscopies. Because of its enhanced signal-to-noise and a detector geometry that minimised optical artefacts associated with conventional CD studies of membrane suspensions, SRCD enabled the measurement of oriented CD spectra. To accomplish this a specially-designed sample cell holder was produced which would maintain constant humidity in hydrated film samples. Distinct spectra were obtained for peptides oriented parallel or normal to the direction of the beam, corresponding to the parallel and perpendicular pi to pi* and n to pi* electronic transitions. To provide similar information for peptides associated with lipid vesicles, SRLD was used to examine suspensions of vesicles in a coquette flow-cell. SRCD studies of the samples in the same couette enabled interpretation of the information. The model systems used in this study were peptides of the KALP family with a number of different phospholipids. In TFE solution and as well in lipid vesicle suspensions, KALP produced CD spectrum typical of an alpha helix in an isotropic solution, whilst in oriented samples different spectra associated with the different directional transitions of the peptide bonds were found for peptides oriented transmembrane or parallel to the membrane surface. The alignments of the peptides under the different conditions were compared with the results obtained by 15N solid state NMR of the peptide in oriented lipid multilayers. Thus, these new approaches to examining peptides in membranes can provide information that is complementary to the secondary structural information present in conventional CD spectra

Design, synthesis, radiolabeling and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential Positron Emission Tomography tracer for the dopamine D4 receptors

Here we describe the design, synthesis, and evaluation of physicochemical and pharmacological properties of D(4) dopamine receptor ligands related to N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (2). Structural features were incorporated to increase affinity for the target receptor, to improve selectivity over D(2) and σ(1) receptors, to enable labeling with carbon-11 or fluorine-18, and to adjust lipophilicity within the range considered optimal for brain penetration and low nonspecific binding. Compounds 7 and 13 showed the overall best characteristics: nanomolar affinity for the D(4) receptor, >100-fold selectivity over D(2) and D(3) dopamine receptors, 5-HT(1A), 5-HT(2A), and 5-HT(2C) serotonin receptors and σ(1) receptors, and log P = 2.37-2.55. Following intraperitoneal administration in mice, both compounds rapidly entered the central nervous system. The methoxy of N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide (7) was radiolabeled with carbon-11 and subjected to PET analysis in non-human primate. [(11)C]7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D(4) receptors

Synchrotron radiation circular dichroism (SRCD) spectroscopy: an enhanced method for examining protein conformations and protein interactions

CD (circular dichroism) spectroscopy is a well-established technique in structural biology. SRCD (synchrotron radiation circular dichroism) spectroscopy extends the utility and applications of conventional CD spectroscopy (using laboratory-based instruments) because the high flux of a synchrotron enables collection of data at lower wavelengths (resulting in higher information content), detection of spectra with higher signal-to-noise levels and measurements in the presence of absorbing components (buffers, salts, lipids and detergents). SRCD spectroscopy can provide important static and dynamic structural information on proteins in solution, including secondary structures of intact proteins and their domains, protein stability, the differences between wild-type and mutant proteins, the identification of natively disordered regions in proteins, and the dynamic processes of protein folding and membrane insertion and the kinetics of enzyme reactions. It has also been used to effectively study protein interactions, including protein-protein complex formation involving either induced-fit or rigid-body mechanisms, and protein-lipid complexes. A new web-based bioinformatics resource, the Protein Circular Dichroism Data Bank (PCDDB), has been created which enables archiving, access and analyses of CD and SRCD spectra and supporting metadata, now making this information publicly available. To summarize, the developing method of SRCD spectroscopy has the potential for playing an important role in new types of studies of protein conformations and their complexes