Improving Telemetry use in the Acute Assessment Unit.

BACKGROUND AND AIMS: Despite published guidelines, telemetry use is inappropriate in 25-43% of cases. This impacts patient safety and telemetry effectiveness. QI methodology was used to review telemetry in a hospital acute medical unit with the aim of reducing inappropriate use and addressing alarm fatigue. METHODS: A 'Telemetry Indication Form' was created. Eight weeks of baseline data was collated before introducing the 'Indication Form'. Four plan-do-study-act cycles were conducted. At each cycle, data was analysed using statistical process control charts. RESULTS: Inappropriate telemetry use significantly reduced from 32% to 4%. Total telemetry use also fell. Unfortunately, interventions to address alarm rates did not result in significant reduction in false alarms. CONCLUSIONS: A 'Telemetry Indication Form' has significant potential to improve patient safety through reducing inappropriate use.

Tautomerization of H+KPGG: Entropic Consequences of Strong Hydrogen-Bond Networks in Peptides.

Ion mobility spectrometry-mass spectrometry and quantum chemical calculations are used to determine the structures and stabilities of the singly protonated peptide H+KPGG. The two peaks making up the IMS distribution are shown to be tautomers differing by the location of the extra proton on either the lysine side chain or the N-terminus. The lysine-protonated tautomer is strongly preferred entropically while being disfavored in terms of the electronic energy and enthalpy. This relationship is shown, through comparison of all low-lying conformers of both tautomers, to be related to the strong hydrogen-bond network of the N-terminally protonated tautomer. A general relationship is demonstrated wherein stronger cross-peptide hydrogen-bond networks result in entropically disfavored conformers. Further effects of the H+KPGG hydrogen-bond network are probed by computationally examining singly and doubly methylated analogues. These results demonstrate the importance of the entropic consequences of hydrogen bonds to peptide stability as well as techniques for perturbing the hydrogen-bond network and folding preferences of peptides via minimal chemical modification.

Unveiling the catalytic mechanism of GTP hydrolysis in microtubules.

Microtubules (MTs) are large cytoskeletal polymers, composed of αß-tubulin heterodimers, capable of stochastically converting from polymerizing to depolymerizing states and vice versa. Depolymerization is coupled with hydrolysis of guanosine triphosphate (GTP) within ß-tubulin. Hydrolysis is favored in the MT lattice compared to a free heterodimer with an experimentally observed rate increase of 500- to 700-fold, corresponding to an energetic barrier lowering of 3.8 to 4.0 kcal/mol. Mutagenesis studies have implicated α-tubulin residues, α:E254 and α:D251, as catalytic residues completing the ß-tubulin active site of the lower heterodimer in the MT lattice. The mechanism for GTP hydrolysis in the free heterodimer, however, is not understood. Additionally, there has been debate concerning whether the GTP-state lattice is expanded or compacted relative to the GDP state and whether a "compacted" GDP-state lattice is required for hydrolysis. In this work, extensive quantum mechanics/molecular mechanics simulations with transition-tempered metadynamics free-energy sampling of compacted and expanded interdimer complexes, as well as a free heterodimer, have been carried out to provide clear insight into the GTP hydrolysis mechanism. α:E254 was found to be the catalytic residue in a compacted lattice, while in the expanded lattice, disruption of a key salt bridge interaction renders α:E254 less effective. The simulations reveal a barrier decrease of 3.8 ± 0.5 kcal/mol for the compacted lattice compared to a free heterodimer, in good agreement with experimental kinetic measurements. Additionally, the expanded lattice barrier was found to be 6.3 ± 0.5 kcal/mol higher than compacted, demonstrating that GTP hydrolysis is variable with lattice state and slower at the MT tip.

Unveiling the Catalytic Mechanism of GTP Hydrolysis in Microtubules.

Microtubules (MTs) are large cytoskeletal polymers, composed of αß-tubulin heterodimers, capable of stochastically converting from polymerizing to depolymerizing states and vice-versa. Depolymerization is coupled with hydrolysis of GTP within ß-tubulin. Hydrolysis is favored in the MT lattice compared to free heterodimer with an experimentally observed rate increase of 500 to 700 fold, corresponding to an energetic barrier lowering of 3.8 to 4.0 kcal/mol. Mutagenesis studies have implicated α-tubulin residues, α:E254 and α:D251, as catalytic residues completing the ß-tubulin active site of the lower heterodimer in the MT lattice. The mechanism for GTP hydrolysis in the free heterodimer, however, is not understood. Additionally, there has been debate concerning whether the GTP-state lattice is expanded or compacted relative to the GDP-state and whether a "compacted" GDP-state lattice is required for hydrolysis. In this work, extensive QM/MM simulations with transition-tempered metadynamics free energy sampling of compacted and expanded inter-dimer complexes, as well as free heterodimer, have been carried out to provide clear insight into the GTP hydrolysis mechanism. α:E254 was found to be the catalytic residue in a compacted lattice, while in the expanded lattice disruption of a key salt bridge interaction renders α:E254 less effective. The simulations reveal a barrier decrease of 3.8 ± 0.5 kcal/mol for the compacted lattice compared to free heterodimer, in good agreement with experimental kinetic measurements. Additionally, the expanded lattice barrier was found to be 6.3 ± 0.5 kcal/mol higher than compacted, demonstrating that GTP hydrolysis is variable with lattice state and slower at the MT tip. Significance Statement: Microtubules (MTs) are large and dynamic components of the eukaryotic cytoskeleton with the ability to stochastically convert from a polymerizing to a depolymerizing state and vice-versa. Depolymerization is coupled to the hydrolysis of guanosine-5'-triphosphate (GTP), which is orders of magnitude faster in the MT lattice than in free tubulin heterodimers. Our results computationally ascertain the catalytic residue contacts in the MT lattice that accelerate GTP hydrolysis compared to the free heterodimer as well as confirm that a compacted MT lattice is necessary for hydrolysis while a more expanded lattice is unable to form the necessary contacts and thereby hydrolyze GTP.

Aromatic Fragmentation Based on a Ring Overlap Scheme: An Algorithm for Large Polycyclic Aromatic Hydrocarbons Using the Molecules-in-Molecules Fragmentation-Based Method.

We present a novel and systematic fragmentation scheme to treat polycyclic aromatic hydrocarbons (PAHs) built off the molecules-in-molecules composite method. Our algorithm generates a set of biphenyl and naphthalene subsystems overlapping by whole sextet rings, ensuring all calculations are performed on aromatic molecules. Hence, our method is called Aromatic Fragmentation Based on a Ring Overlap Scheme (AroBOROS), and the generated fragments may be combined to form a hierarchy of subsystems to reduce errors for more complex PAHs. Errors are reduced to below chemical accuracy by combining subsystems that reflect the lowest energy structures determined by Clar's rule of aromatic sextets, and this is shown on two diverse test sets of PAHs ranging from 18 to 84 carbon atoms. Additionally, evaluations are performed for larger PAHs, as well as a nanotube fragment, containing up to 132 carbon atoms, and it is shown that good results may be achieved even with fragments representing an appreciably small portion of the full system.

Coupling Constants, High Spin, and Broken Symmetry States of Organic Radicals: an Assessment of the Molecules-in-Molecules Fragmentation-Based Method.

We extend the application of our multilayer molecules-in-molecules (MIM) fragmentation-based method to the study of open-shell systems, particularly organic radicals. A test set of organic mono-, di- and polyradicals with a wide range in size, containing up to 360 atoms, was investigated. Total energies computed with MIM using density functional theory (DFT) were compared with full, unfragmented energies to assess the performance of MIM and to develop a systematic protocol for the treatment of large radical systems. More specifically, a two-layer (MIM2) model with a fragmentation scheme along the backbone involving covalently bonded dimers, trimers, or tetramers was considered, with DFT at a smaller basis set serving as the low level of theory. The MIM method was evaluated on the high-spin state and several possible broken-symmetry (BS) states for di- and polyradicals. When relevant spin-spin interactions were considered, the errors in total energies were less than 1 kcal mol-1. In addition, the applicability of MIM2 was extended to predict the intersite magnetic exchange coupling constants (J), which were compared with reference values. Further, since the energy levels derived from Hamiltonian diagonalization are physically more meaningful, the calculated J values estimated from the BS-DFT methodology were used to obtain the lower spin state energies of the polyradicals. The difference in calculated total energies of the lower spin state between full and MIM2 lie within 1 kcal mol-1 in the majority of these cases. Our rigorous, quantum chemical study demonstrates that MIM can be successfully applied to the study of large organic radicals reliably and accurately within the framework of BS-DFT.

Untangling Hydrogen Bond Networks with Ion Mobility Spectrometry and Quantum Chemical Calculations: A Case Study on H+XPGG.

Ion mobility spectrometry-mass spectrometry and quantum chemical calculations are used to determine the structures and stabilities of singly protonated XaaProGlyGly peptides: H+DPGG, H+NPGG, H+EPGG, and H+QPGG. The IMS distributions are similar, suggesting the peptides adopt closely related structures in the gas phase. Quantum chemical calculations show that all conformers seen in the experimental spectrum correspond to the cis configuration about the Xaa-Pro peptide bond, significantly different from the behavior seen previously for H+GPGG. Density functional theory and quantum theory of atoms in molecules (QTAIM) investigations uncover a silent drama as a minor conformer not observed in the H+DPGG spectrum becomes the preferred conformer in H+QPGG, with both conformers being coincident in collision cross section. Investigation of the highly coupled hydrogen bond network, replete with CH···O interactions and bifurcated hydrogen bonds, reveals the cause of this effect as well as the absence of trans conformers from the spectra. A series of generalized observations are provided to aid in enzyme and ligand design using these coupled hydrogen bond motifs.

Theoretical Study of Protein-Ligand Interactions Using the Molecules-in-Molecules Fragmentation-Based Method.

We have recently significantly expanded the applicability of our Molecules-in-Molecules (MIM) fragmentation method to large proteins by developing a three-layer model (MIM3) in which an accurate quantum-mechanical method is used in conjunction with a cost-effective, dispersion-corrected semiempirical model to overcome previous computational bottlenecks. In this work, we develop MIM3 as a structure-based drug design tool by application of the methodology for the accurate calculation of protein-ligand interaction energies. A systematic protocol is derived for the determination of the geometries of the protein-ligand complexes and to calculate their accurate interaction energies in the gas phase using MIM3. We also derive a simple and affordable procedure based on implicit solvation models and the ligand solvent-accessible surface area to approximate the ligand desolvation penalty in gas-phase interaction energy calculations. We have carefully assessed how closely such interaction energies, which are based on a single protein-ligand conformation, display correlations with the experimentally determined binding affinities. The performance of MIM3 was evaluated on a total of seven data sets comprising 89 protein-ligand complexes, all with experimentally known binding affinities, using a binding pocket involving a quantum region ranging in size from 250 to 600 atoms. The dispersion-corrected B97-D3BJ density functional, previously known to perform accurately for calculations involving non-covalent interactions, was used as the target level of theory for this work, with dispersion-corrected PM6-D3 as the semiempirical low level to incorporate the long-range interactions. Comparing directly to the experimental binding potencies, we obtain impressive correlations over all seven test sets, with an R2 range of 0.74-0.93 and a Spearman rank correlation coefficient (ρ) range of 0.83-0.93. Our results suggest that protein-ligand interaction energies are useful in predicting binding potency trends and validate the potential of MIM3 as a quantum-chemical structure-based drug design tool.

Electronic Energies Are Not Enough: An Ion Mobility-Aided, Quantum Chemical Benchmark Analysis of H+GPGG Conformers.

Peptides and proteins exist not as single, lowest energy structures but as ensembles of states separated by small barriers. In order to study these species we must be able to correctly identify their gas phase conformational distributions, and ion mobility spectrometry (IMS) has arisen as an experimental method for assessing the gas phase energetics of flexible peptides. Here, we present a thorough exploration and benchmarking of the low energy conformers of the small, hairpin peptide H+GPGG with the aid of ion mobility spectrometry against a wide swath of density functionals (35 dispersion-corrected and uncorrected functionals represented by 21 unique exchange-correlation functionals) and wave function theory methods (15 total levels of theory). The three experimentally resolved IMS peaks were found to correspond to three distinct pairs of conformers, each pair composed of species differing only by the chair or boat configuration of the proline. Two of the H+GPGG conformer pairs possess a cis configuration about the Pro-Gly1 peptide bond while the other adopts a trans configuration. While the experimental spectrum reports a higher intensity for the cis-1 conformer than the trans conformer, 13 WFT levels of theory, including a complete basis set CCSD(T) extrapolation, obtain trans to be favored in terms of the electronic energy. This same effect is seen in 14 of the 18 dispersion-corrected density functionals studied, whereas the remaining 17 functionals show more variety. Only when Gibbs free energies are considered do the WFT methods and dispersion-corrected functionals reflect the experimental distribution. CAM-B3LYP-D3BJ emerges as the best-performing density functional, matching the experimental distribution and the CCSD(T)/CBS relative energies within 6%. Further analysis reveals the trans conformer to be favored electronically, but entropically disfavored, leading to the experimental preference of the cis-1 conformer. These results highlight the danger in considering only the electronic energies, which is common practice in electronic structure theory predictions of conformational energy distributions. Additionally, the effects of temperature and scaling of the frequencies used in obtaining the Gibbs free energies are explored.

Assessment of Fragmentation Strategies for Large Proteins Using the Multilayer Molecules-in-Molecules Approach.

We present a rigorous evaluation of the potential for the multilayer Molecules-in-Molecules (MIM) fragmentation method to be applied to large biomolecules. Density functional total energies of a test set of 8 peptides, sizes ranging from 107 to 721 atoms, were evaluated with MIM and compared to unfragmented energies to help develop a protocol for the treatment of large proteins. Fragmentation schemes involving subsystems of 4 to 5 covalently bonded fragments (tetramer or pentamer schemes) were tested with a single level of theory (MIM1) and produced errors on the order of 100 kcal/mol due to the relatively small size of the subsystems and the neglect of nonbonded interactions. Supplementing the two schemes with nonbonded dimer subsystems, formed from fragments within a specified cutoff distance (3.0 Å), nearly cut the MIM1 errors in half, leading us to employ these new schemes as starting points in multilayer calculations. When employing a DFT low level with a substantially smaller basis set (MIM2), the dimer-supplemented schemes produce errors below our target accuracy of 2 kcal/mol in the majority of cases. However, for the larger test systems, such as the 45 residue slice of a human protein kinase with over 10,000 basis functions in the high level, the low level calculation over the full molecule becomes the bottleneck for MIM2 calculations. To overcome any associated limitations, we explored, for the first time, 3-layer MIM methods (MIM3) with a distance-based medium level of fragmentation and dispersion-corrected semiempirical methods (e.g., PM6-D3) as the low level. A modestly sized cutoff distance in the medium level (3.0-3.5 Å), leading to subsystems of 30-50 atoms treated at the medium and low levels of theory, was able to match the low errors of the MIM2 calculations. These results allow us to develop a general prescription for 3-layer calculations wherein a much cheaper low level can be used, while fragment sizes in the high layer stay modest, allowing the MIM method to be applied to very large proteins in the future.

Hidden complexities in the reaction of H2O2 and HNO revealed by ab initio quantum chemical investigations.

Nitroxyl (HNO) and hydrogen peroxide have both been implicated in a variety of reactions relevant to environmental and physiological processes and may contribute to a unique, unexplored, pathway for the production of nitrous acid (HONO) in soil. To investigate the potential for this reaction, we report an in-depth investigation of the reaction pathway of H2O2 and HNO forming HONO and water. We find the breaking of the peroxide bond and a coupled proton transfer in the first step leads to hydrogen nitryl (HNO2) and an endogenous water, with an extrapolated NEVPT2 (multireference perturbation theory) barrier of 29.3 kcal mol-1. The first transition state is shown to possess diradical character linking the far peroxide oxygen to the bridging, reacting, peroxide oxygen. The energy of this first step, when calculated using hybrid density functional theory, is shown to depend heavily on the amount of Hartree-Fock exchange in the functional, with higher amounts leading to a higher barrier and more diradical character. Additionally, high amounts of spin contamination cause CCSD(T) to significantly overestimate the TS1 barrier with a value of 36.2 kcal mol-1 when using the stable UHF wavefunction as the reference wavefunction. However, when using the restricted Hartree-Fock reference wavefunction, the TS1 CCSD(T) energy is lowered to yield a barrier of 31.2 kcal mol-1, in much better agreement with the NEVPT2 result. The second step in the reaction is the isomerization of HNO2 to trans-HONO through a Grotthuss-like mechanism accepting a proton from and donating a proton to the endogenous water. This new mechanism for the isomerization of HNO2 is shown to have an NEVPT2 barrier of 23.3 kcal mol-1, much lower than previous unimolecular estimates not including an explicit water. Finally, inclusion of an additional explicit water is shown to lower the HNO2 isomerization barrier even further.

Variation in Acute Medicine Units: Measuring it, understanding it, and reducing it.

Although there are national recommendations on the function of Acute Medicine Units (AMUs), there is no single agreed best model of care. Additionally, robust data is not always available to determine whether system changes have resulted in improvement. We designed an Excel file to interface with the hospital patient management system to provide real-time data on a number of metrics including AMU length of stay (AMULOS), mortality and readmissions. This demonstrated that improving consultant continuity of care was associated with a reduction in AMULOS and reduced variation in AMULOS. Additionally, the Excel file provides timely access to consultant and individual patient-level data. These data are clinically owned, and critical for both unit governance and quality improvement work. We would encourage all AMUs to develop a similar dataset to allow standardised comparisons between units, and better understanding of the association between models of care and patient outcomes.

Vibrational Circular Dichroism Spectra for Large Molecules through Molecules-in-Molecules Fragment-Based Approach.

We present the first implementation of the vibrational circular dichroism (VCD) spectrum of large molecules through the Molecules-in-Molecules (MIM) fragment-based method. An efficient projection of the relevant higher energy derivatives from smaller fragments to the parent molecule enables the extension of the MIM method for the evaluation of VCD spectra (MIM-VCD). The overlapping primary subsystems in this work are constructed from interacting fragments using a number-based scheme and the dangling bonds are saturated with link hydrogen atoms. Independent fragment calculations are performed to evaluate the energies, Hessian matrix, atomic polar tensor (APT), and the atomic axial tensor (AAT). Subsequently, the link atom tensor components are projected back onto the corresponding host and supporting atoms through the Jacobian projection method, as in the ONIOM approach. In the two-layer model, the long-range interactions between fragments are accounted for using a less computationally intensive lower level of theory. The performance of the MIM model is calibrated on the d- and l-enantiomers of 10 carbohydrate benchmark molecules, with strong intramolecular interactions. The vibrational frequencies and VCD intensities are accurately reproduced relative to the full, unfragmented, results for these systems. In addition, the MIM-VCD method is employed to predict the VCD spectra of perhydrotriphenylene and cryptophane-A, yielding spectra in agreement with experiment. The accuracy and performance of the benchmark systems validate the MIM-VCD model for exploring vibrational circular dichroism spectra of large molecules.

Reducing cardiac arrests in the acute admissions unit: a quality improvement journey.

BACKGROUND: In 2010, the acute admissions unit (AAU) at Stirling Royal Infirmary had the highest number of cardiac arrests of any ward. A quality improvement project was undertaken to reduce this to <1/1000 admissions by December 2011. METHODS: In January 2011, based on initial needs assessment, we selected three initiatives to improve cardiac arrest rate: (1) structured response to deteriorating patients; (2) analysis of adverse events; and (3) improved end-of-life decision-making. We performed a failure modes effects analysis to identify reasons for the failure of early recognition and response. Ward staff conducted weekly safety meetings to engage unit staff and promote a safety culture of continuous improvement. Additionally, in July 2011 the unit adopted a ward-based clinical team structure with twice daily consultant ward rounds. Our primary outcome measure, cardiac arrests per 1000 admissions, was measured from January 2011 to August 2012. RESULTS: Over 17 months, the number of cardiac arrests per 1000 admissions fell from a baseline of 2.8/1000 admissions to 0.8/1000 admissions (71% reduction), referrals to palliative care increased by 22 to 37/1000 admissions per month (68% increase) and the 30-day mortality of patients admitted to the AAU fell from 6.3% to 4.8% (24% relative reduction). CONCLUSIONS: Through adoption of a shared goal, application of improvement methodology including the model for improvement to test new innovations, and promotion of a safety culture in the AAU, cardiac arrests were successfully reduced to <1/1000 admissions per month with an associated significant fall in mortality. This was achieved with negligible cost.

Significant deficiencies in the overnight use of a Standardised Early Warning Scoring system in a teaching hospital.

National Institute for Health and Clinical Excellence guidelines recommend the use of 'Track and Trigger' systems to identify early clinical deterioration. The Standardised Early Warning Score (SEWS) is used in the Royal Infirmary of Edinburgh. Previous work, suggested that the frequency and accuracy of SEWS documentation varied throughout the hospital. A prospective study was performed over a 14-night period looking at SEWS documentation in patients causing clinical concern requiring medical review, or triggering a SEWS of 4 (the 'trigger' score). SEWS charts were examined the following morning. In the ward arc, SEWS documentation was correct in only 21% of cases. The most frequent errors were one or more observations omitted (64%), SEWS total not calculated (55%) or incorrectly calculated (21%). Up to five errors per chart were noted. The observations most frequently omitted were respiratory rate, temperature and neurological status. In contrast, SEWS documentation was correct in 68% of patients in the combined assessment unit (CAU). This study demonstrates significant deficiencies in the overnight use of SEWS, particularly on the ward arc. This is particularly concerning as this study was limited only to patients already causing clinical concern, and highlights that basic observations are often incomplete, and the SEWS chart poorly understood and acted upon. SEWS recording and documentation was significantly better in CAU (P < 0.001, FET), where there is a dedicated, ongoing SEWS education programme for nursing and medical staff. We recommend this is rolled out across the hospital. Alternative methods of improving the use of SEWS are considered.

An unusual cause of fitting in a 20 year old girl.

Native renal artery stenosis resulting in hypertensive encephalopathy is exceptionally rare, with only 3 previous case reports in adults. We report such a case in a previously well 20 year old female.