The effect of coronary revascularization treatment timing on mortality in patients with stable ischemic heart disease in British Columbia.

BACKGROUND: Prior research has shown that patients with stable ischemic heart disease who undergo delayed coronary artery bypass graft (CABG) surgery face higher mortality rates than those who receive CABG within the time recommended by physicians. However, this research did not account for percutaneous coronary intervention (PCI), a widely available alternative to delayed CABG in many settings. We sought to establish whether there was a difference in mortality between timely PCI and delayed CABG. METHODS: We identified 25,520 patients 60 years or older who underwent first-time non-emergency revascularization for angiographically-proven, stable left main or multi-vessel ischemic heart disease in British Columbia between January 1, 2001, and December 31, 2016. We estimated unadjusted and adjusted mortality after index revascularization or last staged PCI for patients undergoing delayed CABG compared to timely PCI. FINDINGS: After adjustment with inverse probability of treatment weights, at three years, patients who underwent delayed CABG had a statistically significant lower mortality compared with patients who received timely PCI (4.3% delayed CABG, 13.5% timely PCI; risk ratio 0.32, 95% CI 0.24-0.40). INTERPRETATION: Patients who undergo CABG with delay have a lower risk of death than patients who undergo PCI within appropriate time. Our results suggest that patients who wish to receive CABG as their revascularization treatment will receive a mortality benefit over PCI as an alternative strategy.

The effect of treatment timing on repeat revascularization in patients with stable ischemic heart disease.

Objectives: In patients with stable ischemic heart disease, there is no evidence for the effect of revascularization treatment timing on the need for repeat procedures. We aimed to determine if repeat revascularizations differed among patients who received coronary artery bypass graft surgery after the time recommended by physicians compared with those who had timely percutaneous coronary intervention. Methods: We identified 25,520 British Columbia residents 60 years or older who underwent first-time nonemergency revascularization for angiographically proven, stable left main or multivessel ischemic heart disease between January 1, 2001, and December 31, 2016. We estimated unadjusted and adjusted cumulative incidence functions for repeat revascularization, in the presence of death as a competing risk, after index revascularization or last staged percutaneous coronary intervention for patients undergoing delayed coronary artery bypass grafting compared with timely percutaneous coronary intervention. Results: After adjustment with inverse probability of treatment weights, at 3 years, patients who underwent delayed coronary artery bypass grafting had a statistically significant lower cumulative incidence of a repeat revascularization compared with patients who received timely percutaneous coronary intervention (4.84% delayed coronary artery bypass grafting, 12.32% timely percutaneous coronary intervention; subdistribution hazard ratio, 0.16, 95% CI, 0.04-0.65). Conclusions: Patients who undergo delayed coronary artery bypass grafting have a lower cumulative incidence of repeat revascularization than patients who undergo timely percutaneous coronary intervention. Patients who want to wait to receive coronary artery bypass grafting will see the benefit of lower repeat revascularization over percutaneous coronary intervention unaffected by a delay in treatment.

Prediction of viral protease inhibitors using proteochemometrics approach.

Being widely accepted tools in computational drug search, the (Q)SAR methods have limitations related to data incompleteness. The proteochemometrics (PCM) approach expands the applicability area by using description for both protein and ligand structures. The PCM algorithms are urgently required for the development of new antiviral agents. We suggest the PCM method using the TLMNA descriptors, combining the MNA descriptors of ligands and protein sequence N-grams. Our method was validated on the viral chymotrypsin-like proteases and their ligands. We have developed an original protocol allowing us to collect a comprehensive set of 15 protein sequences and more than 9000 ligands from the ChEMBL database. The N-grams were derived from the 3D-based alignment, accurately superposing ligand-binding regions. In testing the ligand set in SAR mode with MNA descriptors, an accuracy above 0.95 was determined that shows the perspective of the antiviral drug search in virtual chemical libraries. The effective PCM models were built with the TLMNA descriptor. The strong validation procedure with pair exclusion simulated the prediction of interactions between the new ligands and new targets, resulting in accuracy estimation up to 0.89. The PCM approach shows slightly lower accuracy caused by more uncertainty compared with SAR, but it overcomes the problem of data incompleteness.

Lanthanide Contraction in LnF3 (Ln = Ce-Lu) and Its Chemical and Structural Consequences: Part 1: Location of YF3 in the LnF3 Series According to Its Chemical and Structural Characteristics.

A lanthanide contraction(LC) of 14 lanthanides (Ln) from 58Ce to 71Lu consists of the interaction of Ln nucleus with 4f-electrons. Rare earth elements (REEs-R) include Sc, Y, La, and 14 Ln. They are located in 4-6th periods of the subgroup of group III. The electronic structure divides R into short (d- Sc, Y, La) and long (14 f-elements Ce-Lu) homologous series. The most important chemical consequence of LC is the creation of a new conglomerate of 16 RF3 by mixing fluorides of d- (Y, La) and f-elements. This determines the location of YF3 among LnF3. The location of YF3 depends on the structural (formula volumes-Vform) and thermochemical (temperatures and heats of phase transformations, phase diagrams) properties. The location of YF3 between HoF3 and ErF3 was determined by Vform at a standard pressure (Pst) and temperature (Tst). The location of YF3 according to heats of phase transformations ΔHfus and ΔHtrans is in a dimorphic structural subgroup (SSGr) D (Ln = Er-Lu), but without the exact "pseudo ZY". According to the temperatures of phase transformations (Ttrans) in LnF3 (Ln = Dy-Lu), YF3 is located in the SSGr D between ErF3 and TmF3. The ErF3-YF3 and YF3-TmF3 phase diagrams show it to be between ErF3 and TmF3. The crystals of five ß-LnF3 (Ln = Ho-Lu) and ß-YF3 were obtained in identical conditions and their crystal structures were studied. Vform (at Pst and Tst) with "pseudo" atomic numberZY = 67.42 was calculated from the unit cell parameters, which were defined with ±5 × 10-4 Å accuracy. It determines the location of YF3 between HoF3 and ErF3.

Lanthanide Contraction in LnF3 (Ln = Ce-Lu) and Its Chemical and Structural Consequences: Part 2: Specialized Empirical System of R3+ (R = Y, La, and 14 Ln) and F1- Ionic Radii for RF3 Series.

A specialized empirical (Spec-zd Emp) system of ionic radii (SIR) for R = Y3+, La3+, Ln3+, and F1- (R rare earth elements (REE)) was derived from the dependence of lanthanide contraction (LC) on the atomic number (Z) of lanthanides (Ln). LC decreased the radius of the cation with increasing Z. The structures of t-RF3 (LaF3-NdF3, "pseudot-SmF3") of the LaF3 type, 11 ß-LnF3 (Ln = Sm-Lu), and ß-YF3 of the ß-YF3 type were studied. The empirical basis of the shortest (F-F)min and (R-F)min distances was calculated from the structural data for the RF3 complete series. The dependence of (F-F)min on Z reached saturation at Z = 67 (Ho). The base F1- radius r- = 1.2539(16) Å was calculated as the arithmetic mean of five (F-F)min in LnF3 with Ln = Ho-Lu. For the LnF3 series with Ln contributions up to 75 % wt., the dependence of (Ln-F)min on Z reflected the non-uniformity of the 4f orbital filling. SIR was calculated as the difference in the empirical constants of RF3 (ionic radii of (R,Ln)3+ (r+) and F1- (r-)), the change in which was continuous over the series and did not depend on the type of structure: r+ = (ZR-F)min - ½(F-F)min (Z = 57-71). The changes in LC in the LnF3 series were described by a third-degree polynomial. LC reduced r+ by 24% (percentage relative to less) from 1.1671(16) Å (La3+) to 0.9439(17) Å (Lu3+). In the Spec-zd Emp SIR, r+ were constants that did not require corrections for a coordination number (CN). A comparison of r+ in the Spec-zd Emp SIR with other SIRs was performed.

Thermodynamic Origin of Negative Thermal Expansion Based on a Phase Transition-Type Mechanism in the GdF3-TbF3 System.

Multicomponent fluorides of rare earth elements (REEs-R) are phase transition-type negative thermal expansion (NTE-II) materials. NTE-II occurs in RF3-R'F3 systems formed by "mother" single-component dimorphic RF3 (R = Pm, Sm, Eu, and Gd) with a giant NTE-II. There are two structural types of RF3 polymorphic modifications: low-temperature ß-YF3 (ß-) and high-temperature LaF3 (t-). The change in a structural type is accompanied by a density anomaly: a volume of one formula unit (Vform) Vß- >Vt-. The empirical signs of volumetric changes ΔV/V of NTE-II materials were considered. For the GdF3-TbF3 model system, an "operating-temperature window ΔT" and a two-phase composition of NTE-II materials follows from the thermodynamics of chemical systems: the phase rule and the principle of continuity. A necessary and sufficient sign of NTE-II is a combination of polymorphism and the density anomaly. Isomorphism in RF3-R'F3 systems modifies RF3 chemically by forming two-component t- and ß- type R1-xR'xF3solid solutions (ss). Between the two monovariant curves of ss decay, a two-phase area with ΔTtrans > 0 (the "window ΔT") forms. A two-phase composite (t-ss + ß-ss) is an NTE-II material. Its constituent t-ss and ß-ss phases have different Vform corresponding to the selected T. According to the lever rule on a conode, Vform is calculated from the t-ss and ß-ss compositions, which vary with T along two monovariant curves of ss decay. For the GdF3-TbF3 system, ΔV/V = f(T), ΔV/V = f(ΔT) and the "window ΔT" = f(x) dependencies were calculated.

Physiotherapists' perspectives of barriers and facilitators to effective community provision after hip fracture: a qualitative study in England.

PURPOSE: to investigate physiotherapists' perspectives of effective community provision following hip fracture. METHODS: qualitative semi-structured interviews were conducted with 17 community physiotherapists across England. Thematic analysis drawing on the Theoretical Domains Framework identified barriers and facilitators to implementation of effective provision. Interviews were complemented by process mapping community provision in one London borough, to identify points of care where suggested interventions are in place and/or could be implemented. RESULTS: four themes were identified: ineffective coordination of care systems, ineffective patient stratification, insufficient staff recruitment and retention approaches and inhibitory fear avoidance behaviours. To enhance care coordination, participants suggested improving access to social services and occupational therapists, maximising multidisciplinary communication through online notation, extended physiotherapy roles, orthopaedic-specific roles and seven-day working. Participants advised the importance of stratifying patients on receipt of referrals, at assessment and into appropriately matched interventions. To mitigate insufficient staff recruitment and retention, participants proposed return-to-practice streams, apprenticeship schemes, university engagement, combined acute-community rotations and improving job description advertisements. To reduce effects of fear avoidance behaviour on rehabilitation, participants proposed the use of patient-specific goals, patient and carer education, staff education in psychological strategies or community psychologist access. Process mapping of one London borough identified points of care where suggested interventions to overcome barriers were in place and/or could be implemented. CONCLUSION: physiotherapists propose that effective provision of community physiotherapy following hip fracture could be improved by refining care coordination, utilising stratification techniques, employing enhanced recruitment and retainment strategies and addressing fear avoidance behaviours.

Two-Component Rare-Earth Fluoride Materials with Negative Thermal Expansion Based on a Phase Transition-Type Mechanism in 50 RF3-R'F3 (R = La-Lu) Systems.

The formation of materials with negative thermal expansion (NTE) based on a phase transition-type mechanism (NTE-II) in 50 T-x (temperature-composition) RF3-R'F3 (R = La-Lu) systems out of 105 possible is predicted. The components of these systems are "mother" RF3 compounds (R = Pm, Sm, Eu, and Gd) with polymorphic transformations (PolTrs), which occur during heating between the main structural types of RF3: ß-(ß-YF3) → t-(mineral tysonite LaF3). The PolTr is characterized by a density anomaly: the formula volume (Vform) of the low-temperature modification (Vß-) is higher than that of the high-temperature modification (Vt-) by a giant value (up to 4.7%). In RF3-R'F3 systems, isomorphic substitutions chemically modify RF3 by forming R1-xR'xF3solid solutions (ss) based on both modifications. A two-phase composite (ß-ss + t-ss) is a two-component NTE-II material with adjustable parameters. The prospects of using the material are estimated using the parameter of the average volume change (ΔV/Vav). The Vav at a fixed gross composition of a system is determined by the ß-ss and t-ss decay (synthesis) curves and the temperature T. The regulation of ΔV/Vav is achieved by changing T within a "window ΔT". The available ΔT values are determined using phase diagrams. A chemical classification (ChCl) translates the search for NTE-II materials from 15 RF3 into an array of 105 RF3-R'F3 systems. Phase diagrams are divided into 10 types of systems (TypeSs), in four of which NTE-II materials are formed. The tables of the systems that comprise these TypeSs are presented. The position of Ttrans of the PolTr on the T scale for a short quasi-system (QS) "from PmF3 to TbF3" determines the interval of the ΔTtrans offset achievable in the RF3-R'F3 systems: from -148 to 1186 ± 10 °C. NTE-II fluoride materials exceed known NTE-II materials by almost three times in this parameter. Equilibrium in RF3-R'F3 systems is established quickly. The number of qualitatively different two-component fluoride materials with the giant NTE-II can be increased by more than ten times compared to RF3 with NTE-II.

The effect of recognition on survival after out-of-hospital cardiac arrest and implications for biosensor technologies.

BACKGROUND: Biosensor technologies have been proposed as a solution to provide recognition and facilitate earlier responses to unwitnessed out-of-hospital cardiac arrest (OHCA) cases. We sought to estimate the effect of recognition on survival and modelled the potential incremental impact of increased recognition of unwitnessed cases on survival to hospital discharge, to demonstrate the potential benefit of biosensor technologies. METHODS: We included cases from the British Columbia Cardiac Arrest Registry (2019-2020), which includes Emergency Medical Services (EMS)-assessed OHCAs. We excluded cases that would not have benefitted from early recognition (EMS-witnessed, terminal illness, or do-not-resuscitate). Using a mediation analysis, we estimated the relative benefits on survival of a witness recognizing vs. intervening in an OHCA; and estimated the expected additional number of survivors resulting from increasing recognition alone using a bootstrap logistic regression framework. RESULTS: Of 13,655 EMS-assessed cases, 11,412 were included (6314 EMS-treated, 5098 EMS-untreated). Survival to hospital discharge was 191/8879 (2.2%) in unwitnessed cases and 429/2533 (17%) in bystander-witnessed cases. Of the total effect attributable to a bystander witness, recognition accounted for 84% (95% CI: 72, 86) of the benefit. If all previously unwitnessed cases had been bystander witnessed, we would expect 1198 additional survivors. If these cases had been recognized, but no interventions performed, we would expect 912 additional survivors. CONCLUSION: Unwitnessed OHCA account for the majority of OHCAs, yet survival is dismal. Methods to improve recognition, such as with biosensor technologies, may lead to substantial improvements in overall survival.

Frequency, duration, and type of physiotherapy in the week after hip fracture surgery - analysis of implications for discharge home, readmission, survival, and recovery of mobility.

PURPOSE: To examine the association between physiotherapy access after hip fracture and discharge home, readmission, survival, and mobility recovery. METHODS: A 2017 Physiotherapy Hip Fracture Sprint Audit was linked to hospital records for 5383 patients. Logistic regression was used to estimate the association between physiotherapy access in the first postoperative week and discharge home, 30-day readmission post-discharge, 30-day survival and 120-days mobility recovery post-admission adjusted for age, sex, American Society of Anesthesiology grade, Hospital Frailty Risk Score and prefracture mobility/residence. RESULTS: Overall, 73% were female and 40% had high frailty risk. Patients who received ≥2 hours of physiotherapy (versus less) had 3% (95% Confidence Interval: 0-6%), 4% (2-6%), and 6% (1-11%) higher adjusted probabilities of discharge home, survival, and outdoor mobility recovery, and 3% (0-6%) lower adjusted probability of readmission. Recipients of exercise (versus mobilisation alone) had 6% (1-12%), 3% (0-7%), and 11% (3-18%) higher adjusted probabilities of discharge home, survival, and outdoor mobility recovery, and 6% (2-10%) lower adjusted probability of readmission. Recipients of 6-7 days physiotherapy (versus 0-2 days) had 8% (5-11%) higher adjusted probability of survival. For patients with dementia, improved probability of survival, discharge home, readmission and indoor mobility recovery were observed with greater physiotherapy access. CONCLUSION: Greater access to physiotherapy was associated with a higher probability of positive outcomes. For every 100 patients, greater access could equate to an additional eight patients surviving to 30-days and six avoiding 30-day readmission. The findings suggest a potential benefit in terms of home discharge and outdoor mobility recovery. CONTRIBUTION OF THE PAPER.

The method predicting interaction between protein targets and small-molecular ligands with the wide applicability domain.

Prediction of protein-ligand interaction is necessary for drug design, gene regulatory networks investigation, and chemical probes detection. The existing methods commonly demonstrate high prediction accuracy for the particular groups of protein and their ligands. We developed an approach suited for the wider applicability and tested it on three dataset types significantly differing by protein homology. The study included three typical scenarios of assessing the target-ligand interaction: 1st - predicting protein targets by ligand structures' comparisons; 2nd - predicting ligands by target sequences' comparisons; 3rd - predicting both the uncharacterized targets and ligands with the fuzzy coefficients based on ligand comparisons. The 1st scenario implemented showed a high prediction accuracy of 0.96-0.99, providing fuzzy coefficients of target-ligand interactions in the 3rd scenario. Testing by 2nd scenario displayed the accuracy of 0.97-0.99 for predicting within the particular protein families, sets non-ordered by protein homology, and accuracy higher than 0.90 for most HIV sets, each presenting the close mutant proteins differing by point substitutions. The 3rd scenario displayed that fuzzy classification can reveal reasonable accuracy 0.86-0.94 at simulated data incompleteness. Thus, our approach provides high prediction accuracy with the wide applicability domain, including data differing in heterogeneity and completeness.

Factors affecting mortality after coronary bypass surgery: a scoping review.

OBJECTIVES: Previous research reports numerous factors of post-operative mortality in patients undergoing isolated coronary artery bypass graft surgery. However, this evidence has not been mapped to the conceptual framework of care improvement. Without such mapping, interventions designed to improve care quality remain unfounded. METHODS: We identified reported factors of in-hospital mortality post isolated coronary artery bypass graft surgery in adults over the age of 19, published in English between January 1, 2000 and December 31, 2019, indexed in PubMed, CINAHL, and EMBASE. We grouped factors and their underlying mechanism for association with in-hospital mortality according to the augmented Donabedian framework for quality of care. RESULTS: We selected 52 factors reported in 83 articles and mapped them by case-mix, structure, process, and intermediary outcomes. The most reported factors were related to case-mix (characteristics of patients, their disease, and their preoperative health status) (37 articles, 27 factors). Factors related to care processes (27 articles, 12 factors) and structures (11 articles, 6 factors) were reported less frequently; most proposed mechanisms for their mortality effects. CONCLUSIONS: Few papers reported on factors of in-hospital mortality related to structures and processes of care, where intervention for care quality improvement is possible. Therefore, there is limited evidence to support quality improvement efforts that will reduce variation in mortality after coronary artery bypass graft surgery.

Time of coronary revascularization: methodology of a mediation analysis study.

BACKGROUND: The advantage of coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI), established in trials, may not be generalizable to populations in which the method of treatment determines the time to treatment. We sought to describe the methodology of a population-based observational study for assessing how changes in time to treatment may affect the comparative effectiveness of these 2 methods of coronary revascularization. METHODS: We propose a framework of causal mediation analysis to compare the outcomes of choosing CABG over PCI, if patients selected for either method waited the same amount of time had they undergone a PCI. We will include patients who underwent a first-time, nonurgent isolated CABG or single-session PCI for multivessel or left main coronary artery disease from January 2001 to December 2016, in British Columbia. We will use absolute risk difference as a measure of the total effect of choosing CABG over PCI and partition it into the direct effect of the treatment choice and the effect mediated by the treatment-specific timing. INTERPRETATION: Understanding how time to treatment mediates the relation between method of revascularization and outcomes will have implications for treatment selection, resource allocation and planning benchmarks. Findings on the benefits and risks of performing PCI or CABG within a certain time will guide multidisciplinary teams in determining the appropriate revascularization method for individual patients.

A systematic, concept-based method of developing the exposure measure for drug safety and effectiveness studies.

PURPOSE: In drug safety and effectiveness studies based on secondary data, the choice of an appropriate exposure measure for a given outcome can be challenging. Different measures of exposure can yield different estimates of treatment effect and safety. There is a knowledge gap with respect to developing and refining measures of drug exposure, to ensure that the exposure measure addresses the study question and is suitable for statistical analysis. METHODS: We present a transparent, step-by-step approach to the development of drug exposure measures involving secondary data. This approach would be of interest to students and investigators with initial training in pharmacoepidemiology. We illustrate the approach using a study about Parkinson's disease. RESULTS: We described the exposure specifications according to the study question. Next, we refined the exposure measure by linking it to knowledge about four major concepts in drug safety and effectiveness studies: drug use patterns, duration, timing, and dose. We then used this knowledge to guide the ultimate choice of exposure measure: time-varying, cumulative 6-month exposure to tamsulosin (a drug used to treat prostate hyperplasia). CONCLUSIONS: The proposed approach links exposure specifications to four major concepts in drug safety and effectiveness studies. Formulating subject-matter knowledge about these major concepts provides an avenue to develop the rationale and specifications for the exposure measure.

Orthopaedic physiotherapists' perceptions of mechanisms for observed variation in the implementation of physiotherapy practices in the early postoperative phase after hip fracture: a UK qualitative study.

OBJECTIVE: to explore physiotherapists' perceptions of mechanisms to explain observed variation in early postoperative practice after hip fracture surgery demonstrated in a national audit. METHODS: a qualitative semi-structured interview study of 21 physiotherapists working on orthopaedic wards at seven hospitals with different durations of physiotherapy during a recent audit. Thematic analysis of interviews drawing on Normalisation Process Theory to aid interpretation of findings. RESULTS: four themes were identified: achieving protocolised and personalised care; patient and carer engagement; multidisciplinary team engagement across the care continuum and strategies for service improvement. Most expressed variation from protocol was legitimate when driven by what is deemed clinically appropriate for a given patient. This tailored approach was deemed essential to optimise patient and carer engagement. Participants reported inconsistent degrees of engagement from the multidisciplinary team attributing this to competing workload priorities, interpreting 'postoperative physiotherapy' as a single professional activity rather than a care delivery approach, plus lack of integration between hospital and community care. All participants recognised changes needed at both structural and process levels to improve their services. CONCLUSION: physiotherapists highlighted an inherent conflict between their intention to deliver protocolised care and allowing for an individual patient-tailored approach. This conflict has implications for how audit results should be interpreted, how future clinical guidelines are written and how physiotherapists are trained. Physiotherapists also described additional factors explaining variation in practice, which may be addressed through increased engagement of the multidisciplinary team and resources for additional staffing and advanced clinical roles.

Prediction of Protein-ligand Interaction Based on Sequence Similarity and Ligand Structural Features.

Computationally predicting the interaction of proteins and ligands presents three main directions: the search of new target proteins for ligands, the search of new ligands for targets, and predicting the interaction of new proteins and new ligands. We proposed an approach providing the fuzzy classification of protein sequences based on the ligand structural features to analyze the latter most complicated case. We tested our approach on five protein groups, which represented promised targets for drug-like ligands and differed in functional peculiarities. The training sets were built with the original procedure overcoming the data ambiguity. Our study showed the effective prediction of new targets for ligands with an average accuracy of 0.96. The prediction of new ligands for targets displayed the average accuracy 0.95; accuracy estimates were close to our previous results, comparable in accuracy to those of other methods or exceeded them. Using the fuzzy coefficients reflecting the target-to-ligand specificity, we provided predicting interactions for new proteins and new ligands; the obtained accuracy values from 0.89 to 0.99 were acceptable for such a sophisticated task. The protein kinase family case demonstrated the ability to account for subtle features of proteins and ligands required for the specificity of protein-ligand interaction.

Variation in surgical demand and time to hip fracture repair: a Canadian database study.

BACKGROUND: Competing demands for operative resources may affect time to hip fracture surgery. We sought to determine the time to hip fracture surgery by variation in demand in Canadian hospitals. METHODS: We obtained discharge abstracts of 151,952 patients aged 65 years or older who underwent surgery for a hip fracture between January, 2004 and December, 2012 in nine Canadian provinces. We compared median time to surgery (in days) when demand could be met within a two-day benchmark and when demand required more days, i.e. clearance time, to provide surgery, overall and stratified by presence of medical reasons for delay. RESULTS: For persons admitted when demand corresponded to a 2-day clearance time, 68% of patients underwent surgery within the 2-day benchmark. When demand corresponded to a clearance time of one week, 51% of patients underwent surgery within 2 days. Compared to demand that could be served within the two-day benchmark, adjusted median time to surgery was 5.1% (95% confidence interval [CI] 4.1-6.1), 12.2% (95% CI 10.3-14.2), and 22.0% (95% CI 17.7-26.2) longer, when demand required 4, 6, and 7 or more days to clear the backlog, respectively. After adjustment, delays in median time to surgery were similar for those with and without medical reasons for delay. CONCLUSION: Increases in demand for operative resources were associated with dose-response increases in the time needed for half of hip fracture patients to undergo surgery. Such delays may be mitigated through better anticipation of day-to-day supply and demand and increased response capability.

Constructing treatment episodes from concomitant medication logs: a prospective observational study.

OBJECTIVES: To describe an approach using concomitant medication log records for the construction of treatment episodes. Concomitant medication log records are routinely collected in clinical studies. Unlike prescription and dispensing records, concomitant medication logs collect utilisation data. Logs can provide information about drug safety and drug repurposing. DESIGN: A prospective multicentre, multicohort observational study. SETTING: Twenty-one clinical sites in the USA, Europe, Israel and Australia. PARTICIPANTS: 415 subjects from the de novo cohort of the Parkinson's Progression Markers Initiative. METHODS: We construct treatment episodes of concomitant medication use. The proposed approach treats temporal gaps as a stoppage of medication and temporal overlaps as simultaneous use or changes in dose. Log records with no temporal gaps were combined into a single treatment episode. RESULTS: 5723 concomitant medication log records were used to construct 3655 treatment episodes for 65 medications. There were 405 temporal gaps representing a stoppage of medication; 985 temporal overlaps representing simultaneous regimens of the same medication and 2696 temporal overlaps representing a change in dose regimen. The median episode duration was 37 months (IQ interval: 11-73 months). CONCLUSIONS: The proposed approach for constructing treatment episodes offers a method of estimating duration and dose of treatment from concomitant medication log records. The accompanying recommendations guide log data collection to improve their quality for drug safety and drug repurposing.

Functional and structural features of proteins associated with alternative splicing.

The alternative splicing is a mechanism increasing the number of expressed proteins and a variety of these functions. We uncovered the protein domains most frequently lacked or occurred in the splice variants. Proteins presented by several isoforms participate in such processes as transcription regulation, immune response, etc. Our results displayed the association of alternative splicing with branched regulatory pathways. By considering the published data on the protein proteins encoded by the 18th human chromosome, we noted that alternative products display the differences in several functional features, such as phosphorylation, subcellular location, ligand specificity, protein-protein interactions, etc. The investigation of alternative variants referred to the protein kinase domain was performed by comparing the alternative sequences with 3D structures. It was shown that large enough insertions/deletions could be compatible with the kinase fold if they match between the conserved secondary structures. Using the 3D data on human proteins, we showed that conformational flexibility could accommodate fold alterations in splice variants. The investigations of structural and functional differences in splice isoforms are required to understand how to distinguish the isoforms expressed as functioning proteins from the non-realized transcripts. These studies allow filling the gap between genomic and proteomic data.

Prediction of Protein-Ligand Interaction Based on the Positional Similarity Scores Derived from Amino Acid Sequences.

The affinity of different drug-like ligands to multiple protein targets reflects general chemical-biological interactions. Computational methods estimating such interactions analyze the available information about the structure of the targets, ligands, or both. Prediction of protein-ligand interactions based on pairwise sequence alignment provides reasonable accuracy if the ligands' specificity well coincides with the phylogenic taxonomy of the proteins. Methods using multiple alignment require an accurate match of functionally significant residues. Such conditions may not be met in the case of diverged protein families. To overcome these limitations, we propose an approach based on the analysis of local sequence similarity within the set of analyzed proteins. The positional scores, calculated by sequence fragment comparisons, are used as input data for the Bayesian classifier. Our approach provides a prediction accuracy comparable or exceeding those of other methods. It was demonstrated on the popular Gold Standard test sets, presenting different sequence heterogeneity and varying from the group, including different protein families to the more specific groups. A reasonable prediction accuracy was also found for protein kinases, displaying weak relationships between sequence phylogeny and inhibitor specificity. Thus, our method can be applied to the broad area of protein-ligand interactions.