Detecting Deteriorating Patients in the Hospital: Development and Validation of a Novel Scoring System.

Rationale: Late recognition of patient deterioration in hospital is associated with worse outcomes, including higher mortality. Despite the widespread introduction of early warning score (EWS) systems and electronic health records, deterioration still goes unrecognized. Objectives: To develop and externally validate a Hospital- wide Alerting via Electronic Noticeboard (HAVEN) system to identify hospitalized patients at risk of reversible deterioration. Methods: This was a retrospective cohort study of patients 16 years of age or above admitted to four UK hospitals. The primary outcome was cardiac arrest or unplanned admission to the ICU. We used patient data (vital signs, laboratory tests, comorbidities, and frailty) from one hospital to train a machine-learning model (gradient boosting trees). We internally and externally validated the model and compared its performance with existing scoring systems (including the National EWS, laboratory-based acute physiology score, and electronic cardiac arrest risk triage score). Measurements and Main Results: We developed the HAVEN model using 230,415 patient admissions to a single hospital. We validated HAVEN on 266,295 admissions to four hospitals. HAVEN showed substantially higher discrimination (c-statistic, 0.901 [95% confidence interval, 0.898-0.903]) for the primary outcome within 24 hours of each measurement than other published scoring systems (which range from 0.700 [0.696-0.704] to 0.863 [0.860-0.865]). With a precision of 10%, HAVEN was able to identify 42% of cardiac arrests or unplanned ICU admissions with a lead time of up to 48 hours in advance, compared with 22% by the next best system. Conclusions: The HAVEN machine-learning algorithm for early identification of in-hospital deterioration significantly outperforms other published scores such as the National EWS.

A Comparison of the Quick Sequential (Sepsis-Related) Organ Failure Assessment Score and the National Early Warning Score in Non-ICU Patients With/Without Infection.

OBJECTIVES: The Sepsis-3 task force recommended the quick Sequential (Sepsis-Related) Organ Failure Assessment score for identifying patients with suspected infection who are at greater risk of poor outcomes, but many hospitals already use the National Early Warning Score to identify high-risk patients, irrespective of diagnosis. We sought to compare the performance of quick Sequential (Sepsis-Related) Organ Failure Assessment and National Early Warning Score in hospitalized, non-ICU patients with and without an infection. DESIGN: Retrospective cohort study. SETTING: Large U.K. General Hospital. PATIENTS: Adults hospitalized between January 1, 2010, and February 1, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the quick Sequential (Sepsis-Related) Organ Failure Assessment score and National Early Warning Score to 5,435,344 vital signs sets (241,996 hospital admissions). Patients were categorized as having no infection, primary infection, or secondary infection using International Classification of Diseases, 10th Edition codes. National Early Warning Score was significantly better at discriminating in-hospital mortality, irrespective of infection status (no infection, National Early Warning Score 0.831 [0.825-0.838] vs quick Sequential [Sepsis-Related] Organ Failure Assessment 0.688 [0.680-0.695]; primary infection, National Early Warning Score 0.805 [0.799-0.812] vs quick Sequential [Sepsis-Related] Organ Failure Assessment 0.677 [0.670-0.685]). Similarly, National Early Warning Score performed significantly better in all patient groups (all admissions, emergency medicine admissions, and emergency surgery admissions) for all outcomes studied. Overall, quick Sequential (Sepsis-Related) Organ Failure Assessment performed no better, and often worse, in admissions with infection than without. CONCLUSIONS: The National Early Warning Score outperforms the quick Sequential (Sepsis-Related) Organ Failure Assessment score, irrespective of infection status. These findings suggest that quick Sequential (Sepsis-Related) Organ Failure Assessment should be reevaluated as the system of choice for identifying non-ICU patients with suspected infection who are at greater risk of poor outcome.

What impact does nursing care left undone have on patient outcomes? Review of the literature.

AIMS AND OBJECTIVES: Systematic review of the impact of missed nursing care on outcomes in adults, on acute hospital wards and in nursing homes. BACKGROUND: A considerable body of evidence supports the hypothesis that lower levels of registered nurses on duty increase the likelihood of patients dying on hospital wards, and the risk of many aspects of care being either delayed or left undone (missed). However, the direct consequence of missed care remains unclear. DESIGN: Systematic review. METHODS: We searched Medline (via Ovid), CINAHL (EBSCOhost) and Scopus for studies examining the association of missed nursing care and at least one patient outcome. Studies regarding registered nurses, healthcare assistants/support workers/nurses' aides were retained. Only adult settings were included. Because of the nature of the review, qualitative studies, editorials, letters and commentaries were excluded. PRISMA guidelines were followed in reporting the review. RESULTS: Fourteen studies reported associations between missed care and patient outcomes. Some studies were secondary analyses of a large parent study. Most of the studies used nurse or patient reports to capture outcomes, with some using administrative data. Four studies found significantly decreased patient satisfaction associated with missed care. Seven studies reported associations with one or more patient outcomes including medication errors, urinary tract infections, patient falls, pressure ulcers, critical incidents, quality of care and patient readmissions. Three studies investigated whether there was a link between missed care and mortality and from these results no clear associations emerged. CONCLUSIONS: The review shows the modest evidence base of studies exploring missed care and patient outcomes generated mostly from nurse and patient self-reported data. To support the assertion that nurse staffing levels and skill mix are associated with adverse outcomes as a result of missed care, more research that uses objective staffing and outcome measures is required. RELEVANCE TO CLINICAL PRACTICE: Although nurses may exercise judgements in rationing care in the face of pressure, there are nonetheless adverse consequences for patients (ranging from poor experience of care to increased risk of infection, readmissions and complications due to critical incidents from undetected physiological deterioration). Hospitals should pay attention to nurses' reports of missed care and consider routine monitoring as a quality and safety indicator.

Development of a national maternity early warning score: centile based score development and Delphi informed escalation pathways.

Objective: To derive a new maternity early warning score (MEWS) from prospectively collected data on maternity vital signs and to design clinical response pathways with a Delphi consensus exercise. Design: Centile based score development and Delphi informed escalation pathways. Setting: Pregnancy Physiology Pattern Prediction (4P) prospective UK cohort study, 1 August 2012 to 28 December 2016. Participants: Pregnant people from the 4P study, recruited before 20 weeks' gestation at three UK maternity centres (Oxford, Newcastle, and London). 841, 998, and 889 women provided data in the early antenatal, antenatal, and postnatal periods. Main outcome measures: Development of a new national MEWS, assigning numerical weights to measurements in the lower and upper extremes of distributions of individual vital signs from the 4P prospective cohort study. Comparison of escalation rates of the new national MEWS with the Scottish and Irish MEWS systems from 18 to 40 weeks' gestation. Delphi consensus exercise to agree clinical responses to raised scores. Results: A new national MEWS was developed by assigning numerical weights to measurements in the lower and upper extremes (5%, 1%) of distributions of vital signs, except for oxygen saturation where lower centiles (10%, 2%) were used. For the new national MEWS, in a healthy population, 56% of observation sets resulted in a total score of 0 points, 26% a score of 1 point, 12% a score of 2 points, and 18% a score of ≥2 points (escalation of care is triggered at a total score of ≥2 points). Corresponding values for the Irish MEWS were 37%, 25%, 22%, and 38%, respectively; and for the Scottish MEWS, 50%, 18%, 21%, and 32%, respectively. All three MEWS were similar at the beginning of pregnancy, averaging 0.7-0.9 points. The new national MEWS had a lower mean score for the rest of pregnancy, with the mean score broadly constant (0.6-0.8 points). The new national MEWS had an even distribution of healthy population alerts across the antenatal period. In the postnatal period, heart rate threshold values were adjusted to align with postnatal changes. The centile based score derivation approach meant that each vital sign component in the new national MEWS had a similar alert rate. Suggested clinical responses to different MEWS values were agreed by consensus of an independent expert panel. Conclusions: The centile based MEWS alerted escalation of care evenly across the antenatal period in a healthy population, while reducing alerts in healthy women compared with other MEWS systems. How well the tool predicted adverse outcomes, however, was not assessed and therefore external validation studies in large datasets are needed. Unlike other MEWS systems, the new national MEWS was developed with prospectively collected data on vital signs and used a systematic, expert informed process to design an associated escalation protocol.

Outlier detection of vital sign trajectories from COVID-19 patients.

In this work, we present a novel trajectory comparison algorithm to identify abnormal vital sign trends, with the aim of improving recognition of deteriorating health.There is growing interest in continuous wearable vital sign sensors for monitoring patients remotely at home. These monitors are usually coupled to an alerting system, which is triggered when vital sign measurements fall outside a predefined normal range. Trends in vital signs, such as increasing heart rate, are often indicative of deteriorating health, but are rarely incorporated into alerting systems.We introduce a dynamic time warp distance-based measure to compare time series trajectories. We split each multi-variable sign time series into 180 minute, non-overlapping epochs. We then calculate the distance between all pairs of epochs. Each epoch is characterized by its mean pairwise distance (average link distance) to all other epochs, with clusters forming with nearby epochs.We demonstrate in synthetically generated data that this method can identify abnormal epochs and cluster epochs with similar trajectories. We then apply this method to a real-world data set of vital signs from 8 patients who had recently been discharged from hospital after contracting COVID-19. We show how outlier epochs correspond well with the abnormal vital signs and identify patients who were subsequently readmitted to hospital.

Multivariable prediction models for atrial fibrillation after cardiac surgery: a systematic review protocol.

INTRODUCTION: Dozens of multivariable prediction models for atrial fibrillation after cardiac surgery (AFACS) have been published, but none have been incorporated into regular clinical practice. One of the reasons for this lack of adoption is poor model performance due to methodological weaknesses in model development. In addition, there has been little external validation of these existing models to evaluate their reproducibility and transportability. The aim of this systematic review is to critically appraise the methodology and risk of bias of papers presenting the development and/or validation of models for AFACS. METHODS: We will identify studies that present the development and/or validation of a multivariable prediction model for AFACS through searches of PubMed, Embase and Web of Science from inception to 31 December 2021. Pairs of reviewers will independently extract model performance measures, assess methodological quality and assess risk of bias of included studies using extraction forms adapted from a combination of the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist and the Prediction Model Risk of Bias Assessment Tool. Extracted information will be reported by narrative synthesis and descriptive statistics. ETHICS AND DISSEMINATION: This systemic review will only include published aggregate data, so no protected health information will be used. Study findings will be disseminated through peer-reviewed publications and scientific conference presentations. Further, this review will identify weaknesses in past AFACS prediction model development and validation methodology so that subsequent studies can improve upon prior practices and produce a clinically useful risk estimation tool. PROSPERO REGISTRATION NUMBER: CRD42019127329.

Protocol describing a systematic review and mixed methods consensus process to define the deteriorated ward patient.

INTRODUCTION: Most patients admitted to hospital recover with treatments that can be administered on the general ward. A small but important group deteriorate however and require augmented organ support in areas with increased nursing to patient ratios. In observational studies evaluating this cohort, proxy outcomes such as unplanned intensive care unit admission, cardiac arrest and death are used. These outcome measures introduce subjectivity and variability, which in turn hinders the development and accuracy of the increasing numbers of electronic medical record (EMR) linked digital tools designed to predict clinical deterioration. Here, we describe a protocol for developing a new outcome measure using mixed methods to address these limitations. METHODS AND ANALYSIS: We will undertake firstly, a systematic literature review to identify existing generic, syndrome-specific and organ-specific definitions for clinically deteriorated, hospitalised adult patients. Secondly, an international modified Delphi study to generate a short list of candidate definitions. Thirdly, a nominal group technique (NGT) (using a trained facilitator) will take a diverse group of stakeholders through a structured process to generate a consensus definition. The NGT process will be informed by the data generated from the first two stages. The definition(s) for the deteriorated ward patient will be readily extractable from the EMR. ETHICS AND DISSEMINATION: This study has ethics approval (reference 16399) from the Central Adelaide Local Health Network Human Research Ethics Committee. Results generated from this study will be disseminated through publication and presentation at national and international scientific meetings.

A fast and automated solution for accurately resolving protein domain architectures.

MOTIVATION: Accurate prediction of the domain content and arrangement in multi-domain proteins (which make up >65% of the large-scale protein databases) provides a valuable tool for function prediction, comparative genomics and studies of molecular evolution. However, scanning a multi-domain protein against a database of domain sequence profiles can often produce conflicting and overlapping matches. We have developed a novel method that employs heaviest weighted clique-finding (HCF), which we show significantly outperforms standard published approaches based on successively assigning the best non-overlapping match (Best Match Cascade, BMC). RESULTS: We created benchmark data set of structural domain assignments in the CATH database and a corresponding set of Hidden Markov Model-based domain predictions. Using these, we demonstrate that by considering all possible combinations of matches using the HCF approach, we achieve much higher prediction accuracy than the standard BMC method. We also show that it is essential to allow overlapping domain matches to a query in order to identify correct domain assignments. Furthermore, we introduce a straightforward and effective protocol for resolving any overlapping assignments, and producing a single set of non-overlapping predicted domains. AVAILABILITY AND IMPLEMENTATION: The new approach will be used to determine MDAs for UniProt and Ensembl, and made available via the Gene3D website: http://gene3d.biochem.ucl.ac.uk/Gene3D/. The software has been implemented in C++ and compiled for Linux: source code and binaries can be found at: ftp://ftp.biochem.ucl.ac.uk/pub/gene3d_data/DomainFinder3/ CONTACT: yeats@biochem.ucl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Exploring the structure and function paradigm.

Advances in protein structure determination, led by the structural genomics initiatives have increased the proportion of novel folds deposited in the Protein Data Bank. However, these structures are often not accompanied by functional annotations with experimental confirmation. In this review, we reassess the meaning of structural novelty and examine its relevance to the complexity of the structure-function paradigm. Recent advances in the prediction of protein function from structure are discussed, as well as new sequence-based methods for partitioning large, diverse superfamilies into biologically meaningful clusters. Obtaining structural data for these functionally coherent groups of proteins will allow us to better understand the relationship between structure and function.

The CATH classification revisited--architectures reviewed and new ways to characterize structural divergence in superfamilies.

The latest version of CATH (class, architecture, topology, homology) (version 3.2), released in July 2008 (http://www.cathdb.info), contains 114,215 domains, 2178 Homologous superfamilies and 1110 fold groups. We have assigned 20,330 new domains, 87 new homologous superfamilies and 26 new folds since CATH release version 3.1. A total of 28,064 new domains have been assigned since our NAR 2007 database publication (CATH version 3.0). The CATH website has been completely redesigned and includes more comprehensive documentation. We have revisited the CATH architecture level as part of the development of a 'Protein Chart' and present information on the population of each architecture. The CATHEDRAL structure comparison algorithm has been improved and used to characterize structural diversity in CATH superfamilies and structural overlaps between superfamilies. Although the majority of superfamilies in CATH are not structurally diverse and do not overlap significantly with other superfamilies, approximately 4% of superfamilies are very diverse and these are the superfamilies that are most highly populated in both the PDB and in the genomes. Information on the degree of structural diversity in each superfamily and structural overlaps between superfamilies can now be downloaded from the CATH website.

How long do nursing staff take to measure and record patients' vital signs observations in hospital? A time-and-motion study.

INTRODUCTION: Monitoring vital signs in hospital is an important part of safe patient care. However, there are no robust estimates of the workload it generates for nursing staff. This makes it difficult to plan adequate staffing to ensure current monitoring protocols can be delivered. OBJECTIVE: To estimate the time taken to measure and record one set of patient's vital signs; and to identify factors associated with the time required to measure and record one set of patient's vital signs. METHODS: We undertook a time-and-motion study of 16 acute medical or surgical wards across four hospitals in England. Two trained observers followed a standard operating procedure to record the time taken to measure and record vital signs. We used mixed-effects models to estimate the mean time using whole vital signs rounds, which included equipment preparation, time spent taking vital signs at the bedside, vital signs documentation, and equipment storing. We tested whether our estimates were influenced by nurse, ward and hospital factors. RESULTS: After excluding non-vital signs related interruptions, dividing the length of a vital signs round by the number of vital signs assessments in that round yielded an estimated time per vital signs set of 5 min and 1 second (95% Confidence Interval (CI) = 4:39-5:24). If interruptions within the round were included, the estimated time was 6:26 (95% CI = 6:01-6:50). If only time taking each patient's vital signs at the bedside was considered, after excluding non-vital signs related interruptions, the estimated time was 3:45 (95% CI = 3:32-3:58). We found no substantial differences by hospital, ward or nurse characteristics, despite different systems for recording vital signs being used across the hospitals. DISCUSSION: The time taken to observe and record a patient's vital signs is considerable, so changes to recommended assessment frequency could have major workload implications. Variation in estimates derived from previous studies may, in part, arise from a lack of clarity about what was included in the reported times. We found no evidence that nurses save time when using electronic vital signs recording, or that the grade of staff measuring the vital signs influenced the time taken. CONCLUSIONS: Measuring and recording vital signs is time consuming and the impact of interruptions and preparation away from the bedside is considerable. When considering the nursing workload around vital signs assessment, no assumption of relative efficiency should be made if different technologies or staff groups are deployed.

FLORA: a novel method to predict protein function from structure in diverse superfamilies.

Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2-3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (alpha, beta, alphabeta) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues.

Night work for hospital nurses and sickness absence: a retrospective study using electronic rostering systems.

There is conflicting evidence on the effect of night work on sickness absence. Most previous studies used self-reporting to identify shift patterns and measure levels of sickness absence. In contrast, this study used objective data from electronic rosters to explore the association of nurses' patterns of night work and sickness absence. This was a retrospective longitudinal study of nurse roster data from 32 general medical and surgical wards in a large acute hospital in England. We used data from 3 years and included both registered nurses and unregistered nursing assistants. We used generalized linear-mixed models to explore the association between night work and the subsequent occurrence of sickness absence. Of 601,282 shifts worked by 1944 nursing staff, 38,051 shifts were lost due to sickness absence. After controlling for potential confounders including proportion of long (≥12 h) shifts worked, proportion of overtime shifts, proportion of shifts worked in the past 7 days, and staff grade, we found that staff working more than 75% of their shifts in the past 7 days as night shifts were more likely to experience sickness absence (aOR = 1.12; 95% CI: 1.03-1.21), compared to staff working on day only schedules. Sub-group analysis found that an association between a high proportion of night shifts worked and long-term sickness (aOR = 1.31; 95% CI: 1.15-1.50), but not short-term sickness. Working high proportions of night shifts, likely representing permanent night work schedules, is associated with a higher risk of long-term sickness absence for nurses working in inpatient adult wards in acute hospitals. The higher sickness absence rates associated with permanent night shifts could result in additional costs or loss of productivity for hospitals. This study challenges the assumption that permanent night schedules maximize circadian adjustment and, therefore, reduce health problems.

Trajectories of vital signs in patients with COVID-19.

BACKGROUND: The global pandemic of coronavirus disease 2019 (COVID-19) has placed a huge strain on UK hospitals. Early studies suggest that patients can deteriorate quickly after admission to hospital. The aim of this study was to model changes in vital signs for patients hospitalised with COVID-19. METHODS: This was a retrospective observational study of adult patients with COVID-19 admitted to one acute hospital trust in the UK (CV) and a cohort of patients admitted to the same hospital between 2013-2017 with viral pneumonia (VI). The primary outcome was the start of continuous positive airway pressure/non-invasive positive pressure ventilation, ICU admission or death in hospital. We used non-linear mixed-effects models to compare changes in vital sign observations prior to the primary outcome. Using observations and FiO2 measured at discharge in the VI cohort as the model of normality, we also combined individual vital signs into a single novelty score. RESULTS: There were 497 cases of COVID-19, of whom 373 had been discharged from hospital. 135 (36.2%) of patients experienced the primary outcome, of whom 99 died in hospital. In-hospital mortality was over 4-times higher in the CV than the VI cohort (26.5% vs 6%). For those patients who experienced the primary outcome, CV patients became increasingly hypoxaemic, with a median estimated FiO2 (0.75) higher than that of the VI cohort (estimated FiO2 of 0.35). Prior to the primary outcome, blood pressure remained within normal range, and there was only a small rise in heart rate. The novelty score showed that patients with COVID-19 deteriorated more rapidly that patients with viral pneumonia. CONCLUSIONS: Patients with COVID-19 who deteriorate in hospital experience rapidly-worsening respiratory failure, with low SpO2 and high FiO2, but only minor abnormalities in other vital signs. This has potential implications for the ability of early warning scores to identify deteriorating patients.

Managing new-onset atrial fibrillation in critically ill patients: a systematic narrative review.

OBJECTIVES: The aim of this review is to summarise the latest evidence on efficacy and safety of treatments for new-onset atrial fibrillation (NOAF) in critical illness. PARTICIPANTS: Critically ill adult patients who developed NOAF during admission. PRIMARY AND SECONDARY OUTCOMES: Primary outcomes were efficacy in achieving rate or rhythm control, as defined in each study. Secondary outcomes included mortality, stroke, bleeding and adverse events. METHODS: We searched MEDLINE, EMBASE and Web of Knowledge on 11 March 2019 to identify randomised controlled trials (RCTs) and observational studies reporting treatment efficacy for NOAF in critically ill patients. Data were extracted, and quality assessment was performed using the Cochrane Risk of Bias Tool, and an adapted Newcastle-Ottawa Scale. RESULTS: Of 1406 studies identified, 16 remained after full-text screening including two RCTs. Study quality was generally low due to a lack of randomisation, absence of blinding and small cohorts. Amiodarone was the most commonly studied agent (10 studies), followed by beta-blockers (8), calcium channel blockers (6) and magnesium (3). Rates of successful rhythm control using amiodarone varied from 30.0% to 95.2%, beta-blockers from 31.8% to 92.3%, calcium channel blockers from 30.0% to 87.1% and magnesium from 55.2% to 77.8%. Adverse effects of treatment were rarely reported (five studies). CONCLUSION: The reported efficacy of beta-blockers, calcium channel blockers, magnesium and amiodarone for achieving rhythm control was highly varied. As there is currently significant variation in how NOAF is managed in critically ill patients, we recommend future research focuses on comparing the efficacy and safety of amiodarone, beta-blockers and magnesium. Further research is needed to inform the decision surrounding anticoagulant use in this patient group.

Prophylactic use of platelets in critically ill patients with thrombocytopaenia: A retrospective two-centre observational study.

PURPOSE: We report the use and effect of prophylactic platelet transfusions in critically ill thrombocytopaenic patients, comparing patients with or without bone marrow failure as a cause of thrombocytopaenia. METHODS: A retrospective observational study of admissions to three intensive care units (ICU) in the UK. We identified thrombocytopaenic patients who received a platelet transfusion and extracted the platelet count prior and subsequent to platelet transfusion. We grouped patients with or without suspected bone marrow failure, defined by a total white cell count ≤1.0 × 109/L. RESULTS: Of 11,757 admissions, 399 (3.4%) patients received a platelet transfusion for thrombocytopaenia. The median [IQR] platelet count prior to transfusion in patients without bone marrow failure was 42 [28-64] × 109/L versus 14 [7-24] × 109/L (p < .0001) in those with. The median [IQR] increment in platelets following transfusion was lower in patients with marrow failure (12 [-1-23] × 109/L) compared to those without (18 [5-36] × 109/L) (p = .006). CONCLUSIONS: Platelet transfusions were given at a higher median platelet count than suggested by guidelines. Patients with bone marrow failure were transfused at a lower threshold and experienced a smaller increment in platelet count when compared to patients without marrow failure.

Improving classification in protein structure databases using text mining.

BACKGROUND: The classification of protein domains in the CATH resource is primarily based on structural comparisons, sequence similarity and manual analysis. One of the main bottlenecks in the processing of new entries is the evaluation of 'borderline' cases by human curators with reference to the literature, and better tools for helping both expert and non-expert users quickly identify relevant functional information from text are urgently needed. A text based method for protein classification is presented, which complements the existing sequence and structure-based approaches, especially in cases exhibiting low similarity to existing members and requiring manual intervention. The method is based on the assumption that textual similarity between sets of documents relating to proteins reflects biological function similarities and can be exploited to make classification decisions. RESULTS: An optimal strategy for the text comparisons was identified by using an established gold standard enzyme dataset. Filtering of the abstracts using a machine learning approach to discriminate sentences containing functional, structural and classification information that are relevant to the protein classification task improved performance. Testing this classification scheme on a dataset of 'borderline' protein domains that lack significant sequence or structure similarity to classified proteins showed that although, as expected, the structural similarity classifiers perform better on average, there is a significant benefit in incorporating text similarity in logistic regression models, indicating significant orthogonality in this additional information. Coverage was significantly increased especially at low error rates, which is important for routine classification tasks: 15.3% for the combined structure and text classifier compared to 10% for the structural classifier alone, at 10-3 error rate. Finally when only the highest scoring predictions were used to infer classification, an extra 4.2% of correct decisions were made by the combined classifier. CONCLUSION: We have described a simple text based method to classify protein domains that demonstrates an improvement over existing methods. The method is unique in incorporating structural and text based classifiers directly and is particularly useful in cases where inconclusive evidence from sequence or structure similarity requires laborious manual classification.

Cancer-associated mutations are preferentially distributed in protein kinase functional sites.

Protein kinases are a superfamily involved in many crucial cellular processes, including signal transmission and regulation of cell cycle. As a consequence of this role, kinases have been reported to be associated with many types of cancer and are considered as potential therapeutic targets. We analyzed the distribution of pathogenic somatic point mutations (drivers) in the protein kinase superfamily with respect to their location in the protein, such as in structural, evolutionary, and functionally relevant regions. We find these driver mutations are more clearly associated with key protein features than other somatic mutations (passengers) that have not been directly linked to tumor progression. This observation fits well with the expected implication of the alterations in protein kinase function in cancer pathogenicity. To explain the relevance of the detected association of cancer driver mutations at the molecular level in the human kinome, we compare these with genetically inherited mutations (SNPs). We find that the subset of nonsynonymous SNPs that are associated to disease, but sufficiently mild to the point of being widespread in the population, tend to avoid those key protein regions, where they could be more detrimental for protein function. This tendency contrasts with the one detected for cancer associated-driver-mutations, which seems to be more directly implicated in the alteration of protein function. The detailed analysis of protein kinase groups and a number of relevant examples, confirm the relation between cancer associated-driver-mutations and key regions for protein kinase structure and function.

The association between nurse staffing levels and the timeliness of vital signs monitoring: a retrospective observational study in the UK.

OBJECTIVES: Omissions and delays in delivering nursing care are widely reported consequences of staffing shortages, with potentially serious impacts on patients. However, studies so far have relied almost exclusively on nurse self-reporting. Monitoring vital signs is a key part of nursing work and electronic recording provides an opportunity to objectively measure delays in care. This study aimed to determine the association between registered nurse (RN) and nursing assistant (NA) staffing levels and adherence to a vital signs monitoring protocol. DESIGN: Retrospective observational study. SETTING: 32 medical and surgical wards in an acute general hospital in England. PARTICIPANTS: 538 238 nursing shifts taken over 30 982 ward days. PRIMARY AND SECONDARY OUTCOME MEASURES: Vital signs observations were scheduled according to a protocol based on the National Early Warning Score (NEWS). The primary outcome was the daily rate of missed vital signs (overdue by ≥67% of the expected time to next observation). The secondary outcome was the daily rate of late vital signs observations (overdue by ≥33%). We undertook subgroup analysis by stratifying observations into low, medium and high acuity using NEWS. RESULTS: Late and missed observations were frequent, particularly in high acuity patients (median=44%). Higher levels of RN staffing, measured in hours per patient per day (HPPD), were associated with a lower rate of missed observations in all (IRR 0.983, 95% CI 0.979 to 0.987) and high acuity patients (0.982, 95% CI 0.972 to 0.992). However, levels of NA staffing were only associated with the daily rate (0.954, CI 0.949 to 0.958) of all missed observations. CONCLUSIONS: Adherence to vital signs monitoring protocols is sensitive to levels of nurse and NA staffing, although high acuity observations appeared unaffected by levels of NAs. We demonstrate that objectively measured omissions in care are related to nurse staffing levels, although the absolute effects are small. STUDY REGISTRATION: The data and analyses presented here were part of the larger Missed Care study (ISRCTN registration: 17930973).