Bio-entity extraction is a pivotal component for information extraction from biomedical literature. The dictionary-based bio-entity extraction is the first generation of Named Entity Recognition (NER) techniques.This paper presents a hybrid dictionary-based bio-entity extraction technique. The approach expands the bio-entity dictionary by combining different data sources and improves the recall rate through the shortest path edit distance algorithm. In addition, the proposed technique adopts text mining techniques in the merging stage of similar entities such as Part of Speech (POS) expansion, stemming, and the exploitation of the contextual cues to further improve the performance.The experimental results show that the proposed technique achieves the best or at least equivalent performance among compared techniques, GENIA, MESH, UMLS, and combinations of these three resources in F-measure.The results imply that the performance of dictionary-based extraction techniques is largely influenced by information resources used to build the dictionary. In addition, the edit distance algorithm shows steady performance with three different dictionaries in precision whereas the context-only technique achieves a high-end performance with three difference dictionaries in recall. The extraction of biomedical entities from scientific literature is a challenging task encountered in many applications such as system biology, molecular biology, and bioinformatics. One of the early, continuously adopted approaches is the dictionary-based entity extraction. Dictionary-based entity extraction extracts all the matched strings from a given text by entities defined in a dictionary. Based on the lemma for a given term, it recognizes a term by searching the most similar  one in the dictionary. This makes dictionary-based approaches particularly useful for practical information extraction from biomedical documents as the first step for extraction . In addiHowever, dictionary-based approaches have two major performance bottlenecks. First, the false positives, inherent with using short names, significantly degrade the overall accuracy. Exclusion of short names from the dictionary may resolve this issue, but it is not the ultimate solution in that such a solution disallows for recognizing short protein or gene names. Second, spelling variation makes dictionary-based approaches less usable. For example, the gene name "DC2-dopamine receptor" has many spelling variants such as "dopamine DC2 receptor," and "dopamine DC2 receptor." Exact matching techniques mainly employed by dictionary-based approaches treat these terms as distinct ones.We alleviate this problem by using an approximate string matching method in which surface-level similarities between terms are considered. In order to mitigate the low recall problem associated with dictionary-based approaches, we combine entity extraction with soft-matching scheme that is capable of handling variant entity names. To this end, we propose a new entity extraction technique comprised of several different techniques. The proposed technique consists of 1) the approximate string distance algorithm to retrieve candidate entries, 2) shortest-path edit distance algorithm (SPED), and 3) text mining techniques such as Part-Of-Speech (POS) tagging and utilization of syntactical properties of terms. The experimental results show that in most cases, the performance of the proposed technique is superior to other approaches.The rest of the paper is organized as follows: Section 2 describes the studies related to the present paper. Section 3 explains the proposed technique in depth. Section 4 reports on the data collection and the experimental results. Section 5 concludes the paper with a discussion of future research.The dictionary-based entity extraction is still widely used method for biomedical literature annotation and indexing . The majStemming from the development of the GENIA corpus , many stBesides hand-crafted methods, machine learning methods have also been explored in the domain of extract bio-entities. Nenadic et al.  used a mIn this section, we provide in-depth details of the proposed technique. The algorithm is described in Table We utilized the Medical Subject Headings (MeSH) tree as one of the sources to construct an entity mapping dictionary. MeSH contains 25,588 term descriptors 2010 version) that denote various general medical terms such as Anatomy Disorders and Physiologic Function, as well as specific terms such as B-Lymphocytes, Regulatory and Langerhans Cells. MeSH is managed by domain experts and indexers at the National Library of Medicine (NLM). Their primary task is to assign the most specific terms in the MeSH tree to a PubMed record. MeSH terms are structured in a tree hierarchy that defines the hierarchical relationship among terms. Figure 0 versionDescriptors provided in MeSH are grouped into 16 categories. For example, category A, B, C, and C are related to anatomic terms, organisms, diseases, drugs and chemicals, respectively. Each category consists of an array of subcategories, and in each subcategory, descriptors are structured in the form of an upside down tree. Although MeSH categories do not officially represent an authoritative subject classification scheme, they help guide indexers to assign subject headings to documents or researchers to search for literature. In this paper, MeSH tree enables us to build a dictionary where each MeSH term in the sub-trees is mapped to the top label term. To expand the idea of the dictionary construction, we make use of GENIA as well as UMLS to examine the influence of the source on mapping accuracy.GENIA is a gene corpus consisting of 1,999 MEDLINE records to help develop and evaluate information extraction and text mining systems for the medical domain. The corpus is annotated with various levels of linguistic and semantic information related to genes. UMLS stands for Unified Medical Language System developed by the National Library of Medicine. UMLS consists of three knowledge sources: the Metathesaurus, the Semantic Network, and the SPECIALIST Lexicon. The Metathesaurus is a vocabulary database that contains information about biomedical related concepts and the relationships among them. The semantic network categorizes all concepts represented in the UMLS Metathesaurus and provides a set of useful relationships between these concepts. The SPECIALIST Lexicon provides the lexical information needed for the SPECIALIST NLP tool.The exact match technique is the simplest one to utilize a dictionary to spot candidate terms. Several fast exact match algorithms such as Boyer-Moore algorithm  have beeUnlike this exact matching algorithm, the approximated matching technique is based on weighted edit distance of strings from dictionary entries. In other words, it is a fuzzy dictionary matching strategy. The data structure for the underlying dictionary is a trie in order to support efficient search for matches. The approximate string matching technique is implemented based on the algorithm proposed by . The algSPED, an extension of algorithm from Rudniy et al. , calculaS and T are aligned on the sides of a rectangular. String S is placed along the top horizontal side while string T is aligned along the left vertical side. The two strings are divided into the substrings of the same length L, which is an adjustable parameter. The last substring of S or T may be longer when their lengths are not a multiple of L. The rectangle is divided into boxes. Each box is assigned to the pair of corresponding substrings of S and T as shown on Figure The goal of the SPED algorithm is to calculate a string distance score for a pair of strings. The score shows how similar or dissimilar these strings are. Two strings ij xis computed by formula (1).For each box, a score Then, the grid is transformed into a weighted directed acyclic graph, where each box becomes a graph node. The graph is shown in Figure The incidents edges on each node are assigned the weight of the corresponding node. Then, by applying the Pulling algorithm, the shortest path between the origin and the bottom right node is computed, accordingly. To normalize the distance, the weight of the path is divided by the number of edges traversed. Now, two strings are checked for the presence of a common prefix. If such a prefix is found, the final score is adjusted by a re-scorer:Prefix| is the length of the common prefix, SPED' is the normalized weight of the shortest path.Where SPED is the final value of the string distance, |The SPED algorithm's tasks are twofold; firstly, identification of the shortest path from a directed weighted acyclic graph, secondly, computation of the edit distance among strings. We construct nodes lattice, which represents substring interactions The NS interaction among two strings defines a lattice element. The NS edit operation result into value, which is assigned to a lattice node. The edit operation results into a weight value, corresponding to a pair of NSs; which is the transformation cost of converting a substring from the first string into a substring from the second string. Five different methods are taken into consideration for weight assignment, which are used and tested in the experiments.After the lattice is constructed, it is transformed into a graph, which is weighted, directed, and acyclic, see Figure In this paper, the aforementioned idea is applied by converting each lattice cell to a graph vertex. A source vertex is added at the left top side and connected to the vertex  of the graph by a diagonal edge. A gap cost is assigned to edges, which is selected during a learning phase. As discussed earlier, a weight value is assigned to each diagonal edge; this weight value is a result of an NS edit operation, which is stored in the lattice cell. Since the source vertex is a placeholder, it is used as a starting point by the algorithm. In the SPED algorithm, the calculation of a string distance value between two strings becomes the shortest path calculation task from the source to the destination vertices. The destination vertex corresponds to the pair of last NSs of strings S and T. The graph is a directed, weighted, and acyclic.To handle the issue of similar concepts, we combine them into a representative one by the following rule: The shorter term is merged into the longer term when 1) the starting position of both terms is identical, 2) they have the same top category - contextual cues, 3) they are either noun term or phrases - POS tagging, and 4) they share similar lexical properties.To measure the performance of the proposed technique in a comprehensive manner, we used three different data sources: 1) GENIA, 2) Mesh Tree, and 3) UMLS. GENIA ontology is a taxonomy of 47 biologically relevant nominal categories . GENIA cFor evaluation of the proposed techniques, we used JNLPBA 2004 dataset. JNLPBA 2004 data consists of 33,306 biomedical entities . In the As the evaluation measure, we used precision, recall and F1. We also adopted 10-fold cross validation and reported the average value of 10 trials. Precision is defined as the percentage of true positives over the total number of positives predicted by the system (Precision=TP/(TP+FP) where TP denotes the number of true positives and FP denotes the number of false positives). Recall is defined as the percentage of the number of true positives over the total number of positives in evaluation entries  where FN is the number of false negatives). The F1 score is the ensemble of precision and recall and defined as the inverse of the arithmetic mean of the reciprocal values of precision and recall.Table The second evaluation is whether and how sub components of the proposed technique  have an impact on the performance. In particular, in terms of precision, the performance of entity extraction based on context-enabled text mining (described in the Merging Strategy section) gets significantly worse whereas the performance of entity extraction based on SPED does not change much. In the case of the proposed technique (which combines context and SPED), the performance drop is moderate. In terms of recall, the more data sources are combined, the better performance is observed. This is an expected outcome in that the dictionary size correlates with the performance of dictionary-based entity extraction. One interesting observation is that the performance of the proposed technique on the test set A does not increase when the dictionary is based on the combination of three sources compared to one source (GENIA). We are currently undertaking a close investigation of possible causes for this outcome.The performance is also measured by F1. As shown in Figure Figure Figure As shown in Figure In addition, we compare the proposed technique with other techniques reported in the literature. We choose the proposed technique with the dictionary constructed by the combination of the three data sources. In the conference of JNLPBA, the best performance is achieved by Zhou and Su's technique .As shown in Table A series of experiments show that the performance of dictionary-based extraction techniques is largely influenced by the information resources used to build the dictionary. In addition, the edit distance algorithm shows a steady performance with the three different dictionaries in precision whereas the context only technique achieves high-end performance with those dictionaries in recall.This paper proposed a hybrid dictionary-based entity extraction technique. The proposed technique consists of 1) an approximate string matching technique, 2) a shortest path edit distance technique, and 3) context-enabled text mining techniques.The novel feature of our method lies in the two-level string matching technique where SPED is applied to candidate sets of matched entries from a dictionary. We conducted comprehensive evaluation of the proposed technique on the JNLPBA 2004 test data. We examined the impact of the dictionary on the performance by combining three different data sources: GENIA, MeSH, and UMLS. The experimental results show that the proposed technique outperforms the approaches with text mining techniques only as well as with SPED only by F measure in most cases. In addition, the experimental results show that the proposed technique performs better than the state-of-the-art technique which achieved the best performance at the JNLPBA 2004.As a follow-up study, we plan to improve the text mining technique where the context only option performs the worst. In several instances, we observe that it exacerbates the performance. Another research direction is to exploit various data sources, such as Gene Ontology (GO) and PharmGKB to study how an entity-specific dictionary could impact on the performance of entity extraction.The authors declare that they have no competing interests.MS conducted the statistical analyses and drafted the manuscript together with WSH and HJY. Both authors contributed to the design and conception of this work. All authors have read and approved the final version of the manuscript.


We investigate the interfacial dynamics of a 2D self-organized mixed layer made of silica nanoparticles interacting with phospholipid (DPPC) monolayers at the air/water interface. This system has biological relevance, allowing investigation of toxicological effects of nanoparticles on model membranes and lung surfactants. It might also provide bio-inspired technological solutions, exploiting the self-organization of DPPC to produce a non-trivial 2D structuration of nanoparticles. The characterization of interfacial dynamics yields information on the effects of NPs on the mechanical properties, important to improve performances of systems such as colloidosomes, foams, creams. For this, we combine micro-tracking in real-space with measurement in momentum-space via x-ray photon-correlation spectroscopy and Digital Fourier Microscopy. Using these complementary techniques, we extend the spatial range of investigation beyond the limits of each one. We find a dynamical transition from Brownian diffusion to an arrested state driven by compression, characterized by intermittent rearrangements, compatible with a repulsive glass phase. The rearrangement and relaxation of the monolayer structure results dramatically hindered by the presence of NPs, which is relevant to explain some the mechanical features observed for the dynamic surface pressure response of these systems and which can be relevant for the respiratory physiology and for future drug-delivery composite systems. Self-assembly and self-organization of nanoparticles (NP)–surfactant mixed layers at the liquid-liquid or air-liquid interface are exploited in biomedicine, materials science, food science or renewable energy15111415Our work focuses therefore on the study of the microscopic spontaneous fluctuations of a model system, employing a combination of scattering and microscopy techniques to cover a broad spatial and temporal region . The sysdirectly in Q-space by a scattering technique, namely Grazing Incidence X-ray Photon Correlation Spectroscopy (GI-XPCS), with real-space imaging data.In multicomponent systems such as that studied in this work, the complexity of the interfacial dynamics results from the superposition and coupling of different dynamic processes. The very appearance, time-scales and peculiarities of these dynamic processes are strictly dependent on the morphology and structure. To tackle this complexity, different approaches have been proposed, including mechanical and optical techniques. A very recent study of the coarsening dynamic of a colloidal gel’s spinodal decompositionThe phase behavior of DPPC at the air/water interface has been widely investigated also for its relevance to the understanding of the mechanical behavior of alveoli during the respiratory cycle232420d is distance in real space. However, experimental results have to be interpreted through a model to yield significant quantities, and the choice of the model is a crucial point. Some of the most relevant dynamic regimes are sketched in Despite their apparent distinct nature, colloidal suspensions, gels, metallic glasses, fluid lubricants, pharmaceutical compounds, window glasses, granular media and emulsions owe their properties to the fact that they can be driven into an out-of-equilibrium configuration, in which they cease to flowR is limited and it saturates at Epifluorescence microscopy was used to follow the morphological changes in the film during compression. Such situation is thus drastically different from pristine DPPC monolayers, since the presence of NPs hinders the formation of a continuous layer of the DPPC LC phase.The results reported in A direct approach to the measurement of the dynamics is to track in time the position of the black, disks that characterize the film morphology. This approach is strictly analogous to the more common Multiple Particle Tracking (MPT) techniqueR.From the trajectories measured at different values ofDS can be defined asA linear growth of At intermediate times (approximately m quantifies the linear (m = 1), sub-linear (m < 1) and super-diffusive (m > 1) trends respectively.In which the exponent Diffusive regimes of large flat inclusions in an interfacial film have been studied theoretically long ago by Hughes and coworkersWhere T is the temperature (293 K in the present case) and DS as a function of the inverse of the radius 1/R, for different values of In Additional insight into this arrested state is gained by computing the self-part of the van Hove correlation function of the displacements from the trajectories of the individual domains. Following the approach proposed by Doliwa and HeuerAt low surface concentration  of the individual components of the displacements, either x or y, to the second moment μ2The population of long-range moving objects can be indirectly quantified by means of the non-Gaussian parameter α2 increases, reaching This parameter is zero for a strictly Gaussian distribution and becomes larger when the tails of the distribution become more important than in the Gaussian case. It is reported in To verify if this deviation arises from caging effects, following the literaturet0) for three different disks, measured at Which corresponds to the projection of i) to extend the spatial range, and ii) to improve the statistics by measuring a larger portion of surface at the same time. In order to achieve this, in the following, we compare the results obtained in direct space with those found in the reciprocal space.The arrest transition, along with the hints of the presence of rearrangements found in the arrested state by means of the van Hove correlation functions, calls for a detailed investigation of localized dynamics, which somehow hits the limits of the tracking analysis performed so far. In order to gain a deeper insight, we apply a scattering technique, which holds the promise directly compared with those from microscopy imaging by employing a novel technique named Digital Fourier Microscopy (DFM)This motivates the investigation by Grazing Incidence X-ray Photon Correlation Spectroscopy (GI-XPCS), a scattering technique that allows a quantitative characterization of the interfacial dynamics2941The basic quantity measured by XPCS (and DFM) is the autocorrelation function We track the evolution of the dynamics as a function of In combination, these parameters allow us to discriminate between different dynamical regimes within the limits cases of diffusive . Then, between γ and n. As the concentration is increased above 50%, the shape linearly increases towards faster-than-exponential decays  the increase of the non-Gaussian parameter ii) the change in the shape of the relaxation, which turns from simple exponential (compatible with the Brownian case) to compressed shape, reported in iii) the Q dependence of We have then a consistent picture in which the growth of relaxation times goes together with γ varying from γ than theoretically predicted. From that, a nice master curve could be deduced, from which the typical length of the jump could be extracted.A compressed relaxation shape is predicted within a detailed model proposed by Bouchaud and Pitardγ on The present case seems to be quite different, as the strong dependence of Since the mechanical moduli of this mixed monolayer are somewhat smaller than those of the pure DPPC monolayer at the same pressure, it seems reasonable to assume that the disks behave as rigid bodies (as they are formed by pure DPPC in LC phase) which repel each other and are surrounded by a softer phase. Then the system would be more similar to a repulsive glass than to a gel-forming system, as described by the aforementioned models.In this respect, we note that the dilational elasticity Finally, one could ask whether the nanoparticle size plays an important role in this complex phenomenology. We tested different sizes of NPs, namely 9 nm, 15 nm and 60 nm particles. As the results displayed in Through the combined use of GI-XPCS and epifluorescence microscopy measurements (MT and DFM), we have been able to characterize the dynamical regimes of a hybrid, self-organized phospholipid/NP monolayer observed while increasing its surface pressure and concentration.Silica NPs are incorporated into the film: a stable NP/DPPC mixed matrix is formed, that surrounds regions of tightly packed DPPC molecules in LC domains. Those form rigid disks, which retain their own individuality and cage each other as the surface is compressed. As the packing fraction of the disks increases, we observed a dynamical transition from Brownian diffusion to an arrested dynamical regime, featuring intermittent, cooperative rearrangements in a fashion closely resembling that found in simulations55The observed peculiar structure of the mixed particle-DPPC monolayer- and its dynamic characteristics- can be used to explain some of the observations already reported on the chemico-physical features of these monolayers. In particular, in all range of investigated surface pressures, the rearrangement and relaxation of the monolayer structure is dramatically affected by the presence of NPs, which explains the increased non linearity of the surface pressure response to area oscillatory cycles and its large hysteresis on compression/expansion cycles.The reported results can also be important in relation to possible effects of NPs on the dynamics of cell membrane , which have been so far poorly investigated.More generally, we want to stress here the importance of using a comprehensive suite of experimental tools to characterize the slow dynamics of soft and bio-systems, often strongly deviating from a simple Brownian behavior. This is particularly true in view of possible applications that exploit slow, relaxation mechanisms to extend performances and enhance key features e.g. in the fields of drug release and of self-healing materials. The partial overlap of spatial scales explored by MT, DFM and GI-XPCS allowed us to successfully combine them to gain a deeper insight into the dynamics of the system, exploiting the strong points of each technique while extending the spatial range probed: by microscopy we tracked the dynamics on lengths from The NP suspensions used here are obtained by dilution with pure water of different commercial colloidal dispersions products: Levasil 300/30, Levasil 200/30 and Levasil 50/50, all from H.C. Starck (Germany). The NPs in the three dispersions are spherical and narrowly distributed around diameters of 9, 15 and 60 nm, respectively. The dispersions are extremely stable because of the large negative surface charge of the particles, obtained in the specific production process. The NP DPPC . The subphase temperature is controlled by means of water circulation between the trough basement and a LAUDA thermostat, set at 20 °C.Small constant velocity drifts of the Langmuir film are inevitable: in order to minimize them, a steel ring (1 cm diameter) is placed in the subphase, centered under the measurement region. There, it reduces the subphase depth around the measurement region, effectively minimizing subphase motions. A chloroform solution of DPPC is spread at the interface between air and the aqueous suspension of NP. The trough is covered with a plastic cap to avoid dust deposition and an incubation time of 1 hour is considered: the process of formation of the composite monolayer needs the adsorption of NP at the interface, which is presumably a slow equilibration between NPs in subphase and at the interface.Subsequently, the trough’s area is reduced by means of the barrier motion, to reach the desired surface pressure value. Barriers have been halted before starting any measurement. All the techniques employed  act on a much shorter time scale than that of the equilibration process between surface and bulk. Moreover, once the structures of A close insight into the properties of the mixed layer has been obtained by fluorescence microscopy analysis. Measurements were performed using a Nikon Ti-Eclipse inverted microscope equipped with a high-sensitivity Andor Clara camera.x2 of the objects at a given surface pressure. We take advantage of the large number of objects (N > 100) in the field of view to subtract the film drift motion by calculating the MSD from the variation of the inter-object distances over time:To track the dynamics, in correspondence of several surface pressure points on the Langmuir isotherm, videos have been recorded with 50× magnification , at 7 frames per seconds, with exposure time of The average is performed along the statistical ensemble of inter-object distances in the field of view. Moreover, each trajectory has been divided into smaller portion that were subsequently included in the average, in order to improve the accuracy of Photon correlation spectroscopy experiments have been performed in grazing-incidence, small angle scattering geometry (GI-XPCS) using partially coherent X-rays at the ID10 beamline of the European Synchrotron Radiation Facility. A Si (111) crystal monochromator is used to select radiation of wavelength Speckle patterns are recorded with exposure times in the range As usual, in the case of Langmuir monolayers45using a fast and efficient multi-tau algorithm coded in Matlab.Information on the microscopic dynamics of the sample can be re-cast in the momentum space: from the very same epifluorescence images used for microscopic tracking we calculated the power spectrum of the 2D Fourier transform of each image of a given sequence. Then, each pixel of the transformed image corresponds to a well-defined momentum vector Q. Pixels are grouped in rings, in the range How to cite this article: Orsi, D. et al. 2D dynamical arrest transition in a mixed nanoparticle-phospholipid layer studied in real and momentum spaces. Sci. Rep. 5, 17930; doi: 10.1038/srep17930 (2015).


Background. The ischemic damage of the sinus node (SN) is a well known cause of cardiac arrhythmias and can be a consequence of any flow abnormality in the sinus node artery (SNA). Accordingly we aimed this retrospective study to: (1) evaluate the suitability of the standard coronary angiography to study the SNA and (2) determine if the percentage of subjects with a positive retrospective history of supra-ventricular arrhythmias (SVA) differs in patients with normal and diseased SNA ascertained at the time of coronary angiography.Methods and Results. Out of the 541 coronary angiograms reviewed the SNA was visible for its entire course in 486 cases (89.8%). It was found to arise from the right side of the coronary circulation in 266 cases (54.7%) slightly more often than from the left, 219 cases (45.1%). One patient had 2 distinct SNA arising from either side of the coronary circulation. For the second objective, we studied the 333 patients with: (a) coronary artery disease (CAD), (b) properly evaluable SNA and (c) complete clinical history available. In 51 (15.3%) a SNA disease was found, 41.2% of them had a positive SVA history, mainly atrial fibrillation (AF), whereas only 7.4% of patients with a positive history of SVA could be found in the non-SNA diseased. This difference was statistically significant (P < 0.001).Conclusions. (1) The evaluation of the SNA is feasible in clinical practice during a standard coronary angiography; (2) this may be relevant since angiographically detectable SNA disease was significantly associated with a positive history of SVA. The supraventricular arrhythmias, especially AF, have a high prevalence in the general population and, especially in patients with CAD, are a major social and economic burden in terms of mortality and morbidity . AlthougThe association between the obstruction of the atrial coronary branches with the occurrence of such arrhythmias during the first phase of a myocardial infarction was already shown several years ago with classical anatomical and imaging studies ; unfortuIn the present study, we retrospectively analyzed the coronary angiograms performed in the catheterization laboratory of our hospital form May 2013 to May 2014. In those cases where a patient repeated the coronary angiogram procedure, only the older images were taken into account. The coronary angiograms of subjects who had previously undergone bypass surgery were not reviewed. All these exams were suitable for the first and second objective of the study. To achieve the third objective, which focused on the prevalence of the disease the SVA in subjects with and without a previous clinical history of SVA, some exclusion criteria were set up: (a) the subjects in which the SNA could not be entirely and properly evaluated were excluded; this group includes patients with acute coronary syndrome (ACS) where the SNA branched downstream the culprit lesion; (b) the subjects whose clinical report was not available or incomplete were also excluded as those in which intact coronary arteries were detected.For each patient, the required variables up to the time of the coronary catheterization were extracted from the clinical report of the hospitalization when the coronary angiography was performed; in particular, we carefully collected all the information related to a positive history of SVA and to the presence of known risk factors for CAD and SVA, as well as the main echocardiographic data and any active anti-arrhythmic therapy. To ensure that the experimenters were effectively blinded to the identity of the patients, we have worked on a fully de-identified database containing only the variables in study with a random assignment of an identification code that does not allow investigators to retrieve the identity of the subjects; thus also the need for approval by the IRB was waived.In the present study, we have included in the SVA all the rhythm disturbances originating from the tissues above the level of the ventricles; furthermore, the atrio-vetricular blocks or conduction delays have not been taken into account as they are a consequence of a lesion of the atrio-ventricular node which does not depend on the SNA for its blood supply. Finally, we excluded the cases where the SVA has arisen for the first time in the early phase of an ACS since the pathogenesis of these acute events is not the object of the present study.All the coronary angiographies were performed for diagnostic and therapeutic purposes, including both urgent procedures in patients with ACS and elective procedures in patients with stable coronary artery disease or candidates to heart surgery. The selective right and left coronary angiography was performed using a digital cineangiography imaging system . All images were stored as DICOM data and were analyzed off-line. Since the angiographies were standard procedures, no specific projections were available to study the SNA; thus, all the coronary angiograms were carefully analyzed to assess the SNA, including its presence and origin.For the third objective of the study, among the examinations where the SNA was fully assessable, those with intact coronary arteries were excluded; however, angiograms showing a subcritical diffuse coronary artery disease or an already-in-place stent were included. Thus, the images were analyzed for the presence of a lesion involving the SNA and the patients were then grouped accordingly. The SNA disease was assessed by applying the standard criteria commonly used for the main subepicardial coronary arteries; not only were critical stenosis taken into account, but also a diffuse irregularity of the arterial wall was considered expression of a pathological vessel. When a chronic lesion of the left circumflex coronary artery (LCX) or the right coronary artery (RCA) was found upstream from the SNA origin, the patient was assigned to the group with SNA disease.2 test was used to test for differences in categorical variables, unless more than 20% of the cells of the 2 × 2 table had an expected value <5; in these cases, the exact Fisher test was performed. Multivariate analysis was performed to evaluate the relationship between demographic and clinical data. Odds ratios and 95% CI were calculated.Continuous variables were expressed as median and interquartile ranges. Categorical variables were expressed as absolute numbers and percentages. The differences in continuous variables were assessed using the Mann–Whitney U test when not normally distributed, and the Student t test when normally distributed. The XAll tests were 2-sided, and a probability value <0.05 was considered statistically significant.Statistical analyses were performed using SPSS software .β = 0, 9976), with a type I error rate of 5%. Out of the 541 coronary angiograms reviewed, the SNA was detectable and was visible for its entire course in 486 cases (89.8%); it was found to arise from the right side of the coronary circulation in 266 cases (54.7%) slightly more often than from the left, which had 219 cases (45.1%). One patient had 2 distinct SA nodal arteries arising from either side of the coronary circulation  (P = 0.004), a significantly lower left ventricle ejection fraction  and a significantly higher use of beta-blockers  and thienopyridines  than non-SNA diseased. As expected, in subjects with a clinical history of SVA, irrespective of the presence of SNA disease, a higher prevalence of risk factors for arrhythmia, including a higher prevalence of reduced left ventricle ejection fraction and atrial dilatation, was found alongside with a significantly higher consumption of antiarrhythmic drugs  . When ta< 0.001) . The preic drugs .With the present study, we demonstrated that the evaluation of the vessel deputed to vascularization of the SN is feasible without any particular effort during a standard coronary angiography. We found that the SNA could be entirely visualized in 89.8% of the examined cases. Previous studies aimed to visualize the SNA by using the same technique have reported an higher percentage of visualization . This diIn addition, we wanted to explore the relationship between heart rhythm and atherosclerosis of the SNA. It has already been demonstrated that SVA, and in particular AF, are associated with an increased prevalence of CAD  and evenDifferent studies were carried on to investigate the possible relationship between SVA, mainly AF, atherosclerosis in general, and with coronary arteries atherosclerosis in particular. A cohort study demonstrated that the risk of AF was associated with carotid intima-media thickness (IMT) and severity of carotid plaques . A furthA case-control study found a higher prevalence of obstructive CAD, assessed by Multislice Computed Tomography Coronary Angiography among patients with paroxysmal or persistent AF . On the The present study is a step in the understanding of the complex role of atherosclerotic disease and CAD in the genesis of supra-ventricular rhythm disturbances for different reasons. First, we demonstrated a statistically significant association between SNA disease at the time of coronary angiography and the prevalence of a retrospective clinical history of SVA attributable to a SN hypoperfusion, in a context different from the acute phase of an ACS and in a population of patients wider than the candidates for by-bass surgery. Second, the results of this study suggest an interesting physiopathological mechanism of chronic SVA, even if the design of this study does not allow us to draw any conclusion regarding a causal relationship between the disease of the SNA and SVA. Nevertheless, we have already explained the different pathophysiological ways through which a lesion that determines a flow abnormality in the SNA may affect the heart rhythm; that said, we do not think that SNA disease is necessary, although it may be sufficient, to provoke a SVA, but it should be regarded as one of the SVA risk factors along with arterial hypertension, heart failure, valvular disease and so on.This study has some limitations that should be acknowledged. First, it is a case-control study, the limitations of which are well known. A larger study, with follow-up data, may provide more conclusive information. Second, this study is limited by attempting to correlate angiographic anatomy rather than ischemia per se, but there is currently no reliable means of assessing atrial ischemia. Third, angiographic images are the current gold standard to show alterations of the arterial lumen, but they cannot give definite information regarding the their atherosclerotic nature. An IVUS study should be more conclusive in this sense, but it is currently unavailable for such a narrow vessel as the SNA. These limitations do not diminish the value of the result of this study, which provides new data supporting the association between the disease of a specific branch of the coronary circulation and a positive history of SVA.10.7717/peerj.1156/supp-1Supplemental Information 1Raw dataset.Click here for additional data file.


Understanding and improving hospital discharge has assumed major importance since it represents an error-prone transition in care. One barrier to improvement is the lack of detailed understanding of how hospital discharge is organized, including its interdependencies and influential performance-shaping factors (PSFs). This study examines the discharge of elderly patients using the Functional Resonance Analysis Method, developed to analyze performance variability in complex systems. Our main aim was to identify hospital discharge functions, variability, and PSFs that may explain the variability and different outcomes in discharge practices by incorporating multiple-stakeholder perceptions .The data consisted of moderate participant observations of 20 elderly patients (>75) discharged from hospital to primary health care. The data comprised 90 hours’ observations at hospital wards, including 173 conversations with patients, next of kin, and health-care personnel involved in discharge.timing, duration, and precision. Duration is a significant source of variability, primarily determined by the time of day the patient was determined medically fit for discharge. Precision issues related to (1) decision-making criteria concerning the medical fitness decision and appropriate level of care, (2) quality of discharge planning, (3) degree of patient involvement, and (4) quality of information transfer. PSFs were temporal conditions (degree of time pressure), individual and team characteristics, patient factors, organizational factors , work environment factors  and regulatory influences .We identified 10 common functions in the discharge of elderly patients to primary health care. We found substantial variability in terms of The study provides a detailed understanding of the discharge of elderly patients by describing common functions and variability in performance caused by multiple PSFs. Our findings indicate the necessity for studying multiple factors related to discharge, interdependencies, and their effects on a range of discharge outcomes incorporating a multiple-stakeholder perspective. We argue that the existing sequential approaches to the complexity surrounding hospital discharge are inadequate. Given the interdependencies among functions, there is a need for corresponding multi-factorial interventions.The online version of this article (doi:10.1186/1472-6963-14-365) contains supplementary material, which is available to authorized users. Understanding and improving the process of hospital discharge has assumed major importance  since itMainstream patient safety research has tended to be reactive: it investigates adverse events to identify cause-and-effect relationships, from which improvements can be formulated . We arguIn the health-care context, the wide variety in patients, their relatives, geographic settings, professional groups, and working conditions means that continuous adaptations are essential toward ensuring overall performance . VariabiThis paper applies an integrated approach to the study of hospital discharge, focusing on functions, interdependencies, and performance-shaping factors from a multiple-stakeholder perspective. Qualitative observational case studies of the hospital discharge of elderly patients are used to identify functions and demonstrate the performance variability that surrounds hospital discharge practices by applying the Functional Resonance Analysis Method (FRAM). The FRAM is an innovative method that is developed to analyze performance variability in complex systems . SpecifiThe functions of hospital discharge;The areas of variations within those functions, and;The performance shaping factors (PSFs) that may explain those variations.To accomplish these aims we gather and incorporate the perceptions of not just healthcare providers, but patients and their next of kin.Before introducing the case study and findings, we describe the characteristics and practical approach of the FRAM. We explain how it was used analytically to determine the details of elderly patient discharges in a Norwegian setting.The FRAM is a systemic, non-linear approach that defines complex systems in terms of both their overall and constituent functions. “Functions” here refers to the activities or sets of activities that are necessary to produce a particular outcome, e.g., hospital discharge of the elderly. The aim is to identify and assess the interdependencies among functions within complex systems. In practice, this involves a description of what individuals or groups do to achieve their functional aim—as opposed to analyzing prescribed models of behaviors, e.g., standard operating procedures or care pathways . The FRAIn practical terms, the FRAM consists of a five-step approach . The firThe five-step approach of the FRAM can serve a number of purposes. The aim in the present study was to use the method to gain a detailed understanding of the functioning of hospital discharge among elderly patients. This paper thus applies the first three steps of the FRAM—identifying essential discharge functions, variability, and PSFs—which may account for variability and different outcomes across discharge practices.An important consideration with the FRAM is determining the basis or categorization of successful functioning. With the FRAM, it is proposed that this categorization be developed based on a mutual understanding among a team of experts consisting of the people performing the functions under consideration . HoweverThe observational case study approach of the present investigation was appropriate for examining local systems and organizational processes . The useThe Norwegian health-care system comprises two organizational structures: primary care ; and specialized secondary care. Primary care is managed by local municipalities, whereas specialized health care is provided in state-owned hospitals and operated by four regional health authorities. The Coordination Reform  was implThe research was conducted in two hospitals in Norway  situated within the same regional health authority. The observations took place in three types of wards  with the intention of developing cross-case comparisons of activity patterns across settings and among different patient groups. Seven wards were included in the study: one geriatric, three orthopedic, and three medical wards. In those seven wards, we selected 20 elderly patients (>75 years old) with orthopedic and medical conditions who would be in need of municipal services after discharge, e.g., rehabilitation, nursing home care, and home health care. To provide a comprehensive insight into hospital discharge practices, we sought to sample across the broad range of stakeholders involved in the process, i.e., health-care personnel groups, patients, and their next of kin. The broad inclusion criteria applied in this study  was intended to maximize data variation . Table 1We investigated the discharge of the 20 elderly patients; in line with the requirements of the FRAM approach, using moderate participant observations [The data were collected from March to October 2012. The data consisted of 90 hours of observation, including 173 conversations with patients, their next of kin, and health-care providers involved in the discharge processes. The first author (nursing background) conducted the observations based on a semi-structured observation guide, which is in accordance with the FRAM approach. The guide included topics that are relevant to hospital discharge, e.g., coordination, multi-disciplinary approach, information exchange, patient and family involvement, discharge planning, and challenges or barriers. In addition, the guide allowed for issues to emerge from the observations. In this way, it was intended to provide a detailed description of how discharge works. Observations started in the morning of the day of expected discharge, and they focused on interaction, coordination, and dialogue among health-care personnel and patients. During the observations, the researcher was dressed in hospital clothing so as to be inconspicuous .Conversations with health-care personnel and patients were carried out in situ to clarify work practices and obtain assessments and viewpoints regarding the current discharge process . The purCopies of discharge summaries (with person-identifiable information deleted) were collected so that community-based health-care personnel could be asked to assess the written documentation and evaluate the overall quality of the current discharge process. No recording was made of the conversations owing to ethical considerations  and to the fact that numerous health-care providers, patients, and next of kin were involved (sound recording issues). Observation notes were written during the observations, and a summary of each, including researcher reflections opinions, was written immediately afterward.In line with the FRAM, data analysis involved a two-stage process: first, we identified common functions in the discharge process; second, we determined variability and PSFs within those functions. We identified common functions through an iterative process. All observational materials (150 written pages of field note summaries) were thoroughly reviewed individually by the first and second authors and then within a team of four researchers involved in the project . The functions were revised several times until final consensus was reached. A detailed description of the functions  was then developed based on an aggregated analysis of the 20 patient discharge cases, including the conversations with health-care personnel, patients, and their next of kin. Legally binding contracts  for the hospitals and municipalities included in this study were also used to support the description of functions.The aggregated description of the functions and associated aspects was used for the analysis of variability and PSFs. The variability of each singular function was examined based on the descriptors from the various cases as well as the conversations with health-care personnel, patients, and relatives. Three analytic themes emerged through this process, which characterized the functional variability among the 20 patients: timing, duration, and precision in performance. PSFs were elaborated in the final step of the analysis using the aggregated description of the functions and associated aspects compared across the patient cases. The appropriate level of analysis at which to operationalize variety in organizational work processes has been questioned . In the Ethical approval was obtained from the Committee for Medical and Health Ethics of Norway . This study was based on informed, voluntary consent among the patients, their next of kin, and health-care personnel. Ethical issues related to consent capacity were taken into consideration during the recruitment process. Recruitment during hospitalization may be ethically challenging owing to the ability of elderly patients to provide informed consent as a result of functional decline, strain, and cognitive impairments. The health-care providers at the hospitals assessed the cognitive functioning and overall situation of the patients and judged them as being suitable for recruitment. The researchers did not contact patients before they had provided their verbal consent to be contacted and informed about the study. Next of kin were included only if the patient approved of such contact. Next of kin were contacted by phone and informed about the study. The paper follows the STROBE guidelines for reporting of observational studies. An additional file shows the completed STROBE checklist [see Additional file Hospital discharge takes place on a day-to-day basis, and involves complex, interdependent functions that require interaction and coordination among a multidisciplinary team of stakeholders, i.e., doctors, nurses, receiving health-care providers, patients, next of kin, and patient coordinators. This study identified 10 common functions that constitute the daily routine for discharging elderly patients from the hospital to primary health-care services in the municipality. The set of functions represent essential activities necessary for hospital discharge to succeed. The set of functions involve;Review of hospital inpatients—classifying patients that are medically fit for dischargeNotifying the municipality that the patient is medically fitInforming the patient that they are ready for dischargeAssigning an appropriate post-discharge site of care and notifying the hospitalNotifying and informing the patient’s next of kin (if any)Preparing a nursing discharge recordPreparing a medical discharge letterProviding oral information about the transfer to post-discharge care providersOrdering transportationTransferring the patient to the post-discharge site of care and ensuring the transfer of written informationA brief description of the identified functions, including a description of the essential associated aspects, is presented in Table The functional descriptions provided in Table Timing (the time of day the discharge functions were carried out),Duration (the time spent performing the functions) and,Precision (performance characteristics and perceived success of the function by the various stakeholders)Our data indicated substantial variability in the way discharge functions are performed. Accordingly, patients, their next of kin, and health-care personnel reported some discharge practices as having been more successful than others. Success here was defined in terms of reported quality of information transfer, the level of post-discharge care, the duration of the process, and level of satisfaction. We found considerable variability in the discharge functions in three main dimensions:We found time to be a main source of variability. The temporal range in the functional variability was the duration of the discharge process, and it varied considerably among the 20 patients, from a few hours to a few days. The main variations in precision were related to the following: (1) decision-making criteria with respect to medical fitness and post-discharge arrangements; (2) the quality of the discharge planning process; 3) patient participation and engagement of their next of kin; and (4) the quality of the information transfer. The variability for each function and the recognized and reported outcome variability are presented in Table  patient A PSF is anything that affects the health-care provider’s performance of a function within the health-care system . We founTemporal variability across the observed cases was typically determined by the three functions indicated below. These functions served either to activate or delay the discharge process, and they thereby influenced the overall duration of the discharge processes . Variability in these three linked functions created time constraints on associated functions. The three functions were as follows:Review of hospital inpatients—classifying patients that are medically fit for discharge.Notifying the municipality that the patient is medically fit.Assigning an appropriate post-discharge site of care and notifying the hospital that site.“It’s busy . . . of course there is an increased chance or risk that you forget something.” “It’s clear that things can happen a lot faster toward the end of the day.” “After the decision was made that I was ready to be discharged, it was a rush right up to the time I left . . . It was like I had to get dressed and get out.” One of the most critical functions is the review of hospital inpatients to determine whether a patient is medically fit for discharge. This function activates the overall discharge process and affects all subsequent functions by determining when they are initiated. Considerable variations were identified in terms of the actual time (hour of day) the patient was determined medically fit; the range was from 9 a.m. to 1:30 p.m. The discharge process was found to be more rushed when the patients were declared medically fit later in this period, i.e., after noon. This was because of the reduced possibility to prepare the discharge requirements for care transfer if the transfer was to take place the same day. The health-care personnel clearly stated that time pressure potentially increased performance variability, affecting precision issues. The following statements reflect these concerns: Other factors stated as influencing the duration were as follows: the quality of the discharge planning process; patient characteristics; the degree of simultaneous responsibilities among the clinical team; the degree of familiarity with the inpatients; and the availability of sufficient resources, i.e. updated patient information. Doctors often referred to pending lab and test results as a factor that guided the decision about medical fitness; this affected the duration and completeness of the decision-making process.The temporal completeness of the decision about medical fitness determined the time (hour of day) of notifying the local municipality. This function activates the discharge process for the receiving municipality ; if there are delays through late notification, this puts time pressure on the municipality personnel. Bed availability in the receiving municipality determined whether the patient was assigned a post-discharge site of care on the day they were determined medically fit or if they had to spend additional days in the hospital—a delay in the discharge process.Time variations in determining medical fitness have knock-on effects across the system. In particular, when decisions are made later in the day, this created time pressure for local municipality personnel, who had to initiate the functions related to care planning and post-care transfer. This time pressure was exacerbated by financial penalties for delayed discharge; these encourage municipal staff to rush care planning to avoid paying the daily fee. Such time pressure could have a knock-on effect in terms of the precision of care planning. Only five of the 20 patients in our study spent additional days at the hospital: the time varied from 1 to 5 days. It was emphasized, especially by nurses, that there was better time to prepare and perform the discharge functions if the patient spent additional days at the hospital. Some nurses acknowledged that the available time could affect precision issues in particular related to patient and next of kin involvement, discharge planning, and quality of information transfer. This was confirmed by the patients and their next of kin. Patients who spent additional days in the hospital stated that they had more time to prepare mentally for the discharge, and this appeared to be connected with a higher level of patient and next-of-kin satisfaction.We identified considerable variability in the decision-making criteria concerning both the decision about medical fitness and post-discharge arrangements. The quality of the discharge planning process also varied among the patients, as did patient involvement and quality of information transfer. As indicated above, the temporal conditions  are a major PSF that influences the precision issues. Below, we describe other PSFs that influence precision.There was variability in the criteria for the decision about medical fitness and its quality, especially among the hip fracture patients. For example, doctors appeared to put different emphasis on involving and consulting with the responsible nurse or the patient in their decision-making process. At one ward (orthopedic), nurses were not present when the decision for medical fitness was determined. This was explained as being due to institutionalized routine and effectiveness. The contribution of nurses to the decision-making process varied. Some were passive and did not interact with the doctor; others participated more actively. Work experience, relationship with the doctor, the doctor’s characteristics, and the degree of familiarity with the patient were cited as possible explanatory factors for this. In several cases, doctors and nurses were unfamiliar with the patient; this was explained as being due to time off work, the patient’s short hospital stay, and high patient turnover. The degree of familiarity  was observed to affect the level of knowledge sharing among the doctors and nurses in the decision-making process. Some orthopedic doctors also indicated that they were more thorough (spent more time) with patients for whom they felt responsible , and this potentially influenced the decision-making process.Nurses in municipal services experienced variability in the doctors’ criteria for regarding patients as medically fit. Some wards seemed to pay more attention to the patients’ overall health-care status rather than the strict clinical condition; this was particularly true of hip fracture patients. For example, there was a lack of attention to the underlying social or physical causes of a patient’s fall and hip fracture. In contrast, geriatric wards appeared to make more holistic decisions and took into account factors beyond the medical determinants, such as assessing activities of daily living, cognition, social support, psychological well-being, and psychosocial factors.Another factor that affected the decision-making criteria was bed availability. Doctors were particularly under pressure to discharge patients when units were crowded. In one case, it was observed that the head of a medical department on a morning visit informed the head nurse that they should discharge patients that day since there had been many new arrivals in the emergency unit.The level and site of post-discharge care varied among the patients; these especially affected the patient and next-of-kin satisfaction with the discharge process. The next of kin appeared to be more pleased if the patient was discharged to a nursing home rather than to home with health-care services. The majority of the patients in this study were discharged to a higher level of post-discharge care than the care they had received prior to admission. Of the 20 patients, 18 were admitted to the hospital from home; of these, 16 were discharged for a short-time stay at a nursing home. The remaining four patients were discharged directly to home with home health-care services. Not all the patients in this study had next of kin; however, for those that did, the next of kin played an important role as advocates in the decision making. In some cases, the next of kin questioned whether their involvement and persistence had an impact on the level of post-discharge care offered.According to the patient coordinators (responsible for determining the appropriate level of post-discharge care), a number of factors influenced the decision-making process. These factors included the following: information and recommendations provided by the hospital; the quality of the discharge-planning process; prior knowledge or familiarity with the patient (the nature of the patient’s current home and its suitability for the patient’s condition and the presence of next of kin); degree of pressure from the next of kin; financial incentives; and current availability of beds and resources in the receiving municipality. According to hospital providers, some municipalities struggled more with availability than others. For some patients, the patient coordinator and assigned municipality staff tried to negotiate a later discharge date if the municipality had limited capacity. Hospital providers also stated that owing to a lack of bed availability and to avoid paying the daily fee, municipalities could decide to discharge patients directly to home with home-based nursing care—even if a short-term nursing home stay was recommended by the hospital.The degree of compliance with discharge planning agreements varied among the patients. Municipality personnel, i.e., patient coordinators and assigned contact people, stressed the importance of good discharge planning  in determining the most appropriate setting for post-discharge care and to avoid delays. Short hospital stays were a challenge in the discharge planning process. For example, it was not unusual for municipality personnel to receive the medical and nursing records describing the patient’s activity level and cognitive status on the same day as they received the decision for medical fitness. As such, patient coordinators had less time to make the preparations for the necessary post-discharge care. It was also apparent that some units were more efficient than others in notifying the municipality early on the day of discharge. Ward leadership seemed to play a key role in this regard. Some head nurses were more active in communicating with the care team. They verified compliance with the discharge planning agreements and reminded the responsible nurses to send notification about the patient being medically fit for discharge to the municipality.This study also found considerable variability in how patients and their relatives were involved in the discharge planning process; this influenced the success of the post-discharge planning and overall satisfaction. The notification about discharge was often unexpected, which indicates that patients and their next of kin may have been insufficiently involved in the discharge planning process.New discharge planning demands  increased administrative work, and documentation limited the interaction between health-care providers  and patients and their next of kin. We found that the interaction between health-care personnel and patients varied according to the following: the type of information provided; the language used; how the personnel approached the patient ; the engagement with patient preferences; and different degree of encouragement.The time allotted to each patient when providing the discharge information also varied considerably—from 3 to 10 minutes. Doctors and nurses offered several explanations for this variability, such as individual characteristics and communication skills, patient characteristics, various conditions and preferences for participation, and time pressure. The patient’s characteristics  and preferences also showed great variation. Some patients were more active than others or had more knowledge of their situation, diagnoses, and medications; this appeared to affect the degree of information and knowledge sharing between patients and doctors.The quality of the information transfer, i.e., nursing records and medical discharge summaries, was reported to vary considerably among the patients. A nursing record was present for 16 of the 20 observed patients, and a medical discharge letter was available for all the observed patients. With 11 patients, health personnel outside the hospital reported information inconsistencies or inaccuracies, such as missing information about medicine regimes, lab test results, or follow-up care plans. For three patients, the medication list was lacking (hip fracture patients), and two patients were discharged with the wrong medication list.The receiving health-care providers generally found that the discharge letters prepared by the medical doctors, especially geriatric doctors, were of good quality; conversely, the surgical discharge summaries tended to have more incomplete or missing information. For three patients, there was inconsistency between what the nurse wrote and what the doctor wrote about the same patient. Variability in the content and quality here may be explained by the character of the hospital unit and the doctor’s specialization and preferences. Deficiencies in the nursing records at discharge were explained by the hospital nurses as being due to the lack of care continuity, a short hospital stay, insufficient and poor documentation, temporal conditions, and the degree of simultaneous responsibilities . Information provided in nursing records was often characterized by cutting and pasting from previous documents if nurses were unfamiliar with the patient.Senior doctors often delegated the responsibility for preparing the medical discharge summary to interns, junior doctors, or medical students. However, we found variations in the senior doctors’ quality assessment of records before being sent with the patient or to receiving health-care personnel. At some hospital wards, it was a standard procedure for all discharge letters to be approved by a senior doctor, but in others this was not normal practice. Hospital doctors referred to several influential factors that affected both temporal and precision issues. These included the following: level of familiarity with the patient; degree of available and accurate information; patient characteristics ; information input overload ; time pressure (influenced by the time of day the letter was prepared); and the degree of simultaneous responsibilities . Nurses at the orthopedic wards reported inconsistencies and unpredictable patterns related to the doctors’ presence in the wards, which resulted in difficulties in preparing a medical discharge document on time.In summary, this study identified multiple, diverse PSFs that influenced the functioning of hospital discharge. They included the following: variations attributed to temporal conditions  surrounding the discharge process; the characteristics of the individuals and care team involved ; variability in patient factors ; organizational factors ; and local work environment factors .Most research about hospital discharge has tended to focus on particular, isolated aspects  –31, specThis paper demonstrates that the FRAM is a powerful method for studying and analyzing the complexity of hospital discharge practice; it provides a detailed, systemic analysis of hospital discharge for elderly patients, which has not previously been presented. Our findings illustrate how hospital discharge for elderly patients is a commonly occurring function, though it varies in numerable ways. By observing the everyday practice of hospital discharge for these patients, we have identified the common functions that typically occur on the day of discharge and the multiple, diverse sources of performance variability among those functions .Individual characteristics are an important determinant of performance , and stuIndividual and team performance is further influenced by organizational factors, e.g., unit, specialization, leadership, work organization, and institutionalized routines. Hospital wards are highly specialized and are perceived as shaping the clinician’s and care team’s preferences, attention, information exchange, and decision-making criteria. In this study, the unit of analysis  had an impact on outcome . The receiving health-care care providers appeared to make more negative remarks about the process related to patients discharged from orthopedic wards than from medical, especially geriatric, wards. The importance of geriatric knowledge and assessment has been investigated in previous studies , 42, 43;Our findings also raise the awareness of the temporal aspects related to the current discharge processes. The results of this study strongly suggest that the time of day the patient is declared medically fit is important: this determines the temporal conditions (degree of time pressure) for the subsequent actions. This decision about medical fitness being made later in the day (after noon) was associated with increased time pressure; it led to variability, and it affected duration and precision issues. Previous studies have addressed the importance of the timing of discharge ; they inA key contextual factor that was perceived as affecting the temporal completeness of the decision about medical fitness was availability of beds. The problem of crowded wards and its implications on performance have been illustrated with the notion of “going solid” , and it The results presented here further emphasize the role of the elderly patient  and that of their next of kin  in the reported satisfaction with the discharge process and outcome. Patient factors have been found to affect the elderly patient’s ability to be involved or participate in the discharge process ; howeverWith the inclusion of the multiple-stakeholder perspective, our findings also reveal one of the main challenges with the FRAM approach in the context of health-care delivery. The FRAM appears to emphasize health-care providers’ definitions and concepts of acceptable, successful outcomes without considering the experiences of patients and their next of kin. Our results illustrate that the various stakeholders had different concerns and used different measures to evaluate the degree of successful hospital discharge functioning. This study implies that the assessment of acceptable, successful outcomes depends on the focus of the stakeholder groups. We argue that the process of determining successful outcomes must incorporate all stakeholder groups. The multiple perspectives of all stakeholders, including patients and their next of kin, have not received systematic attention in the literature on hospital discharge ; it has From our results, we would argue that the multiple PSFs related to hospital discharge and multiple-stakeholder perspectives have not been fully considered in interventional studies targeted at improving this process. Our findings illustrate that it is insufficient to isolate functions  as independent activities  owing to the functional dependencies on which hospital discharge performance relies. Future studies on hospital discharge should consider the health-care providers involved, the available resources, the patient being discharged, their next of kin, the organizational setting, and the current situational factors related to the functioning of discharge. Without considering these interdependencies, progress on hospital discharge improvements will be constrained , 53, 54.There are several limitations that should be considered when interpreting our results. The observations took place during regular working hours (8 a.m. to 4 p.m.). Thus, evenings, nights, and weekends were excluded owing to practical and resource-based issues. This represents a possible limitation because other performance issues  may be influential at other times. This study was performed in the context of the Norwegian health-care system with a relatively small sample size (20 patients) in two hospitals, which restricts the generalizability of the findings. Possible observer bias should also be mentioned since the observations were conducted by a single researcher (first author) with a nursing background, which entails a pre-understanding of the context. Such an inside perspective may advance data collection but also affect the accuracy of the observations. An observation team with a minimum of two researchers with different backgrounds could better cover the complexity of the observation setting involving both professional and patient or next-of-kin perspectives. We tried to control this observer bias by setting up weekly meetings or updates in the observation periods with the larger research team  to discuss preliminary impressions. Triangulation during the analysis process was carried out, with the three authors and members of the research team all being active in discussing the findings. Following the aims of the paper we have chosen to focus on the FRAM`s applicability to hospital discharge to explore its characteristics (e.g. functions) and general patterns of variability in discharge practices rather than addressing the specificities of each case. Finally, the study focused on the final stage of hospitalization, i.e., the actual discharge process. It would have been valuable for the study to have acquired data on the patients’ course from the day of admission to the end of their hospital stay.Hospital discharge is a complex multi-agency care process that is composed of multi-functional activities; it has multiple purposes, but its core activities are decision making and knowledge sharing. Through the application of the FRAM and use of observational methods, we have provided detailed insight into the range of functions that are performed during hospital discharge. We have called attention to the ways in which these functions vary, and we gained insight into the multiple PSFs that can be attributed to a range of contextual features . Such multifaceted understanding of PSFs is necessary in improving hospital discharge practices.Based on our findings, we argue that the existing, sequential approaches to the complexity of hospital discharge are inadequate. Given the interdependence among the functions, there is a need for corresponding multi-factorial interventions. Future research should focus on understanding the relationships between various functions and PSFs and their impact on hospital discharge practices and outcomes.Study results illustrate that the FRAM represents a powerful methodology, enabling new insight into complex inter-organizational processes. Further on study findings emphasize that functional performance and outcomes entail various stakeholder perspectives whereby assessment of acceptable, successful performance and discharge outcomes depends on each individual perspective. These differences in outcome values need to be acknowledged in order to create a common ground on what constitutes acceptable, successful discharge functioning.STROBE Statement—checklist of items that should be included in reports of observational studies.(DOC 88 KB)Additional file 1:


The importance of preventing and treating incomplete data in effectiveness studies is nowadays emphasized. However, most of the publications focus on randomized clinical trials (RCT). One flexible technique for statistical inference with missing data is multiple imputation (MI). Since methods such as MI rely on the assumption of missing data being at random (MAR), a sensitivity analysis for testing the robustness against departures from this assumption is required. In this paper we present a sensitivity analysis technique based on posterior predictive checking, which takes into consideration the concept of clinical significance used in the evaluation of intra-individual changes. We demonstrate the possibilities this technique can offer with the example of irregular longitudinal data collected with the Outcome Questionnaire-45 (OQ-45) and the Helping Alliance Questionnaire (HAQ) in a sample of 260 outpatients. The sensitivity analysis can be used to (1) quantify the degree of bias introduced by missing not at random data (MNAR) in a worst reasonable case scenario, (2) compare the performance of different analysis methods for dealing with missing data, or (3) detect the influence of possible violations to the model assumptions . Moreover, our analysis showed that ratings from the patient's and therapist's version of the HAQ could significantly improve the predictive value of the routine outcome monitoring based on the OQ-45. Since analysis dropouts always occur, repeated measurements with the OQ-45 and the HAQ analyzed with MI are useful to improve the accuracy of outcome estimates in quality assurance assessments and non-randomized effectiveness studies in the field of outpatient psychotherapy. Missing data that occur if patients drop out, either from the treatment or from the whole study, are a serious source of bias in the evaluation of treatment effectiveness. There are numerous works demonstrating the implementation of multiple imputation (MI) in the analysis of longitudinal data with missing values Enders, . Howeverwide format and imputed in the same way as cross-sectional data   and one after the end of the therapy (post), included, among other things, structured diagnostic interviews based on DSM-IV . Participants were predominately female (67%). Among them, 10% had a low, 35% a middle, and 55% a high level of education. The most frequent Axis I diagnoses were affective (38%), anxiety (24%), and adjustment disorders (17%). A lifetime history of psychiatric disorders was present in 60% of the subjects. Two thirds of the sample had one or more current comorbidity disorders. The proportion of patients with Axis II disorders were 40%; of personality disorders (PD) diagnosed more of the half belonged to Cluster C. The mean duration of the treatments was 39 sessions (SD = 31). Therapies were monitored with measurements after each 5th session. At the beginning of the therapy the frequency was usually 1 treatment session per week and was lowered during treatment progress. The mean interval between the last three measurements was 14 and 17 weeks, respectively. Treatments were on average monitored by eight process measurements .For the present analysis data were used from therapies either terminated by mutual consent, or discontinued as a result of the patient's decision. The former are referred below as completers, the latter as dropouts. The percentages in Table Table Our protocol can be basically applied to all three imputation procedures . We generated the imputations following the second approach and using the functions from the R package mi  was regressed on the session number ijs. Intercept β0 and slope β1 were used as predictors in the imputation models. Solely process measurements were used .Pre-values (OQ-45) and values from the last two process measurements .In addition the following subject-level covariates were taken in consideration in building the imputation equations: sociodemographic data, clinical history, Axis I and Axis II diagnoses, treatment orientation, number of sessions, time interval between last therapy session and post-assessment. Both the time-varying and the subject-level covariates built a pool of 110 potential predictors. Given the ratio of variables to cases, the inclusion of all predictors in the single regression equations increase the risk of multicollinearity. Therefore, we reduced the number of predictors in each equation using the following criteria:Use of monotone data imputation, if applicable. Scales, which are intended to be completed by the same person on the same occasion, contain possible missing values contemporaneously. Hence, we treated these scales with the monotone pattern imputation . In these models, single input variables that contribute to the multicollinearity are removed. Variables with the highest p-values are dropped first. In case there is lack of convergence of the imputation process, then the number of predictors in the model is reduced, until all VIF values fall below 5.improved. The remaining 78 cases were divided into 69 unchanged and 9 deteriorated patients who form in the following analyses the group labeled as not improved. The maximum bias to which the imputation procedure is exposed under an MNAR mechanism arises if the 50 cases with missing outcome are all either improved or not improved. The robustness of the imputation models in these scenarios will be tested using the following steps:Preliminary results with the current data indicated that, in the presence of MNAR, the amount of bias in estimates obtained from multiply imputed data depends on the composition of the observed sample, on the amount of missing data and on the difference between the true parameter value and the estimate obtained from the observed data. No rules of thumb can be formulated concerning the question as to in which situations multiple imputation delivers robust estimates, regardless of the underlying missing mechanism. Therefore, an approach to assess the accuracy and robustness of estimates obtained in different data sets is needed. The posterior predictive checking is a flexible approach from the Bayesian statistics used to test whether the model's predictions are consistent with the data .Take one imputed data set as the basis of a simulation.Check the model fit to the data by examining the accuracy of MI under MAR conditions.Multiple imputation of values satisfying the MAR condition leads to unbiased estimates, unless assumptions of the applied model are violated. For instance, imputing normally distributed values by a linear model can lead to overestimating the central tendency in rating data that exhibit a floor effect (right skewed): this can be the case with ratings of the symptom distress collected at the end of the treatment. Substantial biases detected in MAR simulations are a sign that the imputation model is misspecified and needs to be revised before continuing the analyses . In our checks we simulated non-response with a probability based on outcome values observed at earlier time points . In our example we had b = 132, c = 78, and d = 50. Further let γ be the pre-post effect size .Let Y, X, and M denote the outcome score, the covariates, and the missingness indicator, respectively  = E + Δ, which adds a constant value to values imputed from an MAR model in order to get MNAR imputations .b = 132, c = 78, and d = 50. The post-assessment values of 50 not improved cases were deleted.MNAR1: The sampling procedure was executed with b = 132, c = 78 but with d = 50 improved cases. The post-assessment values of 50 improved cases were deleted.MNAR2: The sampling procedure was executed with In each of the four simulation trials the analyses were additionally carried out using two simple techniques: complete case analysis  and last-observation-carried-forward analysis (LOCF). For each estimator point estimates and confidence intervals based on percentiles  and the type of termination (Model B)? The initial improvement was defined as the difference between OQ total pre and OQ total at 5th session. HAQ-P and HAQ-T scores at 5th session were taken as indicators of the initial alliance quality.it predict the subsequent improvement (Model C)? The difference between OQ total on occasion it and OQ total on occasion ti + 1 was taken as subsequent improvement.Can the HAQ scores measured during the therapy on occasion n = 260) within therapists (n = 70) within treatment approaches (n = 10), whereas in Model C measurement occasions (n = 2032) were nested within patients (n = 260). Continuous independent (input) variables were rescaled by centering and dividing by two standard deviations so as to make their regression coefficients comparable to those of binary predictors , missing values were re-imputed under the MNAR assumption as described in step 5. On average, the pre-post difference of the 50 cases with missing outcome data was overestimated by 4.5 points. This deviance was taken as Δ for the adjustment model. The selection model was conducted under the assumption of an MNAR-linear missingness. Both correction approaches reduced the bias to under 1% in the MNAR1 simulations.In the original data set the effect size estimated by the delta-adjustment and the selection model were 1.00 and 1.02, respectively and did not differ substantially from the 1.08 obtained under the MAR assumption.The re-analysis, under the MNAR assumption, of the models presented in Tables R2 = 0.63). By adding as predictors the scores collected at the third last process measurement did not incremented significantly the proportion of explained outcome variance.The capability of the imputation model in reducing the bias under MNAR conditions argues for the predictive value of the OQ-45 and HAQ ratings. The scores of the OQ total and of the HAQ scales collected in the two last process measurements are the best predictors of the score at the end of the treatment  = 7.7, p = 0.006]. Concerning the propensity to dropout, the only significant predictor is the initial alliance quality judged by the therapists (Model B).With Models A and B the predictive value of the initial ratings together with other relevant covariates was tested Table . The preF = 4.7, p = 0.004].Model C tests whether HAQ-P-H, which is the alliance subscale the most sensitive to change, can, with its collected scores during the therapy, predict subsequent improvement Table . When coThe present paper proposes a strategy to carry out MI with inclusive sensitivity analysis in quality assurance assessments or in non-randomized effectiveness studies in the field of mental health treatments. Longitudinal data collected in this kind of projects are, independently of their completeness, irregular, in the sense that, the number of measurement occasions and the overall monitored period is varying from subject to subject. Therefore, analysis methods considering MAR data, such as mixed models or MI, need to be adapted in order to adequately consider this irregularity. We proposed to summarize longitudinal data, which are used as predictors in the imputation of the missing outcome data at the end of the treatment, in two different ways: (1) as subject-specific intercepts and slopes, (2) by taking only the pre-values and the values from the two last process measurements. The first type of predictors can be useful in the imputation of missing diagnostic data at intake. Obviously using both type of variables contemporaneously create a certain redundancy, therefore it is important to check the multicollinearity of the imputation models in advance.We tested the robustness of our MI models with a simulation procedure based on the Bayesian technique of posterior predictive checking.The proposed approach can be used for the following purpose:Quantifying the degree of bias introduced by MNAR mechanisms in a possible worst reasonable case scenario (MNAR simulations).Comparing the performance of different analysis methods for dealing with missing data (MAR as well MNAR simulations).Detecting the influence of possible violations to the regression model assumptions such as lack of normality (MAR simulations).clinically plausible worst-case scenario is estimated by simulations. Our procedure integrates the concept of clinical significance used in the evaluation of the outcome quality of psychotherapies. Clinical significance consists in classifying patient outcome into four categories: improved, remitted, unchanged, and deteriorated. Due to the small number of deteriorated cases, we simplified in our example the categorization in a positive outcome (improved) and a negative outcome (not improved) (Lutz et al., MI, which can be used as primary analysis method in outcome evaluations, leads to unbiased results under the MAR assumption. However, since it is likely that some missing data are MNAR, these primary results should be compared with results obtained under MNAR assumptions. In order to test the impact of MNAR mechanisms and, if necessary, to obtain indications on defining a suitable model for an alternative outcome estimation under MNAR conditions, we have suggested a procedure, in which the maximal degree of bias under a The simulation procedure allows, taking account of the composition of the observed data, to answer the question: How accurate are the estimates when subjects with missing outcome data have all a negative outcome? In line with Graham , who favWith the simulation trials we also took the opportunity to compare the performance of MI with that of two simple methods: CC and LOCF. This comparison addresses the question of cost-benefit ratio: “Is it worth carrying out multiple imputations? Can satisfactory results also be obtained with simple approaches?” Our results shown that already with a missing rate of about 20% CC estimates are affected by a percentage bias greater than 10%. Users not familiar with the taxonomy of missing data mechanisms often ask about the maximum percentage of missing values with only a negligible effect on results obtained with CC. According to the literature this threshold is at about 10% (Barzi and Woodward, The other simple technique, LOCF, proved to be particularly conservative and led often to a substantial under-estimation of the pre-post effect in the whole sample. In turn, MI demonstrated a better capability to discriminate between improved and not improved subjects. This kind of flexibility is important as not every missing outcome measurement is the consequence of treatment failures; withdrawing the assessment can be the consequence of previous negative experiences with the assessment itself.In order to obtain with MI a robust outcome estimate at the end of the treatment, repeated measurements of relevant predictors not only of missingness but also of outcome are essential. Published simulation studies demonstrated that including auxiliary variables, which correlate with outcome but not necessarily with missingness, can considerably reduce the bias caused by MNAR (Collins et al., The question concerning the range of data collection refers particularly to the benefit of an additional measurement of the therapeutic alliance for the robustness of MI results. There is no doubt about the importance of the therapeutic alliance for the success of psychotherapy. What remains unclear is whether alliance questionnaires really ascertain information that is not already delivered by questionnaires measuring the patient's progress. The predictive value of the HAQ was therefore tested with different regression models, in which additionally the OQ-45 score was controlled. The results show that the initial alliance quality rated by the patient can predict the overall improvement, whereas the initial rating delivered by the therapist can predict the discontinuation decided by the patient. The latter result is in contrast with previous research related to the OQ-45, in which the capability of therapist in predicting the outcome of their patients, without feedback from a routine outcome measurement, was tested (Hannan et al., Another positive result from our analyses concerns the capability of the Helpfulness score rated by the patient during the final therapy phase to improve the prediction of subsequent improvement. The HAQ has often been criticized because it does not separate between alliance and symptomatic improvement (Luborsky et al., All in all, we can recommend repeated measurements with the OQ-45 and the HAQ in the evaluation of outpatient psychotherapy. Collected data do not only serve improvement of accuracy of the outcome estimate, they can also be used as feedback instruments for therapists and patients.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.