Herpes simplex virus type 1 (HSV-1) establishes latency in neurons and can cause severe disseminated infection with neurological impairment and high mortality. This neurodegeneration is thought to be tightly associated with virus-induced cytoskeleton disruption. Currently, the regulation pattern of the actin cytoskeleton and the involved molecular mechanisms during HSV-1 entry into neurons remain unclear. Here, we demonstrate that the entry of HSV-1 into neuronal cells induces biphasic remodeling of the actin cytoskeleton and an initial inactivation followed by the subsequent activation of cofilin, a member of the actin depolymerizing factor family that is critical for actin reorganization. The disruption of F-actin dynamics or the modulation of cofilin activity by mutation, knockdown, or overexpression affects HSV-1 entry efficacy and virus-mediated cell ruffle formation. Binding of the HSV-1 envelope initiates the epidermal growth factor receptor (EGFR)-phosphatidylinositide 3-kinase (PI3K) signaling pathway, which leads to virus-induced early cofilin phosphorylation and F-actin polymerization. Moreover, the extracellular signal-regulated kinase (ERK) kinase and Rho-associated, coiled-coil-containing protein kinase 1 (ROCK) are recruited as downstream mediators of the HSV-1-induced cofilin inactivation pathway. Inhibitors specific for those kinases significantly reduce the virus infectivity without affecting virus binding to the target cells. Additionally, lipid rafts are clustered to promote EGFR-associated signaling cascade transduction. We propose that HSV-1 hijacks cofilin to initiate infection. These results could promote a better understanding of the pathogenesis of HSV-1-induced neurological diseases.
The actin cytoskeleton is involved in many crucial cellular processes and acts as an obstacle to pathogen entry into host cells. Because HSV-1 establishes lifelong latency in neurons and because neuronal cytoskeletal disruption is thought to be the main cause of HSV-1-induced neurodegeneration, understanding the F-actin remodeling pattern by HSV-1 infection and the molecular interactions that facilitate HSV-1 entry into neurons is important. In this study, we showed that HSV-1 infection induces the rearrangement of the cytoskeleton as well as the initial inactivation and subsequent activation of cofilin. Then, we determined that activation of the EGFR-PI3K-Erk1/2 signaling pathway inactivates cofilin and promotes F-actin polymerization. We postulate that by regulating actin cytoskeleton dynamics, cofilin biphasic activation could represent the specific cellular machinery usurped by pathogen infection, and these results will greatly contribute to the understanding of HSV-1-induced early and complex changes in host cells that are closely linked to HSV-1 pathogenesis.
Scrubbing identifying information from narrative clinical documents is a critical first step to preparing the data for secondary use purposes, such as translational research. Evidence suggests that the differential distribution of protected health information (PHI) in clinical documents could be used as additional features to improve the performance of automated de-identification algorithms or toolkits. However, there has been little investigation into the extent to which such phenomena transpires in practice. To empirically assess this issue, we identified the location of PHI in 140,000 clinical notes from an electronic health record system and characterized the distribution as a function of location in a document. In addition, we calculated the ‘word proximity’ of nearby PHI elements to determine their co-occurrence rates. The PHI elements were found to have non-random distribution patterns. Location within a document and proximity between PHI elements might therefore be used to help de-identification systems better label PHI.
To understand the nature of emerging electronic documentation practices, disconnects between documentation workflows and computing systems designed to support them, and ways to improve the design of electronic documentation systems.
Materials and methods
Time-and-motion study of resident physicians' note-writing practices using a commercial electronic health record system that includes an electronic documentation module. The study was conducted in the general medicine unit of a large academic hospital.
During the study, 96 note-writing sessions by 11 resident physicians, resulting in close to 100 h of observations were seen. Seven of the 10 most common transitions between activities during note composition were between documenting, and gathering and reviewing patient data, and updating the plan of care.
The high frequency of transitions seen in the study suggested that clinical documentation is fundamentally a synthesis activity, in which clinicians review available patient data and summarize their impressions and judgments. At the same time, most electronic health record systems are optimized to support documentation as uninterrupted composition. This mismatch leads to fragmentation in clinical work, and results in inefficiencies and workarounds. In contrast, we propose that documentation can be best supported with tools that facilitate data exploration and search for relevant information, selective reading and annotation, and composition of a note as a temporal structure.
Time-and-motion study of clinicians' electronic documentation practices revealed a high level of fragmentation of documentation activities and frequent task transitions. Treating documentation as synthesis rather than composition suggests new possibilities for supporting it more effectively with electronic systems.
Electronic documentation; time and motion studies (F02.784.412.846.707); electronic health records (E05.318.308.940.968.625.500); workflow (L01.906.893); knowledge bases; Ontologies; human-computer interaction and human-centered computing; delivering health information and knowledge to the public; knowledge acquisition and knowledge management; developing/using computerized provider order entry; communications; networking methods; mobility; developing/using clinical decision support (other than diagnostic) and guideline systems; collaborative technologies; personal health records and self-care systems; systems supporting patient-provider interaction; data mining
The authors found that CPOE implementation did not negatively affect time available for direct patient care and that workflow fragmentation decreased, which is likely beneficial.
Little is known about the impact of computerized prescriber order entry (CPOE) systems on inpatient hematology/oncology services. The objective of this study was to quantify the impact of an inpatient CPOE implementation on workflow, with an emphasis on ordering and direct patient care time.
We conducted a direct-observation time-and-motion study of the provider team of a hematology/oncology inpatient service both before and after CPOE implementation, characterizing workflow into 60 distinct activity categories. The provider team comprised physician assistants supervised by attending physicians. Results were adjusted to account for variations in the census. We also conducted an analysis of computer logs to assess CPOE system usage.
Study participants were observed for 228.0 hours over 53 observation sessions. There was little change in the proportion of census-adjusted time spent on ordering (10.2% before v 11.4% after) and on direct patient care (50.7% before v 47.8% after). Workflow fragmentation decreased, with providers spending an average of 131.2 seconds on a continuous task before implementation and 218.3 seconds after (P < .01). An eight-fold decrease in the number of pages was observed during the course of the study.
CPOE implementation did not negatively affect time available for direct patient care. Workflow fragmentation decreased, which is likely beneficial.
Long-term strain improvements through repeated mutagenesis and screening have generated a hyper-producer of cellulases and hemicellulases from Penicillium decumbens 114 which was isolated 30 years ago. Here, the genome of the hyper-producer P. decumbens JU-A10-T was sequenced and compared with that of the wild-type strain 114-2. Further, the transcriptomes and secretomes were compared between the strains. Selective hyper-production of cellulases and hemicellulases but not all the secreted proteins was observed in the mutant, making it a more specific producer of lignocellulolytic enzymes. Functional analysis identified that changes in several transcriptional regulatory elements played crucial roles in the cellulase hyper-producing characteristics of the mutant. Additionally, the mutant showed enhanced supply of amino acids and decreased synthesis of secondary metabolites compared with the wild-type. The results clearly point out that we can target gene regulators and promoters with minimal alterations of the genetic content but maximal effects in genetic engineering.
In this study, we used a substance P (SP) immunohistochemical method to analyze the expression localization of osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) in giant cell tumor (GCT) of the bone, and to detect the clinical significance of their expression. The data showed that the positive expression rate of OPG in the multinucleated giant cells (MGCs) and stromal cells (STCs) of GCT was 80.65 and 74.19%, respectively. The positive expression rate of OPG in MGCs was correlated with age and prognosis (P<0.05), but not in STCs. The strength of positive OPG expression in MGCs and STCs was negatively correlated with prognosis (rs=−0.397, P<0.05; rs=−0.390, P<0.05, respectively). The positive expression rate of OPGL in the MGCs and STCs was 41.94 and 67.74%, respectively. The positive expression rate of OPGL in the MGCs was correlated with age and prognosis (P<0.05); the strength of OPGL expression in MGCs was positively correlated with Campanicci’s grade and recurrence. Additionally, the positive expression rate of OPGL in STCs was correlated with age and Jaffe’s grade (P<0.05). The strength of OPGL expression in STCs was negatively correlated with Jaffe’s grade (rs=−0.534, P<0.05). In conclusion, OPG and OPGL are expressed in MGCs and STCs in GCT of the bone. The invasion of tumor cells was positively correlated with OPGL in MGCs, which confirmed that MGCs participate in the process of osteolytic destruction of GCT of bone.
giant cell tumor of bone; osteoprotegerin; osteoprotegerin ligand; immunohistochemistry
Herpes simplex virus 1 (HSV-1) invades the nervous system and causes pathological changes. In this study, we defined the remodeling of F-actin and its possible mechanisms during HSV-1 infection of neuronal cells. HSV-1 infection enhanced the formation of F-actin-based structures in the early stage of infection, which was followed by a continuous decrease in F-actin during the later stages of infection. The disruption of F-actin dynamics by chemical inhibitors significantly reduced the efficiency of viral infection and intracellular HSV-1 replication. The active form of the actin-depolymerizing factor cofilin 1 was found to increase at an early stage of infection and then to continuously decrease in a manner that corresponded to the remodeling pattern of F-actin, suggesting that cofilin 1 may be involved in the biphasic F-actin dynamics induced by HSV-1 infection. Knockdown of cofilin 1 impaired HSV-1-induced F-actin assembly during early infection and inhibited viral entry; however, overexpression of cofilin 1 did not affect F-actin assembly or viral entry during early infection but decreased intracellular viral reproduction efficiently. Our results, for the first time, demonstrated the biphasic F-actin dynamics in HSV-1 neuronal infection and confirmed the association of F-actin with the changes in the expression and activity of cofilin 1. These results may provide insight into the mechanism by which HSV-1 productively infects neuronal cells and causes pathogenesis.
Sargassum naozhouense is a brown seaweed used in folk medicine and applied for thousands of years in Zhanjiang, Guangdong province, China. This study is the first time to investigate its chemical composition and antiviral activity. On the dry weight basis, this seaweed was constituted of ca. 35.18% ash, 11.20% protein, 1.06% lipid and 47.73% total carbohydrate, and the main carbohydrate was water-soluble polysaccharide. The protein analysis indicated the presence of essential amino acids, which accounted for 36.35% of the protein. The most abundant fatty acids were C14:0, C16:0, C18:1 and C20:4. The ash fraction analysis indicated that essential minerals and trace elements, such as Fe, Zn and Cu, were present in the seaweed. IR analysis revealed that polysaccharides from cultivated S. naozhouense may be alginates and fucoidan. The polysaccharides possessed strong antiviral activity against HSV-1 in vitro with EC50 of 8.92 μg/mL. These results demonstrated cultivated S. naozhouense has a potential for its use in functional foods and antiviral new drugs.
Sargassum naozhouense; seaweed; chemical composition; antiviral activity
To develop a theoretically informed and empirically validated survey instrument for assessing prescribers' perception of computerized drug–drug interaction (DDI) alerts.
Materials and methods
The survey is grounded in the unified theory of acceptance and use of technology and an adapted accident causation model. Development of the instrument was also informed by a review of the extant literature on prescribers' attitude toward computerized medication safety alerts and common prescriber-provided reasons for overriding. To refine and validate the survey, we conducted a two-stage empirical validation study consisting of a pretest with a panel of domain experts followed by a field test among all eligible prescribers at our institution.
The resulting survey instrument contains 28 questionnaire items assessing six theoretical dimensions: performance expectancy, effort expectancy, social influence, facilitating conditions, perceived fatigue, and perceived use behavior. Satisfactory results were obtained from the field validation; however, a few potential issues were also identified. We analyzed these issues accordingly and the results led to the final survey instrument as well as usage recommendations.
High override rates of computerized medication safety alerts have been a prevalent problem. They are usually caused by, or manifested in, issues of poor end user acceptance. However, standardized research tools for assessing and understanding end users' perception are currently lacking, which inhibits knowledge accumulation and consequently forgoes improvement opportunities. The survey instrument presented in this paper may help fill this methodological gap.
We developed and empirically validated a survey instrument that may be useful for future research on DDI alerts and other types of computerized medication safety alerts more generally.
Decision support systems; clinical (L01.700.508.300.190); medical order entry systems (L01.700.508.300.408.600); drug interactions (G07.690.812.240); psychology; social (F01.829); Questionnaires (L01.280.800); collaborative technologies; personal health records and self-care systems; personal health records and self-care systems; developing/using clinical decision support (other than diagnostic) and guideline systems; systems supporting patient-provider interaction; human-computer interaction and human-centered computing; improving healthcare workflow and process efficiency; system implementation and management issues; social/organizational study; qualitative/ethnographic field study; pharmacy; clinical decision support; outcome; quality improvement; medications; surveys; business intelligence; quality improvement; patient satisfaction; employee satisfaction; pharmacy; quality; patient safety; machine learning; knowledge bases
Despite mandates and incentives for electronic health record (EHR) adoption, little is known about factors predicting physicians’ satisfaction following EHR implementation.
To measure predictors of physician satisfaction following EHR adoption.
A total of 163 physicians completed a mailed survey before and after EHR implementation through a statewide pilot project in Massachusetts. Multivariable logistic regression identified predictors of physician satisfaction with their current practice situation in 2009 and generalized estimating equations accounted for clustering.
The response rate was 77% in 2005 and 68% in 2009. In 2005, prior to EHR adoption, 28% of physicians were very satisfied with their current practice situation compared to 25% in 2009, following EHR adoption (P < .001). In multivariate analysis, physician satisfaction following EHR adoption was correlated with self-reported ease of EHR implementation (adjusted odds ratio [OR] = 5.7, 95% CI 2.1 - 16), resources for practice improvement (adjusted OR = 2.6, 95% CI 1.2 - 6.1), pre-intervention satisfaction (adjusted OR = 4.8, 95% CI 1.5 - 15), and stress (adjusted OR = 5.3, 95% CI 1.1 - 25). Male physicians reported lower satisfaction following EHR adoption (adjusted OR = 0.3, 95% CI 0.2 - 0.6).
Interventions to expand EHR use should consider additional support for practices with fewer resources for improvement and ensure ease of EHR implementation. EHR adoption may be a factor in alleviating physicians’ stress. Addressing physicians’ satisfaction prior to practice transformation and anticipating greater dissatisfaction among male physicians will be essential to retaining the physician workforce and ensuring the quality of care they deliver.
electronic health record; physician satisfaction; implementation; Massachusetts eHealth collaborative
In this study, we quantified the use of uncertainty expressions, referred to as ‘hedge’ phrases, among a corpus of 100,000 clinical documents retrieved from our institution’s electronic health record system. The frequency of each hedge phrase appearing in the corpus was characterized across document types and clinical departments. We also used a natural language processing tool to identify clinical concepts that were spatially, and potentially semantically, associated with the hedge phrases identified. The objective was to delineate the prevalence of hedge phrase usage in clinical documentation which may have a profound impact on patient care and provider–patient communication, and may become a source of unintended consequences when such documents are made directly accessible to patients via patient portals.
To present a partnership-based and community-oriented approach designed to ease provider anxiety and facilitate the implementation of electronic health records (EHR) in resource-limited primary care settings.
Materials and Methods
The approach, referred to as partnership model, was developed and iteratively refined through the research team's previous work on implementing health information technology (HIT) in over 30 safety net practices. This paper uses two case studies to illustrate how the model was applied to help two nurse-managed health centers (NMHC), a particularly vulnerable primary care setting, implement EHR and get prepared to meet the meaningful use criteria.
The strong focus of the model on continuous quality improvement led to eventual implementation success at both sites, despite difficulties encountered during the initial stages of the project.
There has been a lack of research, particularly in resource-limited primary care settings, on strategies for abating provider anxiety and preparing them to manage complex changes associated with EHR uptake. The partnership model described in this paper may provide useful insights into the work shepherded by HIT regional extension centers dedicated to supporting resource-limited communities disproportionally affected by EHR adoption barriers.
NMHC, similar to other primary care settings, are often poorly resourced, understaffed, and lack the necessary expertise to deploy EHR and integrate its use into their day-to-day practice. This study demonstrates that implementation of EHR, a prerequisite to meaningful use, can be successfully achieved in this setting, and partnership efforts extending far beyond the initial software deployment stage may be the key.
Collaborative technologies; community health care; developing/using clinical decision support (other than diagnostic) and guideline systems; electronic health records (E05.318.308.940.968.625.500); health information technology for economic and clinical health act (N03.706.615.049); human–computer interaction and human-centered computing; improving healthcare workflow and process efficiency; nurse-managed health centers; personal health records and self-care systems; qualitative/ethnographic field study; regional extension centers; social/organizational study; system implementation and management issues; systems supporting patient–provider interaction
Unpredictable yet frequently occurring exception situations pervade clinical care. Handling them properly often requires aberrant actions temporarily departing from normal practice. In this study, the authors investigated several exception-handling procedures provided in an electronic health records system for facilitating clinical documentation, which the authors refer to as ‘data entry exit strategies.’ Through a longitudinal analysis of computer-recorded usage data, the authors found that (1) utilization of the exit strategies was not affected by postimplementation system maturity or patient visit volume, suggesting clinicians' needs to ‘exit’ unwanted situations are persistent; and (2) clinician type and gender are strong predictors of exit-strategy usage. Drilldown analyses further revealed that the exit strategies were judiciously used and enabled actions that would be otherwise difficult or impossible. However, many data entries recorded via them could have been ‘properly’ documented, yet were not, and a considerable proportion containing temporary or incomplete information was never subsequently amended. These findings may have significant implications for the design of safer and more user-friendly point-of-care information systems for healthcare.
Electronic health records (E05.318.308.940.968.625.500); workflow (L01.906.893); documentation (L01.453.245); exit strategy; exception-handling; collaborative technologies; personal health records and self-care systems; developing/using clinical decision support (other than diagnostic) and guideline systems; systems supporting patient–provider interaction; human–computer interaction and human-centered computing; improving healthcare workflow and process efficiency; system implementation and management issues; social/organizational study; qualitative/ethnographic field study; cognitive study (including experiments emphasizing verbal protocol analysis and usability); methods for integration of information from disparate sources; information storage and retrieval (text and images); data exchange; communication and integration across care settings (inter- and intraenterprise); visualization of data and knowledge; developing/using computerized provider order entry; diamond
Antibody glycosylation is a common post-translational modification and has a critical role in antibody effector function. The use of glycoengineering to produce antibodies with specific glycoforms may be required to achieve the desired therapeutic efficacy. However, the modified molecule could have unusual behavior during development due to the alteration of its intrinsic properties and stability. In this study, we focused on the differences between glycosylated and deglycosylated antibodies, as aglycosyl antibodies are often chosen when effector function is not desired or unimportant. We selected three human IgG1 antibodies and used PNGase F to remove their oligosaccharide chains. Although there were no detected secondary or tertiary structural changes after deglycosylation, other intrinsic properties of the antibody were altered with the removal of oligosaccharide chains in the Fc region. The apparent molecular hydrodynamic radius increased after deglycosylation based on size-exclusion chromatography analysis. Deglycosylated antibodies exhibited less thermal stability for the CH2 domain and less resistance to GdnHCl induced unfolding. Susceptibility to proteolytic cleavage demonstrated that the deglycosylated version was more susceptible to papain. An accelerated stability study revealed that deglycosylated antibodies had higher aggregation rates. These changes may impact the development of aglycosyl antibody biotherapeutics.
monoclonal antibody; glycosylation; stability; liquid chromatography-mass spectroscopy; Fourier transform infrared; fluorescence spectroscopy; size-exclusion chromatography; differential scanning calorimetry
We report a case study of an IgG1 with a unique basic charge variant profile caused by C-terminal proline amidation on either one or two heavy chains. The proline amidation was sensitive to copper ion concentration in the production media during cell culture: the higher the Cu2+ ion concentration, the higher the level of proline amidation detected. This conclusion was supported by the analysis of samples that revealed direct correlation between the proline amidation level observed from peptide maps and the level of basic peaks measured by imaged capillary isoelectric focusing and a pH gradient ion-exchange chromatography method. The importance of these observations to therapeutic antibody production is discussed.
antibody; basic charge variants; proline amidation; copper; mass spectrometry
To identify ways for improving the consistency of design, conduct, and results reporting of time and motion (T&M) research in health informatics.
Materials and methods
We analyzed the commonalities and divergences of empirical studies published 1990–2010 that have applied the T&M approach to examine the impact of health IT implementation on clinical work processes and workflow. The analysis led to the development of a suggested ‘checklist’ intended to help future T&M research produce compatible and comparable results. We call this checklist STAMP (Suggested Time And Motion Procedures).
STAMP outlines a minimum set of 29 data/ information elements organized into eight key areas, plus three supplemental elements contained in an ‘Ancillary Data’ area, that researchers may consider collecting and reporting in their future T&M endeavors.
T&M is generally regarded as the most reliable approach for assessing the impact of health IT implementation on clinical work. However, there exist considerable inconsistencies in how previous T&M studies were conducted and/or how their results were reported, many of which do not seem necessary yet can have a significant impact on quality of research and generalisability of results. Therefore, we deem it is time to call for standards that can help improve the consistency of T&M research in health informatics. This study represents an initial attempt.
We developed a suggested checklist to improve the methodological and results reporting consistency of T&M research, so that meaningful insights can be derived from across-study synthesis and health informatics, as a field, will be able to accumulate knowledge from these studies.
Time and motion studies (F02.784.412.846.707); workflow (L01.906.893); health information technology (L01.700); medical informatics applications (L01.700.508); collaborative technologies; personal health records and self-care systems; developing/using clinical decision support (other than diagnostic) and guideline systems; systems supporting patient-provider interaction; human-computer interaction and human-centered computing; improving healthcare workflow and process efficiency; system implementation and management issues; social/organizational study; qualitative/ethnographic field study; cognitive study (including experiments emphasizing verbal protocol analysis and usability); methods for integration of information from disparate sources; information storage and retrieval (text and images); data exchange; communication; integration across care settings (inter- and intra-enterprise); visualization of data and knowledge; developing/using computerized provider order entry
A critical aspect of clinical and translational science (CTS) is interdisciplinary and collaborative research, which increasingly requires a wide range of computational and human resources. However, few studies have systematically analyzed such resource needs of CTS researchers.
To improve our understanding of CTS researchers’ needs for computational and human resources in order to build useful and useable supporting informatics tools.
We conducted semistructured interviews of 30 CTS researchers from the University of Michigan, followed by qualitative analysis of the interview transcripts.
The analysis identified three recurring themes: the need for the federation of information, the need to address information overload, and the need to humanize computing, including strong and well-informed views about the use of social networking tools for research collaboration. These findings helped us to narrow down the available design choices for assisting CTS researchers, and helped to identify potential deficiencies of well-known theoretical frameworks used to guide our study, with suggestions for future remedies.
The user needs identified through the study, along with concrete design suggestions, provided key design, methodological, and theoretical insights, which are being used to guide the design and development of a CTS resource portal. The results and interview instrument should be useful to other institutions with Clinical and Translational Science Awards that face similar challenges related to helping CTS researchers make more effective use of computational and human resources.
Translational research; collaborative computing; Clinical and Translational Science Awards; CTSA; Resource Discovery
A full-text search engine can be a useful tool for augmenting the reuse value of unstructured narrative data stored in electronic health records (EHR). A prominent barrier to the effective utilization of such tools originates from users' lack of search expertise and/or medical-domain knowledge. To mitigate the issue, the authors experimented with a ‘collaborative search’ feature through a homegrown EHR search engine that allows users to preserve their search knowledge and share it with others. This feature was inspired by the success of many social information-foraging techniques used on the web that leverage users' collective wisdom to improve the quality and efficiency of information retrieval.
The authors conducted an empirical evaluation study over a 4-year period. The user sample consisted of 451 academic researchers, medical practitioners, and hospital administrators. The data were analyzed using a social-network analysis to delineate the structure of the user collaboration networks that mediated the diffusion of knowledge of search.
The users embraced the concept with considerable enthusiasm. About half of the EHR searches processed by the system (0.44 million) were based on stored search knowledge; 0.16 million utilized shared knowledge made available by other users. The social-network analysis results also suggest that the user-collaboration networks engendered by the collaborative search feature played an instrumental role in enabling the transfer of search knowledge across people and domains.
Applying collaborative search, a social information-foraging technique popularly used on the web, may provide the potential to improve the quality and efficiency of information retrieval in healthcare.
Collaborative technologies; personal health records and self-care systems; developing/using clinical decision support (other than diagnostic) and guideline systems; systems supporting patient-provider interaction; human–computer interaction and human-centered computing; improving healthcare workflow and process efficiency; system implementation and management issues; social/organizational study; qualitative/ethnographic field study; cognitive study (including experiments emphasizing verbal protocol analysis and usability); methods for integration of information from disparate sources; information storage and retrieval (text and images); data exchange; communication; integration across care settings (inter- and intraenterprise); visualization of data and knowledge; developing/using computerized provider order entry
The objectives of this work were to express the EC5 domain of E-cadherin and determine its structural characteristics as well as to evaluate the binding properties of HAV and BLG4 peptides to EC5 using spectroscopic methods. Homophilic interactions of E-cadherins are responsible for cell-cell adhesion in the adherens junctions of the biological barriers (i.e., intestinal mucosa and blood-brain barriers). The EC5 domain of E-cadherin has an important role in T-cell adhesion to intestinal mucosa via αEβ7 integrin-E-cadherin interactions. In this study, the expressed EC5 has a high thermal stability (Tm = 64.3 °C); it also has two stable conformations at room temperature, which convert to one conformation at approximately 54.5 °C. NMR and FTIR showed that HAV and BLG4 peptides bind to EC5. HSQC-NMR showed that either Asn or Gln of EC5 was involved in the interactions with HAV and BLG4 peptides. EC5 underwent a conformational change upon interaction with the HAV and BLG4 peptides. Finally, the binding properties of both peptides were modeled by docking experiments, and the results suggest that Asn-46 and Asn-75 of EC5 could be involved during the interaction with the peptides and that the Ser and Trp residues of the HAV and BLG4 peptides, respectively, were important for binding to EC5.
E-cadherin; EC5 domain; conformation; spectroscopy; adherens junction; cell-cell adhesion; peptide binding
The development of protein drugs has been hampered by difficulties in formulating them due to their inherent chemical and physical stability, which could generate problems during the late stages of development. Thus, a basic understanding of the effect of structural features on the physicochemical stability of proteins can provide fundamental solutions to the formation of proteins. In this work, the physical stability of the EC5 protein under variable pH, temperature, and ionic strength and the role of the disulfide bond on the physical stability of EC5 were evaluated. All spectroscopic measurements were integrated in empirical phase diagrams, and these diagrams showed the stable and unstable regions of EC5. The native EC5 is more stable at high than at low ionic strength in a wide pH range during temperature elevation to 70°C. The empirical phase diagrams also show that the reduced EC5 has lower stability than the parent EC5. The reduced EC5 has secondary structure only at pH 3 and 4 and is unfolded at other pH values. Finally, the reduced EC5 rapidly forms a precipitate at pH 4 and 5 upon heating. In conclusion, this study shows that ionic strength and the presence of the disulfide bonds are critical for the stability of EC5.
EC5; protein stability; CD; intrinsic fluorescence; UV absorbance; optical density; phase diagram
Health IT implementations often introduce radical changes to clinical work processes and workflow. Prior research investigating this effect has shown conflicting results. Recent time and motion studies have consistently found that this impact is negligible; whereas qualitative studies have repeatedly revealed negative end-user perceptions suggesting decreased efficiency and disrupted workflow.
We speculate that this discrepancy may be due in part to the design of the time and motion studies, which is focused on measuring clinicians' ‘time expenditures’ among different clinical activities rather than inspecting clinical ‘workflow’ from the true ‘flow of the work’ perspective. In this paper, we present a set of new analytical methods consisting of workflow fragmentation assessments, pattern recognition, and data visualization, which are accordingly designed to uncover hidden regularities embedded in the flow of the work. Through an empirical study, we demonstrate the potential value of these new methods in enriching workflow analysis in clinical settings.
Regular participation in physical activity can prevent many chronic health conditions. Computerized self-management programs are effective clinical tools to support patient participation in physical activity. This pilot study sought to develop and evaluate an online interface for primary care providers to refer patients to an Internet-mediated walking program called Stepping Up to Health (SUH) and to monitor participant progress in the program.
In Phase I of the study, we recruited six pairs of physicians and medical assistants from two family practice clinics to assist with the design of a clinical interface. During Phase II, providers used the developed interface to refer patients to a six-week pilot intervention. Provider perspectives were assessed regarding the feasibility of integrating the program into routine care. Assessment tools included quantitative and qualitative data gathered from semi-structured interviews, surveys, and online usage logs.
In Phase I, 13 providers used SUH and participated in two interviews. Providers emphasized the need for alerts flagging patients who were not doing well and the ability to review participant progress. Additionally, providers asked for summary views of data across all enrolled clinic patients as well as advertising materials for intervention recruitment. In response to this input, an interface was developed containing three pages: 1) a recruitment page, 2) a summary page, and 3) a detailed patient page. In Phase II, providers used the interface to refer 139 patients to SUH and 37 (27%) enrolled in the intervention. Providers rarely used the interface to monitor enrolled patients. Barriers to regular use of the intervention included lack of integration with the medical record system, competing priorities, patient disinterest, and physician unease with exercise referrals. Intention-to-treat analyses showed that patients increased walking by an average of 1493 steps/day from pre- to post-intervention (t = (36) = 4.13, p < 0.01).
Providers successfully referred patients using the SUH provider interface, but were less willing to monitor patient compliance in the program. Patients who completed the program significantly increased their step counts. Future research is needed to test the effectiveness of integrating SUH with clinical information systems over a longer evaluation period.
Pedometer; family medicine; Internet-mediated intervention; physical activity; walking; primary care; patient-centered medical home
To study how social interactions influence physician adoption of an electronic health records (EHR) system.
A social network survey was used to delineate the structure of social interactions among 40 residents and 15 attending physicians in an ambulatory primary care practice. Social network analysis was then applied to relate the interaction structures to individual physicians' utilization rates of an EHR system.
The social network survey assessed three distinct types of interaction structures: professional network based on consultation on patient care-related matters; friendship network based on personal intimacy; and perceived influence network based on a person's perception of how other people have affected her intention to adopt the EHR system. EHR utilization rates were measured as the proportion of patient visits in which sentinel use events consisting of patient data documentation or retrieval activities were recorded. The usage data were collected over a time period of 14 months from computer-recorded audit trail logs.
Neither the professional nor the perceived influence network is correlated with EHR usage. The structure of the friendship network significantly influenced individual physicians' adoption of the EHR system. Residents who occupied similar social positions in the friendship network shared similar EHR utilization rates (p<0.05). In other words, residents who had personal friends in common tended to develop comparable levels of EHR adoption. This effect is particularly prominent when the mutual personal friends of these ‘socially similar’ residents were attending physicians (p<0.001).
Social influence affecting physician adoption of EHR seems to be predominantly conveyed through interactions with personal friends rather than interactions in professional settings.
Distrust in the Internet as a source of health information remains common among older adults. The influence of this distrust on Internet use for health-related purposes, however, is unclear.
The objective of our study was to explore how older adults’ trust in the Internet influences their online health-related activities, and to identify potential targets for improving health-related Internet resources for older adults.
Data were obtained from a nationally representative, random digit-dial telephone survey of 1450 adults 50 years of age and older in the United States. A model was developed to conceptualize the hypothesized relationships among individual characteristics, distrust, and avoidance of the Internet as a health resource. Multivariate logistic regression analyses were conducted to examine the association between trust in online health information and use of the Internet for health-related purposes. Additional multivariate logistic regression analyses were conducted to identify the key characteristics associated with trust in online health information, adding sequentially the variables hypothesized to account for distrust among older adults: sociodemographic and health characteristics, inexperience and technical difficulties with the Internet, negative feelings toward the Internet, and lack of awareness about the sources providing the health information found online.
The mean (SD) age of the study population was 63.7 (10.6) years. Of the 823 (56.8%) Internet users, 628 (76.3%) reported using the Internet as a health resource. Trust in the Internet as a source of health information was associated with using the Internet for a number of health activities, including searching for information about a specific health condition (adjusted OR 4.43, P < .001), purchasing prescription drugs (adjusted OR 2.61, P = .03), and talking with a health care provider about information found online (adjusted OR 2.54, P = .002). Older adults (age ≥65 years) were less likely to trust the Internet as a source of health information (OR 0.63, P = .04), even after adjusting for other sociodemographic characteristics and health and function. This age effect was only slightly attenuated (adjusted OR 0.69, P = .13) after adjusting for inexperience and technical difficulties with the Internet, but it disappeared entirely (adjusted OR 0.96, P = .91) after adjusting for other hypothesized contributors to distrust (including finding the Internet confusing because it provides “too much information,” and lacking awareness about the source providing health information found online).
Website design features that clearly identify the source and credibility of information and minimize confusion may build trust among older adults and offer an opportunity to increase the utility of the Internet as a health resource for this population.
Older adults; Trust; Online health information
While a growing body of research has investigated the diffusion of health IT among providers, no empirical research has yet focused on health IT vendor switching by hospitals. Vendor switching is one indicator of a competitive commercial vendor market, and competition among vendors can spur innovations which contribute to better products over time. This study examines the interaction of hospitals with commercial vendors in the recent past to serve as a baseline for future investigations into how the federal health IT incentive program influences changes in the vendor market and vendor-provider relationships. We find that there has been considerable switching between vendors by hospitals, including some hospitals switching away from automated systems all together. Furthermore, our descriptive cross-sectional analysis reveals various hospital characteristics which are associated with vendor switching and dropping, including lower constraints on hospitals’ financial resources, nonprofit ownership, and having some form of integrated arrangement with physicians.