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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.10.045 Byline: Henrietta Szutorisz (1), Andrew Georgiou (1), Laszlo Tora (2), Niall Dillon (1) Abstract: The ability of stem cells to activate different gene expression programs requires the choreographed assembly of trans-acting factors at enhancers and promoters during cell differentiation. In this study, we show that the proteasome acts on specific regulatory regions in embryonic stem (ES) cells to prevent incorrect transcriptional initiation. Chemical or siRNA-mediated inhibition of proteasome activity results in increased transcription factor and RNA polymerase II binding and leads to activation of cryptic promoters. Analysis of the binding profiles of different proteasome subunits in normal ES cells and following RNAi knockdown of individual subunits provides evidence for a targeted assembly of the 26S proteasome at specific regulatory elements. Our results suggest that the proteasome promotes a dynamic turnover of transcription factor and Pol II binding at tissue-specific gene domains in ES cells, thereby restricting permissive transcriptional activity and keeping the genes in a potentiated state, ready for activation at later stages. Author Affiliation: (1) Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 ONN, UK (2) Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), CNRS UMR 7104, INSERM, ULP, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France Article History: Received 13 April 2006; Revised 28 August 2006; Accepted 13 October 2006 Article Note: (miscellaneous) Published: December 28, 2006

Highlights: [•] The key attributes and behaviours related to successful health IT adoption. [•] The development of a long-term vision for health IT. [•] Research evidence to inform clinical leaders about health IT adoption. [•] A new extended framework to enhance clinical leaders’ IT competence. [ABSTRACT FROM AUTHOR]

Abstract: Background: Medication safety is a pressing concern for residential aged care facilities (RACFs). Retrospective studies in RACF settings identify inadequate communication between RACFs, doctors, hospitals and community pharmacies as the major cause of medication errors. Existing literature offers limited insight about the gaps in the existing information exchange process that may lead to medication errors. The aim of this research was to explicate the cognitive distribution that underlies RACF medication ordering and delivery to identify gaps in medication-related information exchange which lead to medication errors in RACFs. Methods: The study was undertaken in three RACFs in Sydney, Australia. Data were generated through ethnographic field work over a period of five months (May–September 2011). Triangulated analysis of data primarily focused on examining the transformation and exchange of information between different media across the process. Results: The findings of this study highlight the extensive scope and intense nature of information exchange in RACF medication ordering and delivery. Rather than attributing error to individual care providers, the explication of distributed cognition processes enabled the identification of gaps in three information exchange dimensions which potentially contribute to the occurrence of medication errors namely: (1) design of medication charts which complicates order processing and record keeping (2) lack of coordination mechanisms between participants which results in misalignment of local practices (3) reliance on restricted communication bandwidth channels mainly telephone and fax which complicates the information processing requirements. The study demonstrates how the identification of these gaps enhances understanding of medication errors in RACFs. Conclusions: Application of the theoretical lens of distributed cognition can assist in enhancing our understanding of medication errors in RACFs through identification of gaps in information exchange. Understanding the dynamics of the cognitive process can inform the design of interventions to manage errors and improve residents’ safety. [Copyright &y& Elsevier]

Study objective: We identify and describe emergency physicians'' and nurses'' perceptions of the effect of an integrated emergency department (ED) information system on the quality of care delivered in the ED. Methods: A qualitative study was conducted in 4 urban EDs, with each site using the same ED information system. Participants (n=97) were physicians and nurses with data collected by 69 detailed interviews, 5 focus groups (28 participants), and 26 hours of structured observations. Results: Results revealed new perspectives on how an integrated ED information system was perceived to affect incentives for use, awareness of colleagues'' activities, and workflow. A key incentive was related to the positive effect of the ED information system on clinical decisionmaking because of improved and quicker access to patient-specific and knowledge-base information compared with the previous stand-alone ED information system. Synchronous access to patient data was perceived to lead to enhanced awareness by individual physicians and nurses of what others were doing within and outside the ED, which participants claimed contributed to improved care coordination, communication, clinical documentation, and the consultation process. There was difficulty incorporating the use of the ED information system with clinicians'' work, particularly in relation to increased task complexity; duplicate documentation, and computer issues related to system usability, hardware, and individuals'' computer skills and knowledge. Conclusion: Physicians and nurses perceived that the integrated ED information system contributed to improvements in the delivery of patient care, enabling faster and better-informed decisionmaking and specialty consultations. The challenge of electronic clinical documentation and balancing data entry demands with system benefits necessitates that new methods of data capture, suited to busy clinical environments, be developed. [Copyright &y& Elsevier]

Abstract: Background: Poor clinical handover has been associated with inaccurate clinical assessment and diagnosis, delays in diagnosis and test ordering, medication errors and decreased patient satisfaction in the acute care setting. Research on the handover process in the residential aged care sector is very limited. Purpose: The aims of this study were to: (i) Develop an in-depth understanding of the handover process in aged care by mapping all the key activities and their information dynamics, (ii) Identify gaps in information exchange in the handover process and analyze implications for resident safety, (iii) Develop practical recommendations on how information communication technology (ICT) can improve the process and resident safety. Methods: The study was undertaken at a large metropolitan facility in NSW with more than 300 residents and a staff including 55 registered nurses (RNs) and 146 assistants in nursing (AINs). A total of 3 focus groups, 12 interviews and 3 observation sessions were conducted over a period from July to October 2010. Process mapping was undertaken by translating the qualitative data via a five-category code book that was developed prior to the analysis. Results: Three major sub-processes were identified and mapped. The three major stages are Handover process (HOP) I “Information gathering by RN”, HOP II “Preparation of preliminary handover sheet” and HOP III “Execution of handover meeting”. Inefficient processes were identified in relation to the handover including duplication of information, utilization of multiple communication modes and information sources, and lack of standardization. Conclusion: By providing a robust process model of handover this study has made two critical contributions to research in aged care: (i) a means to identify important, possibly suboptimal practices; and (ii) valuable evidence to plan and improve ICT implementation in residential aged care. The mapping of this process enabled analysis of gaps in information flow and potential impacts on resident safety. In addition it offers the basis for further studies into a process that, despite its importance for securing resident safety and continuity of care, lacks research. [Copyright &y& Elsevier]

Abstract: Background: The provision of relevant clinical information on pathology requests is an important part of facilitating appropriate laboratory utilization and accurate results interpretation and reporting. Purpose: (1) To determine the quantity and importance of handwritten clinical information provided by physicians to the Microbiology Department of a hospital pathology service; and (2) to examine the impact of a Computerized Provider Order Entry (CPOE) system on the nature of clinical information communication to the laboratory. Methods: A multi-method and multi-stage investigation which included: (a) a retrospective audit of all handwritten Microbiology requests received over a 1-month period in the Microbiology Department of a large metropolitan teaching hospital; (b) the administration of a survey to laboratory professionals to investigate the impact of different clinical information on the processing and/or interpretation of tests; (c) an expert panel consisting of medical staff and senior scientists to assess the survey findings and their impact on pathology practice and patient care; and (d) a comparison of the provision and value of clinical information before CPOE, and across 3 years after its implementation. Results: The audit of handwritten requests found that 43% (n =4215) contained patient-related clinical information. The laboratory survey showed that 97% (84/86) of the different types of clinical information provided for wound specimens and 86% (43/50) for stool specimens were shown to have an effect on the processing or interpretation of the specimens by one or more laboratory professionals. The evaluation of the impact of CPOE revealed a significant improvement in the provision of useful clinical information from 2005 to 2008, rising from 90.1% (n =749) to 99.8% (n =915) (p <.0001) for wound specimens and 34% (n =129) to 86% (n =422) (p <.0001) for stool specimens. Conclusion: This study showed that the CPOE system provided an integrated platform to access and exchange valuable patient-related information between physicians and the laboratory. These findings have important implications for helping to inform decisions about the design and structure of CPOE screens and what data entry fields should be designated or made voluntary. [Copyright &y& Elsevier]

Abstract: One of the challenges associated with the implementation of e-health systems is the effect they have on the temporal landscape (how time is conceived, structured and monitored) of an organisation particularly as it relates to the way that work is prioritised, allocated, synchronised and coordinated. This study aims to identify the impact of the introduction of a new e-health system on key aspects of the temporal and organisational functioning of a hospital pathology service. The study employed qualitative methods including interviews, focus groups and observation sessions. It was carried out in the period of August 2005 to August 2008 across a hospital pathology service in Sydney, Australia during the introduction of a new laboratory information system and electronic ordering system. The results revealed a number of temporal layers which can be defined as organisational (how the service synchronises its work with other settings); clinical (coordination of work to ensure the appropriate laboratory contribution to effective patient care); procedural (allocating work according to scientific and pathologic processes); and informational and electronic (how and what information is communicated and accessed). The introduction of a new e-health system was shown to have a major impact on the temporal landscape of the pathology service. Specific examples of this were revealed in changes to the way the pathology service: (1) tracked and monitored specimens within the laboratory; and (2) communicated and coordinated its work internally and externally. The use of qualitative methods longitudinally provided key insights into the way that temporal factors operate within pathology laboratories and their interrelationship with the performance, distribution and allocation of work. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To identify the main concerns of a broad range of hospital staff about the implementation of a new Computerized Provider Order Entry (CPOE) system for medication management. Methods: The study was conducted in a large Australian teaching hospital using semi-structured interviews (n =20) and focus groups (six focus groups involving a total of 30 participants) from a broad section of health professionals including doctors, nurses, managers, pharmacists and senior health executives. Systematic concurrent analysis of the data was undertaken by a team of researchers. Results: We identified 20 recurrent themes related to nine areas of shared concern including work practices, software/hardware, relationships/communication, education and training, inexperienced staff and de-skilling. A higher level of analysis identified four interrelated constructs that highlight what people are concerned about: (1) Will it help? (2) Will it work? (3) Will we cope? (4) Will it impair existing interaction? Limitations: The research provides a snapshot overview of perceptions from a range of hospital personnel in the lead up to CPOE implementation. Generalizability is limited by the size of the sample and the contextual circumstances of the hospital being studied. Discussion: This work contributes valuable evidence about an often-neglected dimension in the evaluation of computer systems in hospitals, namely the pre-implementation concerns of staff. These pre-conceptions can have a significant effect on how technology is implemented and utilised. Acknowledging and addressing people''s concerns can contribute to the establishment of durable channels of negotiation and communication. Further research informed by the findings of this study will help advance this process. [Copyright &y& Elsevier]

Abstract: Purpose: The purpose of this study was to identify the key implications of the implementation of a computerized physician order entry (CPOE) system on pathology laboratory services. Methods: An in-depth qualitative study using observation, focus groups and interviews with pathology staff, managers, clinicians and information systems staff during implementation of a CPOE system in 2004 at a major Australian teaching hospital. Results: Pathology laboratories experienced a shift in their work roles resulting in altered work practices, responsibilities and procedures. These changes were marked by terminological and procedural changes in the test order process from when clinicians issued a request for a test, to the new system that established clinical orders at the point of care. This change was accompanied by some organizational dysfunctions including the emergence of a new category of “frustrated” orders without specimens; problems with the procedure of adding tests to previously existing specimens; the appearance of discrepancies in the recorded time of specimen collection. In response to these changes, hospital and pathology staff adopted a variety of means to cope with their changed circumstances. These ranged from efforts to increase clinical awareness to compensatory laboratory workarounds and enforced rule changes. Conclusions: CPOE systems can have a major impact on the nature of the work of pathology laboratories. Understanding how and why these changes occur can be enhanced through considering the organizational and social contexts involved. The effectiveness of CPOE systems will rely on how administrators and staff approach and deal with these challenges. [Copyright &y& Elsevier]

Abstract: Purpose: Computerised physician order entry (CPOE) systems hold the promise of significant improvements to health care delivery and patient care. The implementation of such systems is costly and complex. The purpose of this paper is to review current evidence of the impact of CPOE on hospital pathology services. Methods: This paper presents a review of the literature (1990–August 2004) about CPOE systems and identifies indicators for measuring the impact of CPOE on pathology services. Results: Nineteen studies which contained some form of ‘control’ group, were identified. They featured a variety of designs including randomised controlled trials, quasi-experimental and before and after studies. We categorised these into three groups: studies comparing pathology CPOE systems (with no decision support) to paper systems; pathology CPOE systems (with decision support) to paper systems; and pathology CPOE systems with specific pathology features compared to systems without those features. We identified 10 areas of impact assessment and 39 indicators used to measure the impact of CPOE on different stages of the pathology test ordering and reporting process. Conclusion: We conclude that while some data suggest that CPOE systems are beneficial for clinical and laboratory work processes, these data are limited, and further research is needed. Few data are available regarding the impact of CPOE on patient outcomes. [Copyright &y& Elsevier]

Study objective: We undertake a systematic review of the quantitative literature related to the effect of computerized provider order entry systems in the emergency department (ED). Methods: We searched MEDLINE, EMBASE, Inspec, CINAHL, and CPOE.org for English-language studies published between January 1990 and May 2011. Results: We identified 1,063 articles, of which 22 met our inclusion criteria. Sixteen used a pre/post design; 2 were randomized controlled trials. Twelve studies reported outcomes related to patient flow/clinical work, 7 examined decision support systems, and 6 reported effects on patient safety. There were no studies that measured decision support systems and its effect on patient flow/clinical work. Computerized provider order entry was associated with an increase in time spent on computers (up to 16.2% for nurses and 11.3% for physicians), with no significant change in time spent on patient care. Computerized provider order entry with decision support systems was related to significant decreases in prescribing errors (ranging from 17 to 201 errors per 100 orders), potential adverse drug events (0.9 per 100 orders), and prescribing of excessive dosages (31% decrease for a targeted set of renal disease medications). Conclusion: There are tangible benefits associated with computerized provider order entry/decision support systems in the ED environment. Nevertheless, when considered as part of a framework of technical, clinical, and organizational components of the ED, the evidence base is neither consistent nor comprehensive. Multimethod research approaches (including qualitative research) can contribute to understanding of the multiple dimensions of ED care delivery, not as separate entities but as essential components of a highly integrated system of care. [Copyright &y& Elsevier]

Objective To determine physician perspectives about direct notification of normal and abnormal test results. Methods We conducted a cross-sectional survey at five clinical sites in the US and Australia. The US-based study was conducted via web-based survey of primary care physicians and specialists between July and October 2012. An identical paper-based survey was self-administered between June and September 2012 with specialists in Australia. Results Of 1417 physicians invited, 315 (22.2%) completed the survey. Two-thirds (65.3%) believed that patients should be directly notified of normal results, but only 21.3% were comfortable with direct notification of clinically significant abnormal results. Physicians were more likely to endorse direct notification of abnormal results if they believed it would reduce the number of patients lost to follow-up (OR = 4.98, 95%CI = 2.21–1.21) or if they had personally missed an abnormal test result (OR = 2.95, 95%CI = 1.44–6.02). Conversely, physicians were less likely to endorse if they believed that direct notification interfered with the practice of medicine (OR = 0.39, 95%CI = 0.20–0.74). Conclusion Physicians we surveyed generally favor direct notification of normal results but appear to have substantial concerns about direct notification of abnormal results. Practice implications Widespread use of direct notification should be accompanied by strategies to help patients manage test result abnormalities they receive. [ABSTRACT FROM AUTHOR]

Objectives (1) to describe Emergency Department (ED) physicians’ and nurses’ perceptions about the sequence of work related to patient management with use of an integrated Emergency Department Information System (EDIS), and (2) to measure changes in the sequence of clinician access to patient information. Methods A mixed method study was conducted in four metropolitan EDs. Each used the same EDIS which is a module of the hospitals’ enterprise-wide clinical information system composed of many components of an electronic medical record. This enabled access to clinical and management information relating to patients attending all hospitals in the region. Phase one – data were collected from ED physicians and nurses ( n = 97) by 69 in-depth interviews, five focus groups (28 participants), and 26 h of observations. Phase two – physicians ( n = 34) in one ED were observed over 2 weeks. Data included whether and what type of information was accessed from the EDIS prior to first examination of the patient. Results Clinicians reported, and phase 2 observations confirmed, that the integrated EDIS led to changes to the order of information access, which held implications for when tests were ordered and results accessed. Most physicians accessed patient information using EDIS prior to taking the patients’ first medical history (77/116; 66.4%, 95% CI: 57.8–75.0%). Previous discharge summaries (74%) and past test results (61%) were most frequently accessed and junior doctors were more likely to access electronic past history information than their senior colleagues ( χ 2 = 20.717, d.f. = 1, p < 0.001). Conclusions The integrated EDIS created new ways of working for ED clinicians. Such changes could hold positive implications for: time taken to reach a diagnosis and deliver treatments; length of stay; patient outcomes and experiences. [ABSTRACT FROM AUTHOR]

Abstract: The λ5 and VpreB genes encode the components of the surrogate light-chain which forms part of the pre-B cell receptor and plays a key role in B cell development. In the mouse, the λ5 and VpreB1 genes are closely linked and are co-regulated by a multi-component locus control region. To identify the sequences that regulate λ5 and VpreB1 expression during B cell development, we have comprehensively mapped the DNaseI hypersensitive sites (HS) in the λ5-VpreB1 functional domain. The active domain contains 12 HS that are distributed at high density across the 18.3kb region that forms the λ5 and VpreB1 functional unit. Analysis of a reporter gene driven by the VpreB1 promoter in transgenic mice identified a novel enhancer associated with two HS located upstream of λ5. The λ5-VpreB1 locus was also found to be closely linked to the ubiquitously expressed Topoisomerase-3β (Topo3β) gene. The VpreB1 and Topo3β genes have entirely different expression patterns despite the fact that the two promoters are separated by a distance of only 1.5kb. [Copyright &y& Elsevier]

Abstract Background : Patients with communication disability, associated with impairments of speech, language, or voice, have a three-fold increased risk of adverse events in hospital. However, little research yet examines the causal relationship between communication disability and risk for specific adverse events in hospital. Objective : To examine the impact of a patient's communication disability on their falls risk in hospital. Methods : This systematic review examined 61 studies on falls of adult hospital patients with communication disability, and patients at high risk of communication disability, to determine whether or not communication disability increased risk for falls, and the nature of and reasons for any increased risk. Results : In total, 46 of the included studies (75%) reported on participants with communication disability, and the remainder included patients with health conditions placing them at high risk for communication disability. Two thirds of the studies examining falls risk identified communication disability as contributing to falls. Commonly, patients with communication disability were actively excluded from participation; measures of communication or cognition were not reported; and reasons for any increased risk of falls were not discussed. Conclusions : There is some evidence that communication disability is associated with increased risk of falls. However, the role of communication disability in falls is under-researched, and reasons for the increased risk remain unclear. Practical applications: Including patients with communication disability in falls research is necessary to determine reasons for their increased risk of adverse events in hospital. Their inclusion might be helped by the involvement of speech-language pathologists in falls research teams. Highlights • This systematic review examined the relationship between falls and communication disability in adult hospital patients. • People with communication disability are often actively excluded from research examining falls in hospital. • There is some evidence to suggest that communication disability is a causal factor in falls for some patients. • Falls research including patients at risk of communication disability should include adequate reporting on communication. • Falls research teams should include speech-language pathologists for identifying and reporting on communication disability. [ABSTRACT FROM AUTHOR]

Objective To examine home care service-related and person-based factors associated with time to entry into permanent residential aged care. Design Longitudinal cohort study using routinely collected client management data. Setting A large aged care service provider in New South Wales and the Australian Capital Territory, Australia. Participants A total of 1116 people aged 60 years and older who commenced home care services for higher-level needs between July 1, 2015 and June 30, 2016. Methods Survival analysis methods were used to examine service-related and person-based factors that were associated with time between first home care service and entry into permanent residential aged care. Predictors included service hours per week, combination of service types, demographics, needs, hospital leave, and change in care level. Cluster analysis was used to determine patterns of types of services used. Results By December 31, 2016, 21.1% of people using home care services had entered into permanent residential care (n = 235). After adjusting for significant factors such as age and care needs, each hour of service received per week was associated with a 6% lower risk of entry into residential care (hazard ratio = 0.94, 95% confidence interval 0.90-0.98). People who were predominant users of social support services, those with an identified carer, and those born in a non-main English-speaking country also remained in their own homes for longer. Conclusions Greater volume of home care services was associated with significantly delayed entry into permanent residential care. This study provides much-needed evidence about service outcomes that could be used to inform older adults’ care choices. [ABSTRACT FROM AUTHOR]

Summary With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo , increasing the CD8 + to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches. [ABSTRACT FROM AUTHOR]