Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study.

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10-2,000 mg) or multiple ascending dose (MAD; dose range 100-1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21-65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5-3.5 hours, terminal half-life of 11.4-19.1 hours, and exhibited dose-dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL-17A levels within 12 hours of dosing. Four participants from the 400-mg (n = 1) and 1,000-mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post-last LY3509754 dose), consistent with drug-induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte-rich, moderate-to-severe lobular inflammation. We theorize that the DILI relates to an off-target effect rather than IL-17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.

Implementing Tap-to-Witness Technology in the Electronic Medical Record.

The implementation of an organisation-wide EMR system in 2019 included single sign-on technology for nurses and midwives. This first-in-Australia study extended the use of this technology to enable nurses and midwives to tap-to-witness for high-risk medications, blood and blood products, and expressed breast milk. A saving of 7 seconds per interaction was observed with nurses and midwives reporting appreciation for ongoing EMR enhancement to reduce EMR-related documentation burden.

Voting with Their Thumbs: Assessing Communication Technology Use by Medical, Nursing, Midwifery, and Allied Health Clinicians.

BACKGROUND: Timely multidisciplinary communication is crucial to prevent patient harm related to miscommunication of clinical information. Many health care organizations provide secure communications systems; however, clinicians often use unapproved platforms on personal devices to communicate asynchronously. OBJECTIVE: The aim of the study is to assess clinical communication behaviors by clinicians in a hospital setting. METHODS: Medical, nursing and allied health staff working across seven hospital sites of a large health care organization were invited to complete an anonymous survey on the methods, behaviors, and rationale for clinical communication technology use. The survey included questions on communication methods used by clinicians for intra- and inter-disciplinary communication and sending and receiving clinical information or images. Demographics and qualitative comments were also collected. RESULTS: A total of 836 surveys were completed (299 medical, 317 nursing, and 220 allied health staff). Staff in all clinical groups reported using an unapproved messaging platform to communicate patient information more than three times per day (medical staff n = 167, 55.9%; nursing staff n = 106, 33.4%; allied health staff n = 67, 30.5%). Not one medical staff member indicated they only use the approved methods (n = 0, 0%) while one-third of nursing and allied health respondents only used approved methods (n = 118, 37.2% and n = 64, 29.1%, respectively). All clinician groups reported wasted time from communications sent with missing information, or time spent waiting for responses for further information. Qualitative comments expressed dissatisfaction and frustration with current clinical communication methods and a desire for improved systems. CONCLUSION: Workarounds are being used by all clinician groups to send text and image clinical communications. There are high levels of dissatisfaction with this situation and clinicians are keen for consistency and to have the right tools available. There is a need to ensure standardized clinical communication methods and approved digital platforms are in place and utilized to provide safe, high-quality patient care.

Disruptive Technology, Leadership and the Future of Nursing.

Nurses need to take a strategic leadership role in managing disruptive health technologies that can be adopted to improve health and care within the population. While innovative technology developments continue to advance quickly, systematic changes to the health and care systems are not always geared to take advantage of these advances at the same rate. This panel will look at how disruptive technology will impact nursing practice and strategic leadership factors that shape acceptance/resistance to new technologies.

Donanemab (LY3002813) dose-escalation study in Alzheimer's disease.

INTRODUCTION: This study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia. METHODS: Patients with AD were enrolled into the single-ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients proceeded into the multiple-ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12-week follow-up period. The relative exposure assessment of an unblinded, single, subcutaneous 3-mg/kg dose of donanemab in patients with AD was also performed, followed by a 12-week follow-up period. One cohort of healthy subjects received an unblinded, single, IV 1-mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase. RESULTS: Donanemab was generally well tolerated up to 10 mg/kg. After single-dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half-life was ≈4 days, increasing to ≈10 days at 10 mg/kg. Only the 10-mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti-drug antibodies at 3 months after a single intravenous dose. DISCUSSION: Intravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half-life.

Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects.

AIMS: The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of single and multiple doses of a novel mGlu2 agonist were assessed in healthy males. METHODS: In two, Phase 1 investigator- and subject-blind, placebo-controlled studies, oral doses of prodrug LY2979165 were evaluated: single doses (20-150 mg, N = 30) and multiple once-daily (QD) doses (20-400 mg; N = 84), using a titration regimen. The plasma and urine PK of LY2979165 and active moiety, 2812223, were measured. Cerebrospinal fluid (CSF) was collected to determine PK and neurotransmitter levels. Safety parameters were assessed throughout. RESULTS: Nausea and vomiting were dose limiting following single doses; dose titration allowed higher doses to be tested over 14 days. The most common adverse events related to LY2979165 were dizziness, vomiting, nausea, somnolence and headache. The plasma PK of 2812223 were approximately linear with minimal accumulation with QD dosing. Conversion of LY2979165 to 2812223 was extensive, with minimal LY2979165 measurable in plasma. There was no effect of food on the PK of LY2979165 and 2812223. After 60 mg LY2979165 single-dose, 2812223 exposure in CSF was approximately 2-6% and plasma exposure and peak concentrations were approximately four-fold higher than the mGlu2 agonist in vitro EC50 value. No consistent effects were observed on CSF neurotransmitter levels. CONCLUSIONS: Oral doses of LY2979165 up to 60 mg as a single dose and up to 400 mg given as multiple QD doses, using a titration regimen, were well tolerated with linear PK. Overall, these data support further clinical evaluation of LY2979165.

Nursing Informatics Competencies for Entry to Practice: The Perspective of Six Countries.

Internationally, countries are challenged to prepare nurses for a future that has ever increasing use of technology and where information management is a central part of professional nursing practice. There has been a growing trend to move nursing to competency-based education, especially for those students undertaking their first nursing qualification. This first nursing qualification may be linked to pre-registration, pre-licensure or undergraduate education; the term used depending on the country. The authors are drawn from the International Medical Informatics Association special interest group, Nursing Informatics (IMIA-NI) Education Working Group and represent New Zealand, the United States of America, England, Australia, Finland and Canada.

A comparison of Australian and Canadian informatics competencies for undergraduate nurses.

Health information technologies (HIT) have changed healthcare delivery. Yet, there are few opportunities for student nurses in their undergraduate studies to develop nursing informatics competencies. More importantly, many countries around the world have not fully specified nursing informatics competencies that will be expected of student nurses prior to their graduation from undergraduate nursing programs. In this paper the authors compare and contrast the undergraduate nursing informatics competencies that were developed by two countries: Australia and Canada. They also identify some of the challenges and future research directions in the area.

Complexity and the science of implementation in health IT--knowledge gaps and future visions.

OBJECTIVES: The intent of this paper is in the examination of health IT implementation processes - the barriers to and facilitators of successful implementation, identification of a beginning set of implementation best practices, the identification of gaps in the health IT implementation body of knowledge, and recommendations for future study and application. METHODS: A literature review resulted in the identification of six health IT related implementation best practices which were subsequently debated and clarified by participants attending the NI2012 Research Post Conference held in Montreal in the summer of 2012. Using the framework for implementation research (CFIR) to guide their application, the six best practices were applied to two distinct health IT implementation studies to assess their applicability. RESULTS: Assessing the implementation processes from two markedly diverse settings illustrated both the challenges and potentials of using standardized implementation processes. In support of what was discovered in the review of the literature, "one size fits all" in health IT implementation is a fallacy, particularly when global diversity is added into the mix. At the same time, several frameworks show promise for use as "scaffolding" to begin to assess best practices, their distinct dimensions, and their applicability for use. CONCLUSIONS: Health IT innovations, regardless of the implementation setting, requires a close assessment of many dimensions. While there is no "one size fits all", there are commonalities and best practices that can be blended, adapted, and utilized to improve the process of implementation. This paper examines health IT implementation processes and identifies a beginning set of implementation best practices, which could begin to address gaps in the health IT implementation body of knowledge.

Developing national level informatics competencies for undergraduate nurses: methodological approaches from Australia and Canada.

Health information systems are being implemented in countries by governments and regional health authorities in an effort to modernize healthcare. With these changes, there has emerged a demand by healthcare organizations for nurses graduating from college and university programs to have acquired nursing informatics competencies that would allow them to work in clinical practice settings (e.g. hospitals, clinics, home care etc). In this paper we examine the methods employed by two different countries in developing national level nursing informatics competencies expected of undergraduate nurses prior to graduation (i.e. Australia, Canada). This work contributes to the literature by describing the science and methods of nursing informatics competency development at a national level.

Engaging undergraduate nursing students in face-to-face tutorials.

Chronic nursing shortages have placed increasing pressure on many nursing schools to recruit greater numbers of students with the consequence of larger class sizes. Larger class sizes have the potential to lead to student disengagement. This paper describes a case study that examined the strategies used by a group of nursing lecturers to engage students and to overcome passivity in a Bachelor of Nursing programme. A non-participant observer attended 20 tutorials to observe five academics deliver four tutorials each. Academics were interviewed both individually and as a group following the completion of all tutorial observations. All observations, field notes, interviews and focus groups were coded separately and major themes identified. From this analysis two broad categories emerged: getting students involved; and engagement as a struggle. Academics used a wide variety of techniques to interest and involve students. Additionally, academics desired an equal relationship with students. They believed that both they and the students had some power to influence the dynamics of tutorials and that neither party had ultimate power. The findings of this study serve to re-emphasise past literature which suggests that to engage students, the academics must also engage.

Comparison of intrinsic clearances in human liver microsomes and suspended hepatocytes from the same donor livers: clearance-dependent relationship and implications for prediction of in vivo clearance.

Intrinsic clearance (CL(int)) of seven probe cytochrome P450 substrates, across a wide range of clearance, was compared in microsomes and cryopreserved hepatocytes from the same four livers. Previous comparisons have shown system dependence, but using preparations from different donor livers. Four-fold average underprediction of microsomal CL(int) by hepatocytes (scaled to whole liver) for high clearance substrates (midazolam, nifedipine, and diclofenac) was observed with relatively unbiased prediction (within 1.5-fold average) for the low/medium clearance substrates (tolbutamide, alprazolam, bufuralol, and triazolam). CL(int) of midazolam and nifedipine corresponded between livers over a tenfold range, but the absolute ranges were lower for hepatocytes, indicating independence of hepatocyte bias from substrate. In contrast, the absolute ranges of CL(int) for the low clearance CYP3A4 substrate alprazolam were similar between the systems, indicating independence of hepatocyte bias from enzyme. The trend in CL(int) between the systems was similar to that in a dataset of published CL(int) for 46 substrates in microsomes and hepatocytes (unrelated liver sources), supporting a fundamental rate limitation of the hepatocyte system. A tendency of decreasing V(max) in hepatocytes relative to microsomes, with increasing clearance, suggests that a capacity limitation, such as cofactor rate limitation, may be involved in this phenomenon.

Prediction of human metabolic clearance from in vitro systems: retrospective analysis and prospective view.

PURPOSE: To provide a definitive assessment of prediction of in vivo CL (int) from human liver in vitro systems for assessment of typical underprediction. METHODS: A database of published predictions of clearance from human hepatocytes and liver microsomes was compiled, including only intravenous CL (b). The influence of liver model (well-stirred (WS) or parallel tube (PT)), plasma protein binding and clearance level on the relationship between in vitro and in vivo CL (int) was examined. RESULTS: Average prediction bias was about 5- and 4-fold for microsomes and hepatocytes, respectively. Reduced bias using the PT model, in preference to the popular WS model, was only marginal across a wide range of clearance with a consequential minor impact on prediction. Increasing underprediction with decreasing fu (b), or increasing CL (int), was found only for hepatocytes, suggesting fundamental in vitro artefacts rather than failure to model potentially unequilibrated binding during rapid extraction. CONCLUSIONS: In contrast to microsomes, hepatocytes give a disproportionate prediction with increasing clearance suggesting limitations either at the active site, such as cofactor exhaustion, or with intracellular concentration equilibrium, such as rate-limiting cell permeability. A simple log linear empirical relationship can be used to correct hepatocyte predictions.

The impact of Health Information Technology (I-HIT) Scale: the Australian results.

One of role of the nurse in the clinical setting is that of co-ordinating communication across the healthcare team. On a daily basis nurses interact with the person receiving care, their family members, and multiple care providers thus placing the nurse in the central position with access to a vast array of information on the person. Through this nurses have historically functioned as "information repositories". With the advent of Health Information Technology (HIT) tools there is a potential that HIT could impact interdisciplinary communication, practice efficiency and effectiveness, relationships and workflow in acute care settings [1][3]. In 2005, the HIMSS Nursing Informatics Community developed the I-HIT Scale to measure the impact of HIT on the nursing role and interdisciplinary communication in USA hospitals. In 2007, nursing informatics colleagues from Australia, Finland, Ireland, New Zealand, Scotland and the USA formed a research collaborative to validate the I-HIT in six additional countries. This paper will discuss the background, methodology, results and implications from the Australian I-HIT survey of over 1,100 nurses. The results are currently being analyzed and will be presented at the conference.

Australian Nursing Informatics Competency Project.

A study of Australian nurses on their use of information technology in the workplace was undertaken by the Australian Nursing Federation (ANF) in 2007. This study of over 4000 nurses highlighted that nurses recognise benefits to adopting more information technology in the workplace although there are significant barriers to their use. It also identified gross deficits in the capacity of the nursing workforce to engage in the digital processing of information. Following the release of the study last year, the ANF commenced work on a number of key recommendations from the report in order to overcome identified barriers and provide opportunities for nurses to better utilise information technology and information management systems. One of these recommendations was to seek research funding to develop national information technology and information management competency standards for nurses. This project has now received Federal Government funding to undertake this development. This project is being developed in collaboration with the ANF and the Queensland University of Technology. This paper will discuss the methodology, development and publication of the Australian Nursing Informatics Competency Standards Project which is currently underway and due for completion in May 2009. The Australian Nursing Informatics Competencies will be presented at the conference.

Validation of the Impact of Health Information Technology (I-HIT) Scale: an international collaborative.

In 2005, the Healthcare Information Management Systems Society (HIMSS) Nursing Informatics Community developed a survey to measure the impact of health information technology (HIT), the I-HIT Scale, on the role of nurses and interdisciplinary communication in hospital settings. In 2007, nursing informatics colleagues from Australia, England, Finland, Ireland, New Zealand, Scotland and the United States formed a research collaborative to validate the I-HIT across countries. All teams have completed construct and face validation in their countries. Five out of six teams have initiated reliability testing by practicing nurses. This paper reports the international collaborative's validation of the I-HIT Scale completed to date.

Teaching undergraduate nursing students renal care in a 3D Gaming Environment.

The original program on renal care was developed between 1995-1997 using 'Toolbook' software, which presented the content in a non interactive graphical way without tracking student progress or recording of results and was available to students via a CDRom. The content described the clinical decision making process that practitioners had to follow when diagnosing and managing renal diseases. These processes followed a learning sequence whereby a series of decisions lead to the next phase of the diagnosis and treatment. The purpose was to simulate the live clinical decision making processes for practitioners. An additional build-in 'Ask the Expert'-button (Help function) guided students in correct clinical decision making. One of the problems encountered in the original program is that the navigation is not intuitive to the user and students could get easily lost while going through the step-by-step introduction as well as the lack of interactivity. The original program still has relevant learning content, but the software, illustrations and tracking of learning outcomes are out-of-date. Therefore a re-design of the original program using a 3D Gaming Environment with updated content is being undertaken. This paper will discuss the methodology underpinning the new development, a demonstration of the program and the results from student feedback which will be undertaken in February - March 2009.