Developing a process to measure actual harm from medication errors in paediatric inpatients: From design to implementation.

AIMS: The potential harm associated with medication errors is widely reported, but data on actual harm are limited. When actual harm has been measured, assessment processes are often poorly described, limiting their ability to be reproduced by other studies. Our aim was to design and implement a new process to assess actual harm resulting from medication errors in paediatric inpatient care. METHODS: Prescribing errors were identified through retrospective medical record reviews (n = 26 369 orders) and medication administration errors through direct observation (n = 5137 administrations) in a tertiary paediatric hospital. All errors were assigned potential harm severity ratings on a 5-point scale. Multidisciplinary panels reviewed case studies for patients assigned the highest three potential severity ratings and determined the following: actual harm occurrence and severity level, plausibility of a link between the error(s) and identified harm(s) and a confidence rating if no harm had occurred. RESULTS: Multidisciplinary harm panels (n = 28) reviewed 566 case studies (173 prescribing related and 393 administration related) and found evidence of actual harm in 89 (prescribing = 22, administration = 67). Eight cases of serious harm cases were found (prescribing = 1, administration = 7) and no cases of severe harm. The panels were very confident in 65% of cases (n = 302) where no harm was found. Potential and actual harm ratings varied. CONCLUSIONS: This harm assessment process provides a systematic method for determining actual harm from medication errors. The multidisciplinary nature of the panels was critical in evaluating specific clinical, therapeutic and contextual considerations including care delivery pathways, therapeutic dose ranges and drug-drug and drug-disease interactions.

Can old drugs learn new tricks? Achieving registration and public subsidy listing for off-patent medicines with novel therapeutic applications.

With the increasing costs of drug development, repurposing of low-cost medicines for new indications has never been more important. However, there are multiple barriers to repurposing, particularly for off-patent medicines, and limited incentives for the pharmaceutical industry to sponsor registration and public subsidy listing. Here, we explore these barriers and their consequences and provide examples of successful repurposing strategies.

Estriol serum levels in new and chronic users of vaginal estriol cream: A prospective observational study.

AIMS: To quantify estriol serum concentrations in "new" and "chronic users" of topical estriol cream using quantitative liquid chromatography tandem mass spectrometry. METHODS: In this singlecentre prospective observational study, postmenopausal women with urogynaecological complaints were enrolled: 40 had not used topical estriol previously ("new users") and 50 had been applying estriol cream for more than 12 weeks ("chronic users"). In "new users," serum estriol levels were measured at baseline and after 12 weeks use. Estriol cream 1 mg/g was used daily for 3 weeks, then twice weekly with applicator (group 1A) or digitally (group 1B) or three times per week digitally (group 1C). "Chronic users" applied the cream twice (n = 7) or three (n = 43) times per week. Serum samples were taken in the morning after using cream the previous night. The main outcome measures were estriol serum concentrations in "new" and "chronic users" of estriol cream. RESULTS: Baseline serum estriol concentrations were less than 5 pmol/L in all 40 "new users." At 12 weeks, the 12-hour serum estriol levels ranged from less than 5 to 494 pmol/L (median 22.8; Interquartile range [IQR] 9.2-108.5). Seven "new users" had levels more than 100 pmol/L. Most of the 50 "chronic users" also had 12-hour levels less than 100 pmol/L (median 15.1 pmol/L [IQR 2.7-33.9]: three had levels more than 100 pmol/L. CONCLUSIONS: This study reports serum estriol concentrations in a large number of "new" and "chronic users" of vaginal estriol cream, employing a novel highly sensitive and specific technique. Overall, the results are reassuring: 87% had 12-hour estriol levels less than 100 pmol/L.

The management of severe hypertension in Australian general practice.

BACKGROUND: Severe hypertension (SHT) (Blood Pressure, BP ≥ 180/110 mmHg) is associated with considerable morbidity and mortality, yet little is known about how it is managed. The purpose of this study is to examine the management of SHT by Australian general practitioners (GPs) and to explore its variance across patient characteristics and clinical practices. METHODS: Review of electronic medical records for a year before and after a recorded measure of SHT in 7,499 patients by 436 GPs in 167 clinics throughout Australia during 2008-2009. Outcome measures included follow-up, referral, changes to antihypertensive drug treatment, and BP control (normotensive reading, BP < 140/90 mmHg, and whether subsequent recorded measures were also in the normal range--sustained normotension). RESULTS: Of 7,499 patients with an electronic BP record of SHT, 94% were followed up (median time 14 days); 8% were referred to an appropriate specialist (median time 89 days--2% within 7 days) and 86% were managed by GPs. GPs initiated or changed antihypertensive drugs in 5,398 patients (72% of cohort); of these, 46% remained hypertensive (4% with SHT) and 7% achieved sustained normotension; 6% had no further electronic BP records. The remaining 14% had no medication changes; among these, 43% remained hypertensive (5% with SHT) and 3% achieved sustained normotension; 32% had no further electronic BP records. Some outcome measures displayed a variance across GP clinics that was mostly unexplained by patient or practice characteristics. CONCLUSIONS: Most patients with SHT had at least one follow-up visit and 72% had initiation of, or changes to, antihypertensive drug treatment. Although most of the patients experienced some improvement, blood pressure control was poor. Some clinics showed better performance. Suggestions are made for the development of clinical standards to facilitate appropriate management of this dangerous condition.

BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation.

INTRODUCTION: Inflammation and bone erosion are processes key to the pathogenesis of rheumatoid arthritis, a systemic autoimmune disease causing progressive disability and pain, impacting around 1.3 million people in the United States alone. However, many patients do not respond sufficiently to existing therapies or benefit is not sustained and alternate therapeutic approaches are lacking. We recently identified the dibenzoxazepinone BT2, which inhibits ERK phosphorylation, from a high-throughput chemical screen and identified its ability to inhibit angiogenesis and vascular leakiness. METHODS: Here we evaluated BT2 for potential anti-inflammatory activity in in vitro models of human monocytic-endothelial cell adhesion, monocytic cell extravasation and collagen antibody-induced arthritis in mice. RESULTS: BT2 inhibits human monocytic cell adhesion to IL-1ß-treated human endothelial cells and inhibits monocytic transendothelial migration toward MCP-1. In mice rendered arthritic, single systemic administration of BT2 prevented footpad swelling, bone destruction and TRAP+ cells in the joints. BT2 suppressed inducible circulating levels of IL-1ß, IL-2 and IL-6 to normal levels without affecting levels of IL-4 or IL-10 among other cytokines. BT2 also inhibited the expression of pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 in arthritic joints. There was no evidence of toxicity following intraperitoneal, gavage or intraarticular administration of BT2. CONCLUSION: BT2 is a novel small molecule inhibitor of joint inflammation, bone erosion, pro-inflammatory cytokine and adhesion molecule expression. This suggests the potential clinical utility of BT2 as a new anti-inflammatory agent.

Efficacy and harms of orally, intramuscularly or intravenously administered glucocorticoids for sciatica: A systematic review and meta-analysis.

BACKGROUND: Sciatica can be a debilitating condition and there is limited guidance on the use of glucocorticoids administered via the oral, intramuscular or intravenous route for this condition. These represent viable treatment options in the primary care setting. OBJECTIVE: To evaluate the evidence on efficacy and harms of oral, IM and IV glucocorticoid administration for sciatica. DATABASES AND DATA TREATMENT: MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO (inception to October 2018) were searched for randomised placebo-controlled trials evaluating oral, IV or IM glucocorticoid administration for sciatica. Two authors extracted outcomes data. Continuous pain and disability outcomes were converted to a 0 (no pain/disability) to 100 (worst pain/disability) scale. Data were pooled using a random effects model. Overall quality of evidence was assessed using GRADE. Primary outcomes were leg pain and disability. Primary follow-up period was the immediate-term (<2 weeks from administration). We also considered adverse events. RESULTS: Nine trials were eligible. One study [n = 27] provided low quality evidence of a small reduction in disability with early administration of oral prednisone (within 1 week); MD -13.4 [-23.3, -3.5] but not for pain MD -2.5 [-16.9, 11.9]. There was low quality evidence from one study [n = 78] of moderate reduction in disability and small reduction in pain with early (within 72 hr of symptom onset) single intramuscular administration of methylprednisolone acetate; MD -24.5 [-38.8, -10.2] and -14.0 [-27.4, -0.6], respectively. There were no immediate-term benefits with IV administration. CONCLUSION: The effects of glucocorticoids on immediate-term leg pain or disability are uncertain. Future large high quality trials are needed to resolve this uncertainty.

STANDING Collaboration: a study protocol for developing clinical standards.

INTRODUCTION: Despite widespread availability of clinical practice guidelines (CPGs), considerable gaps continue between the care that is recommended ('appropriate care') and the care provided. Problems with current CPGs are commonly cited as barriers to providing 'appropriate care'.Our study aims to develop and test an alternative method to keep CPGs accessible and up to date. This method aims to mitigate existing problems by using a single process to develop clinical standards (embodied in clinical indicators) collaboratively with researchers, healthcare professionals, patients and consumers. A transparent and inclusive online curated (purpose-designed, custom-built, wiki-type) system will use an ongoing and iterative documentation process to facilitate synthesis of up-to-date information and make available its provenance. All participants are required to declare conflicts of interest. This protocol describes three phases: engagement of relevant stakeholders; design of a process to develop clinical standards (embodied in indicators) for 'appropriate care' for common medical conditions; and evaluation of our processes, products and feasibility. METHODS AND ANALYSIS: A modified e-Delphi process will be used to gain consensus on 'appropriate care' for a range of common medical conditions. Clinical standards and indicators will be developed through searches of national and international guidelines, and formulated with explicit criteria for inclusion, exclusion, time frame and setting. Healthcare professionals and consumers will review the indicators via the wiki-based modified e-Delphi process. Reviewers will declare conflicts of interest which will be recorded and managed according to an established protocol. The provenance of all indicators and suggestions included or excluded will be logged from indicator inception to finalisation. A mixed-methods formative evaluation of our research methodology will be undertaken. ETHICS AND DISSEMINATION: Human Research Ethics Committee approval has been received from the University of South Australia. We will submit the results of the study to relevant journals and offer national and international presentations.

OPAL: a randomised, placebo-controlled trial of opioid analgesia for the reduction of pain severity in people with acute spinal pain. Trial protocol.

INTRODUCTION: Low back pain and neck pain are extremely prevalent and are responsible for an enormous burden of disease globally. Strong analgesics, such as opioid analgesics, are recommended by clinical guidelines for people with acute low back pain or neck pain who are slow to recover and require more pain relief. Opioid analgesics are widely and increasingly used, but there are no strong efficacy data supporting the use of opioid analgesics for acute low back pain or neck pain. Concerns regarding opioid use are further heightened by the risks of adverse events, some of which can be serious (eg, dependency, misuse and overdose). METHODS AND ANALYSIS: OPAL is a randomised, placebo-controlled, triple-blinded trial that will investigate the judicious use of an opioid analgesic in 346 participants with acute low back pain and/or neck pain who are slow to recover. Participants will be recruited from general practice and randomised to receive the opioid analgesic (controlled release oxycodone plus naloxone up to 20 mg per day) or placebo in addition to guideline-based care (eg, reassurance and advice of staying active) for up to 6 weeks. Participants will be followed-up for 3 months for effectiveness outcomes. The primary outcome will be pain severity. Secondary outcomes will include physical functioning and time to recovery. Medication-related adverse events will be assessed and a cost-effectiveness analysis will be conducted. We will additionally assess long-term use and risk of misuse of opioid analgesics for up to 12 months. ETHICS AND DISSEMINATION: Ethical approval has been obtained. Trial results will be disseminated by publications and conference presentations, and via the media. TRIAL REGISTRATION NUMBER: ACTRN12615000775516: Pre-results.