Randomized Trial Comparing Low- vs High-Dose IV Dexamethasone for Patients With Moderate to Severe Migraine.

BACKGROUND AND OBJECTIVES: Dexamethasone decreases the frequency of migraine recurrence after emergency department (ED) discharge. However, the optimal dose of dexamethasone is unknown. We hypothesized that dexamethasone 16 mg IV would allow greater rates of sustained headache relief than 4 mg when coadministered with metoclopramide 10 mg IV. METHODS: This was a randomized double-blind study. Adults who presented with a headache meeting International Classification of Headache Disorders, 3rd edition, migraine criteria were eligible if they rated the headache as moderate or severe in intensity. Pain intensity was assessed for up to 2 hours in the ED and through telephone 48 hours and 7 days later. The primary outcome was sustained headache relief. Secondary outcomes included headache relief within 2 hours and the number of headache days during the subsequent week. Relying on a priori criteria, the data safety monitoring committee recommended halting the study early for futility. RESULTS: A total of 1,823 patients were screened, and 209 patients were randomized. The mean age was 38 years (SD 11). One hundred seventy-nine of 209 (86%) identified as women. One hundred fifty-one of 209 (72%) of the population reported severe intensity; the rest reported moderate. Thirty-five of 102 (34%) participants in the metoclopramide +4 mg arm achieved sustained headache relief as did 42/102 (41%) participants in the metoclopramide +16 mg arm (absolute difference 7%, 95% CI -6% to 20%). Headache relief within 2 hours occurred in 77/104 (74%) low-dose and 82/105 (78%) high-dose participants (absolute difference 4%, 95% CI -8% to 16%). During the week after ED discharge, low-dose participants reported a median of 2 headache days (25th, 75th percentile 1, 5); in the high-dose arm, this was also 2 (25th, 75th percentile 0, 4) (mean difference 0.4, 95% CI -0.3 to 1.2). DISCUSSION: When added to 10 mg IV metoclopramide, doses of dexamethasone greater than 4 mg are unlikely to benefit patients in the ED with migraine. TRIAL REGISTRATION INFORMATION: This study was registered at ClinicalTrials.gov on October 2, 2019 (NCT04112823). The first patient was enrolled on December 22, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 16 mg of IV dexamethasone is unlikely to provide greater rates of sustained headache relief than 4 mg of IV dexamethasone among patients in the ED with migraine treated concurrently with IV metoclopramide.

Novel Note Templates to Enhance Signal and Reduce Noise in Medical Documentation: Prospective Improvement Study.

BACKGROUND: The introduction of electronic workflows has allowed for the flow of raw uncontextualized clinical data into medical documentation. As a result, many electronic notes have become replete of "noise" and deplete clinically significant "signals." There is an urgent need to develop and implement innovative approaches in electronic clinical documentation that improve note quality and reduce unnecessary bloating. OBJECTIVE: This study aims to describe the development and impact of a novel set of templates designed to change the flow of information in medical documentation. METHODS: This is a multihospital nonrandomized prospective improvement study conducted on the inpatient general internal medicine service across 3 hospital campuses at the New York University Langone Health System. A group of physician leaders representing each campus met biweekly for 6 months. The output of these meetings included (1) a conceptualization of the note bloat problem as a dysfunction in information flow, (2) a set of guiding principles for organizational documentation improvement, (3) the design and build of novel electronic templates that reduced the flow of extraneous information into provider notes by providing link outs to best practice data visualizations, and (4) a documentation improvement curriculum for inpatient medicine providers. Prior to go-live, pragmatic usability testing was performed with the new progress note template, and the overall user experience was measured using the System Usability Scale (SUS). Primary outcome measures after go-live include template utilization rate and note length in characters. RESULTS: In usability testing among 22 medicine providers, the new progress note template averaged a usability score of 90.6 out of 100 on the SUS. A total of 77% (17/22) of providers strongly agreed that the new template was easy to use, and 64% (14/22) strongly agreed that they would like to use the template frequently. In the 3 months after template implementation, general internal medicine providers wrote 67% (51,431/76,647) of all inpatient notes with the new templates. During this period, the organization saw a 46% (2768/6191), 47% (3505/7819), and 32% (3427/11,226) reduction in note length for general medicine progress notes, consults, and history and physical notes, respectively, when compared to a baseline measurement period prior to interventions. CONCLUSIONS: A bundled intervention that included the deployment of novel templates for inpatient general medicine providers significantly reduced average note length on the clinical service. Templates designed to reduce the flow of extraneous information into provider notes performed well during usability testing, and these templates were rapidly adopted across all hospital campuses. Further research is needed to assess the impact of novel templates on note quality, provider efficiency, and patient outcomes.

Indications for the Use of Proton Pump Inhibitors for Stress Ulcer Prophylaxis and Peptic Ulcer Bleeding in Hospitalized Patients.

Proton pump inhibitors are widely used throughout the world for the treatment of gastrointestinal disorders that are related to acid secretion, such as peptic ulcer disease and dyspepsia. Another common indication for proton pump inhibitors is stress ulcer prophylaxis. Proton pump inhibitors have proven efficacy for the treatment of acid-related gastrointestinal disorders, but there is concern that their use may be associated with the development of significant complications, such as fractures, Clostridium difficile infection, acute kidney injury, chronic kidney disease, and hypomagnesemia. Proton pump inhibitors are overused in the hospital setting, both for stress ulcer prophylaxis and gastrointestinal bleeding, and then they are often inappropriately continued after discharge from the hospital. This narrative review article outlines the evidence surrounding appropriate proton pump inhibitor use for stress ulcer prophylaxis and peptic ulcer bleeding.

Validation of parsimonious prognostic models for patients infected with COVID-19.

OBJECTIVES: Predictive studies play important roles in the development of models informing care for patients with COVID-19. Our concern is that studies producing ill-performing models may lead to inappropriate clinical decision-making. Thus, our objective is to summarise and characterise performance of prognostic models for COVID-19 on external data. METHODS: We performed a validation of parsimonious prognostic models for patients with COVID-19 from a literature search for published and preprint articles. Ten models meeting inclusion criteria were either (a) externally validated with our data against the model variables and weights or (b) rebuilt using original features if no weights were provided. Nine studies had internally or externally validated models on cohorts of between 18 and 320 inpatients with COVID-19. One model used cross-validation. Our external validation cohort consisted of 4444 patients with COVID-19 hospitalised between 1 March and 27 May 2020. RESULTS: Most models failed validation when applied to our institution's data. Included studies reported an average validation area under the receiver-operator curve (AUROC) of 0.828. Models applied with reported features averaged an AUROC of 0.66 when validated on our data. Models rebuilt with the same features averaged an AUROC of 0.755 when validated on our data. In both cases, models did not validate against their studies' reported AUROC values. DISCUSSION: Published and preprint prognostic models for patients infected with COVID-19 performed substantially worse when applied to external data. Further inquiry is required to elucidate mechanisms underlying performance deviations. CONCLUSIONS: Clinicians should employ caution when applying models for clinical prediction without careful validation on local data.

Reducing Overuse of Proton Pump Inhibitors for Stress Ulcer Prophylaxis and Nonvariceal Gastrointestinal Bleeding in the Hospital: A Narrative Review and Implementation Guide.

Proton pump inhibitors (PPIs) are among the most commonly used medications in the world; however, these drugs carry the risk of patient harm, including acute and chronic kidney disease, Clostridium difficile infection, hypomagnesemia, and fractures. In the hospital setting, PPIs are overused for stress ulcer prophylaxis and gastrointestinal bleeding, and PPI use often continues after discharge. Numerous multifaceted interventions have demonstrated safe and effective reduction of PPI use in the inpatient setting. This narrative review and the resulting implementation guide summarize published interventions to reduce inappropriate PPI use and provide a strategy for quality improvement teams.

Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series.

BACKGROUND: There is increasing recognition of a prothrombotic state in COVID-19. Post-mortem examination can provide important mechanistic insights. METHODS: We present a COVID-19 autopsy series including findings in lungs, heart, kidneys, liver, and bone, from a New York academic medical center. FINDINGS: In seven patients (four female), regardless of anticoagulation status, all autopsies demonstrated platelet-rich thrombi in the pulmonary, hepatic, renal, and cardiac microvasculature. Megakaryocytes were seen in higher than usual numbers in the lungs and heart. Two cases had thrombi in the large pulmonary arteries, where casts conformed to the anatomic location. Thrombi in the IVC were not found, but the deep leg veins were not dissected. Two cases had cardiac venous thrombosis with one case exhibiting septal myocardial infarction associated with intramyocardial venous thrombosis, without atherosclerosis. One case had focal acute lymphocyte-predominant inflammation in the myocardium with no virions found in cardiomyocytes. Otherwise, cardiac histopathological changes were limited to minimal epicardial inflammation (n = 1), early ischemic injury (n = 3), and mural fibrin thrombi (n = 2). Platelet-rich peri­tubular fibrin microthrombi were a prominent renal feature. Acute tubular necrosis, and red blood cell and granular casts were seen in multiple cases. Significant glomerular pathology was notably absent. Numerous platelet-fibrin microthrombi were identified in hepatic sinusoids. All lungs exhibited diffuse alveolar damage (DAD) with a spectrum of exudative and proliferative phases including hyaline membranes, and pneumocyte hyperplasia, with viral inclusions in epithelial cells and macrophages. Three cases had superimposed acute bronchopneumonia, focally necrotizing. INTERPRETATION: In this series of seven COVID-19 autopsies, thrombosis was a prominent feature in multiple organs, in some cases despite full anticoagulation and regardless of timing of the disease course, suggesting that thrombosis plays a role very early in the disease process. The finding of megakaryocytes and platelet-rich thrombi in the lungs, heart and kidneys suggests a role in thrombosis. FUNDING: None.

Bending the cost curve: time series analysis of a value transformation programme at an academic medical centre.

BACKGROUND: Reducing costs while increasing or maintaining quality is crucial to delivering high value care. OBJECTIVE: To assess the impact of a hospital value-based management programme on cost and quality. DESIGN: Time series analysis of non-psychiatric, non-rehabilitation, non-newborn patients discharged between 1 September 2011 and 31 December 2017 from a US urban, academic medical centre. INTERVENTION: NYU Langone Health instituted an institution-wide programme in April 2014 to increase value of healthcare, defined as health outcomes achieved per dollar spent. Key features included joint clinical and operational leadership; granular and transparent cost accounting; dedicated project support staff; information technology support; and a departmental shared savings programme. MEASUREMENTS: Change in variable direct costs; secondary outcomes included changes in length of stay, readmission and in-hospital mortality. RESULTS: The programme chartered 74 projects targeting opportunities in supply chain management (eg, surgical trays), operational efficiency (eg, discharge optimisation), care of outlier patients (eg, those at end of life) and resource utilisation (eg, blood management). The study cohort included 160 434 hospitalisations. Adjusted variable costs decreased 7.7% over the study period. Admissions with medical diagnosis related groups (DRG) declined an average 0.20% per month relative to baseline. Admissions with surgical DRGs had an early increase in costs of 2.7% followed by 0.37% decrease in costs per month. Mean expense per hospitalisation improved from 13% above median for teaching hospitals to 2% above median. Length of stay decreased by 0.25% per month relative to prior trends (95% CI -0.34 to 0.17): approximately half a day by the end of the study period. There were no significant changes in 30-day same-hospital readmission or in-hospital mortality. Estimated institutional savings after intervention costs were approximately $53.9 million. LIMITATIONS: Observational analysis. CONCLUSION: A systematic programme to increase healthcare value by lowering the cost of care without compromising quality is achievable and sustainable over several years.

Promoting High-Value Practice by Reducing Unnecessary Transfusions With a Patient Blood Management Program.

Although blood transfusion is a lifesaving therapy for some patients, transfusion has been named 1 of the top 5 overused procedures in US hospitals. As unnecessary transfusions only increase risk and cost without providing benefit, improving transfusion practice is an effective way of promoting high-value care. Most high-quality clinical trials supporting a restrictive transfusion strategy have been published in the past 5 to 10 years, so the value of a successful patient blood management program has only recently been recognized. We review the most recent transfusion practice guidelines and the evidence supporting these guidelines. We also discuss several medical societies' Choosing Wisely campaigns to reduce or eliminate overuse of transfusions. A blueprint is presented for developing a patient blood management program, which includes discussion of specific methods for optimizing transfusion practice.

Reducing liberal red blood cell transfusions at an academic medical center.

BACKGROUND: Educational and computerized interventions have been shown to reduce red blood cell (RBC) transfusion rates, yet controversy remains surrounding the optimal strategy needed to achieve sustained reductions in liberal transfusions. STUDY DESIGN AND METHODS: The purpose of this study was to assess the impact of clinician decision support (CDS) along with targeted education on liberal RBC utilization to four high-utilizing service lines compared with no education to control service lines across an academic medical center. Clinical data along with associated hemoglobin levels at the time of all transfusion orders between April 2014 and December 2015 were obtained via retrospective chart review. The primary outcome was the change in the rate of liberal RBC transfusion orders (defined as any RBC transfusion when the hemoglobin level is >7.0 g/dL). Secondary outcomes included the annual projected reduction in the number of transfusions and the associated decrease in cost due to these changes as well as length of stay (LOS) and death index. These measures were compared between the 12 months prior to the initiative and the 9-month postintervention period. RESULTS: Liberal RBC utilization decreased from 13.4 to 10.0 units per 100 patient discharges (p = 0.002) across the institution, resulting in a projected 12-month savings of $720,360. The mean LOS and the death index did not differ significantly in the postintervention period. CONCLUSION: Targeted education combined with the incorporation of CDS at the time of order entry resulted in significant reductions in the incidence of liberal RBC utilization without adversely impacting inpatient care, whereas control service lines exposed only to CDS had no change in transfusion habits.

Effects of ivermectin application on the diversity and function of dung and soil fauna: Regulatory and scientific background information.

The application of veterinary medical products to livestock can impact soil organisms in manure-amended fields or adversely affect organisms that colonize dung pats of treated animals and potentially retard the degradation of dung on pastures. For this reason, the authorization process for veterinary medicinal products in the European Union includes a requirement for higher-tier tests when adverse effects on dung organisms are observed in single-species toxicity tests. However, no guidance documents for the performance of higher-tier tests are available. Hence, an international research project was undertaken to develop and validate a proposed test method under varying field conditions of climate, soil, and endemic coprophilous fauna at Lethbridge (Canada), Montpellier (France), Zurich (Switzerland), and Wageningen (The Netherlands). The specific objectives were to determine if fecal residues of an anthelmintic with known insecticidal activity (ivermectin) showed similar effects across sites on 1) insects breeding in dung of treated animals, 2) coprophilous organisms in the soil beneath the dung, and 3) rates of dung degradation. By evaluating the effects of parasiticides on communities of dung-breeding insects and soil fauna under field conditions, the test method meets the requirements of a higher-tier test as mandated by the European Union. The present study provides contextual information on authorization requirements for veterinary medicinal products and on the structure and function of dung and soil organism communities. It also provides a summary of the main findings. Subsequent studies on this issue provide detailed information on different aspects of this overall project. Environ Toxicol Chem 2016;35:1914-1923. © 2015 SETAC.

Pharmaceuticals in the environment: scientific evidence of risks and its regulation.

During the past two decades scientists, regulatory agencies and the European Commission have acknowledged pharmaceuticals to be an emerging environmental problem. In parallel, a regulatory framework for environmental risk assessment (ERA) of pharmaceutical products has been developed. Since the regulatory guidelines came into force the German Federal Agency (UBA) has been evaluating ERAs for human and veterinary pharmaceutical products before they are marketed. The results show that approximately 10% of pharmaceutical products are of note regarding their potential environmental risk. For human medicinal products, hormones, antibiotics, analgesics, antidepressants and antineoplastics indicated an environmental risk. For veterinary products, hormones, antibiotics and parasiticides were most often discussed as being environmentally relevant. These results are in good correlation with the results within the open scientific literature of prioritization approaches for pharmaceuticals in the environment. UBA results revealed that prospective approaches, such as ERA of pharmaceuticals, play an important role in minimizing problems caused by pharmaceuticals in the environment. However, the regulatory ERA framework could be improved by (i) inclusion of the environment in the risk-benefit analysis for human pharmaceuticals, (ii) improvement of risk management options, (iii) generation of data on existing pharmaceuticals, and (iv) improving the availability of ERA data. In addition, more general and integrative steps of regulation, legislation and research have been developed and are presented in this article. In order to minimize the quantity of pharmaceuticals in the environment these should aim to (i) improve the existing legislation for pharmaceuticals, (ii) prioritize pharmaceuticals in the environment and (iii) improve the availability and collection of pharmaceutical data.

Treatment of Leptomeningeal Carcinomatosis in a Patient With Metastatic Cholangiocarcinoma.

A 49-year-old woman with cholangiocarcinoma metastatic to the lungs presented with new-onset unrelenting headaches. A lumbar puncture revealed malignant cells consistent with leptomeningeal metastasis from her cholangiocarcinoma. Magnetic resonance imaging (MRI) of the brain revealed leptomeningeal enhancement. An intrathecal (IT) catheter was placed and IT chemotherapy was initiated with methotrexate. Her case is notable for the rarity of cholangiocarcinoma spread to the leptomeninges, the use of IT chemotherapy with cytologic and potentially symptomatic response, and a possible survival benefit in comparison to previously reported cases of leptomeningeal carcinomatosis secondary to cholangiocarcinoma.

New test strategy for dung beetles during the authorization process of parasiticides.

According to European legislation, an environmental risk assessment (ERA) of veterinary medicinal products (VMPs) for dung fauna is required in the authorization process, if the substance acts as a parasiticide for the treatment of pasture animals. In the past, however, the demonstration of the environmental safety of those VMPs for dung fauna was strongly hampered by the fact that no standardized tests were available. Therefore, starting with recommendations from the Society of Environmental Toxicology and Chemistry (SETAC) advisory group, dung organism toxicity test standardization (DOTTS) test systems for phase II Tier A standardized tests on the mortality of dung fly and dung beetle larvae were developed and published by the Organisation for Economic Co-operation and Development (OECD) in 2008 and 2010. If a risk is identified for dung organisms in phase II Tier A of the ERA process, further tests are required for Tier B. So far, however, no advice is given for such studies in the existing guidelines. Therefore, 4 workshops took place between 2007 and 2009 with international dung fauna experts (Aveiro-Group) to find an appropriate test strategy for dung fauna organisms beyond Tier A mortality testing. For the first time, 2 different Tier B extended laboratory test approaches for dung beetles and test strategies for scenarios beyond Tier B are described in more detail. In case the risk assessment is still not clear, further options for Tier C (i.e., field studies) or Tier D (modeling) are briefly presented. Finally, the role of uncertainty and variability of test results is discussed, including recommendations for assessment factors for the different tiers to be used when assessing the risk of VMPs on dung organisms. The approach, especially the test strategy, will help industry, consultants, and assessors appropriately assess the environmental risk assessments during the authorization procedure of parasiticides.

Strategies for managing risk in a changing aviation environment.

Given the increasing volatility in the economic performance of airlines, partially reflecting the dynamics of demand for air transport and the fixed costs associated with the industry, all stakeholders need to consider appropriate strategies for better managing the risks. Many risks were identified in the literature previously, some even decades ago, however most have yet to be satisfactorily addressed. Urgency is growing. Removal of the remaining barriers to competition at all levels, congestion management, open skies policies across continents, computer-centric air traffic management systems and increased research and development into the processes and technology needed to reduce environmental externalities remain among the top challenges for the next decade.

Flow cytometry as a tool to study phytotoxic modes of action.

The objective of the present investigation was to provide a diagnostic tool for the analysis of phytotoxic interactions between environmental contaminants and algae by application of flow cytometry. Therefore, an experimental design was developed consisting of synchronized Scenedesmus vacuolatus cell populations at defined cell-cycle stages, short-term exposure against different inhibitors with known molecular targets, and fluorochrome labeling of different metabolic processes. To discriminate cells with compromised metabolic processes from intact and metabolically inactive cells, references for every fluorochrome were defined using control and heat-treated populations. The experimental results showed that fluorescence markers are able to detect disturbance of specific cellular characteristics, such as membrane integrity, chlorophyll synthesis, and degradation. A differentiation of impacts on specific metabolic process caused by the reference inhibitors in concentration-dependent patterns could be seen using flow-cytometric fluorochrome analysis. These findings were compared with effects observed for N-phenyl-2-naphthylamine (PNA), a sediment contaminant of high phytotoxicity but unclear mode of action. Rhodamine 123 and cyano-ditolyl tetrazolium chloride detected significant metabolic changes for relevant exposures against PNA, thus pointing to compromised mitochondrial activity and changes in membrane potential as causes of phytotoxicity.

Phytotoxicity assessment of diclofenac and its phototransformation products.

The occurrence of pharmaceuticals in the environment is an emerging issue. Several studies observed that the non-steroidal anti-inflammatory drug diclofenac is ubiquitously present in most of the surveyed surface waters, worldwide. Phototransformation of diclofenac was reported from laboratory assays as well as in natural water systems, raising the question of possible adverse effects of the phototransformation products of diclofenac to aquatic organisms. In this study the phytotoxicity of diclofenac exposed to natural sunlight was evaluated using synchronized cultures of the unicellular chlorophyte Scenedesmus vacuolatus. Diclofenac dissolved in ultra-pure water at 50 mg L(-1) was exposed to natural midsummer sunlight for a maximum of 145 h. Twice a day subsamples were taken for chromatography and parallel phytotoxicity assessment. Inhibition of algal reproduction of the initial diclofenac solution was in the mg L(-1) range indicating no specific toxicity of diclofenac towards S. vacuolatus. Fast degradation of diclofenac was observed with half lives between 3.3 and 6.4 h during the first and the third day of exposure, respectively. Phytotoxicity increased after 3.5 h of exposure of diclofenac to sunlight and showed a maximum of sixfold enhanced toxicity after 53 h of exposure to sunlight. Several phototransformation products were found during the experiment. The time courses of the relative concentration of three transformation products significantly correlated with enhanced phytotoxicity during the experiment. This indicates a high toxicity potential of phototransformation products of diclofenac at concentration levels that may come close to environmental concentrations of residual diclofenac after degradation. We conclude that toxicity assessment of phototransformation products should be included in the risk assessment of pharmaceuticals in the environment.