A decade of Australian methotrexate dosing errors

"OBJECTIVE: Accidental daily dosing of methotrexate can result in life-threatening toxicity. We investigated methotrexate dosing errors reported to the National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN) and Australian Poisons Information Centres (PICs). DESIGN AND SETTING: A retrospective review of coronial cases in the NCIS (2000-2014), and of reports to the TGA DAEN (2004-2014) and Australian PICs (2004-2015). Cases were included if dosing errors were accidental, with evidence of daily dosing on at least 3 consecutive days. MAIN OUTCOME MEASURES: Events per year, dose, consecutive days of methotrexate administration, reasons for the error, clinical features. RESULTS: Twenty-two deaths linked with methotrexate were identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was listed in ten cases in the DAEN, including two deaths. Australian PIC databases contained 92 cases, with a worrying increase seen during 2014-2015. Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists. The recorded clinical effects of daily dosage were consistent with those previously reported for methotrexate toxicity. CONCLUSION: Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade. Further strategies to reduce these preventable harms need to be implemented and evaluated. Recent suggestions include further changes in packet size, mandatory weekly dosing labelling on packaging, improving education, and including alerts in prescribing and dispensing software."NHMRC Program Grant: 105517

The ISCIP Analyst, Volume V, Issue 9

This repository item contains a single issue of The ISCIP Analyst, an analytical review journal published from 1996 to 2010 by the Boston University Institute for the Study of Conflict, Ideology, and Policy

Doppler string phantom for assessment of clinical doppler ultrasound velocity measurement

Purpose: The Doppler string phantom provides accurate velocity of the string motion; it can be used to calibrate Doppler ultrasound (US) velocity measurements and to evaluate variations due to intrinsic spectral broadening. We developed a semi‐automated method to estimate the mode velocity (Vmode) and peak velocity (Vmax) based on duplex US images from a string phantom, and use them to assess clinical Doppler US velocity measurement.Methods: Steady motion of a rubber O‐ring (20 – 110 cm/s) in a CIRS Doppler String phantom (Model 043) was studied using GE LOGIQ E9 system with a 9L probe. 5 s of Doppler spectral data was averaged to generate a mean spectral profile. It was fitted by a Gaussian function and Vmode was defined as the velocity of the Gaussian peak, while Vmax is defined as the velocity at which the spectral profile falls to within 1 SD of the background. Vmode and Vmax were evaluated against the prescribed motor velocity. Repeatability and variation to scanning parameters were analyzed and reported in % range, i.e. (max – min) / mean.Results: Vmode and Vmax had good repeatability over six days (6.0% for Vmode, 2.9% for Vmax). Gain, compression, scale, sample volume (SV) depth and length, frequency and beam steering all had minimal impact on Vmode and Vmax (variations ≤ 4.4%). Doppler angle θ had minimal effect on Vmode (2.2%) but a strong effect on Vmax (26% increase as θ increased from 10° to 60°). Vmode was linearly correlated with but overestimated the motor velocity (Pearson’s r = 1.05, R2 = 1).Conclusion: This study developed a simple yet robust Vmode and Vmax estimation method. Combined with a string phantom, these velocity estimators are shown to be a useful tool to evaluate clinical Doppler US system performance. For the tested system, only Doppler angle has an appreciable impact on Vmax estimation.--------------------------------------------Cite this article as: Zhang Y, Lynch T, Hangiandreou NJ. Doppler string phantom for assessment of clinical doppler ultrasound velocity measurement. Int J Cancer Ther Oncol 2014; 2(2):020246. DOI:10.14319/ijcto.0202.4

Multifunctional layer-by-layer carbon nanotube–polyelectrolyte thin films for strain and corrosion sensing

Since the discovery of carbon nanotubes, researchers have been fascinated by their mechanical and electrical properties, as well as their versatility for a wide array of applications. In this study, a carbon nanotube–polyelectrolyte composite multilayer thin film fabricated by a layer-by-layer (LbL) method is proposed to develop a multifunctional material for measuring strain and corrosion processes. LbL fabrication of carbon nanotube composites yields mechanically strong thin films in which multiple sensing transduction mechanisms can be encoded. For example, judicious selection of carbon nanotube concentrations and polyelectrolyte matrices can yield thin films that exhibit changes in their electrical properties to strain and pH. In this study, experimental results suggest a consistent trend between carbon nanotube concentrations and strain sensor sensitivity. Furthermore, by simply altering the type of polyelectrolyte used, pH sensors of high sensitivity can be developed to potentially monitor environmental factors suggesting corrosion of metallic structural materials (e.g. steel, aluminum).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58148/2/sms7_2_022.pd

Hydrogen-enhanced local plasticity in aluminum: an ab initio study

Dislocation core properties of Al with and without H impurities are studied using the Peierls-Nabarro model with parameters determined by ab initio calculations. We find that H not only facilitates dislocation emission from the crack tip but also enhances dislocation mobility dramatically, leading to macroscopically softening and thinning of the material ahead of the crack tip. We observe strong binding between H and dislocation cores, with the binding energy depending on dislocation character. This dependence can directly affect the mechanical properties of Al by inhibiting dislocation cross-slip and developing slip planarity.Comment: 4 pages, 3 figure

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins.

Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19

Direct Nano-Imaging of Light-Matter Interactions in Nanoscale Excitonic Emitters

Strong light-matter interactions in localized nano-emitters when placed near metallic mirrors have been widely reported via spectroscopic studies in the optical far-field. Here, we report a near-field nano-spectroscopic study of the localized nanoscale emitters on a flat Au substrate. We observe strong-coupling of the excitonic dipoles in quasi 2-dimensional CdSe/CdxZnS1-xS nanoplatelets with gap mode plasmons formed between the Au tip and substrate. We also observe directional propagation on the Au substrate of surface plasmon polaritons launched from the excitons of the nanoplatelets as wave-like fringe patterns in the near-field photoluminescence maps. These fringe patterns were confirmed via extensive electromagnetic wave simulations to be standing-waves formed between the tip and the emitter on the substrate plane. We further report that both light confinement and the in-plane emission can be engineered by tuning the surrounding dielectric environment of the nanoplatelets. Our results lead to renewed understanding of in-plane, near-field electromagnetic signal transduction from the localized nano-emitters with profound implications in nano and quantum photonics as well as resonant optoelectronics.Comment: manuscript + supporting informatio

Value of combining transect counts and telemetry data to determine short-term population trends in a globally threatened species

To evaluate conservation interventions, it is necessary to obtain reliable population trends for short (<10 years) time scales. Telemetry can be used to estimate short-term survival rates and is a common tool for assessing population trends, but it has limitations and can be biased toward specific behavioral traits of tagged individuals. Encounter rates calculated from transects can be useful for assessing changes across multiple species, but they can have large confidence intervals and be affected by variations in survey conditions. The decline of African vultures has been well-documented, but understanding of recent trends is lacking. To examine population trends, we used survival estimates from telemetry data collected over 6 years (primarily for white-backed vultures [Gyps africanus]) and transect counts conducted over 8 years (for 7 scavenging raptors) in 3 large protected areas in Tanzania. Population trends were estimated using survival analysis combined with the Leslie Lefkovitch matrix model from the telemetry data and using Bayesian mixed effects generalized linear regression models from the transect data. Both methods showed significant declines for white-backed vultures in Ruaha and Nyerere National Parks. Only telemetry estimates suggested significant declines in Katavi National Park. Encounter rates calculated from transects also showed declines in Nyerere National Park for lappet-faced vultures (38% annual declines) and Bateleurs (18%) and in Ruaha National Park for white-headed vultures (Trigonoceps occipitalis) (19%). Mortality rates recorded and inferred from telemetry suggested that poisoning is prevalent. However, only 6 mortalities of the 26 presumed mortalities were confirmed to be caused by poisoning, highlighting the challenges of determining the cause of death when working across large landscapes. Despite declines, our data provide evidence that southern Tanzania has higher current encounter rates of African vultures than elsewhere in East Africa. Preventing further declines will depend greatly on mitigating poisoning. Based on our results, we suggest that the use of multiple techniques improves understanding of population trends over the short term.Vulture research in southern Tanzania was funded by the North Carolina Zoological Society and the Wildlife Conservation Society. Donor support provided by Association of Zoos and Aquariums (AZA), AZA SAFE (Saving Animals From Extinction), Dallas Zoo, Disney Conservation Fund, Leiden Conservation Foundation, National Geographic Society, Taronga Conservation Society Australia, The Mohamed bin Zayed Species Conservation Fund, and the Wyss Foundation. Research permission was granted by the Tanzania Wildlife Research Institute (TAWIRI), Tanzania Commission for Science and Technology, and Tanzania National Parks and Tanzania Wildlife Authority (TAWA). We thank Singira Ngoishiye and TAWA Selous GR for invaluable contributions to ensure successful deployment of satellite tags and rapidmobilization of rangers to poisoning events, L. Mlawila for assistance with surveys and retrieving satellite tags from mortalities, and E. Kohi (TAWIRI) for his input on the manuscript. Work in Selous Game Reserve (nowNyerere National Park) was conducted in collaboration with Frankfurt Zoological Society.https://conbio.onlinelibrary.wiley.com/journal/15231739am2024Mammal Research InstituteZoology and EntomologySDG-15:Life on lan

The Lectin Pathway of Complement Activation Is a Critical Component of the Innate Immune Response to Pneumococcal Infection

The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci

A comparison of random vs. chemotaxis-driven contacts of T cells with dendritic cells during repertoire scanning

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83669/1/JTB_article.pd