Critical Dose Research Articles

Modeling critical dosing strategies for stromal-induced resistance to cancer therapy

Modeling critical dosing strategies for stromal-induced resistance to cancer therapy

On Medicine in the Byzantine Empire according to Christian Religious Texts and Church Documents

In the following paper, different religious texts and church documents are being analysed. Some of them pose a dose of criticism towards Byzantine physicians, mostly concerning their capabilities (or lack of such) as well as their motivation for material gains from the ill, contrary to Christian understandings of charitable healing, set as an example by Christ himself and the healer saints. Fragments from saint’s lives tell us of healing methods of the medieval Byzantine medicine, mixed up with miracles and intervention by the saints. In those cases, medical success is combined with divine miracle, showing a symbiosis between medicine and religion. Such an example we find in the 12th century typikon of the Pantokrator monastery, describing a hospital, maintained by the monastery itself. The document emphasizes on the charitable functions of the hospital, as well as the highly trained medical staff. Judging by those medieval texts we can come to a conclusion that the Byzantine church and religious institutions mentioned supported the application and advancement of lay medicine as a tool for helping people.

First Comprehensive Intranasal PET imaging of Insulin using the Aptar device in Nonhuman Primates

AbstractBackgroundInsulin resistance (IR) is associated with abnormal tau‐phosphorylation and IR markers in AD brain co‐localize with neurofibrillary tangles. One strategy to overcome brain IR is to increase brain insulin is via intranasal insulin (INI) administration using specialized intranasal devices that deliver insulin to the brain. Our recent INI vs. placebo‐controlled double‐blinded clinical trial in MCI/AD showed that INI improved CSF biomarkers and slowed symptom progression over the placebo group treated with one type of delivery device (with no benefit with another). While these studies highlight the potential of INI for therapeutic applications, methods are needed to verify the successful INI delivery with specific devices. Here we report our novel [68Ga]‐NOTA‐insulin‐based brain PET imaging and whole‐body dosimetry through intranasal route in healthy vervets using the Aptar Cartridge Pump System (CPS) device for the first time.MethodHuman‐grade insulin was chelated with NOTA and radiolabeled with [68Ga]. 0‐90min and 0‐3h PET scans were conducted for brain and whole‐body dosimetry in healthy vervets (n=4/sex, 9‐12 y) after intranasal administration (2 puffs per nostril) of [68Ga]‐NOTA‐insulin (25‐37 MBq) through the Aptar device. Blood glucose, oxygen, heartbeat, and temperature were collected throughout the scan. Standard uptake values (SUVs), time‐activity curves (TACs), and standard dosimetry organ doses were calculated.Result[68Ga]‐NOTA‐insulin radiochemistry was fully‐optimized: shorter reaction times (∼6‐7min), lower insulin mass (2‐4 units), high radiochemical purity (>99%), and molar activity (108 GBq/µmol). No significant changes were observed in vitals recorded. PET/MRI images showed brain penetration; SUV whole‐brain=0.29±0.11, hippocampus=0.18±0.05, cortex=0.21±0.08, choroid plexus=0.38±0.11, and cerebellum=0.09±0.01. TACs showed that radioactivity peaked in brain within 15‐20min of radiotracer administration and washed out by 90 min. Dosimetry showed nasal cavity and eyes as critical organs and effective dose=0.11 mSv/MBq. No sex differences were seen in brain uptake or dosimetry parameters.ConclusionBrain PET and whole‐body dosimetry PET scans of [68Ga]‐NOTA‐insulin in vervets demonstrate brain penetration and favorable distribution of INI respectively. This preliminary data provides critical information for translating [68Ga]‐NOTA‐insulin PET with intranasal delivery to humans using the Aptar device. This strategy will create a new paradigm for understanding the INI in AD pathogenesis and advance novel therapeutic platforms.

Investigation of ion irradiation effects on mineral analogues of concrete aggregates

Irradiation can cause prominent damage to reactor concrete aggregates leading to amorphization, strength and modulus decrease, radiation induced volume expansion (RIVE) and micro-cracking, which limits their long-term performance. To develop an improved understanding of irradiation effects in concrete, three mineral analogues of concrete aggregates (limestone, marble and quartzite) were irradiated by 5.5 MeV He ions and 13 MeV Ni ions to surface doses of 0.011 displacements per atom (dpa) and 0.23 dpa, respectively, at room temperature. The two different ion species allow irradiation spectrum effects (ionizing and displacive) to be examined. Irradiation induced cracks were observed in He irradiated limestone and marble, and Ni irradiated quartzite. Full amorphization was observed in Ni irradiated quartzite with 14.3 % RIVE, and ∼25 % hardness and modulus decrease, while almost no change was observed in He irradiated quartzite except 4.35 % RIVE, revealing a possible ionization enhanced diffusion effect for high energy light ions. Furthermore, partial amorphization was observed in Ni irradiated marble and limestone matrix with a 12 % hardness decrease in marble while no amorphization was observed for He irradiation with a 20 % hardness increase in limestone matrix. The role of knock-on damage and irradiation spectrum on amorphization, volumetric expansion and mechanical property changes are discussed. Moreover, the onset and critical doses for amorphization and RIVE in quartz are obtained for ion irradiations at room temperature. The dose dependence of RIVE exhibits a delay compared to the amorphization behavior. The superior irradiation resistance of calcite phase compared to quartz phase implies there could be advantages to using calcareous aggregates and lowering the usage of siliceous aggregates for concrete in nuclear power plants for extended operation beyond 60 years. However, other effects such as corrosion, aging and reactions during severe accidents should also be considered, and further investigations are needed.

Salt tolerance strategy in passion fruit genotypes during germination and seedling growth and spectrophotometric quantification of hydrogen peroxide (H2O2)

This study aimed to explore the impact of salinity on the seeds of Passiflora edulis Sims and to define the critical dose of NaCl capable of causing damage to germination and seedling vigor. Additionally, it aimed to assess oxidative stress by quantifying hydrogen peroxide (H2O2) in contrasting species regarding salt tolerance. For this purpose, two experiments were conducted. In the first experiment, five genotypes of P. edulis were evaluated under six levels of electrical conductivity of water (ECw = 0, 3, 6, 9, 12, and 15 dS m-1). In the second experiment, the H2O2 content was determined in four Passiflora species (P. edulis, P. alata, P. gibertii and P. mucronata) under ECw = 0 and 9 dS m-1. With the increase in salt concentrations, there was a significant reduction in germination and seedling vigor parameters, which were more pronounced at conductivities above 9 dS m-1. Under high salinity levels (15 dS m-¹), the reduction in germination percentage and mean germination time were 74 % and 53 %, respectively, compared to the control. The use of a grading scale for phenotypic evaluation was effective in indicating the critical dose at an early stage and in highlighting the variation in response among the genotypes. After the removal of saline conditions, seeds subjected to 9, 12 and 15 dS m-1 achieved germination of 18.9 %, 44.3 % and 67.2 %, respectively. In the H2O2 quantification study, higher accumulation was observed in the seedlings of P. edulis and P. alata, while lower levels were noted in P. mucronata and P. gibertii. In general, P. edulis in the seed phase is tolerant to levels below 6 dS m-1 and presents critical responses from 9 dS m-1 upwards. The results obtained from this study provide valuable new information to support future works on screening of salt-tolerant Passiflora genotypes in early development stages.

Mechanism of Electron-Beam-Induced Structural Degradation in ZIF-8 and its Electron Dose Tolerance.

Zeolitic-imidazolate frameworks (ZIFs) are crystalline microporous materials with promising potential for gas adsorption and catalysis application. Further research advances include studies on integrating ZIFs into nanodevice concepts. In detail for the application, e.g., electron-beam-assisted structural modifications or patterning, there is a need to understand potential structural degradation processes caused by such electron beams. Advanced transmission electron microscopy (TEM) has demonstrated its ability to study structures at the nanoscale. Here, we systematically investigated electron-beam-induced loss in crystallinity in ZIF-8 under various experimental conditions, using as measure the attenuation of the relative intensity and the relative displacement of electron diffraction Bragg planes with increasing cumulative electron dose. The {110} Bragg planes reflect the overall stability of the ZIF-8 unit-cell structure, while the {431} Bragg planes assess the stability of its micropore structure. We considered a relative loss of Bragg plane intensity of 37% as the threshold for determining the critical electron dose, which varied for different Bragg planes, with 35.6 ± 8.4 e-Å-2 for {110} and 11.4 ± 3.0 e-Å-2 for {431}. However, the critical dose per breakage of N-Zn bonds in a ZnN4 tetrahedra per different Bragg plane was found to be ∼3 e-Å-2, which indicates continuous, simultaneous breakage of N-Zn bonds throughout the crystal, confirming radiolysis as the dominant damage mechanism. In addition, we investigated the effects of TEM experiment parameters, including acceleration voltage, electron dose rate, cryogenic sample temperature, in situ sample drying, and change in conductivity of the sample substrate (e.g., graphene). Our results unravel the degradation mechanisms in ZIF-8 and provide threshold parameters for maximizing resolution in electron-beam-assisted experiments and processes.

Ion-induced surface reactions and deposition from Pt(CO)2Cl2 and Pt(CO)2Br2.

Ion beam-induced deposition (IBID) using Pt(CO)2Cl2 and Pt(CO)2Br2 as precursors has been studied with ultrahigh-vacuum (UHV) surface science techniques to provide insights into the elementary reaction steps involved in deposition, complemented by analysis of deposits formed under steady-state conditions. X-ray photoelectron spectroscopy (XPS) and mass spectrometry data from monolayer thick films of Pt(CO)2Cl2 and Pt(CO)2Br2 exposed to 3 keV Ar+, He+, and H2 + ions indicate that deposition is initiated by the desorption of both CO ligands, a process ascribed to momentum transfer from the incident ion to adsorbed precursor molecules. This precursor decomposition step is accompanied by a decrease in the oxidation state of the Pt(II) atoms and, in IBID, represents the elementary reaction step that converts the molecular precursor into an involatile PtX2 species. Upon further ion irradiation these PtCl2 or PtBr2 species experience ion-induced sputtering. The difference between halogen and Pt sputter rates leads to a critical ion dose at which only Pt remains in the film. A comparison of the different ion/precursor combinations studied revealed that this sequence of elementary reaction steps is invariant, although the rates of CO desorption and subsequent physical sputtering were greatest for the heaviest (Ar+) ions. The ability of IBID to produce pure Pt films was confirmed by AES and XPS analysis of thin film deposits created by Ar+/Pt(CO)2Cl2, demonstrating the ability of data acquired from fundamental UHV surface science studies to provide insights that can be used to better understand the interactions between ions and precursors during IBID from inorganic precursors.

Experimental study on fire suppression of NCM lithium-ion battery by C6F12O in a confined space

To investigate the suppression effect of C6F12O on the thermal runaway (TR) of NCM soft-pack lithium-ion battery (LIB) in a confined space, a combustion and suppression experimental platform was established. A 300 W heating panel was employed as an external heat source to induce TR. Results indicate that, in the absence of agents, the TR process of the fully charged NCM soft-pack battery exhibited pronounced gas release and intense jet flames, with the entire event lasting approximately 20 s. The average peak temperature on the back side of the cell (Tb-max) could be reached up to 776.5 ℃, corresponding to an average peak temperature 539.8 ℃ in surrounding environment, highlighting the potential for severe thermal hazards. The critical extinguishing dose (Xext) and the critical thermal suppression dose (Xsup) of C6F12O were determined based on its extinguishing and cooling effects. The application of C6F12O could lead to the extinguishment of battery flames within 3 s, with the Xext not less than 2.62 kg/kWh. However, low dose (0.07 kg and 0.15 kg) of C6F12O can exacerbate the temperature rise of LIBs after TR, potentially leading to re-ignition. Whereas a dosage exceeding of Xsup = 5.48 kg/kWh can exert a positive suppression effect to counteract this influence. This research provides valuable insights for selecting the optimal C6F12O dosage and designing effective firefighting measures against LIB fires, while also offering novel research directions for extinguishing strategies.

Temperature dependence of irradiation-induced amorphization in a high-entropy titanate pyrochlore

The temperature dependence of amorphization in a high-entropy pyrochlore, (Yb0.2Tm0.2Lu0.2Ho0.2Er0.2)2Ti2O7, under irradiation with 600 keV Xe ions has been studied using in situ transmission electron microscopy (TEM). The critical amorphization dose increases with temperature, and the critical temperature for amorphization is 800 K. At room temperature, the critical amorphization dose is larger than that previously determined for this pyrochlore under bulk-like 4 MeV Au ion irradiation but is similar to the critical doses determined in two other high-entropy titanate pyrochlores under 800 keV Kr ion irradiation using in situ TEM, which is consistent with reported behavior in simple rare-earth titanate pyrochlores.Graphical abstract

Degradation of thermoplastic polymers for fused filament fabrication under (S)TEM electron beam irradiation

The structural characterization of polymers and, in particular, of those used in Additive Manufacturing (AM) technologies, is essential to improve the understanding of their structure-property relationship for promising high-performance applications. For this, (scanning) transmission electron microscopy-electron energy loss spectroscopy, (S)TEM-EELS is an outstanding tool for exploring materials chemical and structural characteristics at high spatial resolution. However, the high beam-sensitivity of soft materials, such as polymers, hinders the possibility of probing in-depth analysis provided by (S)TEM-EELS. In this work, we analyse the electron beam irradiation damage of four polymers commonly used in Fused Filament Fabrication (FFF), namely polylactic acid (PLA), polycaprolactone (PCL), acrylonitrile butadiene styrene (ABS) and acrylonitrile styrene acrylate (ASA). For this, sequential low-loss and core-loss EEL spectra have been recorded, and the related signals have been monitored as a function of the accumulated dose. Our results show that the critical electron doses using the specimen thickness variations are larger for polymers containing aromatic groups (ABS and ASA) than for aliphatic polymers (PLA and PCL). Regarding the different elements, a larger sensitivity to the electron beam of oxygen regarding carbon and nitrogen is also evidenced. Our results have shown that polymer degradation occurs to a larger extent in the initial steps of electron irradiation, for very low accumulated electron doses, meaning that care should be taken in the selection of the microscopy settings to avoid artefacts produced by the electron beam. Degradation pathways for the four polymers studied are discussed.

The influence of cardiac substructure dose on survival in a large lung cancer stereotactic radiotherapy cohort using a robust personalized contour analysis

Background/Purpose: Radiation-induced cardiac toxicity in lung cancer patients has received increased attention since RTOG 0617. However, large cohort studies with accurate cardiac substructure (CS) contours are lacking, limiting our understanding of the potential influence of individual CSs. Here, we analyse the correlation between CS dose and overall survival (OS) while accounting for deep learning (DL) contouring uncertainty, α/β uncertainty and different modelling approaches. Materials/Methods: This single institution, retrospective cohort study includes 730 patients (early-stage tumours (I or II). All treated: 2009–2019), who received stereotactic body radiotherapy (≥ 5 Gy per fraction). A DL model was trained on 70 manually contoured patients to create 12 cardio-vascular structures. Structures with median dice score above 0.8 and mean surface distance (MSD) <2 mm during testing, were further analysed. Patientspecific CS dose was used to find the correlation between CS dose and OS with elastic net and random survival forest models (with and without confounding clinical factors). The influence of delineation-induced dose uncertainty on OS was investigated by expanding/contracting the DL-created contours using the MSD ± 2 standard deviations. Results: Eight CS contours met the required performance level. The left atrium (LA) mean dose was significant for OS and an LA mean dose of 3.3 Gy (in EQD2) was found as a significant dose stratum. Conclusion: Explicitly accounting for input parameter uncertainty in lung cancer survival modelling was crucial in robustly identifying critical CS dose parameters. Using this robust methodology, LA mean dose was revealed as the most influential CS dose parameter.

2406: A novel MR-guided treatment planning tool reduces accumulated critical organ dose in prostate cancer

2406: A novel MR-guided treatment planning tool reduces accumulated critical organ dose in prostate cancer

CRITICAL NOREPINEPHRINE DOSE TO PREDICT EARLY MORTALITY DURING CIRCULATORY SHOCK IN INTENSIVE CARE: A RETROSPECTIVE STUDY IN 3423 ICU PATIENTS OVER 4-YEAR PERIOD.

Introduction: The maximal norepinephrine (NE) dose >1 μg/kg/min during circulatory shock apparently is associated with higher mortality, but this threshold needs confirmation. This study aimed at investigating whether NE infusion at a dose >1 μg/kg/min could predict early intensive care unit (ICU) mortality (first 5 days). The secondary objective was to assess the day-by-day relationship between NE dose during the first 4 days of ICU stay and subsequent mortality. Methods: We conducted a retrospective analysis of data from ICU patients receiving NE for circulatory shock at the Nimes University Hospital (France) from January 2016 to December 2019. Results: A total of 5,735 patients were admitted, 3,693 were screened, and 3,423 were analyzed. NE infusion at a dose >1 μg/kg/min was associated with day-5 mortality (hazards ratio: 7.40, P < 0.0001). The area under the receiver operating characteristic was 0.79 to predict day-5 mortality in ICU for maximal NE >1 μg/kg/min. The calculated threshold of 1.13 μg/kg/min for maximal NE was the best prognostic value (sensitivity: 67%, specificity: 80%, positive predictive value: 45%). When the 1.2 μg/kg/min threshold was crossed either on the first, second, third, or fourth day of ICU stay, the probability of subsequent death was 47%, 49%, 60%, and 40%, respectively. Along the first 4 days of ICU stay, the risk of death increased with increasing NE infusion dose. Conclusions: An NE infusion rate >1.13 μg/kg/min predicts day-5 mortality in ICU patients with circulatory shock. The time to reach maximal NE infusion rate was shorter in survivors than in nonsurvivors.

Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers.

In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves "dose-finding" studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose-finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities.

A Multicentric study on a dosimetric comparison of extended SSD technique, VMAT-Based and helical tomotherapy (HT) for total body irradiation (TBI)

PurposeIn study, it was aimed to evaluate the dose volume histograms (DVH) of extended SSD technique, VMAT-based, and helical tomotherapy plans dosimetrically in a multi-institutional context to achieve higher plan quality and to harmonize total body irradiation plans. MethodsFour different clinical centers participated in the study. The CT images of ten patients were used in this study. During the first phase, ten patients enrolled for TBI were planned by multiple centers according to a common protocol. During the second phase, all centers shared their plans’ DVHs. Treatment plans were evaluated according to the critical organ dose limits. Statistical analysis was performed in the SPSS (version 22.0) program (p < 0.05). ResultsIn study, the results indicated that there was a statistically significant and considerable difference in the dose coverage of PTV, beam delivery time and MU, lens doses, and kidney doses between the four techniques (p < 0.001). The mean lung doses of the four centers were below 10 Gy. No significant difference in maximum liver doses between plans was obtained. ConclusionIn conclusion, although four treatment techniques were suitable for TBI treatment, more homogeneous dose distribution, and lower critical organ doses were obtained with the tomotherapy technique. However, treatment time, MU, and dose rate for lung were disadvantages of the tomotherapy technique. When it comes to deciding on the TBI treatment method, it need to be reviewed some important points. It is needed to sufficient data on long-term results to be able to standardize TBI techniques between centers.

Empirical model for a three-dimensional dose verification system and its application in volumetric-modulated arc therapy for heterogeneous and long-target tumors

PurposeTo perform commissioning of the VMAT dose verification system 3DVH from a unique perspective and investigating its clinical applications in unreported cases with heterogeneous organs or long-target tumors. MethodsInitially, the standard ArcCheck calibration process was conducted. Then, the impact of absolute dose calibration values and ArcCheck CT density settings on the accuracy of the 3DVH reconstruction model was assessed. Subsequently, ten lung cancer cases with heterogeneous organ-encased targets and ten cervical cancer cases with large target volumes were selected to receive VMAT treatment with a TrueBeam Linac. Finally, the performance of the 3DVH method in such radiotherapy validations was assessed. ResultsVarious calibration files had distinct impacts on ArcCheck 2D surface dosimetry and 3DVH dose reconstruction, thus requiring separate optimal calibrations files for these two purposes. The 3DVH dose reconstruction mode exhibited the highest accuracy when using the optimal ArcCheck density value of 1.1787 g/cm³ and an absolute dose calibration value of 249.96 cGy. In all test cases, deviations for target Dmean and D95% were within ±4.2% compared to the planned dose, with notable variations in critical organ doses. In structure-based 3D gamma evaluation, differences were observed compared to existing reports. ConclusionsIt's crucial to account for the ArcCheck array calibration and the interplay between CT density settings and absolute dose calibration values to identify the best combination for an optimal 3DVH dose reconstruction model. The performance of 3DVH in verifying VMAT doses for tumors in heterogeneous or longer target areas may exhibit slight variations compared to other regions.

Measuring pharmacy clinical workload in the emergency department: Current status and a plan for action

BackgroundInpatient pharmacy productivity workload ratios historically encompass dispensing functions including numbers of medication orders verified, dispensed, and billed for and full-time equivalents (FTEs) but do not include pharmacy clinical activities. Clinical pharmacy activities are difficult to capture because they generally require manual documentation and vary among health systems. The emergency medicine pharmacists’ (EMPs) role adds additional complexity to capturing clinical activities given that bedside response and verbal recommendations are difficult to capture outside of manual documentation. It is unknown how many health systems use EMP-specific workload metrics. ObjectivesThe purpose of our survey was to determine the percentage of hospital pharmacies that use EMP-specific workload metrics, to describe workload metrics used by EMPs and to quantify time spent on clinical activities, and to describe methods for implementing EMP metrics. MethodsA 13-item questionnaire was developed, pretested, and sent to EMPs practicing in hospitals in the United States through 2 EMP national committee e-mail listservs. Survey completion online included questions on hospital characteristics, number of EMP FTEs, clinical services provided and time spent on these tasks, and current workload metrics used. ResultsFull responses to the survey were received from 100 pharmacists, with an overall response rate of 9.8%. Workload metrics specific to EMP activities were used by 15.1% of responders. Workload metrics were used but not tailored to EMP activities for 43% of responders, and 41.9% responded that no metrics were used whatsoever. Ten responders provided commentary on types of EMP activities tracked, which included bedside response for critical patients, culture callback, drug information and dosing, time to antibiotic administration, and medication histories. No universal software for metric tracking was identified. ConclusionA survey of EMP clinical services and workload metrics indicated that although 43% of responders use non-EMP-specific metrics, only 15.1% reported workload metrics that capture EMP clinical activities.

Властивості вихідних та опромінених фосфідо-галієвих світлодіодів

Spectral features of the original and irradiated with electrons with E = 2 MeV GaP light emitting diodes (LEDs) were studied. Recombination lines of the exciton bound on the N isoelectronic center and on the pair complexes NN1 were detected. The change in the spectral composition of radiation when passing through a section of negative differential resistance is analyzed. Dose dependences of luminescence intensity were obtained for green GaP(N) and red GaP(Zn-O) LEDs. The maximum critical radiation dose was established, after which the LEDs lost their characteristic exciton emission mechanism. The results of the annealing of irradiated LEDs are given.

Toxicity, transfer and metabolization of the pyrethroid insecticides cypermethrin and deltamethrin by reared black soldier fly larvae

Abstract Reared insects such as black soldier fly larvae (Hermetia illucens) are considered a potential alternative feed protein. However, dietary exposure to insecticide residues via the substrate could adversely affect performance indicators (yield/survival) and substance-transfer from substrate to larval biomass could result in non-compliance with low legal limits. Effects of pyrethroid insecticides cypermethrin and deltamethrin were tested at varying concentrations, with or without the synergist piperonyl butoxide (PBO). Concentration/response curves for yield were estimated and samples were analysed to determine concentrations of parent compounds and selected metabolites. Results suggest that deltamethrin is highly toxic to H. illucens larvae: the critical effect dose for 10% yield loss was estimated to be 0.04 mg/kg, compared to a legal limit in wheat of 2.0 mg/kg. Cypermethrin was comparatively less toxic, in line with prior studies, but may also cause significant adverse effects even for exposure levels below the legal limit – especially when combined with PBO. For both substances, transfer from substrate to larvae is a potential issue due to low limits, and transfer as well as toxicity are increased by presence of PBO. Some metabolites could be detected, but more research is needed to determine resistance mechanisms involved.

Characterization of Interventions to Reduce the Frequency of Critical Medication Doses Missed or Delayed During Perioperative and Unit-to-unit Patient Transfers.

When medication administration record (MAR) "hold" capability is enabled in the electronic health record (EHR) during patient transfers, medication doses appear as "held" rather than due. We sought to quantify the incidence of delayed and missed doses of critical medications during MAR hold periods and to implement and evaluate interdisciplinary efforts and technical interventions to reduce missed medication doses during these periods. A list of critical medications was identified. MAR data were collected in patients with at least 1 critical medication dose due during the MAR hold period. MAR times were used to determine if delayed doses or missed doses occurred. Our interventions included: (1) implementation of a patient list indicator to retrospectively identify recently "held" medication doses, and (2) a report for operating room pharmacists to prospectively identify upcoming doses and ensure they were administered on time. Pre- and post-intervention period data were compared using a chi-squared test. During the pre-intervention study period, there were 1044 instances of delayed or missed doses during MAR hold. Most MAR times evaluated were on MAR hold during perioperative patient transfers. Delayed, missed, and multiple missed doses were defined in accordance with internal medication administration policies. There was no significant difference in the incidence of delayed and missed doses (69% vs 66%, P = .31), however, there was a significant reduction in the number of critical medication doses missed multiple times (0.8% vs 6.7%, P < .001) and all missed doses (35% vs 42%, P = .05) between the pre- and post-intervention period. As demonstrated across in both the pre- and post-intervention period of our study, MAR hold is commonly associated with dose delays and missed doses, which has potential negative consequences on patient outcomes. Future considerations will include implementation of a best practice alert (BPA) that directs users to a MAR tab highlighting doses held during transfers.