Real-time Dose Research Articles

Hearing Care: Safe Listening Method and System for Personal Listening Devices.

Excessive use of Personal Listening Devices (PLDs) and prolonged exposure to noise from loud music create many potential risks associated with hearing loss. To this end, the World Health Organization has published Recommendation ITU-T H.870 in 2019, which provides adults and children with a set of recommendations for sound dosage and operating times needed to avoid potential hearing risks. Some studies have investigated noise exposure of related applications for listening safety, resulting in some related recommendations and applications; however, these studies often do not pay attention to measurement error, which is important for human real noise exposure estimation to avoid hearing loss. This paper proposes a method for calculating noise exposure that can accurately calculate the actual noise sound-pressure level (SPL) and PLD dosage based on the WHO-ITU standard. We develop a calculation method and design a listening system that includes (i) a Safe Listening Personal Listening Device (SL-PLD) that can measure the listening dose in real time and control the output volume effectively, (ii) a Safe Listening Application (SL-APP) for assisting the SL-PLD to check the listening status in real time and provide alerts. Our experimental results show that (i) the proposed noise calculation method can reach 0.88 dB deviation under the 76 dB reference SPL and 98.8% accuracy, as compared to the SoundCheck tool measurement, (ii) the proposed SL-PLD controls the SPL output effectively as the dose increases, and (iii) the SL-APP determines the dosage usage and will provide a warning when the dosage exceeds a preset value. Therefore, users can adjust their listening behavior for more secure listening by using our methods and applications.

In situ generation of H2O2 for Fenton oxidation in electrochemical system for the enhancement of sludge dehydration

Fenton methods can effectively improve the dewatering performance of waste activated sludge (WAS). However, the explosive properties of H2O2 and demand of real-time dosing often incur transportation difficulties and high operational costs. It limits large-scale applications of Fenton processes on WAS dewatering. This study introduced the electro-Fenton technique by in-situ H2O2 generation into sludge dewatering for the first time. The responding surface methodology indicated that the yield of H2O2 could reach 10.11 mg/g DS (dry solids) at an optimal iron dose of 8 mg/g DS within 60 min. Compared to WAS, the capillary suction time (CST) and specific resistance to filtration (SRF) of treated sludge decreased from 87.7 ± 0.57 s and 3.67 × 1012 m/kg to 57.65 ± 0.92 s and 3.14 × 1012 m/kg, respectively. The mechanism investigations showed that electro-Fenton treatment reduced surface negative charge of WAS and caused disruption of extracellular polymeric substances and release of intracellular substances, which enhanced the flocculability and filtering performance, but decreased the moisture content, fractal dimension of WAS. Additionally, electro-Fenton treatment altered the secondary structure of proteins, which led to a loose structure of protein, benefiting the exposure of hydrophobic sites or groups in EPS proteins. Furthermore, the dewatering mechanisms involved in the electro-Fenton process were explored and the contribution of individual reactions in sludge dewatering was revealed. Overall, this work will provide both theoretical basis and practical knowledge for electro-Fenton sludge dewatering.

Evaluation of the impact of a pharmacist-run antimicrobial report in reducing delays in subsequent antibiotic administration in patients in the emergency department.

To determine whether the implementation of a pharmacist-run, real-time electronic health record (EHR) antimicrobial report reduces the frequency of delays in subsequent antibiotic medication administration timing in patients in the emergency department (ED). A single-center, retrospective, pre-and-post quasi-experimental study was conducted between July and December 2021 following the implementation of an antimicrobial EHR report of adult patients presenting to the ED who were continued on antibiotic therapy after receiving a one-time dose of an antibiotic in the ED. The primary objective was to determine the impact of the pharmacist-run, real-time EHR antibiotic dosing report in the ED on reducing the number of major delays in subsequent antibiotic administration times. A subanalysis of the primary outcome was performed to evaluate differences in major delays based on specific dosing intervals of 6, 8, and 12 hours. A total of 521 subsequent antibiotic dosing orders from 273 patient encounters were analyzed, with major delays in subsequent antibiotic dosing administration times identified in 20% of the intervention group compared to 27% of the control group (P = 0.047). Major delays were also significantly decreased in the intervention group compared to the control group for antibiotics dosed at 8-hour intervals (18% vs 32%; P = 0.026). No significant difference in delays was observed between the groups for antibiotics dosed at 6-hour intervals (18% vs 27%) or 12-hour intervals (29% vs 21%). Implementing a real-time EHR antimicrobial report run by pharmacists in the ED was associated with significantly fewer major delays in subsequent antibiotic dosing following a first dose.

Characterization of Lab-on-Fiber-based dosimeters in ultra-high dose radiation fields

Next generation High Energy Physics (HEP) accelerators will require new devices and technologies capable of operating in extreme environments characterized by ultra-high radiation doses up to the MGy levels. To this aim, we report on an innovative Lab-On-Fiber (LOF) probe for the real-time dose monitoring. The proposed platform is based on a metallo-dielectric nanostructured grating made of gold and poly(methyl methacrylate) (PMMA) patterned on the termination of single mode fibers. The nanostructure has been judiciously designed to support a plasmonic resonance in the reflection spectrum occurring at near infrared wavelengths. Electron beam lithography was used for the fabrication of two LOF prototypes, which in turn, were exposed to X-rays with a total dose of 2.02 MGy and a dose rate of 88 kGy/h. Reflection spectra acquired during the irradiation revealed a clear dependence of the LOF resonance wavelength and depth on the absorbed dose, confirming the outcomes of our previous proton campaign. Morphological characterization of the irradiated samples showed that the main radiation induced effect is the reduction of the PMMA thickness (ranging between 26 % and 40 %), which in turn strongly affects the resonance behavior. Quantitative morphological measurements have been used to achieve a fair and objective correlation with our numerical modelling. Moreover, we investigated the effect of ultra-high doses of several radiation types, including X-rays, electrons and protons, on the thickness of PMMA nanolayers deposited on planar substrates. Experimental results revealed that the amount of absorbed dose (1.9–16.06 MGy) is the main parameter affecting the PMMA relative compaction (9.5–59.1 %), while the influence of the radiation type, dose rate and initial PMMA thickness can be considered negligible. Overall, these results pave the way to the development of radiation type independent PMMA assisted LOF dosimeters operating at MGy doses for the radiation monitoring in future HEP experiments.

Evaluation of a New Real-Time Dosimeter Sensor for Interventional Radiology Staff.

In 2011, the International Commission on Radiological Protection (ICRP) recommended a significant reduction in the lens-equivalent radiation dose limit, thus from an average of 150 to 20 mSv/year over 5 years. In recent years, the occupational dose has been rising with the increased sophistication of interventional radiology (IVR); management of IVR staff radiation doses has become more important, making real-time radiation monitoring of such staff desirable. Recently, the i3 real-time occupational exposure monitoring system (based on RaySafeTM) has replaced the conventional i2 system. Here, we compared the i2 and i3 systems in terms of sensitivity (batch uniformity), tube-voltage dependency, dose linearity, dose-rate dependency, and angle dependency. The sensitivity difference (batch uniformity) was approximately 5%, and the tube-voltage dependency was <±20% between 50 and 110 kV. Dose linearity was good (R2 = 1.00); a slight dose-rate dependency (~20%) was evident at very high dose rates (250 mGy/h). The i3 dosimeter showed better performance for the lower radiation detection limit compared with the i2 system. The horizontal and vertical angle dependencies of i3 were superior to those of i2. Thus, i3 sensitivity was higher over a wider angle range compared with i2, aiding the measurement of scattered radiation. Unlike the i2 sensor, the influence of backscattered radiation (i.e., radiation from an angle of 180°) was negligible. Therefore, the i3 system may be more appropriate in areas affected by backscatter. In the future, i3 will facilitate real-time dosimetry and dose management during IVR and other applications.

ORIGIN, an EU project targeting real-time 3D dose imaging and source localization in brachytherapy: Commissioning and first results of a 16-sensor prototype

The ORIGIN project targets the production and qualification of a real-time radiation dose imaging and source localization system for both Low Dose Rate (LDR) and High Dose Rate (HDR) brachytherapy treatments, namely radiotherapy based on the use of radioactive sources implanted in the patient’s body. This goal will be achieved through a 16-fiber sensor system, engineered to house in a clear-fiber tip a small volume of the scintillator to allow point-like measurements of the delivered dose. Each fiber is optically coupled to a sensor with single photon sensitivity (Silicon Photomultipliers — SiPMs) operating in counting mode. The readout is based on the CITIROC1A ASIC by WEEROC, embedded in the FERS-DT5202 scalable platform designed by CAEN S.p.A. Linearity and sensitivity together with the fiber response uniformity, system stability, and measurement reproducibility are key features for a instrument aiming to perform dose measurements. Characterization was carried out in the laboratory, using an X-ray cabinet; preliminary dose rate measurements were performed in clinical conditions.

Real-time Environmental Gamma Dose Monitoring around Dhaka University Campus and Estimation of Excess Lifetime Cancer Risk on Public Health

Real-time Environmental Gamma Dose Monitoring around Dhaka University Campus and Estimation of Excess Lifetime Cancer Risk on Public Health

β-Lactam Dosing in Critical Patients: A Narrative Review of Optimal Efficacy and the Prevention of Resistance and Toxicity.

Antimicrobial prescription in critically ill patients represents a complex challenge due to the difficult balance between infection treatment and toxicity prevention. Underexposure to antibiotics and therapeutic failure or, conversely, drug overexposure and toxicity may both contribute to a worse prognosis. Moreover, changes in organ perfusion and dysfunction often lead to unpredictable pharmacokinetics. In critically ill patients, interindividual and intraindividual real-time β-lactam antibiotic dose adjustments according to the patient's condition are critical. The continuous infusion of β-lactams and the therapeutic monitoring of their concentration have both been proposed to improve their efficacy, but strong data to support their use are still lacking. The knowledge of the pharmacokinetic/pharmacodynamic targets is poor and is mostly based on observational data. In patients with renal or hepatic failure, selecting the right dose is even more tricky due to changes in drug clearance, distribution, and the use of extracorporeal circuits. Intermittent usage may further increase the dosing conundrum. Recent data have emerged linking overexposure to β-lactams to central nervous system toxicity, mitochondrial recovery delay, and microbiome changes. In addition, it is well recognized that β-lactam exposure facilitates resistance selection and that correct dosing can help to overcome it. In this review, we discuss recent data regarding real-time β-lactam antibiotic dose adjustment, options in special populations, and the impacts on mitochondria and the microbiome.

Phase 1 Trial of AUC-Targeted Melphalan in Myeloma Patients Undergoing Autologous Transplant (The MyMel Study)

Standard 200 mg/m2 high dose melphalan (HDM) yields a 500% variation in plasma melphalan exposure, i.e. area under the curve (AUC), leading to unpredictable DNA damage and widely variable clinical responses. Strategies to predict melphalan AUC have been unsuccessful given population PK models (Nath, Br J Clin Pharmacol 2010 & Cho Clin Pharmacol Ther 2017) are ineffective on an individual patient level and only explain ~20% of the variability observed, and test dose predictions have failed to accurately represent melphalan AUC for doses >100 mg/m2. PK directed dose adjustment of HDM would require a 24-hour turnaround for sample collection, shipping, processing and data analysis. Previously we described methods for measuring melphalan PK after the Day -2 HDM dose, allowing for real-time dose adjustments (Sweiss, Br J Clin Pharmacol 2020). Here, we set out to perform the first phase 1 study of AUC-targeted HDM in ASCT (NCT04483206). This multicenter phase 1 trial (Fig 1) is designed to test 7 AUC ranges (13-21 mg*h/L) to determine the maximum tolerated systemic exposure (MTSE). The feasibility portion focuses on the first 2 AUCs (phase A, n=20) in patients with ≥2L therapy, where we measure accuracy of achieving target AUCs of 13.5 and 14.5 mg∗h/L, respectively. Patients receive HDM 100 mg/m2 on day -3 with PK measurement and subsequent dose-adjustment on day -1 to achieve the total target AUC. 7 blood samples are drawn, processed and shipped frozen for LC-MS/MS analysis. PK parameter estimations are determined from noncompartmental analysis (NCA) and per FDA guidance used to adjust doses. Nonlinear mixed effects modeling (NONMEM) is performed in parallel to compare PK estimations. Using observed first-dose HDM clearance (Clobs) from NCA and assuming that Cl is consistent between doses, linear dose-proportional adjustments are performed to achieve the target AUC0-inf. After a planned FDA review of these cohorts, we will begin to dose escalate to determine the MTSE with up to 5 AUC levels (15.5-19.5 mg∗h/L). Bone marrow (BM) MRD status will be assessed at Day 90 as part of the Phase B primary objective. Correlatives include measuring DNA damage in circulating PBMCs post-HDM to correlate with AUC, piloting a DNA fiber combing assay on primary MM cells from patient BM samples to quantify DNA replicative stress, and assessing PROs using NCI PRO-CTCAE v.1.0. We have enrolled 8 patients into the first AUC cohort with 110 blood samples collected. Median age was 69 (56-75) years, with 7 (87.5%) males, and 4 (50%) Blacks. The median day -3 HDM Clobs and AUC0-inf were 22.05 (16.3-38.2) L/hr and 9.53 (6.97-11.82) mg∗h/L, respectively. All shipped blood samples were received in suitable frozen condition, and in 7 (87.5%) of 8 patients, LC-MS/MS run with NCA estimation and dose reporting was done within 12 hours of receiving samples. One patient whose samples were delayed from shipping had the dose reported on day-1 resulting in 5 of 7 day-1 samples collected. Covariates of HDM PK (i.e., FFM, hematocrit) were entered into our developed PK model to further enrich our data prediction. All 8 day -1 doses were adjusted, with a resulting median total BSA-based HDM dose of 139.6 (110.93-192.6) mg/m2. After adjustment, median day -1 Clobs and AUC0-inf were 24.48 (19.3-35.8) L/hr and 3.84 (1.7-7) mg∗h/L, respectively. For accuracy of dose adjustment, 107 (97.3%) samples were evaluable for PK parameter estimation, with 3 concentrations excluded (n=3 patients). One subject whose last 2 day -1 samples were not collected was removed from analysis as it resulted in 19% AUC extrapolation and 33% variance between day -3 and -1 Cl values. Of 7 patients, 6 (85.7%) achieved the target AUC, with less than 10% variance in Cl between doses. (Fig 2). In the one patient, it was assessed that the day -1 Cl deviated by 24% as a result of prolonged time from drug admixture to completion of infusion leading to drug degradation. Estimated melphalan Cl generated from NCA and NONMEM correlated well (r=0.99). This is the first trial in MM implementing a novel personalized dosing approach using drug exposure as the target to define each cohort. We demonstrate feasibility of real-time PK sampling, shipping, processing, NCA PK parameter estimation, and dose adjustment of HDM. So far we report a high rate of accuracy in achieving the target AUC which we hypothesize will deliver reliable DNA damage to MM cells. Enrollment is active and mature data will be presented at the conference. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hydroxyurea Pharmacokinetics and Fetal Hemoglobin Response in Ugandan Children with Sickle Cell Anemia

Introduction Over 300,000 infants are born with sickle cell anemia (SCA) in Africa every year, and the under-5 mortality of this population is estimated to be 50-90% without treatment. Hydroxyurea is a safe, oral medication that decreases morbidity and mortality in SCA by increasing protective fetal hemoglobin (HbF) production and reducing inflammation. Hydroxyurea dosing to maximum tolerated dose (MTD) offers the optimal treatment with greatest laboratory responses and clinical benefits. Patients have variable hydroxyurea absorption and elimination rates, so the traditional approach to determining MTD is through incremental dose escalation to achieve mild myelosuppression and reduction in absolute neutrophil count (ANC). In the United States, pharmacokinetic (PK)-guided dosing of hydroxyurea for children with SCA has been shown to decrease time to MTD and to augment treatment responses, with most patients achieving over 30% HbF. Maximizing clinical benefits and minimizing logistical burdens of dosing hydroxyurea would be advantageous for areas with high SCA prevalence, but PK parameters of African children with SCA who might have higher rates of malnutrition, infections, and organ damage that affect drug absorption, distribution, and clearance are yet to be determined. Here we describe hydroxyurea PK exposure-response in Ugandan children with SCA from the Optimizing Hydroxyurea Therapy in Children with Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM MTD Study (NOHARM MTD, NCT03128515). Methods NOHARM MTD was a randomized controlled trial that compared dosing strategies between hydroxyurea at fixed, weight-based dosing (~20 mg/kg/day) and dose escalation to MTD in children with SCA living in Uganda. NOHARM MTD participants underwent PK testing after 18 months of treatment. Children were administered their prescribed hydroxyurea dose in the morning at clinic, and blood was obtained by fingerstick using Mitra® microsampler devices after 20, 60, and 180 minutes. The microsampler devices were frozen at -80C in Uganda and then transported to Cincinnati Children's Hospital for analysis of hydroxyurea concentration via liquid chromatography with tandem mass spectrometry. Using our previously published population PK model, individual hydroxyurea exposures expressed as area-under-the-curve (AUC) were generated by Bayesian estimation using the PK modeling software NONMEM (Version 7.5, ICON Development Solutions, Ellicott City, USA). A hydroxyurea exposure-response analysis was completed with HbF% as the primary pharmacodynamic outcome. Results A total of 90 NOHARM MTD participants completed PK testing; samples from 12 were excluded from full analysis due to an elevated baseline concentration suggesting the participant already received the daily hydroxyurea dose before PK testing (9), supraphysiologic concentration (1), or mislabeling (2). PK profiles were analyzed for the remaining 78 participants (mean age 6.5 years, SD 0.9); of these, 41 were on fixed dose hydroxyurea and 37 were at MTD with mean doses of 18.7 mg/kg/day (SD 1.6) and 28.3 mg/kg/day (SD 4.3), respectively (Table). Those at MTD had a higher AUC with a significantly higher %HbF (mean 19% HbF on fixed dose vs 29% at MTD, p=0.0002) and lower ANC (mean 4.7 x109/L at fixed dose vs 3.2 at MTD, p=0.0045). Eighteen participants (23%) had malnutrition with a body mass index Z-score less than -1.0, and 12 (15%) participants had renal hyperfiltration with an estimated glomerular filtration rate over 150 mL/min/1.73m2; neither condition was associated with differences in AUC. Conclusion This study demonstrates the feasibility of collecting hydroxyurea PK data with timed, sparse sampling in Uganda, and the exposure-response analysis confirms that higher hydroxyurea exposure in Ugandan children with SCA is associated with greater induction of protective HbF and reduction in ANC. Malnutrition and glomerular hyperfiltration did not affect hydroxyurea exposure in this cohort. Further studies of PK-guided dosing to optimize response and time to response in this population are needed. Future directions include building capacity for local analysis of hydroxyurea concentrations using HPLC technology, real-time dose calculation via a PK model-informed algorithm, and prospective evaluation of PK-guided dosing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Demonstrative measurement of proton-nuclear reaction by deconvolving the prompt gamma-ray spectra

In proton therapy, there has been an increasing demand for measuring the employed dose distribution to improve treatment accuracy and quality. One method of estimating radiation dose in real time is to visualize the prompt gamma rays emitted during nuclear reactions between protons and nuclei in the patient’s body. However, this is difficult without accurate measurements of nuclear cross sections, that cover a 10–100 MeV energy range. Herein, we propose a novel method for determining cross section of low-energy protons with 12C and 16O by measuring the prompt gamma rays emitted from stacked slab phantoms placed along the proton path. These emitted gamma rays provide direct information on the nuclear reactions occurring at different proton energies. By applying an iterative inference using the response matrix, the contamination of various prompt gamma rays can be resolved; thus, the cross sections of various reactions were obtained at arbitrary proton energies. As a first step to this study, we applied this method to measure the nuclear reaction of protons with 12C and 16O nuclei, which are the major elements constituting the human body. The cross section of the 12C(p,p)12C∗ reaction, which produces a prominent gamma-ray peak at 4.4 MeV, reproduced the one in literature well, supporting the validity of the proposed method. Furthermore, we show that even weak prompt gamma rays can be resolved for a wide range of proton energies below 70 MeV, for which no cross sectional data have been reported so far.

Patient-specific radiological protection precautions following Cs collagen embedded Cs-131 implantation in the brain.

ObjectiveCesium‐131 brachytherapy is an adjunct for brain tumor treatment, offering potential clinical and radiation protection advantages over other isotopes including iodine‐125. We present evidence‐based radiation safety recommendations from an initial experience with Cs‐131 brachytherapy in the resection cavities of recurrent, previously irradiated brain metastases.MethodsTwenty‐two recurrent brain metastases in 18 patients were resected and treated with permanent Cs‐131 brachytherapy implantation using commercially procured seed‐impregnated collagen tiles (GammaTile, GT Medical Technologies). Exposure to intraoperative staff was monitored with NVLAP‐accredited ring dosimeters. For patient release considerations, NCRP guidelines were used to develop an algorithm for modeling lifetime exposure to family and ancillary staff caring for patients based on measured dose rates.ResultsA median of 16 Cs‐131 seeds were implanted (range 6–46) with median cumulative strength of 58.72U (20.64‐150.42). Resulting dose rates were 1.19 mSv/h (0.28–3.3) on contact, 0.08 mSv/h (0.01–0.35) at 30 cm, and 0.01 mSv/h (0.001–0.03) at 100 cm from the patient. Modeled total caregiver exposure was 0.91 mSv (0.16–3.26), and occupational exposure was 0.06 mSv (0.02–0.23) accounting for patient self‐shielding via skull and soft tissue attenuation. Real‐time dose rate measurements were grouped into brackets to provide close contact precautions for caregivers ranging from 1–3 weeks for adults and longer for pregnant women and children, including cases with multiple implantations.ConclusionsRadiological protection precautions were developed based on patient‐specific emissions and accounted for multiple implantations of Cs‐131, to maintain exposure to staff and the public in accordance with relevant regulatory dose constraints.

Optimising multi-target multileaf collimator tracking using real-time dose for locally advanced prostate cancer patients

Objective. The accuracy of radiotherapy for patients with locally advanced cancer is compromised by independent motion of multiple targets. To date, MLC tracking approaches have used 2D geometric optimisation where the MLC aperture shape is simply translated to correspond to the target’s motion, which results in sub-optimal delivered dose. To address this limitation, a dose-optimised multi-target MLC tracking method was developed and evaluated through simulated locally advanced prostate cancer treatments. Approach. A dose-optimised multi-target tracking algorithm that adapts the MLC aperture to minimise 3D dosimetric error was developed for moving prostate and static lymph node targets. A fast dose calculation algorithm accumulated the planned dose to the prostate and lymph node volumes during treatment in real time, and the MLC apertures were recalculated to minimise the difference between the delivered and planned dose with the included motion. Dose-optimised tracking was evaluated by simulating five locally advanced prostate plans and three prostate motion traces with a relative interfraction displacement. The same simulations were performed using geometric-optimised tracking and no tracking. The dose-optimised, geometric-optimised, and no tracking results were compared with the planned doses using a 2%/2 mm γ criterion. Main results. The mean dosimetric error was lowest for dose-optimised MLC tracking, with γ-failure rates of 12% ± 8.5% for the prostate and 2.2% ± 3.2% for the nodes. The γ-failure rates for geometric-optimised MLC tracking were 23% ± 12% for the prostate and 3.6% ± 2.5% for the nodes. When no tracking was used, the γ-failure rates were 37% ± 28% for the prostate and 24% ± 3.2% for the nodes. Significance. This study developed a dose-optimised multi-target MLC tracking method that minimises the difference between the planned and delivered doses in the presence of intrafraction motion. When applied to locally advanced prostate cancer, dose-optimised tracking showed smaller errors than geometric-optimised tracking and no tracking for both the prostate and nodes.

Clinical implementation of the first Cherenkov imaging system in a community-based hospital.

PurposeTo document experiences with one year of clinical implementation of the first Cherenkov imaging system and share the methods that we developed to utilize Cherenkov imaging to improve treatment delivery accuracy in real-time.MethodsA Cherenkov imaging system was installed commissioned and calibrated for clinical use. The optimal room lighting conditions and imaging setup protocols were developed to optimize both image quality and patient experience. The Cherenkov images were analyzed for treatment setup and beam delivery verification.ResultsWe have successfully implemented a clinical Cherenkov imaging system in a community-based hospital. Several radiation therapy patient setup anomalies were found in 1) exit dose to the contralateral breast, 2) dose to the chin due to head rotation for a supraclavicular field, 3) intrafractional patient motion during beam delivery, and 4) large variability (0.5 cm to 5 cm) in arm position between fractions. The system was used to deliver deep inspiration breath hold (DIBH) treatment delivery of an electron treatment beam. Clinical process and procedures were improved to mitigate the identified issues to ensure treatment delivery safety and to improve treatment accuracy.ConclusionThe Cherenkov imaging system has proven to be a valuable clinical tool for the improvement of treatment delivery safety and accuracy at our hospital. With only minimal training the therapists were able to adjust or correct treatment positions during treatment delivery as needed. With future Cherenkov software developments Cherenkov imaging systems could provide daily surface guided radiotherapy (SGRT) and real time treatment delivery quality control for all 3D and clinical setup patients without adding additional radiation image dose as in standard kV, MV and CBCT image verifications. Cherenkov imaging can greatly improve clinical efficiency and accuracy, making real time dose delivery consistency verification and SGRT a reality.

Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock—a two-centre randomised clinical trial

BackgroundAdequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation.MethodsIn this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury.ResultsAfter inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4–1173.78, p < 0.001). Furthermore, target attainment was faster (26 h, CI 18–42 h, p < 0.001) and better (65% increase, CI 49–84%, p < 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure.ConclusionsIn critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin.Trial registration: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.

Assessment of a Decision Support System for Adults with Type 1 Diabetes on Multiple Daily Insulin Injections.

Introduction: DailyDose is a decision support system designed to provide real-time dosing advice and weekly insulin dose adjustments for adults living with type 1 diabetes using multiple daily insulin injections. Materials and Methods: Twenty-five adults were enrolled in this single-arm study. All participants used Dexcom G6 for continuous glucose monitoring, InPen for short-acting insulin doses, and Clipsulin to track long-acting insulin doses. Participants used DailyDose on an iPhone for 8 weeks. The primary endpoint was % time in range (TIR) comparing the 2-week baseline to the final 2-week period of DailyDose use. Results: There were no significant differences between TIR or other glycemic metrics between the baseline period compared to final 2-week period of DailyDose use. TIR significantly improved by 6.3% when more than half of recommendations were accepted and followed compared with 50% or fewer recommendations (95% CI 2.5%-10.1%, P = 0.001). Conclusions: Use of DailyDose did not improve glycemic outcomes compared to the baseline period. In a post hoc analysis, accepting and following recommendations from DailyDose was associated with improved TIR. Clinical Trial Registration Number: NCT04428645.

Experimental validation of a spectroscopic gamma-ray detector based on a LaBr3 scintillator towards real-time dose monitoring in BNCT

We report the experimental validation of a detection module based on a LaBr3(Ce＋Sr) scintillator crystal, read by a matrix of Silicon Photomultipliers (SiPMs), for the development of a SPECT system for dose monitoring in Boron Neutron Capture Therapy (BNCT). The goal of the system is to detect the gamma rays at 478keV emitted by the excited 7Li produced in the 10B(n, α)7Li reaction, to have a real-time localization and quantification of the local dose released to a patient during BNCT treatment. The good energy resolution of the detector (<3% at 662keV) allows to resolve the photopeak at 478keV from the adjacent annihilation photons photopeak at 511keV, originated from pair production of high energy gamma rays, such as the hydrogen neutron capture gamma rays at 2.2MeV. The results shown in this article demonstrate the suitability of our detector in view of future application in BNCT real-time dose monitoring. Good linearity (RMSE < 2.5cps) between the number of events detected at 478keV and the boron concentration of the 10B-loaded samples has been achieved, down to a boron concentration of 62ppm with a neutron flux of approximately 1 × 105 n/cm2/s.

Low noise optimization of an electron beam current transformer for conventional radiotherapy up to ultra high dose rate irradiations

Ultra high dose rate electron beams also known as FLASH radiotherapy is becoming of importance in several preclinial cancer treatment studies. However, due to the dose rate used during the irradiation sessions, no real time dose monitoring device exists to date. In this work, we present the development of a beam current transformer (BCT), from the choice of the ferromagnetic component and the realisation of the shielding to the design of a front-end electronics based on a trans-impedance circuit in order to perform a low noise optimization of the detector. The BCT prototype is able to monitor a beam current range from 1.2 μA to 200 mA with a rise time constant better than 20 ns and a droop rate of the signal below 0.05% · μs-1. Preliminary in-situ measurements are also presented. The goal is to combine the BCT system which measure in real time the beam current, to an ionisation chamber monitoring the beam shape and position in order to provide a reliable dose monitoring system.

Occupational doses in interventional angiography after radiological protection training and use of a real-time direct display dosimeter

Vascular x-ray guided interventions are complex and may result in high occupational doses to ionising radiation if staff do not take appropriate actions to minimise their exposure. In this prospective intervention study, ten staff members wore an extra personal dosimeter on the upper body above their regular protective clothing during four consecutive periods. Between each period either additional practical radiological protection training was given or a real-time direct display dosimeter were provided to the staff. Each staff’s personal dose equivalent, Hp(10) normalised to the total air kerma-area product for the procedures where each staff were involved, KAPt, was used as the dependent variable. A focus-group interview with the staff were performed about the usefulness of the training and real-time dose rate display system. Our aim was to investigate if the interventions (practical training or real-time dose rate display) did affect the staff doses in the short and long term (five months later). Significant (p < 0.05) reductions of staff doses Hp(10)/KAPt were found after practical radiological protection training, but not after using real-time dose rate displays. Significant reductions were maintained after five months without additional interventions. The results from the focus-group interview indicated that making radiation ‘visible’, during practical training and usage of real-time direct display dosimeter, made it easier to understand how to act to lower occupational doses.

The Acute Stroke Therapy by Inhibition of Neutrophils study - Key features and impact.

The Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN) study, initiated in November of the year 2000, is now widely recognized as having been a landmark study in the history of clinical trials. We look at why this is the case by considering its key features and impact. These key features are: the use of Bayesian design and analysis; the use of the normal dynamic linear model; the response adaptive nature of the study; the use of real-time dosing decisions; and the use of an integrated model to predict 90-day response on the Scandinavian Stroke Scale. Our overall conclusion is that the ASTIN study's main impact came from showing the clinical trial community the feasibility of the novel design and analysis used when most of these key features were rarely used in industry trials, let alone used together in one trial in a disease area with a tremendous unmet medical need.