Dose Difference Research Articles

A Retrospective, Single-Center Assessment of Changes in Pain, Agitation, and Delirium Management Before and During the COVID-19 Pandemic.

Recent studies have found an association between COVID-19 infection and deeper sedation in mechanically ventilated patients, raising concerns about the impact of the COVID-19 pandemic on pain, agitation, and delirium (PAD) management practices overall. This study aimed to assess differences in PAD management in patients without COVID-19 infection in pre- and peri-COVID-19 pandemic timeframes. This was a single-center, retrospective, pre-/post-cohort analysis of mechanically ventilated adult patients without COVID-19 infection admitted to an ICU in Boston, MA. The "pre" and "post" groups enrolled patients in 2019 and 2021, respectively. All PAD data during the first 7 days of mechanical ventilation (MV) were collected. The primary outcome was ventilator-free days (VFDs) during the first 28 days. A multivariable linear regression analysis was performed to assess VFD while controlling for confounders. Secondary outcomes included depth of sedation, total dose of sedatives, and in-hospital mortality. There were 339 patients included in the final analysis. There was no difference in VFD between the pre- and post-groups (22.2 vs. 22.6 d; p = 0.92); this was confirmed by multivariable linear regression (p = 0.91). Patients in the post-group experienced significantly deeper levels of sedation compared with the pre-group (58% vs. 53%; p < 0.01) within the first 48 hours of MV. The median number of Richmond Agitation-Sedation Scale assessments per 24-hour period was greater in the pre-group (13 vs. 12 assessments; p = 0.02) within the first 48 hours of MV. There were no significant differences in total cumulative dose of sedatives or in-hospital mortality between the two groups. This study suggests that PAD practices, including depth of sedation and frequency of assessment, differed between pre- and post-COVID-19 groups in patients without COVID-19. Outcomes including VFD, mortality, and hospital length of stay were not affected. Further studies are needed to understand the broader impact of the COVID-19 pandemic on PAD management practices.

Conduction system pacing using electro-anatomical mapping-guided system vs. fluoroscopy: a systematic review, meta-analysis and economic evaluation

Electro-anatomical mapping (EAM) system has been shown as an alternative procedure to fluoroscopy for conduction system pacing (CSP) in patients with severe bradyarrhythmia, however its beneficial and harmful effects has not been assessed in a systematic review (SR). We sought to assess their safety, effectiveness and cost-effectiveness. A SR of the available scientific literature was conducted on the safety, effectiveness, and cost-effectiveness of CSP using EAM system vs. fluoroscopy in patients with severe bradyarrhythmia. A partial economic evaluation was carried out to compare the costs of both strategies from the perspective of the Spanish National Health System. A budget impact analysis was also conducted with a five-year horizon. Seven comparative observational studies (N = 231), analyzing the use of EAM vs. fluoroscopy were selected. Statistically significant differences were observed in total fluoroscopy time: −9.87 min (95%CI:−14.20, −5.53, p &amp;lt; 0.01; I2 = 95%; k = 7; n = 231); His-lead fluoroscopic time: −8.08 min (95%CI:−10.36, −5.81, p &amp;lt; 0.01; I2 = 0%; k = 2; n = 50); and His-lead radiation dose: −17.21 mGy (95%CI:−24.08, −10.34, p &amp;lt; 0.01; k = 1; n = 20). No differences in total fluoroscopy dose, successful procedure or safety were found. The use of EAM represents an increase of EUR 1,397.81 per patient and a net budget impact of EUR 1.63 million. EAM is a valuable alternative for patients who should not be exposed to ionizing radiation with similar effectiveness and safety than fluoroscopy. However, the inclusion of EAM systems, for the indication under study, in routine clinical practice would mean an increase in costs for the Spanish National Health System.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=421072, identifier (CRD42023421072).

Quantitative Assessment of Delivered Dose in Carbon Ion Spatially Fractionated Radiotherapy (C-SFRT) and Biological Response to C-SFRT

Abstract Objective&amp;#xD;Applying carbon ion beams, which have high linear energy transfer and low scatter within the human body, to Spatially Fractionated Radiation Therapy (SFRT) could benefit the treatment of deep-seated or radioresistant tumors. This study aims to simulate the dose distributions of spatially fractionated beams (SFB) to accurately determine the delivered dose and model the cell survival rate following SFB irradiation.&amp;#xD;Approach&amp;#xD;Dose distributions of carbon ion beams are calculated using the Triple Gaussian Model. The sensitive volume of the detector used in measurements was also considered. If the measurements and simulations show good agreement, the dose distribution and absolute dose delivered by SFB can be accurately estimated. Three types of dose distributions were delivered to human salivary gland cells (HSGc-C5): uniform dose distribution (UDD), and one-dimensional (1D) grid-like dose distributions (GDD) with 6 mm and 8 mm spacing. These provided high (Peak-to-Valley Dose Ratio, PVDR=4.0) and low (PVDR=1.64) dose differences between peak and valley doses, respectively. Linear-Quadratic (LQ) model parameters for HSGc-C5 were derived from the UDD and cell survival fractions (SF) were simulated for 1D GDD using these values.&amp;#xD;Main results&amp;#xD;Good agreement was observed between measurements and simulations when accounting for detector volume. However, the TPS results overestimated dose in steep gradient region, likely due to the 2.0 mm calculation grid size. LQ parameters for HSGc-C5 were α = 0.34 and β = 0.057. The 1D GDD with 6 mm spacing showed good agreement between simulations and experiments, but the 8.0 mm spacing resulted in lower experimental cell survival.&amp;#xD;Significance&amp;#xD;We successfully simulated grid-like dose distributions and conducted SF simulations. The results suggest potential cell-killing effects due to high-dose differences in SFB.&amp;#xD;

Injectable Estradiol Use in Transgender and Gender-Diverse Individuals in the U.S.: A Multicenter Retrospective Study.

Guidelines for use of injectable estradiol esters (valerate [EV] and cypionate [EC]) among transgender and gender diverse (TGD) individuals designated male at birth vary considerably, with many providers noting supraphysiologic serum estradiol concentrations based on current dosing recommendations. 1. Determine dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV. 2. Describe relationship between estradiol concentration relative to timing/dose of last estradiol injection and other covariates. 3. Determine dosing differences between IM/SC EV/EC. Cross-sectional retrospective study across six United States medical centers including TGD adults on same-dose injectable estradiol for >75 days, with confirmed timing of estradiol concentration relative to last injection, from 1/1/2019---12/31/2023. Descriptive statistics were used to describe patient characteristics and weighted linear mixed models to evaluate relationship between various covariates and estradiol concentration. Data from 562 patients were included. Among those injecting every seven days who reached the guideline-recommended estradiol concentration (n=131, 27.5%), the median estradiol dose was 4.0 mg (interquartile range 3.0---5.0 mg). Among all patients, the majority reached supraphysiologic estradiol concentrations (>200 pg/mL [>734 pmol/L]) while dose and timing in the injection cycle were significant covariates for the estradiol concentration. There were no significant dosing differences between IM/SC EV/EC. Injectable estradiol esters effectively reach guideline-recommended estradiol concentrations but at lower doses than previously recommended. Estradiol concentrations are best interpreted relative to timing of last injection. Route of administration and type of ester do not significantly impact estradiol concentrations.

Institutional experience with implanted cardiac device risk level assessment: Comparing calculation and measurement.

The use of in-vivo dosimetry is a long-standing but also labor-intensive component of risk-level assessment for patients with implanted devices. A calculation-only approach, using treatment planning system (TPS)-calculated doses along with imaging doses estimates when relevant, has the potential to streamline the physics workflow without negatively impacting patient safety. To evaluate the feasibility of using a calculation-only approach for risk level assessment for patients with implanted electronic medical devices. A total of 86 patients were included in this retrospective study. For each patient, in-vivo dosimetry measurements using optically stimulated luminescent dosimeter (OSLD) were compared to calculated doses (based on TPS calculated doses and an estimate of imaging doses when relevant). The comparison of OSLD doses and estimated predicted doses was structured in the following manner: (1) direct comparison of both absolute dose difference and percent difference for measured and calculated doses, (2) risk level assessment comparison using measured and estimated doses, and (3) sensitivity and positive predictive value assessment of each method for TG-203 risk level assessment. For all cases, the calculation-based approach yielded a risk level that was equivalent to or more conservative than the risk level from OSLD measurement. For 79 of 86 patients (91.9%), the calculated and measured doses provided the same risk level. For 7 of 86 patients (8.1%), the calculated dose yielded the more conservative risk level. The calculation-based dose estimate provided a sensitivity of 1.00 with a positive predictive value of 0.92. The use of a calculation-only approach has the potential to reduce workload while maintaining the efficacy of risk-level assessment for patients with implanted devices.

Body mass index affects imatinib exposure: Real‐world evidence from TDM with adaptive dosing

AbstractBackgroundImatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure.ObjectivesWe searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing.MethodsWe present data from 60 adult CML patients upon imatinib with therapeutic drug monitoring (TDM) and adaptive dosing.ResultsMean trough levels after treatment initiation were 994.2 ± 560.6 ng/ml with 56% inter‐patient variability). Only 29% of patients were in the therapeutic range. Body weight, height, body surface area, body mass index (BMI), and age were associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with imatinib trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI &lt; 18.5 kg/m2, with exposure +61.5% higher than in patients with 18.5 &lt; BMI ≤ 24.9 and +76.3% higher than in patients with BMI ≥ 25. After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg. No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing.ConclusionOur data suggest that low BMI has a significant impact on imatinib exposure but that pharmacokinetically‐guided dosing limits its clinical impact in patients.

Comparative Study of Cardiac Radiation Dose With Different Types of Surgery in Breast Cancer Patients

Background: It has been demonstrated that radiation therapy lowers both the death rate from breast cancer and its recurrence. Precise calculation of the radiation dose is crucial for treating the target site as well as protecting vital organs like the heart since large doses of radiation therapy significantly increase patient morbidity and death. Objective: To compare the mean heart dose of radiation in breast cancer patients between breast-conserving surgery versus mastectomy, between different radiotherapy doses and fractionation schedules, and between right and left breast cancer irradiation. Patients and Methods: This is a cross-sectional descriptive retrospective comparative study that was conducted in Baghdad Radiotherapy Center from January 2018 to June 2018, carried on 174 breast cancer patients of different age groups selected randomly and their mean heart dose data collected from their files and database in Baghdad Radiotherapy Center. Results: The overall average of the mean dose was 372 cGy (range from 76.4 to 716.2). The greatest difference in the mean heart dose was between (BCS) patients who received 5000 cGy with regional nodal irradiation and (BCS) patients who received 4005 cGy also with regional nodal irradiation (difference in the mean is 639.8, the P – value &lt;0.001). Regarding the side of breast cancer, the greatest difference in mean heart dose was seen between left and right breast cancer patients who did the same type of surgery (MRM) and received the same dose of radiotherapy (4256 cGy) (difference in the mean is 565cGy and the P – value &lt;0.001). No statistically significant difference in the mean dose between breast-conserving surgery and mastectomy was recorded. Conclusion: The mean heart dose of radiotherapy is significantly increased in left-sided breast cancer irradiation as compared to the right side. A dose of 5000 cGy has the greatest effect on the dose received by the heart, especially in left breast cancer. The type of surgery whether breast-conserving surgery or mastectomy did not affect the mean dose received by the heart. Keywords: Breast cancer, cardiac radiation dose, breast cancer surgery, breast cancer treatment.

Impact of Dietitian-Delivered Motivational Interviewing Within a Food is Medicine Intervention Targeting Adults Living With and Beyond Cancer.

Food is medicine (FIM) interventions are a strategy for preventing and managing chronic disease via diet. These interventions often combine the provision of food with access to behavior change support (e.g., from registered dietitians (RDs)), though the ideal approach for the latter is not fully elucidated. The objective of this study is to evaluate integrated motivational interviewing (MI) from an RD (RDMI) on outcomes among adults living with and beyond cancer (LWBC) with overweight and obesity enrolled in a FIM intervention (Clinicaltrials.gov: NCT03489213 (02/09/2018)). Specifically, RDMI with autonomy in the mode of delivery (i.e., phone, email, text, video) and dose (frequency) was offered within a 6-month intensive FIM intervention followed by a 6-month step-down maintenance phase. Dose and engagement with RDMI were measured. There were 52 and 33 participants who requested RDMI during the intensive and maintenance phases, respectively. Completion of ≥ 1 RDMI telephonic encounter significantly predicted weight loss post-intervention (R2 = 0.07, p = 0.03); there were no differences in dose, engagement, or weight loss based on the mode of delivery. The dose during the intensive intervention was moderately and significantly correlated with weight loss post-intervention and maintenance (r = 0.43, p < 0.01; r = 0.33, p = 0.02, respectively); there was a weak correlation for engagement at the same follow-up points (r = 0.28 and r = 0.15). In conclusion, higher doses of RDMI improved weight loss for adults LWBC with overweight or obesity. Careful consideration of the implementation of MI from providers, including RDs, in the context of cancer-focused FIM interventions should be further examined.

A Study Of the effect of Sex on drug dosing, concentrations, and pharmacogenomics in the Montreal Heart Institute Hospital Cohort (SOS-PGx): methodology and research progress.

Women are underrepresented in drug development trials and there is no sex-tailored drug regimen for most medications. It has been repeatedly shown that women have more adverse drug reactions than men for several medications. These differences could be explained by higher dose-adjusted drug concentrations in women. Thus, we aim to identify sex-related differences and to characterize the clinical and genetic predictors of these differences in drug concentrations, dosing, and adherence for 47 commonly used drugs in a large cohort. The objective of this article is to present an overview of the methods and characteristics of the study population. We performed a cross-sectional study that included 10,082 men and women of European ancestry aged ≥ 18years from the Montreal Heart Institute Hospital Cohort taking at least one of the 47 medications regularly. Of the 10,082 participants included, 36% were women. Women had lower weight, height, waist girth, and body mass index than men, but they had higher hip girth (all p < 0.001). Men had a higher level of education and annual income and were more likely to be employed full-time compared to women. Furthermore, men had a higher prevalence of hypertension, type2 diabetes, dyslipidemia, andmyocardial infarction (all p < 0.001) and were more likely receiving lipid-lowering agents, beta-blockers, antidiabetic drugs, and angiotensin-converting enzyme inhibitors. Conversely, proton pump inhibitors were more prevalent in women. Interestingly, nearly half of the women had a history of drug allergy or intolerance, compared with less than one-third of the men (p < 0.001). This study has a high potential in understanding eventual sex differences in drug dosing requirements and will most likely provide useful information to personalize drug regimens in women.

Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52).

Background/Objectives: Post-transplant diabetes mellitus (PTDM) and prediabetes (PreDM) are common after renal transplantation and increase the risk of cardiovascular events and mortality. Compared to immediate-release tacrolimus (IR-Tac), the LCPT formulation, with delayed absorption, offers higher bioavailability and a smoother time-concentration curve, potentially reducing beta-cell stress. Methods: This randomized pilot trial compared de novo immunosuppression with IR-Tac (twice daily) and LCPT (once daily). At-risk recipients (age ≥ 60 years or 18-59 years with metabolic syndrome) were enrolled and followed for 3 months. The primary and secondary outcomes were the incidence of PTDM and PreDM, respectively. Results: 27 patients were randomized to IR-Tac and 25 to LCPT. The incidence of PTDM was comparable between groups [IR Tac: 18.5% (95% CI: 8.2-36.7%) vs. LCPT: 24% (95% CI: 11.5-43.4%); p = 0.7]. Although not statistically significant, the LCPT group exhibited a trend toward a reduction in PreDM incidence [IR-Tac: 40.7% (95% CI: 25-59%) vs. LCPT: 20% (95% CI: 9-39%); p = 0.1]. A sensitivity analysis showed similar results, with no significant differences in cumulative corticosteroid doses or baseline body mass index (BMI) between groups. The LCPT group showed a trend toward higher tacrolimus exposure at the end of the study [trough levels: IR-Tac group 8.3 (6.9-9.2) vs. LCPT group 9.4 (7.4-11.4) ng/mL; p = 0.05)], as well as fewer acute rejection episodes (none vs. three). Delayed graft function was more common in the IR-Tac group (37% vs. 8%; p = 0.01), and the eGFR was lower. Adverse events were comparable between groups. Conclusions: The potential biological activity of LCPT in preventing glucose metabolic alterations in at-risk patients warrants further investigation.

Feasibility of volumetric-modulated arc therapy gating for cardiac radioablation using real-time ECG signal acquisition and a dynamic phantom.

Stereotactic arrythmia radioablation (STAR) is a noninvasive technique to treat ventricular tachycardia (VT). Management of cardiorespiratory motion plays an essential role in VT-STAR treatments to improve treatment outcomes by reducing positional uncertainties and increasing dose conformality. Use of an electrocardiogram (ECG) signal, acquired in real-time, as a surrogate to gate the beam has the potential to fulfil that intent. To investigate the gated delivery of volumetric-modulated arc therapy (VMAT) for STAR on a TrueBeam linear accelerator (linac) using a real-time acquired ECG signal and a dynamic cardiac phantom. Dosimetric characteristics of a 6 MV flattening filter free (FFF) beam from a Varian TrueBeam linac were initially evaluated under high-frequency gating scenarios relevant to cardiac rhythms with respect to dose linearity, beam output, and energy quality. A microcontroller board was used to interface and gate the linac, sending a beam on/off signal. For real-time cardiac gated measurements, an AD8232 Heart Monitor board was used to acquire the ECG signal and synchronize the VMAT delivery to an ArcCHECK detector to a specific phase of the cardiac cycle. Gated dose distributions were compared against those acquired for a non-gated delivery mode. An in-house dynamic cardiac phantom was developed to simulate cardiorespiratory motion that correlates target position with the signal to gate the beam. Measured dose distributions using gafchromic film were also compared against the static (reference) mode in different scenarios with and without gating. Maximum difference in dose per monitor unit (MU) was found to be no greater than 1% as compared to static mode with variation in the chamber response within 0.2% in the range of 50 MUs to 200 MUs. Maximum percentage differences for the beam output and beam qualiy index (TPR20,10) between gated and non-gated modes were 0.91% and -0.44%, respectively. Comparison of delivered dose distributions for the VMAT plan without gating versus ECG synchronized gating modes provided a passing rate 98% for the gamma analysis with 1% relative dose difference, 1mm distance-to-agreement criteria. For the synchronization of dose delivery with target position, passing rates were 98%, 97%, and 99% for the axial, coronal, and sagittal planes, respectively, when gating the beam based on target position for cardiac motion only, for 3%, 3mm tolerance as compared to static mode. Without gating the beam, passing rates of the respective plans are 97%, 94%, and 99% for the cardiac motion only, and 67%, 57%, and 55% when including respiratory component of motion. A 6 MV-FFF TrueBeam is stable for performing gating in STAR under high-frequency gate windows within typical cardiac cycles. Agreement between measured dose distributions for a VMAT plan in static and ECG-synchronized deliveries and between static and target-position gated modes shows that the proposed methodology is feasible and can be implemented on a TrueBeam platform.

Added Value of Biological Effective Dose in Dosiomics-Based Modelling of Late Rectal Bleeding in Prostate Cancer.

Extracting spatial features (texture analysis) from dose distributions (dosiomics) for outcome prediction is a rapidly evolving field in radiotherapy. To account for fraction size differences, the biological effective dose (BED) is often calculated. We evaluated the impact and added value of the BED in the dosiomics prediction modelling of grade ≥ 2 late rectal bleeding (LRB) probability within 5 years after treatment in three parts. For N = 656 prostate cancer patients previously treated in a randomized trial with conventional (CF) or hypofractionated (HF) radiotherapy, 42 dosiomic features were extracted from the dose distributions of the delineated rectum in physical doses and from dose distributions converted to the BED. Part 1: To assess whether an HF BED dosiomics model is generalizable to CF and vice versa, multivariate logistic regression BED models were constructed for HF and CF separately and tested on the other fractionation scheme. Part 2: The BED models were fitted to combined HF and CF data together to test whether this resulted in better models. Part 3: Separate physical HF and CF models were constructed and compared to the BED models. Part 1: Dosiomics related to large-zone and long-run high-dose levels were predictive for both HF and CF. Deviation from the mean gray level was only predictive for HF. The BED HF model calibrations with CF data and vice versa were generally poor. AUCs ranged from 0.55 to 0.65. Part 2: Compared to the separate models, the models fitted to the combined HF and CF data showed better discriminative ability in CF but not in HF. Part 3: The apparent performances of models for the BED and physical dose were similar. Using the BED in the predictive dosiomic modelling of late rectal bleeding after prostate cancer radiotherapy to account for differences in fraction doses was of limited value.

Radiation dose and image quality in pediatric bitewing imaging.

Bitewing examinations are used to examine the pediatric dental status. The aim of this study was to compare the image quality and radiation dose between two different X-ray systems used for pediatric bitewing imaging. Data were obtained from both pediatric in vivo bitewing studies and phantom studies. Two X-ray systems were used: Trophy CCX digital (TCCX) (Trophy Irix 70, Marne-la-Vallee, France) and Planmeca Pro X (PPX) (Planmeca, Helsinki, Finland). An Unfors dosimeter (Unfors EDD-30, Billdal, Sweden) was used to measure the skin dose. Image quality was evaluated blindly by three experienced dentists using a Likert scale of 1-5 based on the visual representation of the anatomical structures with emphasis on caries. The highest scoring in vivo bitewing images were obtained with TCCX, but the skin dose was 36% higher (mean 3029±613 μGy) and 113% higher (mean 1364±276 μGy) with standard settings than with compared to PPX. The evaluation of image quality revealed a higher median value for all ratings of TCCX compared to PPX for both the patient and phantom studies, meaning that the images of TCCX were rated as higher quality than the images from PPX. No correlation was found between the median score and the skin dose or between the median score and the exposure times. A significant difference in radiation dose and image quality was found between TCCX and PPX in bitewing imaging. TCCX generally produced higher doses and better graded images, although all images were suitable for diagnosis.

Magnetic Resonance Imaging Reveals Novel Insights into the Dual Mode of Action of Bisacodyl: A Randomized, Placebo-controlled Trial in Constipation.

Bisacodyl is a widely used laxative that stimulates both motility and secretion. Our aim was to exploit the unique capabilities of MRI to define bisacodyl's mode of action. Two placebo-controlled cross-over trials were performed, one using a single dose of Bisacodyl 5 mg while the second dosed daily for 3 consecutive days. Serial MRI was performed every 75 minutes. Primary endpoint: ascending colon water content as assessed by T1AC AUC300-450 minutes. Secondary endpoints included: small bowel water content, whole gut transit time (WGTT), colonic volumes, stool frequency, and consistency using Bristol Stool Form Score (BSFS). Exploratory endpoints: changes in the serial segmental volumes were quantified from the number of "mass movements" defined as episodes when segmental volume change from the previous scan was > 20% of baseline volume. We also measure the time to defecate after dosing. After 3 days of bisacodyl, ascending colon water content (T1) was 62% greater than after placebo, mean difference T1 AUC300-450 minutes 50.2 (61.0) sec.min, 95% CI (9.2, 91.2), P = 0.02, while after a single dose difference was only 11% (P = 0.58). Both single and repeated doses shortened WGTT (P < 0.049) and time to defecate (P 0.01). Only repeated doses significantly increased small bowel water content (P < 0.03), the number of "mass movements" (P = 0.048), bowel frequency (P = 0.006), and BSFS (P = 0.03). Repeated, compared to single dosing of Bisacodyl, additionally increases small bowel and colon water content and increases the number of "mass movements" thereby increasing its laxative effect. MRI is a non-invasive, patient-acceptable technique for evaluating drugs which alter secretion and/or motility.

How Consistent are Anti-Infective Drug Dosing Recommendations Across Three European Paediatric Formularies?

Drug dosing recommendations in paediatrics are mainly based on the age and bodyweight of the child. Because of the limited amount of label information, several paediatric drug formularies have been developed. This study compares anti-infective drug dosing recommendations across three European formularies. Recommendations from three paediatric formularies (German Pediatric Formulary [GPF], SwissPedDose [SPD] and the British National Formulary for Children [BNF]) were collected. Using population growth curves, we simulated one child for each month from 1 month up to 18 years of age. The recommendations from each formulary were used to calculate doses for each simulated child. Equivalence and difference in calculated doses were analysed. In total, dosing recommendations for 34 anti-infective substances were collected with 74 corresponding indications, which resulted in 47,154 calculated doses. The mean (± standard deviation) proportion of equivalent doses (difference ≤10%) across all three formularies was 40% (±16), while for pairwise comparisons it was 53% (±19) for GPF versus BNF, 67% (±14) for GPF versus SPD and 52% (±19) for SPD versus BNF. The median [25th quantile, 75th quantile] differences in daily doses across all three formularies were 0%, [0, 26] while for pairwise comparisons it was 4% [0, 32] for GPF versus BNF, 0% [0, 17] for GPF versus SPD and 7% [0, 33] for SPD versus BNF. The majority of recommended anti-infective drug doses were consistent, with the highest equivalence found between GPF and SPD. Maintaining formularies is resource intensive; therefore, a common standard in Europe could prove beneficial when moving towards digitalisation of the healthcare systems.

Robotic-Assisted Direct Anterior Approach Total Hip Arthroplasty: A 6.5-fold Reduction in Fluoroscopic Radiation Exposure.

Direct anterior approach (DAA) for total hip arthroplasty (THA) is increasing in popularity. Fluoroscopy is commonly utilized during DAA THA to increase the accuracy of component placement. The objective of this study was to compare the mean fluoroscopy time and radiation dose for DAA THA when utilizing robotic-assisted (RA), computer-assisted navigation (CAN), or manual (M) technique. A retrospective review identified 6,541 patients who underwent primary unilateral DAA THA between 2016 and 2023, including 4,333 M-THA, 1,158 RA-THA, and 1,050 CAN-THA. The mean age was 65 years (range, 20 to 96), the mean body mass index was 26 (range, 15 to 56), and 63% were women. The mean fluoroscopy time (seconds) and radiation dose in milliGray (mGy) were compared between cohorts. Regression analysis controlled for differences in baseline demographics. The RA-THA cohort had a shorter mean fluoroscopy time (4.4 ± 5.6seconds) than both the CAN-THA (17.6 ± 9.1seconds, P < 0.001) and M-THA (21.8 ± 39.4seconds, P < 0.001) cohorts. The CAN-THA cohort also had a shorter mean fluoroscopy time than M-THA cases (P < 0.001). The RA-THA cohort had a smaller mean fluoroscopic radiation dose (0.4 ± 0.6 mGy) than both CAN-THA (2.6 ± 2.2 mGy, P < 0.001) and M-THA (2.5 ± 2.5 mGy, P < 0.001). There was no difference in fluoroscopic radiation dose between the M-THA and CAN-THA cohorts (P= 0.822). In this series of DAA THA, RA-THA required a 4.0- to 5.0-fold shorter mean fluoroscopy time and a 6.5-fold smaller mean fluoroscopic radiation dose compared to CAN-THA and M-THA. As DAA THA volume increases, surgeons should consider the cumulative radiation exposure to themselves, patients, and operating room staff.

Clinical validation of MR-generated synthetic CT by MRCAT for brain tumor radiotherapy.

MRI is an emerging modality in radiotherapy (RT). Accuracy synthetic CT is the prerequisite for implementing MR-only RT planning. This study validated the commercial algorithm of MR for calculating attenuation (MRCAT) in terms of image quality and dosimetric agreement. Brain tumor cases with 18 treated using intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), and 15 treated using stereotactic radiosurgery (SRS) were analyzed. Synthetic CTs were resampled referencing planning CT. Treatment plan calculated on planning CT was recalculated on resampled MRCAT. Image quality of selected metrics and dosimetric agreements were assessed by dose-volume-histogram and 3D gamma analysis. For IMRT/VMAT and SRS cases, mean error were 23.42±1.05 and 28.39±3.17 HU; mean absolute error were 38.03±1.42 and 52.36±2.63 HU; root mean squared error were 89.09±6.65 and 108.38±12.23 HU; peak signal-to-noise ratio were 29.11±0.60 and 27.65±0.59dB; and structural similarity index measures were 0.88±0.00 and 0.70±0.01 respectively. No significant differences were identified for DVH metrics accounting the target coverage. Most OARs did not have significant dose deviation, except left lens with 0.70% higher in D-mean after recalculation (p<0.001). For criteria of 3mm/3%, 2mm/2%, and 1mm/1%, gamma passing rates for IMRT/VMAT were 99.92%, 99.42%, and 96.47%, while SRS were 99.86%, 99.52%, and 97.57% respectively. Correlation between passing rate and image quality metrics was established in IMRT/VMAT cases, with higher similarity yield better dosimetric agreement between planning and synthetic CT. This study has validated the MRCAT for clinical use in terms of comparable image quality and dosimetric agreement with planning CT. Further case selection and MR-compatible immobilization device would be required.

Quantifying the spatial distribution of the accumulated dose uncertainty using the novel delta index.

Inter- and intra-fractional anatomical changes during a radiotherapy treatment can cause differences between the initially planned dose and the delivered dose. The total delivered dose can be accumulated over all fractions by using Deformable Image Registration (DIR). However, there is uncertainty in this process which should be accounted for. The aim of this study is to propose a novel metric estimating the spatial distribution of the accumulated dose uncertainty and to evaluate its performance for multi-fraction online adaptive treatments.&#xD;&#xD;Approach: We postulate a new metric, the delta (δ) index, to estimate the uncertainties associated with the dose accumulation process. This metric is calculated for each voxel and takes into account the spatial uncertainty in DIR and local dose differences. For the spatial uncertainty of the DIR, the Distance Discordance Metric (DDM) was used. The accumulated dose and the δ index were determined for ten lung Stereotactic Body Radiation Therapy (SBRT) patients. The δ index was complemented by a more understandable metric, the δ index passing rate, which is the percentage of points satisfying the passing criteria in a region. &#xD;&#xD;Main Results: The spatial distribution of the δ index and the δ index passing rates showed that voxels failing the criteria were predominantly in lower-dose regions. The mean percentage of voxels passing the criterion increased from 65% to 78%, for threshold doses of 20% and 90% of the prescription doses, respectively. &#xD;&#xD;Significance: The δ index was postulated to quantify the spatial distribution of the uncertainties associated with the dose accumulation process. The metric gives an intuitive understanding of the reliability of accumulated dose distributions and derived DVH metrics. The performance of the δ index was evaluated for multi-fraction online adaptive treatments, where a case of sub-optimal image registration was identified by the metric.

Investigating LETd optimization strategies in carbon ion radiotherapy for pancreatic cancer: a dosimetric study using an anthropomorphic phantom.

Clinical carbon ion beams offer the potential to overcome hypoxia-induced radioresistance in pancreatic tumors, due to their high dose-averaged Linear Energy Transfer (LETd), as previous studies have linked a minimum LETd within the tumor to improved local control. Current clinical practices at the Heidelberg Ion-Beam Therapy Center (HIT), which use two posterior beams, do not fully exploit the LETd advantage of carbon ions, as the high LETd is primarily focused on the beams' distal edges. Different LETd-boosting strategies, such as Spot-scanning Hadron Arc (SHArc), could enhance LETd distribution by concentrating high-LETd values in potential hypoxic tumor cores while sparing organs at risk. This study aims to investigate and verify different LETd-boosting strategies using an anthropomorphic pancreas phantom. Various LETd-boosting strategies were investigated for a cylindrical and a pancreas-shaped target in an anthropomorphic pancreas phantom. Treatment plans were optimized using single field optimization (SFO) or multi field optimization (MFO), with objective functions based on either physical dose (Phys), relative biological effectiveness(RBE)-weighted dose, or a combination of RBE and LETd-based objectives (LETopt). The LETd-boosting planning strategies were optimized with the goal of increasing the minimum LETd in the tumor without compromising its homogeneous dose coverage. Beam configurations investigated included the two-beam in-house clinical standard (2-SFOPhys, 2-SFORBE and 2-MFORBE-LETopt), a three-beam configuration (3-MFORBE and 3-MFORBE-LETopt) and SHArc (SHArcPhys, SHArcRBE and SHArcRBE-LETopt) using step-and-shoot delivery. The different plans were verified using an anthropomorphic pancreas phantom at HIT and compared to treatment planning system (TPS) predictions. All investigated LETd-boosting strategies altered the LETd distribution while meeting optimization goals and constraints, resulting in varying degrees of LETd enhancement. For the cylindrical volume, the SHArc plan resulted in the highest LETd concentration in the tumor core, with the minimum LETd in the GTV scaling up to 91keV/µm. For the pancreas-shaped volume, however, the 3-MFORBE-LETopt achieved a higher minimum LETd in the GTV than SHArcRBE (75.6 and 62.3keV/µm, respectively). When combining SHArc with LETd optimization, a minimum LETd of 76.3keV/µm was achieved, suggesting a potential benefit from this combined approach. Most dosimetric verifications showed dose deviations to the TPS within a 5% range, for both beam-per-beam and total dose. LETd-optimized and SHArc plans exhibited slightly higher mean dose deviations (2.0%-4.6%) compared to the standard RBE-based plans (<1.5%). This study demonstrated the feasibility of enhancing LETd in pancreatic tumors using carbon ion arc delivery coupled with LETd optimization. The possibility of delivering these plans was verified through irradiation of an anthropomorphic pancreas phantom, which showed agreement between dose measurements and predictions.

International survey on diagnostic reference levels based on clinical indications in plain radiography.

To collect and analyze radiation dose-related data as part of international cooperation; to define diagnostic reference levels (DRL) for 24 X-ray projections in plain radiography (DX) considering anatomical region, clinical task, and procedural technique; and to harmonize the exposure practice across country borders. A multicenter study was performed in Austria, Germany, Italy, and Switzerland in 2022-23 to provide dose-related data. Healthcare facilities were asked to provide processed data from their dose management systems. A 5%-level was used for assessing the statistical significance of dose differences between various groups. Dose-related data from 85 radiographic systems in academic and non-academic, public, and private healthcare facilities were analyzed. Dose-related parameters differed significantly for many projections with different clinical tasks and techniques. Dose-related data of the procedures varied by a maximum factor of 16 for the same system, and median dose values also differed between hospitals by a maximum factor of 31. A fifth of the surveyed systems exhibit doses above more than half of the new DRLs defined in this study. Apart from the three reference procedures, no significant dose differences were observed between X-ray systems of different ages, from different manufacturers, or from different countries. This is the first survey in which exposure practices were investigated in institutions in different central European countries by establishing clinical DRLs for radiography. The observed dose variations could be explained by different reasons, such as non-optimized dose protocols. The new DRLs help to harmonize the exposure practice across country borders. Question What is the exposure practice for plain radiography procedures for which no clinical diagnostic reference levels (DRLs) have been defined? Are there differences between countries? Findings The dose for the same clinical task and technique can vary considerably among institutions but, on average, do not significantly differ between neighboring countries in Europe. Clinical relevance In this international multicenter study, clinical DRLs were defined for 24 plain radiography projections to promote the optimization of the exposure practice, to reduce dose variations among institutions even across national borders, and to strengthen international cooperation among users.