Patient Dose Research Articles

DRL as a common language in patient dose reduction and optimization: A short note from AsiaSafe in 2024 RCRT-RST Annual Congress, Bangkok, Thailand

The AsiaSafe Asian Oceanian Symposium at the 2024 RCRT-RST Annual Congress discussed the situation and role of radiology in patient dose reduction and optimization using Diagnostic Reference Levels (DRLs) as a common language. The scientific committee of the Royal College of Radiologists of Thailand (RCRT) and Radiological Society of Thailand (RST) established the Collaboration Symposia to discuss hot health topics with participated Asian Radiological societies. At the 2024 RCRT-RST Collaboration Symposia, different views, initiatives, and ideas were presented by representatives from societies.

A study of polarity effect for various ionization chambers in kilovoltage x-ray beams.

Ionization chambers play an essential role in dosimetry measurements for kilovoltage (kV) x-ray beams. Despite their widespread use, there is limited data on the absolute values for the polarity correction factors across a range of commonly employed ionization chambers. This study aimed to investigate the polarity effects for five different ionization chambers in kV x-ray beams. Two plane-parallel chambers being the Advanced Markus and Roos and three cylindrical chambers; 3D PinPoint, Semiflex and Farmer chamber (PTW, Freiburg, Germany), were employed to measure the polarity correction factors. The kV x-ray beams were produced from an Xstrahl 300 unit (Xstrahl Ltd., UK). All measurements were acquired at 2cm depth in a PTW-MP1 water tank for beams between 60 kVp (HVL 1.29mm Al) and 300 kVp (HVL 3.08mm Cu), and field sizes of 2-10cm diameter for 30cm focus-source distance (FSD) and 4 × 4 cm2 - 20 × 20 cm2 for 50cm FSD. The ionization chambers were connected to a PTW-UNIDOS electrometer, and the polarity effect was determined using the AAPM TG-61 code of practice methodology. The study revealed significant polarity effects in ionization chambers, especially in those with smaller volumes. For the plane-parallel chambers, the Advanced Markus chamber exhibited a maximum polarity effect of 2.5%, whereas the Roos chamber showed 0.3% at 150 KVp with the 10cm circular diameter open-ended applicator. Among the cylindrical chambers at the same beam energy and applicator, the Pinpoint chamber exhibited a 3% polarity effect, followed by Semiflex with 1.7%, and Farmer with 0.4%. However, as the beam energy increased to 300 kVp, the polarity effect significantly increased reaching 8.5% for the Advanced Markus chamber and 13.5% for the PinPoint chamber at a 20 × 20 cm2 field size. Notably, the magnitude of the polarity effect increased with both the field size and beam energy, and was significantly influenced by the size of the chamber's sensitive volume. The findings demonstrate that ionization chambers can exhibit substantial polarity effects in kV x-ray beams, particularly for those chambers with smaller volumes. Therefore, it is important to account for polarity corrections when conducting relative dose measurements in kV x-ray beams to enhance the dosimetry accuracy and improve patient dose calculations.

Alerts to improve occupational protection during Interventional Radiology. More attention is needed for simple but frequent procedures

Occupational protection could be improved in interventional radiology. The monthly personal dosimetry cannot alert on some occupational doses with anomalous values for certain procedures. Active electronic personal dosimeters linked wireless to a dose management system (DMS), allow for the measurement of occupational doses per procedure, integrating this information with patient dose indicators and with technical and geometrical conditions of the procedures.We analysed around 3100 occupational dose values for individual procedures collected during the last two years, in an interventional radiology laboratory of a University Hospital and two groups, with patient doses higher than 100 Gy.cm2, and lower than 30 Gy.cm2.An unshielded reference dosimeter located at the C-arm registers the ambient dose equivalent (ADE) per procedure to be compared with the personal dose equivalent (PDE) over the apron. The ratio between both values PDE/ADE is a good indication of occupational protection. Alerts for occupational protection optimisation are suggested.For the full sample, 8.4 % of occupational doses measured over the protective apron of the interventionists were higher than 100 µSv and 3.8 % higher than 200 µSv per procedure. Occupational protection for complex procedures (>100 Gy.cm2) had median values of 46 µSv for PDE and 3.3 % for PDE/ADE. However, for simple procedures, (<30 Gy.cm2) the median values were 10 µSv and 28.4 %. This last percentage is 9 times higher than the value for complex procedures. This lack of protection should be corrected and the need to reduce some occupational doses reinforced in radiation protection training programmes for interventionists.

E022 Audit on the baricitinib dose in elderly and patients with chronic kidney disease among a cohort of rheumatoid arthritis patients

Abstract Background/Aims Baricitinib use among elderly patients and in patients with chronic kidney disease needs modification of the dose. Baricitinib dose should be reduced to 2mg daily in patients who are 75 years or older given the associated increased risks in this age group. Additionally, baricitinib should be avoided in patients with creatinine clearance of less than 30 ml/min and dose needs to be reduced in patients with a creatinine clearance between 30-60 ml/min because it is primarily renally excreted drug. Methods All the blueteq requests for baricitinib at University Hospitals Coventry and Warwickshire, from 05/07/2021 to 05/07/2023 were evaluated. There were 128 patients who have been on baricitinib during this period. Twenty patients out of this, were 75 years or above. The baricitinib dose in patients above the age of 75 and in patients with chronic kidney disease was assessed by using NICE guidance on the use of baricitinib in patients with rheumatoid arthritis and the BNF as the audit standards respectively. Results Of the 20 patients who were 75 years and above, 13 patients were still on baricitinib. Ten patients were on a dose of 2mg daily which is in keeping with NICE guidance while 3 patients were still receiving a dose of 4mg daily. Seven patients were started on baricitinib after 75 years and 4 of them were started on 4mg daily which is not keeping with NICE guidance. Of the 128 patients, none of them had a creatinine clearance less than &amp;lt;30 ml/min while there were 16 patients who had received baricitinib (at some point) with a creatinine clearance of 30-60 ml/min. Of them, 14 patients were at some point on 4mg daily dose of Baricitinib which is not in keeping with guidance. Of those 14 patients, 6 patients were still receiving a dose of 4mg daily. Conclusion In conclusion, it appears that we have not completely adhered to standard criteria laid down by NICE guidelines and in the BNF. This presentation aims to raise awareness among rheumatologists regarding these guidelines. Also, changing the format of the prescription to include the age and renal functions would prompt the prescriber to amend the dose accordingly. The use of baricitinib may reduce in the future due to concerns of increased cardiovascular disease. However, there is a group of patients who are already on baricitinib and will want to continue, despite these concerns, given the significant improvements in disease control. Disclosure C. Rosa: None. J. Joseph: None. G. Kasavkar: None.

The impact of automatic tube current modulation related settings of a modern GE CT scanner on image quality and patient dose; details do matter.

To investigate the operation principles of the automatic tube current modulation (ATCM) of a modern GE healthcare CT scanner, and the impact of related settings on image quality and patient dose. A dedicated phantom (Mercury 4.0) was scanned using two of the most frequently used clinical scanning protocols (chest and abdomen-pelvis). The preset protocol settings were used as starting points (reference conditions). Scan direction, scan mode (helical vs. axial), total beam width, tube potential (kVp), and ATCM settings were then modified individually to understand their impact on radiation dose and image quality. Regarding the ATCM settings, the SmartmA minimum and maximum mA limits, and the noise index (NI) values were varied. As surrogates of patient dose, the CTDIvol and DLP values of each scan were used. As surrogates of image quality were used the image noise and the detectability index (d') of five different materials (air, solid water, polystyrene, iodine, and bone) embedded in the Mercury phantom calculated with the ImQuest software. The scanning direction did not have any effect on ATCM curves, unlike what has been observed in CT scanners from other manufacturers. Total beam width does matter, however, the SmartmA limit settings and kVp selection had the greatest impact on image quality and dose. It was seen that improper minimum mA limit settings practically invalidated the ATCM operation. In contrast, when full modulation was allowed without restrictions, noise standard deviation, and detectability index became much more consistent across the wide range of phantom diameters. For lower kVp settings an impressive dose reduction was observed that requires further investigation. SmartmA is a tool that if not properly used may increase the patient doses considerably. Therefore, its settings should be carefully adjusted for each preset different clinical protocol.

Prediction of Pralidoxime Dose in Patients with Organophosphate Poisoning Using Machine Learning Techniques

Background: Early and appropriate antidotal therapy is crucial for patients with organophosphate poisoning. Objectives: Given the lack of a comprehensive consensus on the optimal dose of pralidoxime for patients with organophosphate poisoning, this study aims to develop a machine learning-based prediction model to determine the individualized pralidoxime dose for these patients. Methods: The dataset was divided into training and test sets with a 70:30 ratio. Feature selection was conducted using Pearson’s correlation coefficient (filter approach) method. Both classification and regression were employed to develop the prediction model using the selected features. The performance of the developed models was evaluated using ten-fold cross-validation and various metrics, including sensitivity, specificity, accuracy, F1-score, and AUC. The models were implemented and assessed using the scikit-learn library in Python. Results: After applying exclusion criteria, data from 325 patients were utilized to train and test the machine-learning models. In the classification approach, the random forest method achieved superior performance with an AUC of 98.6. In the regression approach, the gradient boosting regressor, with an R2 value of 65.4, outperformed other algorithms. Feature selection revealed that muscular weakness, plasma cholinesterase activity, and blood urea nitrogen were the most significant predictors of pralidoxime dose in the classification model. In the regression model, the top predictors were age, HCO3-VBG, and atropine bolus. Many of the selected features coincide with those identified in previous studies, with muscular weakness being particularly significant in both models. Conclusions: The most effective algorithms could be employed to develop a clinical decision support system for personalized pralidoxime dosage prediction in patients with organophosphorus poisoning. However, the study is constrained by its small sample size, retrospective design, and the absence of an external validation cohort. Conducting a prospective multicenter study with a larger sample size is crucial to validate the findings of this study.

P001 An audit to assess whether patients who had a delayed or missed denosumab dose during the covid-19 pandemic came to any harm or suffered a subsequent fracture

Abstract Background/Aims Denosumab is licensed by NICE for the secondary prevention of osteoporosis in patients who are unable to comply, have an intolerance, or contraindication to bisphosphonates. With the outbreak of Covid-19, denosumab appointments were delayed. A delay of denosumab doses by more than 16 weeks is associated with an increased risk of vertebral fractures. This audit was carried out to see if the Pandemic caused a delayed (&amp;gt;1 month) or missed (&amp;gt;6 months) dose in patients receiving their denosumab injection and whether this delay/missed dose resulted in patients coming to any harm such as a subsequent fracture. Methods We included 166 patients of which 95% were female. We stratified data utilising the Oberoi consulting clinical audit services which provided a database of patients who were on six monthly repeat prescriptions for Denosumab. Retrospective data was collected including indications for denosumab, start date, duration, missed or delayed doses, reasons for delayed doses and whether a fracture of a pathological nature was sustained. We later reviewed if the missed or delayed doses occurred during the covid pandemic (2020-22) and subsequently, if the fracture occurred as a result of the pandemic. Results 34/166(21%) patients did not receive their Denosumab dose on time during Covid-19. 21/166(12.6%) patients had a delayed dose (6 pre-Covid and 15 post-Covid) and 13/166 (7.8%) patients missed a dose entirely (3 pre-Covid and 10 post-Covid) showing more delays/missed doses occurred during the pandemic. Reasons as to why patients did not receive timely doses include, clinical reasons (7/34 20.6%), patient safety decisions made by clinicians in patients’ best interest 12/34(35.3%) and patient choice related factors 15/34 (44.1%). Reasons for delays include not wanting repeat bloods, being on holiday, chest infection low Vitamin D levels, pre dose bloods delayed, patient had covid, and isolating. Whilst on Denosumab, 8/166(4.8%) patients sustained a fracture of which 6/8(75%) also experienced a delayed/missed dose during Covid-19. Conclusion Of the 34/166 patients that had a delayed/missed dose, eight suffered a fracture bringing the fracture risk to 23.5% which is an increase from baseline (6.6%) confirming that a missed Denosumab dose does increase fracture risk. We can conclude a greater proportion of patients endured a missed or delayed dose as a consequence of the Covid-19 pandemic. 8/166(4.8%) patients sustained a fracture of which six had a missed/delayed dose as a result of the pandemic. The conclusions drawn are in keeping with the MHRA4 alert, a missed dose of Denosumab does increase the risk of pathological treatment discontinuation fractures. This highlights to clinicians the significance of timely doses and uninterrupted treatment. Disclosure S. Rehman: None. S. Sultan: None.

A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease

A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34+ hematopoietic stem and progenitor cells (HSPC). This LVV contains locus control region cores expressing an anti-sickling βAS3-globin gene and two microRNA adapted short hairpin RNA simultaneously targeting BCL11A and ZNF410 transcripts to maximally induce fetal hemoglobin (HbF) expression. This LVV induces high levels of anti-sickling hemoglobins (HbAAS3 + HbF), while concurrently reducing sickle hemoglobin (HbS). The reduction in HbS and increased anti-sickling hemoglobin impedes deoxygenated HbS polymerization and red blood cell sickling at low vector copy per cell in transduced SCD patient CD34+ cells differentiated into erythrocytes. The dual alterations in red cell hemoglobins ameliorated the SCD phenotype in the SCD Berkeley mouse model in vivo. With high titer and enhanced transduction of HSPC at low multiplicity of infection, this LVV will increase the number of patient doses of vector from production lots to reduce costs and help improve accessibility to gene therapy for SCD.

Development of learning-based online C-arm CT imaging technique for image-guided adaptive brachytherapy

Existing protocols for image-guided adaptive brachytherapy (BT) pose distinct limitations, which include: (1) the possible misalignment of the application position as a consequence of patient translocation between the treatment room and the computed tomography (CT)/magnetic resonance imaging (MRI) suite, (2) an inherent inability to continually monitor physiological and anatomical changes during the course of 3–10 fraction treatment regimens, and (3) insufficient tracing of the radioactive source movement within the patient's body. In response to these challenges, this study proposes an innovative deep-learning-based C-arm CT/SPECT imaging system tailored specifically for image-guided adaptive BT. This technological advancement aims to enable the execution of high-precision online adaptive BT, thereby amplifying the adaptability and effectiveness of oncological care. An image dataset of 66 non-contrast pelvic CT studies was acquired and limited-angle cone-beam CT (CBCT) images were generated by mathematically calculating sinograms for voxel phantoms based on these CT images. Using a Generative Adversarial Network (GAN), low-quality CBCT images obtained using a 110° limited-angle rotating C-arm system were transformed into high-quality diagnostic CT images. The performances of these networks were evaluated by comparing them with CBCT images reconstructed using an iterative reconstruction method and ground-truth images. Synthetic CT images were successfully transformed from low-quality CBCT images, considerably reducing streaking artifacts and preserving the anatomical structures. Our deep-learning-based image reconstruction technique could successfully improve the image quality of limited-angle CBCT, similar to the ground-truth image quality, with a faster speed than the latest iterative reconstruction algorithm. We expect that this will be effectively implemented in online image-guided adaptive BT and patient dose verification.

An audit of patient radiation doses during interventional cardiology procedures in Uttarakhand, India, and establishment of local diagnostic reference levels.

The objective of this study was to investigate patient radiation doses by a dose audit of three common interventional cardiology (IC) procedures: coronary angiography (CA), percutaneous transluminal coronary angioplasty (PTCA) and CA-PTCA procedures performed in IC centres in the Uttarakhand state of India, for the establishment of local diagnostic reference levels (DRLs) and the estimation of average effective dose (Eav) for these procedures. For each procedure, the values of kerma-area product (PKA), reference air kerma (Ka,r), fluoroscopy time (FT) and the number of cine images were recorded from 1233 CA, 458 PTCA and 736 CA-PTCA procedures performed over a 12-month period at 13 IC centres of the state. From the recorded dose data, 0.6%, 1.53% and 7.9% patients were identified to have exceeded the PKA trigger level of 500 Gy cm2 for possible skin injury for CA, PTCA and CA-PTCA procedures, respectively. The 3rd quartile of the distribution of the recorded PKA values for each type of procedure was calculated to estimate local DRL values. The estimated values of DRLs and Eav were 37, 153 and 224 Gy cm2, and 6.72, 23.97 and 34.79 mSv for CA, PTCA and CA-PTCA procedures, respectively. For about 77% of the surveyed centres, the recorded patient doses were in agreement with the international standards. The local DRLs proposed in this study may be used to achieve patient dose optimization during IC procedures and the obtained patient dose data may also be archived into national dose database for the establishment of national DRLs.

Prospective dose monitoring using a manual dose management system: experience in brain computed tomography from a tertiary hospital in Nigeria.

A manual radiation dose management system was developed to track the radiation dose and scan parameters of patients for brain computed tomography (CT). Radiation dose in volume computed tomography dose index (CTDIvol) and dose length product (DLP) were monitored to identify procedures that may require optimisation using notification values. The data were analysed and compared with national and international diagnostic reference levels (DRLs). A total of 596 brain CTs were monitored and grouped as <1: 36, 1-<5: 38, 5-<10: 25, 10-<15: 31 and adult: 466. The CTDIvol notification value identified the following number of examinations having high CTDIvol in <1y: 1, 1-<5: 1, 5-<10: 0, 10-<15: 0 and adult (>15): 11. Furthermore, the DLP notification values identified the following examinations with high DLP in <1y: 1, 1-<5:1, 5-<10:1, 10-<15: 1 and adults (>15): 18. The established local paediatric DLP DRLs were 2-3 times higher than the international paediatric DLP DRLs. This calls for a total protocol review and optimisation considering the local CT practices for paediatric imaging.

Theoretical investigations on the laser isotope separation of 175Yb for medical applications

The possibility of laser isotope separation of 175Yb from irradiated natural Yb has been investigated. The optimum process parameters such as powers and bandwidths of the lasers, Doppler broadening and the number density of the atoms have been derived through density matrix calculations. It has been shown that it is possible to produce 175Yb (>42% enriched) at a production rate of 62 μg/hour (or 1.5 mg/day). This corresponds to the production rate of 1350 patient doses (of 7.4 GBq each) per day. The radionuclidic purity of the isotopic mixture is expected to be 99.9999%. The method is highly suitable for the countries having only low-flux nuclear reactors.

Estimation of patient doses and cancer risk to patients during EVAR procedures

Estimation of patient doses and cancer risk to patients during EVAR procedures

Harmonisation of quantitative assessment between different generation of PET/CT: Biograph mCT and Biograph Vision

The usage of modern positron emission tomography scanners, in particular with digital detectors, allows obtaining images with better quality, increases the detection of small pathological lesions, reduces scanning time and the activity administered to the patient which leads to a decrease of patient dose as well. However, the values of the quantitative image parameters shift upward, which can lead to significant differences with the quantitative assessment obtained on the previous generation device. In order to compare quantitative assessments obtained on different generations of PET/CT, it is necessary to harmonise quantitative image parameters and perform regular quality control. The aim of current work is the comparison of different methods for harmonization of quantitative image parameters on the example of harmonisation of two PET/CT: Biograph mCT 128 and Biograph Vision 600. NEMA IEC Body phantom filled with 18F solution was scanned in Listmode in two bed positions with overlap in the sphere area during five minutes per bed position. Recovery coefficient used for harmonisation was measured for each sphere of the phantom. Harmonisation between Vision and mCT was performed using two methods: choosing of harmonised reconstruction parameters and EQ.PET technology. The acceptable divergence range between the recovery coefficients for Vision and for mCT is ±10% (20% range). The recovery coefficients measured for reconstruction: 4 iterations and 5 subsets, ToF+PSF, Gaussian 7 mm, matrix 220x220 completely fit within the 20% range. The recovery coefficients measured using EQ = 6 mm (optimal value) fit within the 20% range except the spheres with a diameter of 10 and 13 mm. Both harmonisation methods allow to approximate the quantitative assessment/ However, EQ.PET has limitations for the small lesions. Choosing harmonised reconstruction parameters is the mostwidely used harmonisation method; the EQ.PET allows to harmonise quantitative assessment without the use of multiple reconstruction protocols and losses in visualization ability

599 To Titrate or Not to Titrate, That Is the Burning Question: Enoxaparin and VTE Prophylaxis

Abstract Introduction Patients who sustain burn injury undergo metabolic and physiologic changes that place them at elevated risk of developing venous thromboembolism (VTE). Although the benefit and safety of enoxaparin titration for prevention of VTE in trauma patients is well established, there is a lack of evidence regarding its applicability for burn injured patients. In this study, we sought to determine the safety and applicability of enoxaparin titration for burn injured patients admitted for treatment of their injury. Methods We performed a single center retrospective study of burn injured patients admitted to our American Burn Association verified burn center from June 2022 to June 2023. In May 2022, our burn center adopted the American Association for Surgeons in Trauma (AAST) protocol for enoxaparin dosing. This includes twice daily administration of enoxaparin, followed by measurement of anti-Xa levels prior to administration of the fourth or fifth dose. We previously administered a standard dose of 30mg twice daily. Anti-Xa levels were used to guide enoxaparin dose adjustments to remain within prophylactic range. Patients hospitalized for under 48 hours, with glomerular filtration rate less than 30, and with repeated refusal of enoxaparin were excluded. Results Eighty seven patients met our inclusion criteria. Fifty six patients started at 40mg twice daily dosing; the remainder started at 30mg twice daily dosing. Of these patients, forty two (48%) required dose adjustments by anti-Xa levels. Of those who required dose adjustment, thirty three (78%) required an increase. There was no significant difference in BMI (p=0.25) or inhalation injury (p=0.62) between patients who did and did not require enoxaparin titration. Patients who required titration had a non-significant trend toward larger percent total body surface area affected (p=0.08). There was also a significantly greater change in dosing for patients who required an increase in dose adjustment as opposed to those who required a decrease in dose adjustment (p &amp;lt; 0.0001). Finally, there was no difference in post-operative bleeding between patients who did and did not require dose titration (p=0.57). Conclusions Our results demonstrate that an individual approach to VTE prevention through enoxaparin titration is necessary in order to maintain appropriate prophylactic doses in burn injured patients. Furthermore, adoption of the AAST guidelines is safe and does not result in an increase in post-operative bleeding events. Applicability of Research to Practice This work highlights the safety and benefit of enoxaparin titration in burn injured patients to prevent VTE.

Using the genomic adjusted radiation dose (GARD) to personalize the radiation dose in nasopharyngeal cancer

BackgroundLocally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control. MethodsA total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR). ResultsDespite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66–76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1–67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66–74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %). ConclusionGARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.

Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

POPULATION PHARMACOKINETICS OF PANTOPRAZOLE IN PATIENTS ON DUAL ANTIPLATELET THERAPY FOLLOWING ACUTE CORONARY SYNDROME

This study investigates factors influencing pantoprazole pharmacokinetics (PK) in patients with acute coronary syndrome (ACS) undergoing dual antiplatelet therapy (DAPT) comprising acetylsalicylic acid and clopidogrel, alongside concomitant pantoprazole to mitigate gastrointestinal risks. We conducted a prospective analysis on 93 ACS patients, assessing pantoprazole PK parameters and their correlation with C-reactive protein (CRP) levels, indicative of inflammation. Blood samples for pantoprazole concentration and CRP levels were collected according to a predefined schedule, post-oral pantoprazole administration at steady state. The study highlights a notable influence of CRP levels on pantoprazole clearance, underscoring inflammation’s impact on drug metabolism. Elevated CRP was associated with altered pantoprazole pharmacokinetics, suggesting that inflammatory status significantly contributes to metabolic variability in this patient population. Our findings suggest the need for personalized pantoprazole dosing in ACS patients on DAPT, considering the inflammatory status as reflected by CRP levels. This approach could optimize therapeutic efficacy and minimize adverse effects, advancing personalized treatment strategies in the management of ACS.

Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Phase I DAVIO Trial: EYP-1901 Bioerodible, Sustained-Delivery Vorolanib Insert in Patients With Wet Age-Related Macular Degeneration

PurposeTo evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan–vascular endothelial growth factor (VEGF) receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy. DesignPhase 1, multicenter, prospective, open-label, dose-escalation trial. ParticipantsPatients with wAMD and evidence of prior anti-VEGF therapy response. MethodsPatients received a single intravitreal injection of EYP-1901. Main Outcome MeasuresThe primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates. ResultsSeventeen patients enrolled in the 440 μg (3 patients), 1030 μg (1 patient), 2060 μg (8 patients), and 3090 μg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline (CFB) in BCVA was –3.7 letters and –5.4 letters at 6 and 12 months. Mean CFB in CST was +1.7 μm and +2.3 μm at 6 and 12 months. Reduction in treatment burden was 76% and 72% at 6 and 12 months. Of 16 study eyes, 13, 9, and 6 were injection-free up to 3, 6, and 12 months. ConclusionIn the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing Phase 2 and planned Phase 3 trials to assess efficacy and safety.