Average Dose Research Articles

The impact of SLCO1B1 single nucleotide polymorphism and non-genetic factors on statin-induced myopathy

Abstract Funding Acknowledgements None. Background Statins, also known as HMG CoA Reductase Inhibitors, are a class of drugs considered the drug of choice for treating hypercholesterolemia. Statins are well tolerated; however, they may cause severe myopathy in 20% to 30% of patients, due to the individual variation regarding its efficacy and related adverse effects. Of these, comes the Single Nucleotide Polymorphism (SNP) T521C of the SLCO1B1 gene that encodes the protein involved in the trafficking of statins from the blood to hepatocytes which is called Organic Anion Transport Protein 1B1 (OATP1B1). The T521C single nucleotide polymorphism (SNP) results in a substitute of valine with alanine resulting in a decreased or lack of functional protein. Purpose The aim is to determine the frequency of the high-risk C allele and to define its impact on statin-induced myopathy in Syrian patients on statins. In addition to the non-genetic factors that may affect the ability to develop statin-induced myopathy. Methods This was an observational case-control study that had ethical approval from Damascus University (No.433/ 2020). The case group included 44 patients on statins who experienced myopathy, 18 patients who had increased creatinine kinase levels (CK), and 26 patients with normal CK levels, while the control group encompassed 56 patients who were taking statins and had no muscular adverse events. The DNA was extracted from each sample and then genotyped using standard sequencing of specific PCR products using a specific pair of primers. Results The age of patients in the case arm ranged between 27 and 84 years with an average ± SD of (58.2 ± 12.7 years), 70% of them were males. In comparison with (53.34 ± 12.4 years) in the control arm, 66% of them were males without a statistically significant differences (p=0.672, 0.057) respectively. The statin type and dose have a statistically non-significant effect, the average statin dose in the case arm and the control arm was 26.02 mg and 31.27 mg respectively (p=0.072). While the statin type treatment varied as 59% used atorvastatin and 39% used rosuvastatin in the case group compared with 71% used atorvastatin and 27% used rosuvastatin in the control group, without a statistically significant difference (p=0.252). The frequency of the C allele reaches 19.3% and is distributed in three genotypes: wild-type TT (68%), heterozygote TC (25%), and homozygote CC (7%) in the case arm, while it does not exceed 8% in the control arm with the absence of the CC genotype. Only a statistically significant difference was found in the frequency of the CC genotype between these two groups (p=0.047). Conclusion Our study is the first to identify the frequency of the 521T>C SNP of the SLCO1B1 gene in Syrian patients taking statins. Our data reveals a high prevalence of risk allele C in the patients who suffer from statin-induced myopathy with a statically significant difference from the control arm (p=0.026).

Dosimetric comparison of proton therapy and CyberKnife in stereotactic body radiation therapy for liver cancers.

Stereotactic body radiation therapy (SBRT) has been increasingly used for the ablation of liver tumours. CyberKnife and proton beam therapy (PBT) are two advanced treatment technologies suitable to deliver SBRT with high dose conformity and steep dose gradients. However, there is very limited data comparing the dosimetric characteristics of CyberKnife to PBT for liver SBRT. PBT and CyberKnife plans were retrospectively generated using 4DCT datasets of ten patients who were previously treated for hepatocellular carcinoma (HCC, N = 5) and liver metastasis (N = 5). Dose volume histogram data was assessed and compared against selected criteria; given a dose prescription of 54Gy in 3 fractions for liver metastases and 45Gy in 3 fractions for HCC, with previously published consensus-based normal tissue dose constraints. Comparison of evaluation parameters showed a statistically significant difference for target volume coverage and liver, lungs and spinal cord (p < 0.05) dose, while chest wall and skin did not indicate a significant difference between the two modalities. A number of optimal normal tissue constraints was violated by both the CyberKnife and proton plans for the same patients due to proximity of tumour to chest wall. PBT resulted in greater organ sparing, the extent of which was mainly dependent on tumour location. Tumours located on the liver periphery experienced the largest increase in organ sparing. Organ sparing for CyberKnife was comparable with PBT for small target volumes.

Measurement of Background Ionizing Radiation Around Beta Glass Plc and Its Environs, Ughelli, Delta State, Nigeria

A study of the background ionizing radiation levels to helps monitor the impact of human activities on the environment, such as mining, farming, glass bottle production and power generation has been carried out around Beta glass Plc and Transcorp Power LTD using a hand-held gamma spectrometer (GAMMA-SCOUT; Geiger counter Radiation meter) and GPS (Oregon-450 Garmin). The study of the BIR levels was carried out between June to July, 2022. The average measured exposure rates (AV. BIR) ranged from 0.007 mRh-1 to 0.013 mRh-1, with 0.010±0.0002 mRh-1 as the average. The estimated mean outdoor absorbed dose rate (ADR) for the study region was 113.10 Gyh-1 to 87.153±2.091 Gyh-1, with an average annual effective dose equivalent (AEDE) of 106.884±2.565 mSvy-1 and an average excess lifetime cancer risk (ELCR) of (0.374±0.009) × 10-3. The measured values of radiological parameters, such as annual dose rate, annual effective dose rate, and excess lifetime cancer, were higher than background radiation levels. The average BIR is in line with the ICRP recommendation of 0.013 (mRh-1), while the effective dose rate (EDR) is somewhat below the ICRP recommendation of 1.00 (mSvy-1) for a normal environment. The obtained values of the radiological indicators, such as ADR, AEDE, and ELCR, are greater than the background radiation norm of 59 (?Gyh-1), 0. 07 (mSvy-1), and 0.29×10-3. The study found that radiation levels and doses in the study location do not immediately harm personnel or residents, but increased lifetime cancer risk values suggest that cumulative dosages may cause cancer.

Urban-rural and socio-economic differences in inhaled corticosteroid treatment for chronic obstructive pulmonary disease: A nationwide register-based cross-sectional study

BackgroundUrban-rural disparities within chronic obstructive pulmonary disease (COPD) have been documented in USA, but not in Europe. Inhaled corticosteroids (ICS) are widely used in COPD despite strict recommendations. We aimed to investigate urban-rural and socioeconomic differences in ICS treatment for COPD. MethodsA Danish nationwide register-based cross-sectional study. All patients alive on the December 31, 2018 with a J44 ICD-10 diagnosis code (COPD) were included (99,057 patients). Daily average ICS dose was calculated from the accumulated ICS use during 2018 based on redeemed prescriptions. Patients were divided into groups: No ICS, low dose ICS, medium dose ICS, high dose ICS. A multinomial logistic regression model including educational level, co-habitation status, age, and sex was performed with “No ICS” as reference group. ResultsCompared to capital municipalities, living in other municipality types was associated with an increased probability of receiving medium and high dose ICS treatment, and increasing odds ratios (ORs) were seen with increasing ICS dose (medium dose ICS: ORs between 1.31 (95 % confidence interval (CI) 1.24–1.38) and 1.35 (95%CI 1.28–1.41), high dose ICS: ORs between 1.73 (95%CI 1.59–1.88) and 1.80 (95%CI 1.68–1.92)). Patients had increased probability of receiving ICS treatment if they were female, were co-habiting, or had completed only primary education. ConclusionPatients with a hospital-registered COPD diagnosis in non-capital municipalities receive more ICS, and in higher doses, compared to patients in capital municipalities. This is the first study to confirm that such urban-rural differences exist in Europe, and further research on this area is warranted.

Функциональные маски неврологических нарушений: дифференциальный диагноз органического и психогенного расстройства

Differentiation of organic and psychogenic disorders is one of the most difficult tasks of neurology and psychiatry, both because of the difficulties in determining the genesis of the condition itself, and because of their frequent comorbidity. A certain commonality of the pathogenetic nature of both disorders allows, when choosing therapeutic tactics, to rely on drugs that affect the central link in the pathophysiology of these processes – an imbalance of mediator systems. The purpose of this study was to study the efficacy and safety of Pantogam Active in patients in the complex therapy of neurological and psychiatric diseases in outpatient settings. The analysis included 120 people divided into 2 groups: group 1 took the main therapy and Pantogam Active on the recommendation of the attending physician at a daily dosage of 600–1200 mg (the average daily dosage is 900 mg), group 2 – only the main therapy. Patients were randomly assigned to groups. The duration of the study was 3 months. The effectiveness and safety were evaluated during a control examination by a specialist and based on the results of evaluation scales. The results of the study demonstrate a positive effect on both subjective feelings (well-being of patients receiving complex therapy) and changes in an objective assessment. The addition of the main therapeutic regimen with Pantogam Active is recommended for patients in order to correct concomitant symptoms that reduce the quality of life and adherence to treatment: asthenic syndrome, anxiety and depressive disorders, cognitive impairment.

A retrospective review of rasburicase utilization in pediatric and adult patients across a large health system.

This study aimed to characterize rasburicase dosing and duration. Secondary objectives included characterizing the indication of rasburicase and identifying the utilization of prophylactic therapy for tumor lysis syndrome (TLS). This retrospective review included patients 0 to 89 years old admitted between 1 January 2021 and 31 December 2021, and received at least one dose of rasburicase. Patients were excluded if they were >89 years old, pregnant, lactating, or received rasburicase outpatient. A total of 192 patients, 176 adults and 16 pediatric patients were included in the retrospective review. Of the total population, 184 received a fixed dose of rasburicase and 8 patients received a weight-based dose (0.15 mg/kg/dose) of rasburicase. The average dose administered was 3.4 mg for fixed and 2.99 mg for weight-based dosing. Nearly half (49.5%) the patients received rasburicase for an elevated uric acid but did not meet Cairo-Bishop criteria for TLS. Only 42.2% received at least one dose of allopurinol within 5 days prior to rasburicase and 18.8% received aggressive hydration within 72 h prior to rasburicase. The majority of rasburicase administered was ordered as fixed dose for a uric acid level ≥7.5 mg/dL. Most patients did not meet criteria for laboratory or clinical TLS and less than half the patients received prophylactic allopurinol and/or aggressive hydration. These study results are supported by recent literature for fixed dose rasburicase as a safe and economical dosing strategy compared to weight-based dosing.

Tackling of challenging accessory pathways utilizing open window mapping, does it add benefit?

Abstract Introduction 3D electroanatomical mapping is beneficial in accessory pathway ablation for better delineation of the anatomy, less procedure and fluro time, it depends on point-by-point mapping to identify the connection sites of the accessory pathway (AP) to the atria or ventricle, or the site of the AP potential. However, this approach requires an accurate interpretation of the local electrograms. In contrast, open window mapping (OWM) doesn’t need to differentiate the signals site of origin, it is based on an automatic annotation process in which the signals with the highest -dV/dt are annotated at each obtained point irrespective of the cardiac chamber. (1) Few reports describe the additional benefit of such technique in patients with complex congenital heart diseases. (2) Purpose To present our centre experience in using OWM technique in addition to early meets late (EML) algorism in accessory pathway ablation especially in patients with complex congenital heart disease or previous failed ablation trials. Methods We reviewed patients who underwent AVRT ablation at our centre from August 2022 to August 2023 with emphasis on cases mapped using OWM &amp; EML techniques using high density mapping catheters. Demographic data, clinical presentation, resting &amp; tachycardia ECGs, and Echo reports were examined thoroughly, additionally, we revised the 3D maps, ablation details, fluro dose, and outcomes of the procedures. Results Over one year, among 74 patients underwent AVRT ablation, open window mapping was used in 4 patients with manifest preexcitation (Rt posteroseptal in 3 of them &amp; Rt free wall in one patient). Among the four patients: 3 were pediatrics, youngest was 5 years old, 19 Kg, 2 patients had previous failed ablation trials, their Echo reports revealed severe form of Ebstein anomaly with large ASD in the first patient, case 2 had single ventricle physiology with bidirectional Glenn while the two other patients had structurally normal heart (Table). The mapping using the OW &amp; EML techniques confirmed the site of AP breakthrough conduction at Rt posteroseptal area in 3 of them and Rt posterolateral area in the remaining one, ablation resulted in immediate loss of preexcitation with no recurrence in all patients. Average fluro dose was 0.1 Gy which is significantly lower than the average dose in the remaining AVRT cases. Over median follow up period of 9 months, there were no recurrence of the accessory pathways &amp; no complications. Conclusion Open window mapping technique is highly beneficial for accurate &amp; fast mapping of accessory pathways especially in those with complex congenital heart where AP ablation remains considerably more challenging. OWM also added benefit in redo cases as the previous ablation trials hampered manual EGM interpretation. Finally, most of our cases were pediatrics where using high density mapping catheters and contact force ablation catheters appears to be safe and effective.Demographic, ECG, Echo &amp; procedure data3D map &amp; Echo in patient 2

Extending culture time to improve Mitotic Index for cytogenetic dosimetry

Purpose To analyze the effects of extending lymphocyte cultivation time on the Mitotic Index, frequency of first-division cells, and dose estimation after irradiating blood samples with different doses of radiation. Materials and methods Blood samples from two healthy male volunteers were separately irradiated with three doses (3, 5, and 6 Gy) using a 60Co gamma source (average dose rate: 1.48 kGy.h−1) and cultivated in vitro for conventional (48 h) and extended (56, 68, and 72 h) amounts of time. Colcemid (0.01 µg.mL−1) was added at the beginning of the culture period. Cells were fixed, stained with fluorescence plus Giemsa (FPG), and analyzed under a light microscope. The effects of prolonged culture duration on the Mitotic Index (MI), frequency of first-division cells (M1 cells), and the First-Division Mitotic Index (FDMI) were investigated. The estimation of delivered doses was conducted using a conventional 48h-culture calibration curve. Results Overall, cells presented higher MI (up to 12-fold) with the extension of culture, while higher radiation doses led to lower MI values (up to 80% reduction at 48 h). Cells irradiated with higher doses (5 and 6 Gy) had the most significant increase (5- to 12-fold) of MI as the cultivation was prolonged. The frequency of M1 cells decreased with the prolongation of culture for all doses (up to 75% reduction), while irradiated cells presented higher frequencies of M1 cells than non-irradiated ones. FDMI increased for all irradiated cultures but most markedly in those irradiated with higher doses (up to 10-fold). The conventional 48h-culture calibration curve proved adequate for assessing the delivered dose based on dicentric frequency following a 72-hour culture. Conclusion Compared to the conventional 48-hour protocol, extending the culture length to 72 hours significantly increased the Mitotic Index and the number of first-division metaphases of irradiated lymphocytes, providing slides with a better scorable metaphase density. Extending the culture time to 72 hours, combined with FPG staining to score exclusively first-division metaphases, improved the counting of dicentric chromosomes. The methodology presented and discussed in this study can be a powerful tool for dicentric-based biodosimetry, especially when exposure to high radiation doses is involved.

P.056 Real-world reduction in oral corticosteroid utilization following efgartigimod initiation in patients with generalized myasthenia gravis

Background: Reducing oral corticosteroids (OCS) use can alleviate the risk of many adverse events related to long-term OCS use. Here, we evaluate real-world utilization of OCS among patients with generalized myasthenia gravis (gMG) over the first 6 months following efgartigimod initiation. Methods: Patients with gMG using OCS who initiated efgartigimod treatment were identified retrospectively from an open US medical and pharmacy claims database (IQVIA Longitudinal Access and Adjudication Data [LAAD], April 2016-April 2023). Average daily dose (ADD) of OCS was analyzed during the 3-month period preceding efgartigimod initiation, and at 3 and 6 months post-efgartigimod initiation. Results: Of 231 patients assessed, 17 (7.4%), 109 (47.1%), and 105 (45.5%) had baseline OCS ADD of 0–5 mg, 5–20 mg, or &gt;20 mg, respectively. At 3 and 6 months post-efgartigimod, 82 (35%) and 99 (43%) patients, respectively, reduced ADD by ≥5 mg. Proportion of patients with ADD of 0–5 mg increased &gt;3-fold (7% baseline vs. 26% 6 months post-efgartigimod) and proportion of patients with ADD of &gt;20 mg decreased by 35% (45% baseline vs. 29% 6 months post-efgartigimod) following efgartigimod initiation. Conclusions: Approximately 43% of patients were able to decrease steroid use or achieved steroid-free status within 6 months of efgartigimod treatment initiation.

Pulsed-field ablation of atrial fibrillation in elderly and frail patients: procedural efficacy and safety from a single-center experience

Abstract Introduction The demographic data shows a growing population, mostly elderly and with multiple comorbidities, therefore becoming increasingly frail. In this context Atrial fibrillation (AF) is the predominant sustained arrhythmia, and over the years trans-catheter isolation of pulmonary veins (PVI) has become a crucial approach in AF treatment. Among the technologies and energy resources employed through the years to perform atrial fibrillation transcatheter ablation, a novel technique has recently begun to gain ground, specifically pulsed-field ablation (PFA). PFA employs sequential brief and high amplitude electrical pulses to induce selective and irreversible electroporation of the myocardium, leading to cell death. The high selectivity of the lesion, ensured by the lower electroporation threshold of myocardial tissue compared to adjacent anatomic structures, allows for a decrease in potential complications associated with conventional thermal ablation. Purpose To assess the efficacy and safety in the use of pulsed field ablation in a selected population of elderly and frail patients undergoing atrial fibrillation ablation. Method We conducted a retrospective study focusing on elderly and frail patients admitted to our centre for paroxysmal or persistent AF ablation. The inclusion criteria were: age greater than 75 years and a Clinical Frailty Scale ≥ 5. The study population consisted of 26 patients [male gender 18, mean age 78 ± 3 years] including 8 who were affected by an oncological or haematological disease at the time of admission. The majority of patients were affected by paroxysmal AF while two of them presented persistent AF (9%). The primary ablation endpoint was the pulmonary vein isolation (PVI) that was achieved by delivering an energy of 2 kV over 8 applications, employing an alternating approach between the two configurations of the basket and flower catheter for each individual vein. Results The short-term success, represented by the complete and verified electrical isolation of the veins was achieved in all 26 patients without any periprocedural complications. First-pass pulmonary vein isolation (FPI) was universally achieved among the patient in study, with a mean skin-to-skin procedural time of 70 ± 30 minutes. From the procedural data perspective, ablation was achieved using an average fluoroscopy time of 22 ± 8.4 minutes and an average dose area product (DAP) of 1320 cGy×cm2. Conclusions In elderly and frail patients, we assessed the efficacy and safety of ablative procedures using the PFA technique. Successful electrical PVI was achieved without additional touch-ups, thanks to a high FPI rate. This results in lower procedural times and shorter intra-operative radiation exposure. These data confer an augmented value within the elderly-frail population, wherein shorter procedural times contribute to a better postoperative course, characterized by reduced bed rest and shorter intra-hospitalization periods.

Experience in implementation of the No-till farming system in the Belgorod region

The research was conducted in a forest-steppe zone of the municipality of “Korochan district” (Belgorod region). Typical and leached chernozem constituted the two types of soils, that were studied. The goal was to evaluate the main results of introduction of the No-till farming system, following the example of LLC “Meat Farms – Iskra”. It was found out that on average, throughout the years of 2018-2022, winter wheat was the most regular (24.5%), alongside sunflower (23.2%). Legumes prevalence was at 32.5% with soy (20.0%). Organic fertilizer wasn’t used in the process; however, the average dose of mineral fertilizers was 66 kg of the substance/ha, which is 42.4% lower than the average for Belgorod region. The usage of the system No-till yield the sunflower, soy and corn-beans, as well as winter wheat plantings corresponded to 2.21, 1.65, 6.35 and 4.43 t/ha, which is lower by 23.5, 20.7, 11.2,10.9% when compared with the average throughout Belgorod region. The quantity of organic substances in the arable layer of the soil underwent an increase of 0, 14%, the quantity of mobile forms of phosphorus and potassium went down by 12 and 28 mg/kg accordingly, the dose of acidic soils decreased by 8,7%. The amount of mobile forms of sulfur and microelements didn’t particularly change. The profitability of crop production using the No-till system was 82.3%, which is 1.29 times higher than the average of the Belgorod region.

Effectiveness of the use of enzyme preparation Hemicell® HT for growing young goslings

Agricultural waterfowl have certain biological characteristics: intensive metabolism and rapid growth, early maturity and signifcant reproduction potential, high body temperature, and resistance to many infectious diseases. The article presents the results of an experimental study of the effect of the exogenous enzyme preparation Hemicell® HT (1 kg contains the active ingredient β-mannase - 160x106 units) on the productive qualities of young goslings of Shadryna and Italian breeds. To achieve this goal, four experimental groups of goslings were formed: Group 1 - control, 2, 3, 4 - experimental, which were fed the enzyme preparation Hemicell® HT as part of a complete feed mixture - 150 g for the second experimental group, 250 g for the third and 310 g for the fourth experimental group per 1 tonne of fodder. It was found that the introduction of the exogenous enzyme preparation Hemicell® in the above doses into the diet of young geese signifcantly affects the growth rate of young geese and metabolic processes in their bodies. If at the end of the frst decade the most positive effect on the body was found in low and high dos- age of the enzyme preparation (birds of the 2nd and 4th groups), as a result of which, compared to the analogues of the 1st control group, the difference in the average daily gain was 3.4 and 2.8 g (p&lt;0.001), then the average dosage of the enzyme preparation in the analogues of the 3rd experimental group provided a difference of only 1.1 g (p&lt;0.01). However, by the end of the frst rearing period (up to 21 days), the highest average daily weight gain was observed in geese of the 3rd experimental group compared to the analogues of the control, 2nd and 4th experimental groups. Thus, while the average daily weight gain in geese of the 1st control group was 43.1 g, this fgure was 2.6 g higher in the 2nd group (p&lt;0.01), 5.1 g in the 3rd group and 3.6 g in the 4th group (p&lt;0.001). This pattern was maintained until the end of the experiment, with signifcant differences in goslings of the 3rd experimental group compared to the control: at the age of 31 days - by 9.7 g (p&lt;0.01), 41 days - by 10.1 g (p&lt;0.05), 66 days - by 9.2 g (p&lt;0.05). In geese of the 2nd and 4th groups, the average daily weight gain was higher than in the control group, but did not have significant differences during the same age period. As a result, in general, the average daily weight gain of goslings of the 1st control group was 59.9 g, in the 2nd experimental group it was 3.1 g (p&lt;0.01), or 5.2%, in the 3rd - 6.6 g (p&lt;0.001), or 11%, and in the 4th group - 4.2 g (p&lt;0.001), or 7.0%, compared to the same indicator of the control. The use of the enzyme preparation had a positive effect on the goslings' organism, which made it possible to realise the genetic potential of goslings' productivity at a higher level in all experimental groups, but the highest growth rate was observed in the 3rd experimental group of geese. Key words: geese, Shadryna breed, Italian breed, enzyme preparation, Hemicell® HT, weight gain, live weight.

TSH Trajectories During Levothyroxine Treatment in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Cohort.

Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time. This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period. Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes. GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.

#2207 CD3(+) T cell depletion does not predict short term outcomes in kidney transplant patients

Abstract Background and Aims Anti-thymocyte globulin (ATG) is the most frequently agent used for immunosuppression induction therapy after kidney transplantation. The efficacy of the ATG treatment is monitored by peripheral blood CD3(+) T cell counts. ATG dosing can be tailored to reach and keep the target commonly accepted as below 50/μL within the week of transplant. In this study, we investigated the significance of reaching CD3(+) T cell target regarding short term adverse outcomes of biopsy-proved rejection, BK viremia and infection related hospitalization in living donor kidney transplant recipients. Method This retrospective observational study was conducted on adult patients who received living donor kidney transplants from January 1, 2015 to October 1, 2022. Demographic, clinical and laboratory information were collected using electronical medical records. The average CD3(+) T cell counts of postoperative first 3 days were calculated. Patients with CD3(+) T cell counts ≤ 50/μL were classified as “Optimally Treated”, while the patients with CD3(+) T cell counts &amp;gt;50/μL were classified as “Suboptimally Treated”. The incidence of biopsy-proven rejection, BK viremia and infection related hospitalization in 6 months following the transplant surgery were compared in these two groups. Results Sixty one patients were included in the study. Twenty eight were women and the average age was 39 ± 12.7 years. Average HLA mismatch count was 3.6 ± 1.7. Ten patients were desensitized before kidney transplant. Average ATG dose was 6.8 ± 2.3 mg/kg. Mean average CD3(+) T cell count of postoperative first 3 days were 93.9 ± 87.8/μL. During 6 months of follow up, 34.4% (n = 21) had at least one biopsy proved rejection episode, 21.3% (n = 13) had at least one infection related hospitalization and 11.4% (n = 7) had BK viremia. According to average CD3(+) T cell counts of postoperative first 3 days, 16 patients were in “Optimally Treated” group, whereas 45 patients were in “Suboptimally Treated” group. The patients in both groups had similar mean age, gender distribution, HLA mismatch, pretransplant desensitization status and total ATG doses. In 6 months of follow-up, the patients in “Optimally Treated” and “Suboptimally Treated” groups had no statistically difference in incidence of biopsy-proved rejection, BK viremia and infection related hospitalization. Conclusion In our study, we could not find any evidence to confirm the significance of reaching CD3(+) T cell target of 50/μL in first 3 days after transplant surgery regarding short term adverse outcomes of biopsy-proved rejection, BK viremia and infection related hospitalization. The value of CD3(+) T cell monitoring to adjust ATG therapy after kidney transplant surgery is questionable. Thus, in the light of our findings, we do not support the use of CD3(+) T cell counts in optimization of induction therapy with ATG after renal transplantation.

#1207 Post transplant diabetes mellitus in kidney transplanted patients: factors related and impact on long-term outcome

Abstract Background Alterations in glucose metabolism are one of the most important complications of renal transplant recipients. The aim of this study was to analyze their prevalence and determinants and assess their influence on the main long-term clinical outcomes in a cohort of kidney transplant recipients. Methods we retrospectively analyzed the data of 832 kidney transplant recipients between 2004 and 2020 in our center. Patients were studied at 1 (T1), 6 (T6), and 12 (T12) months after transplantation and followed clinically for a follow-up time of 103 ± 60 months. At T6, an oral glucose tolerance test (OGTT) was performed in 484 patients. Results The mean age of the cohort studied was 49 ± 13 years, with a mean dialysis vintage of 54 ± 52 months. Hemodialysis was the therapy before KTx in 70.6% of patients, whereas 20.9% had been treated with peritoneal dialysis. The 8.5% of patients received a pre-emptive KTx. Fifty-seven percent of the patients were male and 83.5% had a KTx from a deceased donor. Both at T1 and T12, immunosuppressive therapy was mainly composed of steroids (average cumulative dose at T12: 2914 ± 962 mg), calcineurin inhibitors and mycophenolate. In our cohort at T12, diabetic patients were 237 (28.6%), of which 51 (6.2%) were already affected by diabetes before KTx. Of note, we diagnosed diabetes by OGTT in 23 KTxps, while in 90 KTxps, OGTT showed prediabetic alterations. Patients with glucose metabolism abnormalities were significantly older, had an altered lipid profile associated with higher BMI values and a significantly higher inflammatory index. Interestingly, our data showed that graft loss was not affected by any type of alteration of glucose metabolism. On the contrary, we found that mortality was significantly higher in patients with pre-transplant diabetes and in those with alterations in glucose metabolism detected with OGTT (both including diabetes and considering only IGT and IFG). Conclusions Our data showed that age at transplantation, lipid profile, and the inflammatory state were the variables that most influenced the development of PTDM. Interestingly, mortality was significantly associated with pre-transplant diabetes and alteration in glucose metabolism. This allowed us to highlight the impact of prediabetes status and the importance of OGTT as a screening test in post-transplant and potentially pre-transplant. Future randomized controlled trials will be able to resume the topic, including the analysis of the effects of new antidiabetic drugs.

#2015 Burosumab therapy in adult patients with X-linked hypophosphatemia: a three-year follow-up study

Abstract Background and Aims X-linked hypophosphatemic rickets (XLH) arises from mutations in the PHEX gene, resulting in elevated FGF23 levels, renal phosphate loss, hypophosphatemia, low vitamin D, heightened alkaline phosphatase (AP), and associated bone disorders. In challenging the conventional therapy of vitamin D and phosphate supplements, Burosumab, a monoclonal antibody against FGF23, has shown promise in normalizing phosphate and vitamin D levels in pediatric patients. However, its effectiveness in adult patients with established bone lesions remains an area of investigation. This study aims to present the three-year outcomes of Burosumab therapy on both biochemical and clinical aspects in adult XLH patients. Method The study assessed the efficacy of Burosumab in adult XLH patients (age &amp;gt;18, drug-naïve) before and continuously over three years post-therapy. Monthly assessments of biochemical parameters (phosphatemia, alkaline phosphatase, Tubular Maximum Reabsorption of Phosphate per Glomerular Filtration Rate, TMP/GFR) were conducted before the monthly administration of Burosumab, while clinical improvements were monitored every six months using established tests, including the six-minute walk test, UP and go timed test, and WOMAC Index. Burosumab was administered monthly at a consistent dosage of 1 mg/kg throughout the entire follow-up period. Results In a cohort of five genetically diagnosed XLH patients (average age 45 ± 10 years, average weight 60 ± 10 kg), the average monthly Burosumab dose was 60 ± 10 mg. Baseline values and subsequent changes in Ps, TMP/GFR, WOMAC Index, six-minute walk, and UP and go test are presented in Table 1 and Fig. 1. Importantly, no significant adverse events were reported during the initial year of treatment. Conclusion Burosumab therapy demonstrated excellent tolerability and yielded substantial improvements in biochemical parameters (Ps and TMP/GFR), maintaining stability over the entire three-year follow-up. Alkaline phosphatase levels, initially elevated, exhibited a progressive reduction in the second and third years, eventually reaching values within the normal range. Functional indices, reflective of enhanced strength (improved walk test and UP and go timed test) and diminished pain (optimal WOMAC test score), showcased notable improvements in the first year, persisting with stability during the follow-up period, with the exception of the walk test, which demonstrated a gradual and sustained enhancement. The findings suggest that Burosumab is a well-tolerated and effective therapeutic option for adult XLH patients. The observed reduction in alkaline phosphatase after a year of treatment implies a normalization of bone turnover, while the progressive improvement in the walk test indicates a sustained clinical enhancement likely associated with the chronic positive effects of maintaining biochemical stability.

#1891 Evaluating the safety and effectiveness of Tolvaptan for management of adult Korean ADPKD patients (ESSENTIAL study): final report

Abstract Background and Aims Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by Korean FDA in 2015 as a treatment option in autosomal dominant polycystic kidney disease (ADPKD). In order to prescribe Tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease (CKD) stage 1-3. Method Korean patients aged 19 to 50 with rapidly progressing ADPKD were enrolled in the study. The dose titration was performed every one week for a total of 4 weeks. The patient was prescribed Tolvaptan with the maximum tolerable dose up to 120 mg per day. A total duration of Tolvaptan prescription was 24 months. The primary outcome was the incidence of treatment emergent adverse events (TEAE) including drug-induced liver injury (DILI). The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR). Results A total of 117 patients were included in the analysis. Mean age was 38.7 ± 8.4 years old and male were predominant (58.1%). The average TKV was 2066 ± 1094 mL and mean eGFR was 79.7 ± 27.7 mL/min/1.73 m2. Mean duration of Tolvaptan exposure was 1.7 ± 0.6 years and the average daily dose of Tolvaptan was 94.4 ± 24.1 mg/day. A total of 489 treatment-emergent adverse events (TEAE) occurred in 106 (90.6%) patients during study duration. The drug-induced liver injury and aquaresis-related adverse events were two most common adverse events. A total of 17 DILI cases (14.5%) occurred during the study period and mostly within 18-month period. However, liver enzymes were normalized after drug discontinuation The patients with previous history of liver disease as well as those who were prescribed higher dose of Tolvaptan demonstrated higher frequency of DILI. Mean growth rate of TKV after Tolvaptan treatment was 4.5 ± 0.5% and mean eGFR decline rate was -3.0 ± 0.39 mL/min/1.73 m2/year. Comparing with the predicted value from calculation, Tolvaptan attenuated both TKV growth and eGFR decline rate. Conclusion This study is the first post-marketing survey assessing the safety and efficacy of Tolvaptan in Korean ADPKD patients. The incidence of DILI was higher than the previous studies and especially in those with liver disease and higher Tolvaptan prescription dose. While Tolvaptan can effectively reduce TKV and attenuate eGFR decline, the clinicians should be aware of higher frequency of DILI among Korean population.

Adverse Events in Patients Aged 90 Days or Younger Receiving Ketamine in the Emergency Department.

The aim of this study was to identify the incidence of adverse events of ketamine administration in the pediatric emergency department in patients aged 90 days or younger in order to demonstrate the safety and efficacy of administration in this patient population. An 8-year retrospective chart review of patients aged 90 days or younger who received ketamine in the pediatric emergency department was conducted. All patients who met the age criteria were included in this study. Identified routes of ketamine administration included oral, intramuscular, and intravenous. Fourteen patients were identified who met the inclusion criteria and were included in the final analysis. The median age was 45 days old. Indications for ketamine administration included 7 cases for procedural sedation, 5 cases for RSI, and 2 cases for postintubation sedation. The average dose amount (mg/kg) of ketamine administered was 10, 4.43, and 1.59 for oral, intramuscular, and intravenous routes, respectively. Of the 14 patients, 1 patient was identified to have an adverse event to ketamine administration. A transient desaturation and bradycardic event due to laryngospasm was observed during laryngoscopy performed for RSI that was resolved with administration of anticholinergics and paralytics as well as successful intubation and ventilation. In this study, 1 patient suffered an adverse event due to laryngospasm during intubation. In the pediatric population, the incidence of adverse events of ketamine administration has been found to be variable in the current literature, ranging from 0.71% to 7.26%. In our study, an adverse event occurred in 1 out of 14 administrations (7.1%). The incidence of adverse events associated with ketamine administration in our patients aged 90 days or less appeared to be similar to that reported in the general pediatric population.

Development and characterization of a dedicated dose monitor for ultrahigh-dose-rate scanned carbon-ion beams

The current monochromatic beam mode (i.e., uHDR irradiation mode) of the scanned carbon-ion beam lacks a dedicated dose monitor, making the beam control challenging. We developed and characterized a dedicated dose monitor for uHDR-scanned carbon-ion beams. Furthermore, a simple measurable dose rate (dose rate per spot (DRspot)) was suggested by using the developed dose monitor and experimentally validating quantities relevant to the uHDR scanned carbon-ion beam. A large plane-parallel ionization chamber (IC) with a smaller electrode spacing was used to reduce uHDR recombination effects, and a dedicated operational amplifier was manufactured for the uHDR-scanned carbon-ion beam. The dose linearity of the IC was within ± 1% in the range of 1.8–12.3 Gy. The spatial inhomogeneity of the dose response of the IC was ± 0.38% inside the ± 40-mm detector area, and a systematic deviation of approximately 2% was measured at the edge of the detector. uHDR irradiation with beam scanning was tested and verified for different doses at the corresponding dose rates (in terms of both the average dose rate and DRspot). We confirmed that the dose monitor can highlight the characteristics (i.e., dose, dose rate, and dose profile) of uHDR-scanned carbon-ion beams at several dose levels in the monochromatic beam mode.

Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method.

N-Hydroxyapiosporamide (N-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC-MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N-Hydap was metabolically unstable in various microsomes after 1h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. Despite low bioavailability (0.024%), N-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs.