Total Dose Research Articles

Prediction of First-in-Human Dose of Chimeric Antigen Receptor-T (CAR-T) Cells from Mice.

In this study, six scaling methods were evaluated for the prediction of FIH dose for CAR-T cells. The methods were body weight-based fixed exponents such as 1.0 and 0.75, human equivalent dose (HED) using exponents 0.33, two modified HED methods such as using total animal dose (in place of per kg basis) and body surface area in place of body weight using total animal dose with exponent 0.33 and a physiological factor derived from physiological parameters. The FIH doses of six CAR-T cells were predicted in this study. The predicted human doses were compared with the recommended human dose by the US-FDA for four CAR-T cell products, and the literature data were used for the remaining two CAR-T cells. The results indicated that the two modified HED methods and physiological factor are the best and reliable methods for the prediction of FIH dose for CAR-T cells. The proposed methods are simple and accurate in their predictive power and can be used on a spreadsheet.

Fast onset of thrombolytic effect of efficiently inhalable spray-dried rivaroxaban powder formulations

Pulmonary embolism is a critical medical condition and can lead to cardiovascular arrest or death if left untreated. Pulmonary delivery of an anti-coagulant therapeutic could provide a locally limited and efficient therapy, moreover combined with a potentially fast onset of the therapeutic effect that is demanded in emergency situations. Rivaroxaban (riva) was formulated as an inhalable dry powder that can be administered directly to the lungs in order to reach high local drug doses. Particles obtained spray drying dichloromethane-methanol mixtures yielded an aerodynamic diameter of about or smaller than 5 µm and were found to reach an emitted fine particle fraction (FPFEF) of at least 60 %. Pulmonary administration to rats using a dry powder insufflator revealed a nearly immediate therapeutic onset confirmed by the anticoagulant effects after 5 min in the plasma followed by a plateau over the next 4 h. Such rivaroxaban particles were further formulated in binary blends using different lactose carriers (Inhalac® 70/251/400). These interactive blends resulted in high emitted fractions of at least 87 %, and furthermore, the highest fine particle fraction − total dose (FPFTD) (60 %) of all tested formulations was achieved by using Inhalac® 400 as a carrier. The data strongly suggest a significant therapeutic potential of a rivaroxaban dry powder formulation, combining fast onset and a plateau of plasma concentrations turning it into a potential first aid therapeutic.

Preoperative Tumor Growth Rate Does Not Predict Overall or Progression-free Survival in Patients With Glioblastoma.

Presurgical tumor volume progression in glioblastoma (GBM) may be a predictor of survival. This study aims to evaluate the potential impact of preoperative tumor growth and other clinical as well as laboratory parameters on overall survival (OS) of GBM patients. We retrospectively analyzed 98 adult patients with GBM who received two magnetic resonance imaging (MRI) scans between 2013 and 2023, before primary surgery and concurrent Stupp chemoradiotherapy. Tumor growth rates were calculated to classify GBM into slower and faster growing categories. Statistical analyses, including Kaplan-Meier and multivariable Cox regression survival analyses, were performed to evaluate the impact of various clinical and treatment-related factors on OS and progression-free survival (PFS). Slower growing tumors had a significantly longer doubling time than faster growing lesions. Univariable analysis showed no significant differences in OS (p=0.12) or PFS (p=0.4) when analyzed according to tumor growth. When stratified by O6-methylguanin-DNA-methyltransferase (MGMT) status, there were still no differences in OS (p=0.14), but in PFS (p=0.009). In the multivariable Cox regression analysis, radiation dose (p=0.02) and the number of adjuvant cycles of temozolomide (TMZ) (p=0.002) were significantly associated with OS. MGMT status (p=0.02) and the number of adjuvant TMZ cycles (p<0.001) were significantly associated with prolonged PFS. Specific volume growth rate (SVGR), patient age, baseline tumor volume, Karnofsky performance status, extent of resection, and total radiation dose were not significantly associated with PFS. SVGR was not significantly associated with OS or PFS. In contrast, MGMT status, radiation dose, and number of adjuvant TMZ cycles were identified as predictors of treatment outcomes. These factors can guide physicians when designing personalized treatment concepts for patients with GBM.

Impact of Omicron Variant Infection on Female Fertility and Laboratory Outcomes: A Self-Controlled Study.

Investigating the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on female fertility and laboratory outcomes in patients undergoing assisted reproductive technology (ART) treatment who were initially uninfected but later became infected. This self-controlled study included 197 patients who underwent repeated oocyte retrieval before and after SARS-CoV-2 infection between March 2021 and April 2023, of which 117 used the same ovarian stimulation protocol within a consistent age range. We evaluated the ovarian reserve, ovarian response, and laboratory outcomes in patients before and after SARS-CoV-2 infection. The ovarian reserve (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estrogen [E2], anti-Müllerian hormone [AMH], antral follicle count [AFC]), ovarian response (total Gn dosage, duration of Gn administration, number of follicles ≥14mm on trigger day, number of retrieved oocytes), and laboratory outcomes (cleavage stage good-quality embryo rate, blastocyst formation rate, and cycle freezing rate) showed no significant differences before and after SARS-CoV-2 infection in 117 patients (p>0.05). When stratified by age, the ≤ 35years group showed a higher two pronuclei (2PN) fertilization rate post-infection, while the >35years group had increased mature metaphase II (MII) oocyte and blastocyst stage good-quality embryo rates. Additionally, upon stratified by the time interval between SARS-CoV-2 infection and ART treatment, in the ≤ 3months group, there was an increased post-infection MII oocyte rate, 2PN fertilization rate, and blastocyst stage good-quality embryo rate. Meanwhile, no significant differences were found in any indicators when the interval exceeded threemonths. Our study suggested that undergoing IVF/ICSI treatment after recovering from COVID-19 may not adversely affect female fertility and laboratory outcomes.

PE/PP fibrous adsorbents with bifunctional groups of tertiary amine and phosphate prepared by electron beam induced co-grafting for heavy metal adsorption of both cationic and anionic forms in acidic conditions.

A novel fabric adsorbent having bifunctional groups of tertiary amine and phosphate was prepared by co-graft polymerization of 2-diethylaminoethyl methacrylate (NMA) and 2-hydroxyethyl methacrylate phosphate (PMA) onto a polyethylene/polypropylene nonwoven fabric (PE/PP NF) under low-energy electron beam acceleration. The process involved pre-irradiating the fabric and immersing it in the comonomer solution for grafting. The kinetics of radiation-induced graft polymerization at a total dose of 100 kGy was investigated. For pre-irradiation at 100 kGy, the optimum condition offering highest degree of grafting was at 12 wt% of NMA, 8 wt% of PMA and 4 h of reaction time. The adsorption of anions using hydrogen chromate (HCrO4−) or Cr(VI) and cations using lead (Pb(II)), cadmium (Cd(II)) and copper (Cu(II)) in aqueous solution was carried out. The results demonstrated that the bifunctional adsorbent was able to adsorb both heavy metal anionic and cationic ions from water. The co-grafted adsorbents with tertiary amine and phosphate were able to adsorb 85% Cr(VI) anion and 29% Pb(II) cations from mixed Cr(VI) and Pb(II) solution at pH 3.0 and 71% Pb(II), 13% Cd(II) and 31 % Cu(II) from mixed Pb(II), Cd(II) and Cu(II) solution at pH 5.0. The unique achievement of this study is its hypothesis that a bifunctional adsorbent can be prepared from radiation-induced graft polymerization of two different monomers onto NF, along with proof that the prepared bifunctional adsorbent can actually absorb both cationic or anionic heavy metals forms. Additionally, the adsorbent's preparation offers a rapid and straightforward one-step grafting technique. Therefore, the new bifunctional adsorbents can remove heavy metal ions in aqueous solution, either in the cation or anion form, thus offering highly promising applications in industrial wastewater treatment.

Gamma radiation induced optimized synthesis of amine functionalised poly-glycidyl methacrylate grafted poly-propylene non-woven fabric and its adsorption behaviour towards aqueous Pb(II)

Comprehensive optimization of the functionalization of polypropylene (PP) non-woven fabric through gamma irradiation-induced graft polymerization of glycidyl methacrylate (GMA), results in a material having high grafting yield. The technique, utilizing a mutual irradiation method, produced poly-GMA (PGMA) grafted PP fabric with a remarkable grafting yield of 125 % in a 1:1 acetone–water mixture, subjected to 25 kGy of total dose at a dose rate of 5 kGyh−1. The enhancement of the amination process utilizing PGMA-grafted PP was investigated with polyamines. Under the optimized conditions, the diethylene triamine (DETA) functionalized variant was identified as an effective adsorbent for aqueous Pb2+ ions. The optimized adsorbent exhibited a high saturation capacity of approximately 230 mgg−1 for Pb2+ ions, demonstrating rapid kinetics at near-neutral pH and 25 °C. This low cost innovative material holds significant promise for effective lead removal from drinking water and industrial wastewater, offering a sustainable economical solution for environmental remediation.

Duration of morning hyperinsulinemia determines hepatic glucose uptake and glycogen storage later in the day.

The second-meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 h of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, the same total amount of insulin was administered either over 2 h in the first (Ins2h-A) or second (Ins2h-B) half of the morning or over the entire 4 h (Ins4h) of the morning. In the 4-h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared with the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp.NEW & NOTEWORTHY Morning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulin's ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

The Efficacy Research of Prophylactic PEG-rhG-CSF in Preventing Neutropenia in Early-Stage Breast Cancer Patients Treated With Docetaxel-Based Chemotherapy: A Retrospective Analysis

PurposeDocetaxel-based chemotherapy regimens (DBRs) are commonly used in the treatment of early-stage breast cancer (EBC). The prophylactic use of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been shown to reduce the incidence of neutropenia induced by DBRs. However, the clinical usage of PEG-rhG-CSF in EBC patients undergoing DBRs in China remains unclear. MethodsThis retrospective study was conducted in 137 EBC patients receiving DBRs from September 2022 to February 2024. We compared the incidence of chemotherapy-induced neutropenia (CIN) between patients who was treated with prophylactic PEG-rhG-CSF or not by complete blood counts, evaluating the effectiveness of PEG-rhG-CSF in preventing CIN. Prophylactic PEG-rhG-CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24–48 h following chemotherapy. Meanwhile, we also collected basic patient information, the area under time-concentration curve of docetaxel, and liver and kidney function indicators. Multivariate logistic regression and Receiver operating characteristic (ROC) curve analysis were employed to explore independent factors influencing neutropenia. FindingsIn this study, 87 of 137 EBC patients were administrated with prophylactic PEG-rhG-CSF, while 50 were not. Compared to patients who did not receive PEG-rhG-CSF, those who received prophylactic injections had a significantly lower incidence of grade 3–4 CIN (20% vs. 4.6%, P < 0.05). Higher body surface area (BSA), lower body mass index (BMI), elevated alanine aminotransferase (ALT), and nonprophylactic use of PEG-rhG-CSF were found to be positively correlated with CIN occurrence. ROC curve analysis indicated an area under the curve of 0.756 for predicting CIN in EBC patients when BSA was 1.66 m², BMI was 24.8 kg/m², and ALT was 41 U/L, with a sensitivity of 73.08% and specificity of 73.87%. ImplicationsProphylactic use of PEG-rhG-CSF significantly reduces the incidence of CIN, particularly grades 3 and 4. BSA, BMI, ALT, and PEG-rhG-CSF prophylaxis are independent influencing factors for the occurrence of neutropenia.

Ultrasound-Guided Axillary Access Using a Micropuncture Needle Versus Conventional Cephalic Venous Access for Implantation of Cardiac Devices: A Single-Center Randomized Trial

(1) Background: Ultrasound-guided axillary (USAX) vein puncture is a relatively new method to obtain venous access for the implantation of cardiac implantable electronic devices (CIED). However, its use is limited as most of the operators are not familiar with this technique. Our aim was to investigate the safety and efficacy of the USAX compared with the traditional cephalic vein dissection for venous access in CIED implantation. (2) Methods: This was a single-center, randomized, controlled, superiority trial. A total of 114 patients were randomized (1:1 ratio) to either USAX (u/s axillary group; 59 patients) or cephalic vein access (cephalic group; 55 patients). The primary study endpoint was defined as successful placement of all leads via the chosen access. Secondary study endpoints included time from local anesthetic injection to lead advancement in the SVC, total procedure time (skin to skin), procedure-related complications and pain perception. (3) Results: USAX was superior to cephalic access in terms of primary endpoint (OR: 4.3, 95% CI: 1.3, 14.0; p = 0.012). Total procedure duration was higher in the cephalic group (55.15 ± 16.62 vs. 48.35 ± 12.81 min, p = 0.017) but there was neither a significant difference in fluoroscopy time (p = 0.872) nor in total radiation dose (p = 0.815). The level of pain was higher in the cephalic group (p = 0.016), while the rates of complications were similar in both groups (p &gt; 0.05). (4) Conclusion: USAX was superior to cephalic access regarding success rate, total procedure duration and level of pain, while having no difference in complication rates.

Response of Spontaneous Oral Tumors in Canine Cancer Patients Treated with Stereotactic Body Radiation Therapy (SBRT).

To describe outcome and toxicity for dogs with oral tumors, specifically oral malignant melanoma (OMM), squamous cell carcinoma (SCC), and soft tissue sarcoma (STS) after stereotactic body radiation therapy (SBRT). A single institution retrospective study was conducted. Outcomes were analyzed using Kaplan-Meier analysis and Cox proportional hazard analysis. Treatment responses at different time points were evaluated with Pearson's Chi-squared test to identify prognostic factors. Acute and late toxicities were recorded according to VRTOG criteria and were analyzed to identify risk factors. Adverse events other than acute and late toxicities were recorded. A total of 98 patients met the inclusion criteria (OMM n = 37; SCC n = 18; STS n = 43). The SBRT prescription was 1-6 fractions, with a total dose range of 12-40 Gy. Local progression-free survival (PFS) for OMM, SCC, and STS was 187, 253, and 161 days, respectively. Overall PFS was 152 days and median survival time (MST) was 270 days, with no statistical difference between tumor types. The presence of lymph node metastasis and the use of elective nodal irradiation (ENI) were associated with shorted PFS and MST. Severe acute toxicities to organs at risk affected 10/85 (11.8%) of patients. Osteoradionecrosis and oronasal fistula formation occurred in 23/81 (28.4%) of patients and was significantly associated with tumor type (SCC, P = 0.006). BRT can be offered as a treatment option for oral tumors in dogs. Toxicities were common and warrant risk factor considerations and adjustments to current SBRT protocols.

Эффективность алгоритма назначения диуретической терапии под контролем натрийуреза у пациентов с острой декомпенсацией сердечной недостаточности в отделении реанимации и интенсивной терапии: проспективное интервенционное контролируемое исследование

INTRODUCTION: The European Society of Cardiology suggests using early and repeated assessment of sodium content in urine in patients admitted with heart failure to evaluate diuretic therapy. OBJECTIVES: Evaluation of the effectiveness of the algorithm for diuretic therapy under the control of natriuresis in patients with acute decompensation of chronic heart failure (ADCHF) in the intensive care unit (ICU). MATERIALS AND METHODS: A prospective study included 150 patients hospitalized in the ICU with ADCHF. All patients underwent standard physical, laboratory and instrumental examinations. The starting dose of furosemide was 20 mg i/v. After 2 hours, a quantitative assessment of sodium in urine was performed. If the natriuresis was ≥ 70 mmol/l, furosemide was continued at the same dose every 12 hours. If the natriuresis was &lt; 70 mmol/L, the dose of furosemide was doubled. Natriuresis was monitored every 12 hours. RESULTS: In the natriuresis-controlled group the duration of patients' stay in the ICU was significantly shorter (3 vs. 5 days, p = 0.01), achieving euvolemia was significantly more frequent (42 % vs. 12 %, p &lt; 0.05), the daily diuresis in patients was significantly higher on more daily (120 mg vs. 80 mg, p &lt; 0.05) and the total dose of furosemide (420 mg vs. 240 mg, p &lt; 0.05). There was a pronounced decrease in congestion in the group of patients with natriuresis control with less pulmonary (number of B-lines 9.6 ± 1.2 versus 23.4 ± 2.5) and venous congestion (GRADE 0–56 %, 1–20 %, 2–24 %, 3–0 % against 0–20 %, 1–35 %, 2–18 %, 3–27 %) on the 3rd day of hospitalization. CONCLUSION: The inclusion of an algorithm for diuretic therapy under the control of natriuresis in patients with ADCHF in the ICU is effective and contributes to a more pronounced and rapid reduction of congestion, as well as a 1.5-fold reduction of time in the ICU.

COMPARISON OF TWO DIFFERENT DOSES OF ORAL GABAPENTIN FOR POST OPERATIVE ANALGESIA IN LOWER LIMB SURGERY UNDER SPINAL ANAESTHESIA

Background: Pre-emptive analgesia is a technique of pain control where treatment is initiated before intervention and operational during the surgical procedure in order to reduce the physiological consequences of nociceptive transmission provoked by the procedure. Gabapentin has demonstrated analgesic effects in clinical trials as a preemptive analgesic in acute postoperative pain management with very few side effects. Owing to the protective effect of gabapentin on the nociceptive pathways, preemptive analgesia has the potential to be more effective and hence reduce postoperative pain and development of chronic pain. Objective: We therefore designed this study to compare two different doses of Oral Gabapentin (300mg and 600mg) given as pre-emptive analgesic for post-operative pain relief in lower limb surgeries under spinal anaesthesia. Method: After the approval from ethical committee this prospective randomized double blinded clinical study was conducted over a period of two years in department of anaesthesia in M.G.M.s medical college, Aurangabad. Randomly allocated two groups were given Oral Gabapentin 300mg and 600mg respectively, one hour prior to giving spinal anaesthesia for post operative analgesia in lower limb surgeries. Conclusion: There is no statistically significant difference between group G300 (gabapentin 300mg) and group G600 (gabapentin 600mg) regarding age, gender, duration of analgesia (i.e. demand for first rescue analgesic), total dose of analgesics in first twenty four hours after surgery, duration of sensory block (i.e. L1 regression), highest ramsay sedation score and VAS scores. No significant difference was seen in cases hemodynamic stability and incidence of side effects.

Optimization of Glibenclamide Loaded Thermoresponsive SNEDDS Using Design of Experiment Approach: Paving the Way to Enhance Pharmaceutical Applicability.

Thermoresponsive self-nanoemulsifying drug delivery systems (T-SNEDDS) offer a promising solution to the limitations of conventional SNEDDS formulations. Liquid SNEDDS are expected to enhance drug solubility; however, they are susceptible to leakage during storage. Even though solid SNEDDS offers a solution to this storage instability, they introduce new challenges, namely increased total dosage and potential for drug trapping within the formulation. The invented T-SNEDDS was used to overcome these limitations and improve the dissolution of glibenclamide (GBC). Solubility and transmittance studies were performed to select a suitable oil and surfactant. Design of Experiments (DoE) software was used to study the impact of propylene glycol and Poloxamer 188 concentrations on measured responses (liquefying temperature, liquefying time, and GBC solubility). The optimized formulation was subjected to an in vitro dissolution study. The optimized T-SNEDDS consisted of Kolliphor EL and Imwitor 308 as surfactants and oil. The optimized propylene glycol and Poloxamer 188 concentrations were 13.7 and 7.9% w/w, respectively. It exhibited a liquefying temperature of 35.0 °C, a liquefying time of 119 s, and a GBC solubility of 5.51 mg/g. In vitro dissolution study showed that optimized T-SNEDDS exhibited 98.8% dissolution efficiency compared with 2.5% for raw drugs. This study presents a promising approach to enhance pharmaceutical applicability by resolving the limitations of traditional SNEDDS.

A Comparative Study of Magnesium Sulfate, Lignocaine, and Propofol for Attenuating Hemodynamic Response During Functional Endoscopic Sinus Surgery Under General Anaesthesia: A Prospective Randomized Trial.

This study functional endoscopic sinus surgery (FESS) is a surgical procedure requiring minimal bleeding to optimize the surgical field. This study aimed to evaluate the effectiveness of magnesium sulfate, lignocaine, and propofol in attenuating hemodynamic response. The primary objective of this study was to compare the efficacy of these agents in reducing hemodynamic response. The secondary objectives included assessing the quality of the surgical field, recovery time, and total neuromuscular dose. We randomly allocated 105 patients scheduled for FESS into three groups: lignocaine, propofol, and magnesium sulfate. Heart rate and mean arterial pressure were recorded every 5 min for the first 30 min, followed by measurements every 10 min at the end of the procedure. Moreover, recovery time, total neuromuscular blocking dose, and surgical field score were noted upon completion of the procedure. Statistical analysis was conducted using the number cruncher statistical systems version 9.0.8 software. All three groups showed comparable hemodynamic response and surgical field scores. The recovery time was notably longer in the magnesium sulfate group [10.94 min (2.45)] than in the lignocaine [4.37 min (1.03)] [95% confidence interval (CI) -7.32, -5.83; P=0.000] and propofol groups [4.60 min (0.60)] (95% CI 5.60, 7.095; P=0.000). Moreover, the total neuromuscular blocking agent used was significantly lower in the magnesium sulfate group [5.89 mg (0.47)] than in the lignocaine [6.26 mg (0.56)] (95% CI 0.66, 0.03; P=0.035). Propofol, magnesium sulfate, and lignocaine exerted equal efficacy in attenuating hemodynamic responses during surgery and ensuring a satisfactory surgical field. However, magnesium sulfate led to significantly longer recovery times compared with propofol and lignocaine. In addition, magnesium sulfate required a significantly lower total dose of neuromuscular blocking agents than lignocaine.

Traditional Versus Distal Radial Access for Coronary Diagnostic and Revascularization Procedures: Final Results of the TENDERA Multicenter, Randomized Controlled Study.

Traditional transradial access (TRA) is widely used for coronary and non-coronary interventions with significant improvements in procedural outcomes; however, it is associated with RAO that precludes repeat use of the same artery for possible future TRI and other purposes. Distal radial access (DRA) has been proposed as an effective alternative to decrease RAO rates. Published literature describing the RAO rate after DRA versus TRA from various RCT and clinical registries has shown conflicting results. This study compared the forearm radial artery occlusion (RAO) rate assessed by Doppler ultrasound between distal and conventional radial access at 1-year follow-up after the initial procedure. TENDERA was a multicenter, randomized controlled study comparing DRA versus TRA for coronary diagnostic and interventional procedures using 5 or 6F hydrophilic-coated sheaths. The primary endpoint was forearm RAO at 12 months after radial access. The secondary endpoints included puncture time, sheath insertion and total procedure time, radiation dose, and vascular access site-related complications. Eight hundred and fifty patients were randomized to either TRA (n = 418) and DRA (n = 432) groups. In the intention-to-treat analysis, the rate of forearm RAO at 12 months was observed in 39 patients (4.6%) and was significantly reduced in the DRA group compared with the TRA group (2.5% vs. 6.7%, RR 2.59 [95% CI 1.29-5.59], p = 0.010). Analysis in per protocol population has shown consistent results with forearm RAO rate 2.8% in the DRA group versus 6.5% in the TRA group (p = 0.008). The crossover rate was higher (4.6% vs. 1%, p = 0.013) and median hemostasis time was shorter (156.5 min vs. 180 min, p < 0.001) with DRA. Overall bleeding (BARC 1-2) and postprocedure hematoma > 5 cm occurred less frequently in the DRA group compared with the TRA group (3.2% vs. 20.5%, p < 0.001% and 9.0% vs. 27.0%, p < 0.001, respectively). No significant differences were observed in total procedure time and radiation dose between groups. DRA for coronary diagnostic and interventional procedures is associated with reduced forearm RAO rate and shorter hemostasis time, but a longer sheath insertion time and higher crossover rate compared with TRA. ClinicalTrials.gov: NCT04211584.

Endoscopic transnasal and transoral resection of the odontoid process and C1 combined with occipitocervical fusion for osteoradionecrosis of the upper cervical spine: a case report and literature review

BackgroundOsteoradionecrosis (ORN) of the upper cervical spine is a rare but severe complication of head and neck cancer radiotherapy. To raise awareness of this condition, we describe a patient with a history of nasopharyngeal carcinoma who developed ORN of the upper cervical spine and review the published literature reporting surgical management.Case presentationA 59-year-old female patient with persistent neck pain for one month and limited range of neck motion who had undergone radiotherapy for nasopharyngeal carcinoma with a total dose of 69.96 Gy 15 years ago presented to our hospital. The patient underwent endoscopic transnasal and transoral resection of the odontoid process and C1 anterior arch, combined with occipitocervical fusion. To better understand surgical management of ORN of the upper cervical spine, the literature published in the PubMed, Ovid MEDLINE, and Embase databases was reviewed. Our patient experienced alleviation of cervical pain and did not exhibit any postoperative complications. Since 2005, 11 cases of surgical management of ORN of the upper cervical spine (including the present case) have been published. Basilar invagination and/or atlantoaxial subluxation were observed in 4 /11 cases. Endoscopic procedures were performed in 4/11 cases, and occipitocervical fusion was performed in 8 /11 cases.ConclusionEndoscopic transnasal and transoral resection of the odontoid process and C1 anterior arch is a safe and effective treatment option for ORN of the upper cervical spine. Occipitocervical fusion is useful in patients with basilar invagination and atlantoaxial subluxation.

Improved heterogeneity handling in the collapsed cone dose engine for brachytherapy.

Model-based dose calculation algorithms (MBDCA), such as the Advanced Collapsed cone Engine (ACE) in Oncentra Brachy® can be used to overcome the limitations of the TG-43 formalism. ACE is a point kernel superposition algorithm that calculates the total dose separated into primary, first-scatter, and multiple-scatter dose. Albeit ACE yields accurate results under most circumstances, several studies have reported underestimations of the dose to cortical bone. These underestimations are likely caused by approximations in the handling of multiple-scatter dose for non-water media. Such would result in noticeable deviations where the multiple-scatter is a considerable fraction of the total dose, that is, at greater distances from the source. To improve and test the accuracy of the multiple-scatter dose component in the ACE algorithm to remedy its inaccuracy for non-water geometries. A careful analysis of the transport and absorption of the multiple-scatter energy fluence revealed an inconsistency in the scaling of energy absorption ratios for non-water media of the multiple-scatter kernel. We implemented an updated algorithm version, ACEcorr, and tested it for three different geometries. All had a single 192Ir-source at the center of a cubic water phantom with a box-shaped heterogeneity of either cortical bone or air, positioned at different distances from the source. Dose distributions for the three cases were calculated with ACE and ACEcorr and compared to Monte Carlo simulations, using the percentage dose difference ratio as figure-of-merit. All dose calculation methods scored separately the dose deposited by primary, first-scattered, and multiple-scattered photons. The accuracy of the updated algorithm ACEcorr was superior to ACE. In the cortical bone heterogeneity, the mean percentage dose difference ratio for the total dose improved from to (in the worst case) by our update. Less impact was seen in the air heterogeneity, where both ACE and ACEcorr deviated less than 2% from the Monte Carlo results. The algorithm update mainly concerns the multiple-scattered dose component, but an accompanying data processing update also had a small effect ( 0.5% difference) on the primary and first-scattered dose. The calculation times were not affected. The updates to ACE improved the accuracy of multiple-scatter dose calculation for non-water media, without increasing calculation times.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Improving culprit artery identification with intraprocedural cone-beam CT aortography and its clinical impact in bronchial artery embolization.

To evaluate the impact of intraprocedural cone-beam CT (CBCT) aortography on culprit artery identification and clinical outcomes in patients undergoing bronchial artery embolization (BAE). Two hundred eighty-two patients with 317 BAE procedures were retrospectively reviewed. Patients who underwent preprocedural chest CT angiography (CTA) without intraprocedural CBCT aortography were categorized as Group A (n = 177). Patients who underwent both preprocedural chest CTA and intraprocedural CBCT aortography were categorized as Group B (n = 105). Whether CBCT can provide improved culprit artery identification and whether this improvement has a clinical impact were evaluated by comparing the two Groups. In Group B, CBCT aortography detected more culprit non-bronchial systemic arteries originating from the subclavian arteries compared to chest CTA (16 vs 3, p = 0.026), and the average number of embolized vessels was significantly higher than in Group A (2.47 ± 1.61 vs 2.03 ± 1.17, p = 0.016), while the procedure time was shorter (37.4 ± 22.0 vs 43.6 ± 22.7 min, p = 0.024). The recurrent hemoptysis rate was lower in Group B (17.5% vs 8.7%, p = 0.041), and the proportion of patients requiring subsequent procedures was significantly lower (12.4% vs 4.8%, p = 0.035). The changes in estimated glomerular filtration rate before and 3 days after the procedure (0.1 ± 12.8 vs 0.3 ± 11.0 mL/min/1.73 m2, p = 0.909) and total dose area product (DAP, 6119.5 ± 5725.7 vs 6906.2 ± 5978.6 uGym2, p = 0.279) were not significantly different between the two groups. BAE with intraprocedural CBCT aortography enabled the embolization of more culprit arteries, leading to lower recurrent hemoptysis rates without increasing the risk of renal deterioration and radiation hazards when compared to procedures without it. Question Does intraprocedural CBCT aortography improve culprit artery detection and clinical outcomes in BAE for hemoptysis? Findings CBCT aortography significantly improved the detection of additional culprit arteries, especially from non-bronchial systemic arteries, increasing the number of vessels treated during BAE. Clinical relevance Using CBCT aortography during BAE results in better long-term outcomes by reducing recurrent hemoptysis and the need for additional procedures, without increasing the risk of renal impairment.

A Novel Approach for Predicting the Mid–Long-Term Radiation Dose in the Case of a Hypothetical STSBO Nuclear Accident for an Operating Nuclear Power Plant

Four severe nuclear accident scenarios have been identified for operating nuclear power plants (ONPPs). However, there is a research gap in predicting the mid–long-term radiation doses for these scenarios. This study aims to address this gap by proposing a novel approach for predicting the mid–long-term radiation dose in the case of a hypothetical short-term station blackout (STSBO) scenario, one of the aforementioned scenarios. Firstly, the Weather Research and Forecasting (WRF) model was coupled with the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) (WRF-HYSPLIT) model to establish an atmospheric transport and diffusion model for airborne radionuclides, and the regularity of the atmospheric transport and diffusion for the airborne radionuclides was determined. Subsequently, the Residual Radioactive Material Guidelines (RESRAD) OFFSITE (RESRAD-OFFSITE) code was utilized to establish a radiation dose model for predicting the mid–long-term radiation dose resulting from the airborne radionuclides, and the evolution of the mid–long-term radiation dose was analyzed. Finally, the proposed approach was applied to an ONPP, and the results were used to predict the mid–long-term public radiation dose. The results indicated that the total radiation dose would be lower than the dose limit recommended by the International Commission on Radiological Protection (1 mSv/yr) from the second month to the 100th year after the hypothetical STSBO nuclear accident, and the total radiation dose would decrease slowly over time. Recommendations are made for offsite emergency response measures. These research findings can assist ONPPs in analyzing their environmental impacts in the event of an STSBO scenario.