Safety Assessment Research Articles

Functional genomic characterization reveals the probiotic tendency and safety assessment of Exiguobacterium acetylicum G1–33 isolated from the gut of the hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂)

Functional genomic characterization reveals the probiotic tendency and safety assessment of Exiguobacterium acetylicum G1–33 isolated from the gut of the hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂)

Safety assessment of tranexamic acid: real-world adverse event analysis from the FAERS database

BackgroundIn recent years, with the continuous expansion of the application scope of Tranexamic acid (TXA), its usage has surged. Despite numerous studies demonstrating its powerful efficacy, concerns regarding its adverse reactions persist, necessitating comprehensive safety assessment. This study analyzed real-world data from the U.S. Food and Drug Administration to investigate TXA-related adverse events, aiming to elucidate its safety and optimize patient treatment.MethodsThe adverse drug event data concerning TXA from 2004 Q1 to 2023 Q3 were collected. Following data standardization, a variety of signal quantification techniques, including the reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and empirical Bayes geometric mean were used for analysis.ResultsAfter analyzing 16,692,026 adverse event reports, a total of 1,574 cases of adverse events related to TXA were identified, spanning 23 system organ classes and 307 preferred terms. In addition to the common thrombosis-related Vascular disorders (n = 386) and Cardiac disorders (n = 377), adverse reactions in the Nervous system disorders category were also observed (n = 785), including Myoclonus (n = 70), Status epilepticus (n = 43), and Myoclonic epilepsy (n = 17). Furthermore, this study uncovered adverse effects such as Renal cortical necrosis, Hepatic cyst rupture, and Vascular stent stenosis, which were not previously mentioned in the instructions. Although these occurred infrequently, they exhibited high signal strength. Both Retinal artery occlusion and Vascular stent thrombosis disorder were frequent and exhibited high signal strength as well. It is worth noting that 78 cases of adverse reactions were caused by confusion between incorrect product administration.ConclusionOur research suggests that TXA has some adverse reactions that are being overlooked. As a cornerstone medication in hemorrhage treatment, it’s crucial to monitor, identify, and address these adverse reactions effectively.

Concurrent nimotuzumab and intensity-modulated radiotherapy for elderly patients with locally advanced nasopharyngeal carcinoma.

Because of the common physical condition, reduced organ function, and comorbidities, elderly patients with nasopharyngeal carcinoma (NPC) are often underrepresented in clinical trials. The optimal treatment of elderly patients with locally advanced NPC remains unclear. The purpose of this study was to evaluate the efficacy of concurrent nimotuzumab combined with intensity-modulated radiotherapy (IMRT) in elderly patients with locally advanced NPC. We conducted a single-arm, phase II trial for elderly patients with stage III-IVA NPC (according to UICC-American Joint Committee on Cancer TNM classification, 8th edition). All patients received concurrent nimotuzumab (200 mg/week, 1 week prior to IMRT) combined with IMRT. The primary end-point was complete response (CR) rate. The secondary end-points were survival, safety, and geriatric assessment. Between March 13, 2017 and November 12, 2018, 30 patients were enrolled. In total, 20 (66.7%) patients achieved CR, and objective response was observed in 30 (100.0%) patients 1 month after radiotherapy. The median follow-up time was 56.05 months (25th-75th percentile, 53.45-64.56 months). The 5-year locoregional relapse-free survival, distant metastasis-free survival, cancer-specific survival, disease-free survival, and overall survival were 89.4%, 86.4%, 85.9%, 76.5%, and 78.8%, respectively. Grade 3 mucositis occurred in 10 (33%) patients and grade 3 pneumonia in 3 (10%) patients. Concurrent nimotuzumab combined with IMRT is effective and well-tolerated for elderly patients with locally advanced NPC.

Safety Assessment Method of High-speed Rail Interval Structure Based on Weighted Bayesian Network

Safety Assessment Method of High-speed Rail Interval Structure Based on Weighted Bayesian Network

Challenges of the Application of In Vitro Digestion for Nanomaterials Safety Assessment

Considering the increase in the production and use of nanomaterials (NM) in food/feed and food contact materials, novel strategies for efficient and sustainable hazard characterization, especially in the early stages of NM development, have been proposed. Some of these strategies encompass the utilization of in vitro simulated digestion prior to cytotoxic and genotoxic assessment. This entails exposing NM to fluids that replicate the three successive phases of digestion: oral, gastric, and intestinal. Subsequently, the resulting digestion products are added to models of intestinal cells to conduct toxicological assays, analyzing multiple endpoints. Nonetheless, exposure of intestinal cells to the digested products may induce cytotoxicity effects, thereby posing a challenge to this strategy. The aim of this work was to describe the challenges encountered with the in vitro digestion INFOGEST 2.0 protocol when using the digestion product in toxicological studies of NM, and the adjustments implemented to enable its use in subsequent in vitro biological assays with intestinal cell models. The adaptation of the digestion fluids, in particular the reduction of the final bile concentration, resulted in a reduced toxic impact of digestion products.

Research on safety condition assessment methodology for single tower steel box girder suspension bridges over the sea based on improved AHP-fuzzy comprehensive evaluation

In order to propose a reliable method for assessing the safety condition for single-tower steel box girder Suspension bridges over the sea, a condition monitoring system is established by installing sensors on the bridge structure. The system is capable of gathering monitoring data that influence the safety status of the bridge. These include cable tension, load on the main tower and pylon, bearing displacement, wind direction, wind speed, and ambient temperature and humidity. Furthermore, an improved Analytic Hierarchy Process (AHP) algorithm is developed by integrating a hybrid triangular fuzzy number logic structure. This improvement, coupled with comprehensive fuzzy evaluation methods, improves the consistency, weight determination, and security evaluation capabilities of the AHP algorithm. Finally, taking the No.2 Channel Bridge as an example and based on the data collected by the health monitoring system, the application of the safety assessment method proposed in this paper provides favorable results in evaluating the overall safety status of the bridge in practical engineering applications. This provides a basis for management decisions by bridge maintenance departments. This project confirms that the research results can provide a reliable method for assessing the security status of relevant areas.

Advancing RNAi for Sustainable Insect Management: Targeted Solutions for Eco-friendly Pest Control

Insect pests pose significant challenges to agriculture, forestry, and public health, causing substantial economic losses and threats to food security. Traditional pest control methods, such as chemical insecticides, have limitations due to the development of insecticide resistance, negative impacts on non-target organisms, and environmental concerns. RNA interference (RNAi) has emerged as a promising approach for developing targeted and environmentally safe insect control strategies. This review explores the potential of RNAi-based methods for pest management, discussing the mechanism of RNAi in insects, factors influencing its efficiency, and various delivery strategies. We highlight the advantages of RNAi, such as species-specific targeting and reduced off-target effects, while also addressing challenges and limitations, including variability in RNAi efficiency among insect species and potential resistance development. The review examines the environmental safety and risk assessment of RNAi-based insect control, current applications, and future prospects. We also discuss the socio-economic impact and public perception of RNAi technology, as well as research gaps and future directions. The integration of RNAi-based insect control into integrated pest management programs is crucial for developing sustainable and effective pest control solutions. By providing a comprehensive overview of the current state and future potential of RNAi-based insect control, this review aims to inform research, policy, and practice in this rapidly evolving field.

Real-world evaluation of nivolumab in patients with non-nasopharyngeal recurrent or metastatic head and neck cancer: a retrospective multi-center study by the Turkish Oncology Group (TOG).

Head and neck cancers (HNCs) represent a significant global health concern due to high morbidity and mortality rates. Despite therapeutic advances, the prognosis for advanced or recurrent cases remains challenging. Nivolumab obtained approval for recurrent or metastatic HNC based on the Phase III CheckMate 141 trial. This study aimed to evaluate the real-world outcomes of nivolumab in patients with non-nasopharyngeal HNC. In this multicenter retrospective study, we analyzed 124 patients with recurrent or metastatic non-nasopharyngeal HNC who received nivolumab in the second-line setting and beyond. Data were collected from 20 different cancer centers across Turkey. The effectiveness and safety of the treatment and survival outcomes were evaluated. Nivolumab exhibited favorable clinical responses, yielding an objective response rate of 29.9% and a disease control rate of 55.7%. Safety assessments revealed a generally well-tolerated profile, with no instances of treatment discontinuation or mortality due to side effects. Survival analysis disclosed a median overall survival (OS) of 11.8 (95% CI 8.4-15.2) months. Multivariate analysis revealed that ECOG-PS ≥ 1 (HR: 1.64, p = 0.045), laryngeal location (HR: 0.531, p = 0.024), and neutrophil-to-lymphocyte ratio > 3.5 (HR: 1.97, p = 0.007) were independent predictors of OS. Nivolumab is an effective and safe treatment option for patients with recurrent or metastatic non-nasopharyngeal HNC in real-world settings. Further studies are needed on factors affecting response to treatment and survival outcomes.

Unveiling Safety Concerns in Brazilian Artisanal Cheeses: A Call for Enhanced Ripening Protocols and Microbiological Assessments

Brazilian artisanal cheeses have recently gained significant commercial prominence and consumer favor, primarily due to their distinctive sensory attributes and cultural and historical appeal. Many of these cheeses are made with raw milk and undergo a relatively short ripening period, sometimes ranging from 4 to 8 days, though it is usually shorter than the period stated by law. Moreover, there is insufficient evidence regarding the efficacy of a short ripening period in reducing certain zoonotic foodborne pathogens, such as Brucella spp., Coxiella burnetiid, and Mycobacterium bovis (as part of the Mycobacterium tuberculosis complex). Additionally, a literature analysis revealed that the usual ripening conditions of Brazilian artisanal cheeses made with raw milk may be inefficient in reducing the levels of some hazardous bacterial, including Brucella spp., Listeria monocytogenes, coagulase-positive Staphylococcus, Salmonella, and Coxiella burnetti, to the acceptable limits established by law, thus failing to ensure product safety for all cheese types. Moreover, the assessment of the microbiological safety for this type of cheese should be broader and should also consider zoonotic pathogens commonly found in bovine herds. Finally, a standardized protocol for evaluating the effectiveness of cheese ripening must be established by considering its peculiarities.

Atrial fibrillation cryoablation guided by pressure waveform: a prospective multicentre registry

Abstract Background Cryoballoon ablation (CA) procedures require optimal occlusion of the pulmonary veins (PV), which is conventionally evaluated by iodine contrast injection through the catheter tip. This technique has some weaknesses such as risk of allergic reactions, nephrotoxicity, requirement of fluoroscopy (sometimes at high doses), requirement of a second operator, among others. PV pressure waveform assessment is an alternative method for confirming occlusion, however, multicentre assessment of periprocedural efficacy and safety is lacking. Purpose To describe the intra-procedural performance and safety of routine pressure-based CA. Methods In this independent prospective multicentre observational study, baseline and procedure data from consecutive pressure-guided CB ablations were collected. Operators were not required to have experience in pressure-guided CA for participating in the registry. They were asked to classify the pressure waveform curves into type 1 (presence of "a-wave" and/or symmetric "v-wave", meaning incomplete PV occlusion) and type 2 (absence of "a-wave" and asymmetric "v-wave", meaning complete PV occlusion), Figure 1. The primary endpoint was PV isolation in all veins without use of contrast. Procedure performance and adverse events were also analyzed. Results A total of 150 patients (mean age: 61 ± 10 y.) with paroxysmal (62%) or persistent AF (38%) were included and underwent pressure-guided CA in 9 centres from Spain. Complete PV isolation was achieved in 148 patients (98%). The operators switched to contrast use in 14 cases (9%), mainly to double check the occlusion. Total procedure and fluoroscopy time were 97 ± 39 and 19 ± 10 min respectively. There were 7 (4.7%) procedure related adverse events: 4 phrenic nerve palsy (3 of them were transient), 1 transient coronary ST elevation (before ablation), 1 gastroparesis and 1 femoral pseudoaneurysm. Most relevant results are summarized in Figure 2. Conclusion In this multicentre and multi-brand assessment, CA guided by pressure waveforms provided outstanding procedural outcomes, which were equivalent to those reported with the conventional approach. All operators could easily obtain and identify the waveform without a specific learning curve, avoiding the use of iodine contrast in most cases. The long-term efficacy of this approach will be presented in future analyses.Pressure waveforms types in cryoablationProcedural data

P.045 Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC and LILAC-2 studies

Background: Trofinetide significantly improved core symptoms of Rett syndrome (RTT) with an acceptable safety profile in LAVENDER. Here, we report the safety and efficacy results of LILAC and LILAC-2, open-label extension studies of LAVENDER. Methods: Females with RTT, aged 5–21 years, received twice-daily, oral trofinetide in LILAC for 40 weeks. Participants who completed LAVENDER and LILAC continued trofinetide in LILAC-2, a 32-month extension study. Safety assessments included the incidence of adverse events (AEs). Efficacy endpoints included the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression–Improvement (CGI-I) scale. Results: Overall, 154 patients were enrolled in LILAC. The most common AEs were diarrhea (74.7%) and vomiting (28.6%). The mean (standard error [SE]) change from the LAVENDER baseline to Week 40 in the LILAC study in RSBQ was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean (SE) CGI-I scores compared with the LILAC baseline at Week 40 were 3.1 (0.11) and 3.2 (0.14) for patients treated with trofinetide and placebo in LAVENDER, respectively. Similar safety and efficacy trends were observed in LILAC-2. Conclusions: Trofinetide continued to improve symptoms of RTT in LILAC and LILAC-2 with a safety profile consistent with LAVENDER.

Bioequivalence and Safety of Two Formulations of Tofacitinib Citrate Tablets in Healthy Chinese Volunteers under Fasting and Fed Conditions: Randomized, Open-Label, 2-Period, Single-Dose, Crossover Trials

Purpose. To evaluate the bioequivalence of two different tofacitinib citrate tablets formulations among healthy Chinese subjects under fasting and fed conditions and to observe the safety of test preparation and reference preparation in healthy subjects. Method. This randomized, open-label, 2-period, crossover, bioequivalence study included 64 healthy Chinese subjects (fasting: n = 32, fed: n = 32). The subjects were assigned to receive a single 5-mg dose of the test or a reference tofacitinib citrate tablets. Blood samples were collected at predose and up to 24 hours after dosing. Area under the plasma concentration time curve from zero to the last measurable concentration (AUC0-t), the area from time zero to infinite (AUC0-∞), and maximum plasma concentration (Cmax) were used for bioequivalence assessment. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, from the time the subject receiving the test drug to the end of the last visit. Results. Under fed condition, the 90% CIs of the geometric mean ratios of the test/reference for tofacitinib citrate tablets were 98.40–104.16% for AUC0-t, 89.96–116.70% for Cmax, and 98.50–104.15% for AUC0-∞. Under fasting condition, the 90% CIs of the geometric mean ratios of the test/reference for tofacitinib citrate tablets were 93.65–101.60% for AUC0-t, 90.06–109.15% for Cmax, and 93.88–101.51% for AUC0-∞. There were no serious events. Conclusion. The 90% CI for the geometric mean ratio (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00%–125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under both fasting and fed conditions. They are similar in terms of safety. This trial is registered with CTR20190366.

#1351 Assessment of safety and efficacy of expanded hemodialysis in comparison to HDF

Abstract Background and Aims In end-stage kidney disease, solutes with a wide spectrum of molecular weight, called uremic toxins, are retained due to impaired kidney cleansing capacity. Particularly, the retention of toxins in the middle molecular weight range 15–45 kDa might negatively affects multiple organ systems and metabolic pathways. The removal of such large uraemic toxins is still a challenge. HDF has produced some results although large convective volume, optimal vascular access to increase the blood flow rate and strict water quality management are required. Medium Cut-Off, high Retention Onset membrane have been recently developed introducing the concept therapy called “expanded haemodialysis” (HDx). Furthermore, vitamin E-coated membrane has potential beneficial effects on inflammation and oxidative stress. Method A prospective longitudinal single-center study was conducted for 3 months among 18 chronic haemodialysis patients. Patients were randomly assigned into either HDF with high flux membrane or HDx with Theranova or ViE-X membrane. The primary goal was to assess albumin loss among the three types of dialyzers. Secondary goals included assessment of depurative efficacy for uraemic toxins and clinical outcomes. Throughout the treatment, a proportional part of the dialysis fluid was collected to quantify albumin loss. Blood samples were taken before and after dialysis session in order to calculate the Removal Ratio and at two different intradialytic timepoints from arterial and venous line of the circuit in order to calculate instantaneous clearance. Results Mean albumin loss was significantly higher in patients undergoing HDx with Theranova membrane (ANOVA, p<0.001) without any difference in serum albumin concentration among the three groups. Instantaneous clearance of small and middle molecules was significantly higher in patients undergoing HDF, but we didn't find differences in removal ratio. Reduction of Erythropoietin resistance index was observed in patients treated with ViE-X membrane but it was related to their lower dialysis vintage. Conclusion HDx with Theranova membrane was associated with higher albumin loss without any effect on pre-dialysis serum albumin. Moreover, patients treated Theranova membrane, in the presence lower Qb, lower convective dose and lower instantaneous clearance reached same dialysis efficacy compared to HDF.

#1118 Direct delivery of novel gene therapy to podocytes enables pathway to clinical translation for the treatment of glomerular diseases

Abstract Background and Aims Adeno associated vector (AAV) gene therapy has the potential to treat a wide range of kidney diseases via the targeted delivery of genes to kidney cells to repair cellular and renal function. Despite the potential to impact many kidney conditions, kidney AAV gene therapy has proven challenging due to technical and physiological hurdles limiting the ability of AAV to be effectively delivered to podocytes. We have developed a novel AAV gene therapy, PS-001, and local method of administration, to effectively and safely deliver the podocin gene NPHS2 to podocytes. Biallelic NPHS2 mutations are the most common cause of monogenic childhood nephrotic syndrome. Curative efficacy and resolution of disease phenotype was demonstrated in transgenic murine models following PS-001 gene therapy treatment. The potential for translation of this approach to NPHS2 nephropathy patients in the clinic was also demonstrated in pre-clinical studies in Gottingen Minipigs. Method Transgenic murine models representative of NPHS2-driven nephropathy were treated with an AAV gene therapy encoding NPHS2, including a knock in mouse model (Nphs2R140Q/−) which introduces a R140Q mutation in the podocin gene. Mice were assessed for improvement in disease phenotype via analysis of proteinuria, serum albumin, renal histopathology and survival. Mice were treated with an analogue of PS-001, as the PS-001 capsid is not permissive in rodents. Gottingen minipigs were treated with PS-001 and followed for 4 weeks. Clinically relevant doses and a procedure for local administration specifically to the kidney were established. In-life safety assessments from blood and urine were monitored and at study end pig tissues were assessed for podocin biodistribution using multiple assays (qPCR, RT-qPCR, ELISA, RNAScope and IF) and for toxicological effects via histopathological analysis. Results Using our AAV gene therapy platform, which includes a capsid that is highly effective at transducing human podocytes and promoter that drives gene expression specifically in the podocyte, the gene therapy product PS-001 encoding NPHS2 was generated. Using a murine analogue of PS-001, in vivo proof of concept studies in a translationally relevant murine disease model (Nphs2R140Q/−) showed NPHS2 delivery and podocin expression in glomeruli and efficacy in terms of renal function rescue. This was demonstrated by resolution of severe proteinuria (mean ACR ug/mg 6049 ± 2803 vs 192 ± 51 in PS-001 treated animals, n = 11), improved serum albumin (g/L 27.50 ± 3.33 g/L vs 30.75 ± 2.46 in PS-001 treated animals, P = .021) and reduction in glomerulosclerosis (mean sclerosed glomeruli 81% ± 19 vs 18.75% ± 12 in PS-001 treated animals, P < .0001). The methods to translate the approach to the clinical setting using a local administration were established in pigs. Administration of PS-001 resulted in transgene mRNA expression across 89% ± 11% of kidney glomeruli as assessed by RNAScope (n = 3 pigs), and transgene derived podocin could be specifically detected in podocytes as assessed by IF analysis. Using qPCR, RT-PCR and ELISA it was shown that using local administration, podocin gene expression was restricted exclusively to the kidney glomerulus, with gene expression undetectable in off-target organs including the liver. Additional toxicological assessments of renal and other organ function from urine and blood, and post-study histopathological assessments revealed no pre-clinical treatment-related safety concerns. Conclusion We present data showing development of an AAV gene therapy and method of administration for the delivery of transgenes specifically to podocytes. We have shown transgenes can be efficiently targeted to podocytes to replace defective genes or to use the podocyte as a protein factory to modulate glomerular biology. This technology therefore provides an important novel modality for potentially treating a broad range of glomerular disease. PS-001 is being developed as a novel approach to treat steroid resistant nephrotic syndrome caused by mutated NPHS2, and may become the first podocyte targeted gene therapy to enter clinical development.

Pulsed field ablation in patients with cardiac implantable electronic devices: an ex vivo assessment of safety.

Pulse field ablation (PFA) is a novel catheter ablation technology with potential safety benefits due to its tissue selectivity. It has the potential to directly damage or interact with the functionality of cardiac implantable electronic devices (CIEDs) in the form of electromagnetic interference (EMI). The aim of our study was to assess the impact of PFA on CIEDs. PFA lesions (45 per CIED) were applied from the Farapulse system to CIEDs (< 5 cm from the lead tip and < 15 cm from the generator). All devices were checked before and after PFA application for proper sensing and pacing functionality as well as for integrity of shock circuits in ICDs using a heart simulator. Moreover, devices were then interrogated for any spontaneous reprogramming, mode switching or other EMI effects. In total, 44 CIEDs were tested (16 pacemaker, 21 ICDs, 7 CRT-P/D) with 1980 PFA applications. There was no change in device settings, functionality and electrical parameters, and there was no macroscopic damage to the devices. The risk of damage to the electric components or leads on a patient-based analysis is 0/44 (95% CI 0-8%) and on a PFA pulse-based analysis is 0/1980 (95% CI 0-0.2%). Clinically relevant EMI appeared with oversensing and pacing inhibition but not tachycardia detection. Bipolar PFA appears safe and does not result in damage to CIEDs or leads. Clinically relevant EMI does occur, but appropriate peri-procedural programming may mitigate this. In vivo studies are needed to confirm our findings.

One-year outcomes and safety assessment of faricimab in treatment-naïve patients with neovascular age-related macular degeneration in Japan

This multicentre retrospective study evaluated the 1-year outcomes and safety profile of faricimab in treatment-naïve patients with neovascular age-related macular degeneration (nAMD). Fifty-five patients (57 eyes) underwent loading therapy comprising three monthly faricimab injections. If dryness was achieved by the third month, subsequent treat-and-extend (TAE) follow-up continued at a minimum 8-week interval thereafter. If wet macula persisted at the third month, a fourth dose was administered, followed by the TAE regimen. After 1 year, improvements in visual acuity (0.44 ± 0.46 [baseline] to 0.34 ± 0.48; p < 0.01) and central foveal thickness (326 ± 149 [baseline] to 195 ± 82 μm; p < 0.0001) were significant. Dry macula, characterised by the absence of intraretinal or subretinal fluid, was achieved in 65% of cases. Treatment intervals varied, ranging from 8 to 16 weeks, with 44% of eyes extending to a 16-week interval, followed by 33% at 8 weeks, 16% at 12 weeks, 5% at 14 weeks, and 2% at 10 weeks. Notably, 50% of the polypoidal choroidal vasculopathy patients exhibited complete regression of polypoidal lesions between 12 and 15 months. Faricimab treatment in nAMD patients induced significant improvements in central vision and retinal morphology. Two cases of retinal pigment epithelial tears and one case of iritis were reported as ocular complications.

Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2weeks. A single dose of midazolam (1mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with immunotherapy in early-stage triple-negative breast cancer.

This study aimed to assess safety and efficacy of a modified KEYNOTE 522 protocol, which incorporated pembrolizumab every 6weeks, allowing for concomitant dose-dense (14day) doxorubicin and cyclophosphamide (ddAC). By optimizing this dosing, the intention of this modified protocol was to improve pathologic complete response (pCR) rates in a population associated with a poorer prognosis. This was a retrospective, single-center, cohort study. Patients were included if they had early stage, triple-negative breast cancer, and received at least one dose of AC. The entire cohort received neoadjuvant chemotherapy including weekly carboplatin and paclitaxel with pembrolizumab every 3weeks for 12weeks (4 cycles). The group then received either ddAC with pembrolizumab 400mg every 6weeks, or AC with pembrolizumab 200mg every 3weeks. The primary objective was pCR rate at time of surgery. This study assessed outcomes in 25 patients over 34months. The pCR rate in the pembrolizumab, AC 3-week cohort was 64.3% versus 81.8% in the ddAC and 6-week pembrolizumab group. No pembrolizumab-associated grade 3-4 adverse events occurred in the either cohort. Despite seeing an increased incidence of grade 3-4 toxicities in the ddAC arm, this did not result in additional chemotherapy delays or dose reductions. This study demonstrated tolerability and a potential for favorable outcomes with this patient population, making this modified KEYNOTE 522 protocol a reasonable treatment approach. Larger, prospective studies are warranted to assess the feasibility of this dosing and true optimization of patient outcomes given the small sample size of this study.

Parameter Sensitivity Analysis for Long-Term Nuclide Migration in Granite Barriers Considering a 3D Discrete Fracture–Matrix System

As a geological barrier for high-level radioactive waste (HLW) disposal in China, granite is crucial for blocking nuclide migration into the biosphere. However, the high uncertainty associated with the 3D geological system, such as the stochastic discrete fracture networks in granite, significantly impedes practical safety assessments of HLW disposal. This study proposes a Monte Carlo simulation (MCS)-based simulation framework for evaluating the long-term barrier performance of nuclide migration in fractured rocks. Statistical data on fracture geometric parameters, on-site hydrogeological conditions, and relevant migration parameters are obtained from a research site in Northwestern China. The simulation models consider the migration of three key nuclides, Cs-135, Se-79, and Zr-93, in fractured granite, with mechanisms including adsorption, advection, diffusion, dispersion, and decay considered as factors. Subsequently, sixty MCS realizations are performed to conduct a sensitivity analysis using the open-source software OpenGeoSys-5 (OGS-5). The results reveal the maximum and minimum values of the nuclide breakthrough time Tt (12,000 and 3600 years, respectively) and the maximum and minimum values of the nuclide breakthrough concentration Cmax (4.26 × 10−4 mSv/a and 2.64 × 10−5 mSv/a, respectively). These significant differences underscore the significant effect of the uncertainty in the discrete fracture network model on long-term barrier performance. After the failure of the waste tank (1000 years), nuclides are estimated to reach the outlet boundary 6480 years later. The individual effective dose in the biosphere initially increases and then decreases, reaching a peak value of Cmax = 4.26 × 10−4 mSv/a around 350,000 years, which is below the critical dose of 0.01 mSv/a. These sensitivity analysis results concerning nuclide migration in discrete fractured granite can enhance the simulation and prediction accuracy for risk evaluation of HLW disposal.

Historical Evolution of the Impact of Seismic Incident Angles on the Safety Assessment of Various Building Construction Typologies

In the existing building stock, typically characterised by a high degree of irregularity, the effects of earthquakes are strongly dependent on the epicentre–structure direction and the angle of incidence of the seismic motion. However, the scientific community has not yet reached a unanimous consensus on the evaluation of the effects of seismic incidence angles. Therefore, this paper conducts an extensive investigation of the international literature on current methods to consider seismic directionality, systematically reviewing more than 80 publications on this topic. Following a brief overview of the problem and an analysis of the initial developments of the multidirectionality concept of seismic input, a state-of-the-art review is presented based on the considered analysis methods, specifically response spectrum analysis, nonlinear static analysis, and nonlinear response history analysis. Moreover, the adoption of multidirectional seismic input in popular codes and standards is presented and discussed. This study provides the first comprehensive synthesis of research on the seismic incidence angles across diverse building typologies, offering crucial insights for future code revisions and highlighting significant gaps in current analytical methods and standards, thereby setting a new direction for subsequent empirical investigations. Specifically, the extensive state-of-the-art review revealed that, until now, the evaluation of the angle of incidence was primarily conducted on existing reinforced concrete buildings with a limited number of storeys, analysed with nonlinear response history analysis. This underscores the need for future research to extensively investigate the impact of the angle of incidence on other types of construction typologies.