Safety Evaluation Research Articles

Physiological properties evaluation and exopolysaccharide biosynthesis of Limosilactobacillus fermentum JL-2 from Chinese traditional fermented dairy product based on genomic insight

Limosilactobacillus fermentum JL-2 with high production of exopolysaccharide (EPS) was screened from the traditional fermented dairy product in Xinjiang district (China) in our previous work. In this study, the whole genome of L. fermentum JL-2 was sequenced and the genomic information and function were studied to excavate its genotype, safety and probiotic properties. The safety evaluation in vitro showed that L. fermentum JL-2 was not hemolytic, sensitive to common antibiotics, and it had a weak biogenic amine production capacity. The genes related to EPS biosynthesis and their relationship with EPS production were discussed. The EPS production of L. fermentum JL-2 was 553.6 mg/L. The genome of L. fermentum JL-2 consisted of a circular 1.98 Mbp chromosome. A variety of genes related to probiotic properties such as acid tolerance, bile salt tolerance, adhesion to gut mucosa and environmental stress resistance were contained. A complete EPS gene cluster was found in the genome of L. fermentum JL-2, and the genes related to EPS biosynthesis such as epsA and epsB were found in L. fermentum JL-2. It is worth noting that EPS biosynthesis protein (gene0099) seemed to play a key role in the EPS synthesis of L. fermentum JL-2. These results revealed the potential of L. fermentum JL-2 as a probiotic at the gene level. Therefore, this study laid a theoretical foundation for further research into its potential probiotic function and its application in practice.

A Systematic Review of Efficacy and Safety of Plasma-Derived von Willebrand Factor/Factor VIII Concentrate (Voncento) in von Willebrand Disease.

For the treatment of von Willebrand disease (VWD), von Willebrand factor (VWF) concentrates can be used in on-demand, long-term prophylaxis, and surgical prophylaxis regimens. This systematic literature review was conducted to evaluate the efficacy, consumption, and safety of plasma-derived human coagulation FVIII/human VWF (pdVWF/FVIII; Voncento/Biostate) for the treatment of patients with any inherited VWD type. An electronic search was conducted in MEDLINE and Cochrane Library databases on VWD therapies. All retrieved publications were assessed against predefined inclusion/exclusion criteria following the Cochrane group recommendations. Associated pharmacovigilance data were collected across the same time period. Eleven publications from eight study cohorts were identified for data retrieval. All were from multicenter studies and included both pediatric and adult patients. Eight publications included evaluations of the efficacy of pdVWF/FVIII for on-demand treatment, eight included long-term prophylactic treatment, and eight included surgical prophylaxis. Treatment protocols and VWF administration methods differed between studies, as did safety evaluations. The clinical response was rated as excellent/good for on-demand treatment in 66 to 100% of nonsurgical bleeds, 89 to 100% in the treatment of breakthrough bleeds during long-term prophylaxis treatment, and hemostatic efficacy in surgical procedures was 75 to 100%. Pharmacovigilance data confirmed a low incidence of adverse events in treated patients. This review provides a comprehensive summary of studies that evaluated the use of pdVWF/FVIII in VWD demonstrating the long-term effectiveness and safety of this pdVWF/FVIII across all ages, types of VWD, and treatment settings.

Comparative Analysis of Open and Closed Sphincterotomy for the Treatment of Chronic Anal Fissure: Safety and Efficacy Evaluation.

BACKGROUND Chronic anal fissure is a common condition that causes pain and discomfort and has a significant impact on quality of life. When conservative management fails, surgical sphincterotomy can be successful. This retrospective study from a single center in Turkey included 188 patients with chronic anal fissures and aimed to compare outcomes from open and closed sphincterotomy. MATERIAL AND METHODS This retrospective study included 188 patients treated with lateral internal sphincterotomy (LIS) for chronic anal fissure between January 2015 and December 2021 in our hospital. Open LIS procedure was performed in 91 patients and closed LIS was performed in 97 patients. Demographic characteristics, postoperative complications, and recurrence were compared for these 2 methods. RESULTS Of the 188 patients included in the study, 47.9% were women and 52.1% were men. The mean age was 42.9 (20-84) years. In the open LIS group, recurrence occurred in 2 patients (2.19%), and no incontinence was observed. In the closed LIS group, recurrence occurred in 3 patients (3%; P=0.703), and incontinence developed in 5 patients (5.15%; P=0.035). CONCLUSIONS Comparing the 2 methods used in chronic anal fissure surgery, and considering the recurrence and risk of incontinence, the most feared outcome by the patient and surgeon, open LIS stands out as a superior technique, especially in young male patients.

Transfers and anesthesia-related postoperative outcomes after 3361 same-day cancer surgeries at a freestanding surgery center: An observational retrospective study.

Expanding outpatient surgery to the increasing number of procedures and patient populations warrants continuous evaluation of postoperative outcomes to ensure the best care and safety. We describe adverse postoperative outcomes and transfer rates related to anesthesia in a large sample of patients who underwent same-day cancer surgery at a freestanding ambulatory surgery center. Between January 2017 and June 2021, 3361 cancer surgeries, including breast and plastic, head and neck, gynecology, and urology, were performed. The surgeries were indicated for diagnosis, staging, and/or treatment. We report the incidence of transfers and adverse postoperative outcomes related to anesthesia. Breast and plastic surgeries were the most common (1771, 53%), followed by urology (1052, 31%), gynecology (410, 12%), and head and neck surgeries (128, 4%). Based on patients'first procedure, comorbidity levels were highest for urology (75% American Society of Anesthesiologists physical status score 3, 1.7% score 4) and lowest for breast surgeries (31% score 3, 0.2% score 4). Most gynecology surgeries used general anesthesia (97.6%), whereas breast surgeries used the least (38%). A total of sevenpatients (0.2%; 95% CI: 0.08%-0.4%) were immediately transferred to an outside hospital; fourdue to anesthesia-related reasons. Only 7 (0.2%) patients needed additional postoperative care related to anesthesia-related adverse events, specifically cardiac events (4), difficult intubations (2), desaturation (1), and agitation, nausea, and headache (1). The incidence of anesthesia-related adverse postoperative outcomes is low in cancer patients undergoing outpatient surgeries at our freestanding ambulatory surgery center. This suggests that carefully selected cancer patients, including patients with metastatic cancer, can undergo anesthesia for same-day surgery, making cancer care accessible locally and reducing stress associated with travel for treatment. More research investigating complication rates related to surgery and to cancer disease trajectory are needed to establish a complete evaluation of safety for outpatient cancer surgery.

Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates

Background6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data.Results[11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers.Conclusions[11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.

Efficacy and Safety of Cemiplimab for the Management of Non-Melanoma Skin Cancer: A Drug Safety Evaluation.

Non-melanoma skin cancer includes several types of cutaneous tumors, with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) as the commonest. Among the available therapeutic options, surgical excision is the mainstay of treatment for both tumors. However, tumor features and patients' comorbidities may limit the use of these techniques, making the treatment challenging. As regards BCC, even if hedgehog inhibitors revolutionized the therapeutic scenario, there are still patients unresponsive or intolerant to these drugs. In this context, cemiplimab has been approved as second-line treatment. As regards SCC, cemiplimab was the first systemic therapy approved. The objective of this manuscript was to investigate the efficacy and safety of cemiplimab for the management of BCC and cSCC. Cemiplimab has a durable and significant effect for the management of BCC and CSCC, with a favorable safety profile. Different specialists including oncologists, radiologists, dermatologists, and surgeons are required to guarantee an integrated approach, leading to the best management of patients. Moreover, the collaboration among specialists will allow them to best manage the TEAEs, reducing the risk of treatment suspension or discontinuation. Certainly, ongoing studies and more and more emerging real-world evidence, will allow us to better characterize the role of cemiplimab for the management of advanced non-melanoma skin cancer.

Enhancing the Efficacy and Safety of Methotrexate Treatment: A Focus on Drug Interactions (Review)

INTRODUCTION. Methotrexate (MTX) is the main disease-modifying antirheumatic drug (DMARD) and the gold standard for the safety and efficacy evaluation of biologicals and targeted small molecules. However, its narrow therapeutic range, interpatient variability in pharmacokinetics and pharmacodynamics, and potential clinically relevant drug–drug interactions (DDIs) may lead to treatment failure and increase the risk of adverse drug reactions (ADRs).AIM. The study aimed to describe the main clinically significant DDIs associated with MTX used in rheumatic disease therapy and determine possible approaches to addressing this issue based on a literature review.DISCUSSION. MTX is characterised by pharmacokinetic DDIs during absorption, cell penetration, and elimination. Some non-steroidal anti-inflammatory drugs (NSAIDs), theophylline, sulfasalazine, antibacterial agents, and proton pump inhibitors (PPIs) affect MTX elimination and therapeutic effects. The main ADRs associated with MTX include haematotoxicity, hepatotoxicity, lung tissue damage (interstitial pneumonitis and pulmonary fibrosis), and renal dysfunction. The severity of these ADRs depends on the dose, comorbidities, and concomitant therapy. The toxicity of MTX may be increased by the concomitant administration of medicinal products that exhibit haematotoxicity and affect renal function (impair the elimination of medicines). When co-administering MTX and medicines having clinically significant DDIs described in the literature, healthcare providers should consider the risk factors for each individual patient. The most significant risk factors include moderate to severe renal and hepatic impairment, older age, polypharmacy, and hypoalbuminemia.CONCLUSIONS. This article describes potential clinically significant interactions between MTX and certain NSAIDs, antibacterial agents, and PPIs that depend on individual patient characteristics and may increase the toxicity or decrease the effectiveness of MTX. MTX deprescribing, short-term withdrawal, and dosing optimisation may be considered as approaches to DDI risk mitigation.

Monitoring the crack lengths in composite lap joints under cyclic loading

Abstract Monitoring crack lengths in composites lap joints is crucial for the evaluation of safety and integrity in composite structures. The crack lengths in adhesively bonded single-lap and double-strap joints were characterized by using epoxy adhesive containing aligned graphene. The epoxy adhesive was prepared by adding graphene to epoxy resin and then aligning the graphene through an electrical field. The incorporation of 0.15wt% aligned graphene can have the epoxy adhesive being electrically conductive. The single-lap and double-strap joints containing the graphene epoxy adhesive were tested under cyclic loading. During the cyclic tests, the crack extension and electrical resistance were measured concurrently. In addition, the electrical resistance model expressed in terms of the crack lengths for the lap joints was proposed in the examination. The results illustrated that the crack length and the electrical resistance increased as the cyclic number increased. Moreover, the experimental resistance variation associated with the increased crack length can be described using the electrical resistance model. Thus, the functionalized epoxy adhesive containing aligned graphene can be employed for effectively detecting the length of cracks in composite lap joints under cyclic loading.

A simplified weak coupling dynamic analysis method for running safety evaluation of train on bridges under earthquake excitation

This study proposes a simplified analysis method that couples the bridge and train-track subsystem in a weak form to facilitate the dynamic analysis of the train-track-bridge coupled system (TTBS) under earthquakes. The method includes three main steps: (i) performing dynamic analysis of the bridge under seismic conditions to obtain the response of the bridge deck; (ii) interpolating the bridge displacement beneath each wheelset based on the train's velocity, departure time, and the initial positions of the wheelsets; and (iii) assessing the running safety of the train by incorporating the interpolated bridge response as track irregularity into the train-track coupled system. Steps (i) and (iii) can be analyzed separately using finite element and multibody dynamics software, eliminating the need to create a complex TTBS model that is challenging to achieve within a single software platform. Additionally, based on the method’s assumptions, the earthquake excitation on the train can be separated into the seismic inertial effect and seismic-induced bridge deformation, enabling a quantitative analysis of the impact of these two types of excitations on train safety. Taking a 10-span simply supported bridge and a long-span cable-stayed bridge as examples, the proposed method’s assumptions are verified by comparing its results with those obtained from a complex TTBS model. Furthermore, the impact characteristics of inertial effects and seismic-induced bridge deformation on train safety for these two types of bridges are analyzed. The proposed method offers robust support for seismic design of bridges and facilitates a comprehensive analysis of the mechanisms through which seismic excitations affect train safety.

Enhancing Women's Commuting Experience: A Study of Ladies’ Special Trains in the Mumbai Suburban Railway System

The suburban railway network in Mumbai plays a crucial role in the daily lives of millions of people. To improve safety and comfort for female commuters, Ladies’ Special Trains have been introduced. This research paper undertakes a comparative analysis of Ladies’ Special Trains and conventional local trains, examining their historical backgrounds, developmental trajectory, and influence on the commuting experiences of women. Through the evaluation of safety, comfort, and convenience, we analyse the advantages and disadvantages of both transportation methods to inform future enhancements. The results of this study make a valuable contribution to the scholarly conversation and provide valuable insights for policymakers, transportation authorities, and civil society organizations involved in promoting inclusive and secure mobility solutions in Mumbai.

A Randomized Controlled Trial Comparing Efficacy and Safety of Antidepressant Monotherapy.

The majority of mainstream antidepressants lack the promise of complete amelioration of symptoms. Other pitfalls include the latency period and side effects. These issues prompted investigations concerning thevarious roles of serotonin (5-HT) neurotransmissions in the etiology of depression. In this study, each study participant received vilazodone, vortioxetine, and escitalopram monotherapy for major depressive disorder (MDD)for 16 weeks. After that, the subject's scores on the Hamilton Depression Rating Scale (HDRS)-17 item version and the Montgomery Åsberg Depression Rating Scale (MADRS) were evaluated. In the study population, we kept track of the incidence of adverse events. Ninety-six patients with MDD participated in this open-label, randomized, three-arm study. Participants were allotted into three groups according to a 1:1:1 ratio and given vilazodone (20-40 mg/day), vortioxetine (5-20 mg/day), or escitalopram (10-20 mg/day) for 16 weeks. Vortioxetine and vilazodone are test medications, with escitalopram serving as the control. After the baseline visit, follow-up appointments were scheduled every four weeks. Per-protocol (PP) and intent-to-treat (ITT) populations served as means for efficacy and safety evaluations, respectively. We prospectively registered this research in the Clinical Trial Registry, India (CTRI) (2022/07/043808). Out of the 134 patients we screened, 109 (81.34%) were eligible. Ninety-six (88.07%) of them completed the 16-week trial. In the PP population (n = 96), we analyzed efficacy. They had a mean age of 46.3 ± 6.2 years. At baseline, each group's median HDRS score was 30.0 (p = 0.964). Following 16 weeks of antidepressant therapy, these scores dropped to 15.0, 14.0, and 13.0 (p = 0.002). Baseline MADRS scores for all groups were 36.0 (p = 0.741). They had corresponding values of 20.0, 18.0, and 17.0 at 16 weeks (p < 0.001). Regarding both efficacy endpoints, the post-hoc analysis with the Bonferroni correction demonstrated statistically significant differences (p < 0.001). We performed the safety assessments within our ITT population (n = 109). Ninety-six adverse events were recorded. Nonetheless, none of them seemed serious. Still, five participants opted out because of their side effects. Vomiting and nausea were the most frequent side effects. Compared to escitalopram and vilazodone, vortioxetine demonstrated a statistically significant reduction in HDRS and MADRS scores. It also had fewer and milder side effects. We recommend conducting studies involving a broader population to investigate the antidepressant effects of these medications further.

Enhancement of Biological Activities and Phytochemical Compounds of Oryza sativa L. Extract through Probiotic Fermentation

This study aimed to enhance the biological effects and phytochemical content of probiotic fermented red jasmine rice (Oryza sativa L.) extract to apply as a functional ingredient in anti-aging application. In addition, safety evaluation in terms of cytotoxicity and irritation profile were explored. Lactobacillus plantarum and Lactobacillus rhamnosus were used to ferment the aqueous extract of red jasmine rice to produce fermented extracts as BG and LRB, respectively. The biological potentials in terms of antioxidation, anti-enzymatic effects and anti-inflammation with cytotoxicity of fermented extracts were evaluated and compared with nonfermented extract. In addition, alteration in phytochemical constituents of the probiotic-fermented extracts from nonfermented extract were illustrated by synchrotron radiation–based–FTIR microspectroscopy (SR-FT-IR). The results revealed that BG and LRB demonstrated improved antioxidant and anti-tyrosinase effects compared to the control. Additionally, BG and LRB significantly increased the total phenolic contents corresponding to the enhanced biofunctional effects confirmed by SR-FT-IR. Moreover, BG showed a satisfactory safety in human skin cell lines and Hen's egg chorioallantoic membrane. This study implied augmentative effect of probiotic fermentation on the bioactive efficacy of red jasmine rice. Additionally, the safety investigation confirmed that this fermented extract could be used as a functional novel ingredient for anti-aging nutraceutical and cosmetic applications.

Formulation and Evaluation of Herbal Sunscreen Utilizing Blue Pea Flower Extract

This thesis presents the formulation and evaluation of a novel herbal sunscreen incorporating Blue Pea Flower (Clitoria ternatea) extract as the primary active ingredient. With increasing concerns about the adverse effects of synthetic sunscreens and the growing interest in natural alternatives, the study aims to explore the photoprotective properties of Blue Pea Flower extract, known for its rich anthocyanin and antioxidant content. The research begins with the extraction of Blue Pea Flower bioactive compounds through optimized solvent extraction methods. The formulated herbal sunscreen is developed by incorporating the extract into a suitable base, considering stability, safety, and efficacy. Key evaluation parameters include in vitro Sun Protection Factor (SPF) determination, photostability studies, and assessments of skin compatibility. Characterization of the Blue Pea Flower extract reveals essential bioactive compounds, establishing a foundation for understanding its potential benefits. The herbal sunscreen's physical characteristics and stability are analyzed to ensure a reliable and effective formulation. In vitro SPF testing assesses the photoprotective efficacy, while photostability studies gauge the product's robustness under sun exposure conditions. Safety evaluations, including skin irritation tests and biocompatibility studies, contribute crucial data on the product's safety profile. The results provide insights into the effectiveness of Blue Pea Flower extract as a natural photoprotective agent and the overall suitability of the herbal sunscreen formulation. Comparisons with synthetic sunscreens highlight the potential advantages of the herbal formulation in terms of efficacy and safety. Recommendations for formulation optimization and future research directions are discussed, emphasizing the significance of eco-friendly and sustainable alternatives in the sunscreen industry. In conclusion, this research offers a comprehensive exploration of Blue Pea Flower extract's potential in herbal sunscreen formulations. The findings contribute to the understanding of natural photoprotective agents, fostering the development of safer and environmentally conscious sun protection products.

Miniaturization of hiPSC-derived 3D neural cultures in stirred-tank bioreactors for parallelized preclinical assessment of rAAV.

Introduction: Engineered 3D models employing human induced pluripotent stem cell (hiPSC) derivatives have the potential to recapitulate the cell diversity and structure found in the human central nervous system (CNS). Therefore, these complex cellular systems offer promising human models to address the safety and potency of advanced therapy medicinal products (ATMPs), such as gene therapies. Specifically, recombinant adeno-associated viruses (rAAVs) are currently considered highly attractive for CNS gene therapy due to their broad tropism, low toxicity, and moderate immunogenicity. To accelerate the clinical translation of rAAVs, in-depth preclinical evaluation of efficacy and safety in a human setting is primordial. The integration of hiPSC-derived CNS models in rAAV development will require, amongst other factors, robust, small-scale, high-throughput culture platforms that can feed the preclinical trials. Methods: Herein, we pioneer the miniaturization and parallelization of a 200mL stirred-tank bioreactor-based 3D brain cell culture derived from hiPSCs. We demonstrate the applicability of the automated miniaturized Ambr® 15 Cell Culture system for the maintenance of hiPSC-derived neurospheroids (iNSpheroids), composed of neuronal and glial cells. Critical process parameters were optimized, namely, cell density and agitation mode. Results: Under optimized conditions, stable iNSpheroid cultures were attained in the microbioreactors for at least 15days, with high cell viability and astrocytic and neuronal phenotype maintenance. This culture setup allowed the parallelization of different rAAVs, in different multiplicity of infections (MOIs), to address rAAV-host interactions at a preclinical scale. The iNSpheroids were exposed to rAAV2- and rAAV9-eGFP in the microbioreactors. Transgene expression was detected 14days post-transduction, revealing different astrocyte/neuron tropism of the two serotypes. Discussion: We advocate that the iNSpheroid cultures in miniaturized bioreactors are reliable and reproducible screening tools for addressing rAAV transduction and tropism, compatible with preclinical demands.

Gamma oscillations induced by 40-Hz visual-auditory stimulation for the treatment of acute-phase limb motor rehabilitation after stroke: study protocol for a prospective randomized controlled trial

BackgroundThe incidence of hemiparetic limb dysfunction reaches 85% in stroke patients, emerging as a critical factor influencing their daily lives. However, the effectiveness of current rehabilitation treatments is considerably limited, particularly in patients with upper extremity impairment. This study aims to conduct a prospective clinical trial to validate the safety and effectiveness of gamma oscillations induced by 40-Hz visual-auditory stimulation in treating post-stroke upper limb dysfunction and to explore the relevant mechanisms.MethodsThis trial is a prospective, randomized controlled, double-blind study. All enrolled patients were randomly assigned to two groups. The experimental group received intervention through 40-Hz visual-auditory stimulation, while the control group underwent intervention with randomly matched visual-auditory stimulation frequencies. The primary efficacy endpoint is the change in motor function. Secondary efficacy endpoints include motor-evoked potentials, cerebral hemodynamic changes, neural network connectivity, and alterations in synaptic-related genes. Safety evaluation included major adverse events, all-cause mortality, and photosensitive epilepsy. Assessments will be conducted at baseline, after a 14-day treatment period, and during subsequent follow-up visits (at 3 and 6 months) post-treatment. The differences between the two groups will be compared.DiscussionThis study will evaluate the safety and efficacy of gamma oscillations induced by 40-Hz visual-auditory stimulation in treating patients with upper extremity dysfunction after an acute cerebral stroke. Concurrently, we will explore potential mechanisms, including changes in synaptic-related genes and neural network connectivity. This trial is expected to provide evidence for the effectiveness of this new technique in treating upper extremity dysfunction after a stroke and improving patients’ quality of life.Trial registrationThe study protocol has been registered with the Chinese Clinical Trial Registry (ChiCTR) under registration number ChiCTR2300076579 on October 12, 2023.

Biochemical and molecular-level effects of co-exposure to chlorpyrifos and lambda-cyhalothrin on the earthworm (Eisenia fetida)

Farmland soil organisms frequently encounter pesticide mixtures presented in their living environment. However, the underlying toxic mechanisms employed by soil animals to cope with such combined pollution have yet to be explored. This investigation aimed to reveal the changes in cellular and mRNA levels under chlorpyrifos (CPF) and lambda-cyhalothrin (LCT) co-exposures in earthworms (Eisenia fetida). Results exhibited that the combination of CPF and LCT triggered an acute synergistic influence on the animals. Most exposures resulted in significant alterations in the activities of total superoxide dismutase (T-SOD), copper/zinc superoxide dismutase (Cu/Zn-SOD), caspase 3, and carboxylesterase (CarE) compared to the basal level. Moreover, when exposed to chemical mixtures, the transcription levels of four genes [heat shock protein 70 (hsp70), gst, sod, and calreticulin (crt)] also displayed more pronounced changes compared with their individual exposures. These changes in determined parameters indicated the occurrence of oxidative stress, cell death, detoxification dysfunction, and endoplasmic reticulum damage after co-exposure to CPF and LCT in E. fetida. The comprehensive examination of mixture toxicities of CPF and LCT at different endpoints would help to understand the overall toxicity they cause to soil invertebrates. The augmented deleterious effect of these pesticides in a mixture suggested that mixture toxicity assessment was necessary for the safety evaluation and application of pesticide mixtures.

Daratumumab and venetoclax combined with CAGE for late R/R T-ALL/LBL patients: Single-arm, open-label, phase I study.

The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated.

Occupational Safety Assessment for Surface Mine Systems: The Case in Jordan

Surface mining is one of the hazardous industries that have several risky operations, including transportation, treatment, and mineral extraction. To avoid the risk of disaster, it is important to evaluate safety procedures and determine expected hazards. The aim of this study is to develop a thorough safety evaluation model for the surface mining industry based on the analytic hierarchy process (AHP), one important multi-criteria decision-making approach. A total of 11 criteria and 36 sub-criteria that are both independent and homogeneous were involved in the decision problem. Further, a deep sensitivity analysis was conducted to assess the stability of the ranking preference. The findings indicate that four out of the eleven criteria are particularly significant. To test the model’s applicability and effectiveness, a case study was conducted involving three surface mining companies located in the north of Jordan. The results demonstrate that the model is reliable, applicable, and effective in addressing real-world problems.

P127 Comparison of the Efficacy, Safety and Immunogenicity of a Proposed Biosimilar MSB11456 with Tocilizumab Reference Product in Moderate-to-Severe Rheumatoid Arthritis: Results of a Randomized Double-Blind Study

Abstract Background/Aims Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody indicated for treating rheumatoid arthritis (RA) and other inflammatory diseases. MSB11456 is a proposed biosimilar to US-licensed tocilizumab and EU-approved tocilizumab. It has already shown equivalent pharmacokinetic, pharmacodynamic safety, tolerability, and immunogenicity profiles to these products given subcutaneously (SC) as a single dose in healthy volunteers. This Phase III, multi-centre, randomised, double-blind, multiple fixed-dose, parallel group study compared efficacy, safety and immunogenicity of MSB11456 and EU-approved tocilizumab administered SC in moderate-to-severe RA patients. Methods Patients were randomised to 162mg MSB11456 or EU-approved tocilizumab for 24 weeks (W). At W24, patients receiving EU-approved tocilizumab were re-randomised to continue treatment or switch to MSB11456 for up to W52. Safety evaluations were conducted up to W63. A change from baseline in Disease Activity Score-28 Joint Count-ESR (DAS28-ESR) at W24 was analysed, as the primary efficacy endpoint, using analysis of covariance to determine the least squares mean (LSM) difference between MSB11456 and EU-approved tocilizumab; equivalence was considered if the 90% confidence interval (CI) was entirely within the FDA equivalence interval -0.6 to 0.5. Secondary endpoints were 20% improvement in ACR core set measures at W24 and DAS28-ESR at W12. Additional endpoints included ACR50/70, change in DAS28-CRP, Simplified and Clinical Disease Activity Indexes, evaluation of immunogenicity up to W55 and safety up to W63. Results Clinically relevant LSM decreases from baseline in DAS28-ESR were observed from W2 up to W24 with both treatments. The 90% CI for LSM difference in the change from baseline in DAS28-ESR between treatments was fully included within the predefined equivalence interval, which demonstrated therapeutic equivalence of MSB11456 and EU-approved tocilizumab (Table 1). Other efficacy endpoint analyses supported this conclusion. No discernible patterns in the nature or frequency of treatment-emergent adverse events (TEAEs) were identified to suggest a difference between drugs. Anti-drug antibodies incidence was similar among treatment arms. Switching from EU-approved tocilizumab to MSB11456 had no clinically relevant impact on efficacy or safety. Conclusion Equivalent efficacy, immunogenicity and safety profiles of MSB11456 and EU-approved tocilizumab were demonstrated in moderate-to-severe RA patients, confirming equivalence between MSB11456 and the EU-approved tocilizumab. Disclosure A. Zubrzycka-Sienkiewicz: None. M. Misterska-Skora: None. M. Socik-Pojawa: None. K. Klama: None. M. Ullman: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. C. Petit-Frere: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. A. Illes: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. P. Baker: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Monnet: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Morais: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Brzezicki: None.

Investigating human-derived lactic acid bacteria for alcohol resistance

BackgroundExcessive alcohol consumption has been consistently linked to serious adverse health effects, particularly affecting the liver. One natural defense against the detrimental impacts of alcohol is provided by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), which detoxify harmful alcohol metabolites. Recent studies have shown that certain probiotic strains, notably Lactobacillus spp., possess alcohol resistance and can produce these critical enzymes. Incorporating these probiotics into alcoholic beverages represents a pioneering approach that can potentially mitigate the negative health effects of alcohol while meeting evolving consumer preferences for functional and health-centric products.ResultsFive lactic acid bacteria (LAB) isolates were identified: Lactobacillus paracasei Alc1, Lacticaseibacillus rhamnosus AA, Pediococcus acidilactici Alc3, Lactobacillus paracasei Alc4, and Pediococcus acidilactici Alc5. Assessment of their alcohol tolerance, safety, adhesion ability, and immunomodulatory effects identified L. rhamnosus AA as the most promising alcohol-tolerant probiotic strain. This strain also showed high production of ADH and ALDH. Whole genome sequencing analysis revealed that the L. rhamnosus AA genome contained both the adh (encoding for ADH) and the adhE (encoding for ALDH) genes.ConclusionsL. rhamnosus AA, a novel probiotic candidate, showed notable alcohol resistance and the capability to produce enzymes essential for alcohol metabolism. This strain is a highly promising candidate for integration into commercial alcoholic beverages upon completion of comprehensive safety and functionality evaluations.