Medical progress as enabled by early plasma products has also revealed biological safety challenges. The combination of donor selection, donation testing and virus reduction processes has effectively addressed these concerns, and today medicinal plasma products feature significant safety margins. The safety tripod concept has since been adapted to biotechnology manufacturing platforms and has also ensured the safety of these products. However, cell-based manufacturing processes have occasionally been exposed to adventitious viruses, leading to manufacturing interruptions and unstable supply situations. The rapid progress of advanced therapy medicinal products (ATMPs) needs an innovative approach to ensure the learnings from more traditional biotechnology help to avoid any unwelcome reminder of the universal presence of viruses. The introduction of up-stream virus clearance steps has already been shown to be valuable for any products too complex for down-stream interventions in the sense of both assuring product safety and continuous supply. The gentlest method being virus filtration – the development of which is presented here. The experiments investigated the feasibility of implementing culture media virus filtration with respect to their virus clearance capacities under extreme conditions such as very high process feed loading (up to ~ 19,000 L/m 2), very long duration (up to 31 days), and multiple process interruptions (up to 21, with cumulative interruptions of over 92 hours). Minute virus of mice (MMV) was used as a relevant target virus, and in general, as a model small non-enveloped virus, as these viruses are the main challenge for the investigated virus filters with a stipulated pore-size of about 20 nm. It was found that certain filters – especially of the newer 2 nd generation – are capable of effective virus clearance despite the harsh regimen they were subjected to. At the same time the investigation of biochemical parameters for un-spiked control runs showed the filters to have no measurable impact on the composition of the culture media. Based on these findings, this technology seems to be quite feasible for large volume pre-manufacturing process culture media preparations.

We sought to characterize the effects of engineered beige fat on metabolic diseases by reviewing its history, examining experimental data, exploring putative mechanisms of action, and predicting its therapeutic future.White adipocytes are highly adaptable and can transform into beige adipocytes with thermogenic capacity, which have beneficial effects in treating metabolic diseases. However, access to beige adipocytes is limited, and treatment efficacy decreases over time. Thus, new approaches are needed to enhance the adaptive thermogenic capacity of beige adipocytes. The investigation revealed that engineered techniques, such as induction of stem cell regeneration, adipocyte gene editing, and adipocyte reprogramming techniques, can generate beige adipose tissue via autologous cell induction, adipose tissue remodeling, and functional biomaterials. Engrafted engineered beige adipocytes can generate large amounts of UCP1-positive adipose tissue in patients with metabolic diseases, paving the way for developing metabolically active beige adipose tissue and expanding its functionality in metabolic therapy. Understanding how engineered beige fats treat metabolic diseases will aid in disease prevention and treatment. These sophisticated tissue engineering systems offer new avenues for generating functional beige adipose tissue in patients with metabolic diseases.

Chemical interaction through airborne volatile organic compounds (VOCs) and root exudates plays a vital role in the mutualistic interactions between plants. In response to these chemical cues, a single plant can exhibit a multitude of adaption responses. Nowadays, one of the most troublesome invasive alien species (IAS) in agriculture is common ragweed ( Ambrosia artemesiifolia L.), which causes severe yield losses in various crops. Given that little is known about how chemical cues of this invader contribute to its invasiveness, we investigated the effects of airborne VOCs and root exudates released by common ragweed on growth and allocation patterns of wheat, soybean and maize, and the effects of these crops on common ragweed. Exposure to VOCs released by ragweed induced a significant reduction in the aboveground dry mass of soybean and wheat, whereas maize showed no changes in its biomass production. In contrast, ragweed itself was completely unaffected when exposed to crops or a conspecific. We observed significant changes in plant traits, such as lower biomass production, lower specific leaf area or higher chlorophyll contents after exposure to VOCs of ragweed, all of which can be linked to an increase in stress. Root choice test showed that all crops and ragweed significantly avoided root exudates of common ragweed, indicating that the root exudates as belowground cues play a vital role in ragweed and crop chemical interactions. The present study shows that the plant response to either above or below ground chemical cues is highly dependent not only on the presence but also on the identity of the neighbor pointing out the complexity of plant–plant communication.

Investigating the response characteristics of various hydrological factors to the construction of water conservancy projects and evaluating their impact on the ecological environment is crucial for ecological protection and restoration in the Loess Plateau, China with a complex environment. In this study, we employed a geomorphology-based hydrological model to simulate the hydrological elements of the Qinhe River Basin in the Loess Plateau. Additionally, we explored the response characteristics of the water cycle and hydrological processes to the construction of reservoirs in the basin. We also examined multiyear changes in peak flood volume and sediment discharge during flood seasons influenced by reservoirs. A thorough evaluation of the simulation results indicated their reliability. The sub-basins hosting reservoirs initially showed an increase in evaporation, followed by a decrease. During the change periods, both runoff and soil water decreased, but remained higher than the mean values for the basin during the same period. The Normalized Difference Vegetation Index of sub-basins associated with five reservoirs was significantly higher than the mean value for the basin during the same period. The peak flood volume and sediment discharge in the basin were characterized by decreasing trends, with the latter showing weak sustainability. The value of each index for a sub-basin associated with a reservoir was higher than the average value for the basin. The construction and operation of reservoirs had a positive impact on the ecology of the basin. Water and soil conservation measures, including sediment regulation and storage using reservoirs, significantly decreased water-related disasters and soil erosion in the basin. This study provides a scientific basis for the design of water conservancy projects and ecological governance in the basin.

The electrochemical performance of Polyaniline (PANI) can be significantly improved due to the incorporation of spinel-type transition metal oxide, i.e., 1 wt. % of Nickel Ferrite (NiFe 2O 4) into the PANI matrix. In this report, we have synthesised NiFe 2O 4 (NF), PANI1:1 ratio, PANI1:2 ratio, and PANI/NiFe 2O 4 nanocomposites, i.e., PANI1:1/NF1 and PANI1:2/NF2 nanocomposites by in-situ oxidative polymerization method. The conducting network formed in the nanocomposite significantly increases the multiple valence states of the metal for the electrolytic ions. The PANI/NiFe 2O 4 nanocomposite shows good interaction and was confirmed by Fourier Transform Infra-red Spectroscopy (FTIR) and Raman analysis. The SEM analysis reveals a uniformly porous and agglomerated globular morphology of the nanocomposite. Also, the PANI/NiFe 2O 4 composite (PANI1:1/NF1) exhibits enhanced supercapacitive properties due to improve strong conducting path of PANI, which helps to provide the delocalization of the electrons in the polymeric chain. The highest specific capacitance ~ 758 Fg -1 is achieved for PANI 1:1/NF1 sample as compared to bare PANI1:1 (677 Fg -1), PANI1:2 (500 Fg -1), NF (253 Fg -1) and other PANI1:2/NF2 (686 Fg -1) samples at 10 mV/s scan rate in a two-electrode system due to NF nanoparticles filling the vacant places in the polymeric matrix. The energy density (54 Whkg -1), power density (1705 Wkg -1) and good cycling stability approx. 97 % after 10000 GCD cycles of the device is found for PANI1:1/NF1. The EIS studies further confirm that the PANI 1:1/NF1 device has a lower charge transfer resistance (R ct) ~ 0.35 Ohm in comparison to other fabricated devices. It seems that NiFe 2O 4 acts as a “superhighway” for charge transportation between PANI which is beneficial for supercapacitors.

Colistin is the last resort treatment against resistant Gram-negative bacteria, necessitating reliable and rapid means for sensitivity testing of colistin. Automated-systems like VITEK®2 is adopted to determine minimum inhibitory concentration (MIC) due to its easy usage. Broth microdilution (BMD) for colistin MIC was suggested by EUCAST and CLSI. The objective was to compare and evaluate colistin MIC by BMD and VITEK®2 against Gram-negative organisms from ICU in a tertiary care hospital. Clinically significant organisms isolated from ICU patients were included. MIC was determined using BMD and VITEK®2. Very major error (VME), major error (ME), essential agreement (EA), categorical agreement (CA), positive-predictive value (PPV), negative-predictive value (NPV), sensitivity and specificity were analysed. 533 isolates were obtained from blood (435,81.60%), respiratory samples (57,10.70%), pus and exudates (20,3.80%), urine (18,3.40%) and CSF (3,0.60%). The Enterobacterales were K. pneumoniae (185,34.70%), E. coli (73,13.70%) and E. cloacae (26,4.90%) while non-fermenters were A. baumannii (209,39.20%) and P. aeruginosa (40,7.50%). The VITEK®2 sensitivity was >99%; specificity ranged from 14.28-52.94%. PPV was 93.81% while NPV was 93.75%. VME ranged from 47-100% between isolates. ME was up to 20%. Highest VME was obtained in E. coli (100%). The total EA and CA observed was 68.5% and 99.79% respectively. VITEK®2 failed to detect the resistance in 32(60%) isolates. Obtained VME and ME values were >3%, which is unacceptable as per the standard guidelines. EA of ≥90% wasn’t obtained. Sensitivity for VITEK®2 was >99%, but had low specificity (14.28%). Hence, VITEK®2 is not reliable for colistin susceptibility testing.

Background: Changing morbidity and mortality from COVID-19 has been associated with the emergence of new SARS-CoV-2 variants. Whereby, acquisition of mutations in the Spike glycoprotein enhanced host receptor binding, cell entry and antibody escape. Understanding these can help predict the impact of these changes. We used genome sequence data to investigate mutation rates and entropy of SARS-CoV-2 during pandemic surges between 2020 and 2022. Methods: 1,637 SARS-CoV-2 genomes from Pakistan were analyzed using the Augur phylogenetic pipeline. Substitution rates and entropy of genomes were calculated year wise and, entropy in the Spike gene was compared for 2020, 2021 and 2022 (defined as periods A, B and C). Central Findings: In period A, G clades were predominant and SARS-CoV-2 genome substitution rate was 6.06 x 10 -4 per site per year. In period B, Delta variant were dominant and substitution rates increased to 9.74 x 10 -4. In period C, Omicron variants dominated with substitution rates at 5.02 x 10 -4. The rate of genome-wide entropy was the highest during B particularly, in the Spike gene such as, E484K and K417N. During C, genome-wide mutations were increased whilst entropy was reduced. Conclusions: The highest SARS-CoV-2 genome substitution rates in 2021 were associated with the Delta wave, which had the greatest morbidity and mortality. These stabilized during the Omicron wave in 2022, when COVID-19 numbers were high mortality was lower. Assessment of SARS-CoV-2 evolution should be monitored together with phylogeographical analysis can help predict future outbreaks and guide public health interventions.

The human head louse (Pediculus humanus capitis) is an obligate ectoparasite of humans and has the potential to uncover aspects of human history that cannot be directly inferred from genetic data derived from humans. Previous studies have shown that global louse populations exhibit restricted patterns of genetic variation. However, these studies were restricted both genetically and lacked a global sampling. With the aim of capturing the genetic diversity of head louse populations from around the world, we generated whole genome sequences of human head lice from 43 countries, spanning five continents and Oceania, to determine if louse nuclear diversity mirrors its mitochondrial haplotypes or if population genetic structure, genetic diversity, and population connectivity are associated with geographical regions or host behavior. Here we show that there are five nuclear genetic clusters that are associated with large geographical regions, either at continental or intercontinental levels. High genetic variation was found between African and non-African individuals and the highest genetic diversity was found in samples from sub-Saharan Africa, similar to that of humans. Unlike the mitochondrial clades examined in previous studies, nuclear genetic clusters of lice examined here are highly structured based on geography (continentally and major regions within continents). Results from our genome analyses revealed that host-mediated global dispersal as the likely primary process in shaping diversity and maintaining genetic population boundaries within the nuclear genome of the human head louse.

Acquisition of new genes often results in the emergence of novel functions and is a key step in lineage-specific adaptation. As the only group of sessile crustaceans, barnacles establish permanent attachment through initial cement secretion at the larval phase followed by continuous cement secretion in juveniles and adults. However, the origins and evolution of barnacle larval and adult cement proteins remain poorly understood. By performing microdissection of larval cement glands, transcriptome and shotgun proteomics and immunohistochemistry validation, we identified 30 larval and 27 adult cement proteins of the epibiotic turtle barnacle Chelonibia testudinaria, of which the majority are stage- and barnacle-specific. While only two proteins, SIPC and CP100K, were expressed in both larvae and adults, detection of protease inhibitors and the cross-linking enzyme lysyl oxidase paralogs in larvae and adult cement suggested functional convergence. Other barnacle specific cement proteins such as CP100k and CP52k likely share a common origin dating back at least to the divergent of Rhizocephala and Thoracica. Different CP52k paralogs could be detected in larval and adult cement, suggesting stage-specific cement proteins may arise from duplication followed by changes in expression timing of the duplicates. Interestingly, the biochemical properties of larval- and adult-specific CP52k paralogs exhibited remarkable differences, reflecting the composition of cement in different life stages of turtle barnacle might be chemically different. We conclude that de novo gene formation and duplicate neofunctionalization are pivotal to the evolution of lineage-specific cement toolkits in barnacles, which may explain how barnacles can inhabit diverse marine substrata.

Sperm morphology is considered a species-specific character and has been used as a tool in the classification of numerous mammalian taxa. Neotropical bats have been poorly studied, and important aspects on sperm morphology have not been elucidated. The aim of the present study was to describe and compare the sperm morphology and morphometry of Molossus molossus and Molossops temminckii. 14 adults specimens were analyzed from the Colección Mamíferos Lillo, Universidad Nacional de Tucumán: five Molossus molossus and nine Molossops temminckii. The epididymis were extracted and macerated in Farmer’s solution, followed by a coloration with different stains. To carry out the description and morphometric analysis, microphotographs were taken under an optical, epifluorescence and scanning electron microscope. A total of 50 sperm from each individual were measured for morphometric analysis. The length and width of the head, midpiece and tail were taken as variables. Sperm from M. molossus and M. temminckii were practically identical, both morphologically and morphometrically. In both species, a distal bulge was observed at the end of the intermediate piece in a percentage greater than 85%. The main characteristics shared between the species were: presence of acrosomal blebs in the upper half of the head of the spermatozoa; cephalic equatorial segment with filiform ornamentations; intermembrane space of head apex wedge-shaped; helical middle piece and annulus at the end of middle piece. In the present study, scanning electron microscopy allowed us to visualize structures, such as acrosomal vesicles, that were not detected with other types of microscopy.

Emerging evidence suggest that oroxylin A, a natural flavonoid compound, induces apoptosis in HCC through multiple mechanisms. However, whether oroxylin A-induced apoptosis could exhibit modulatory effect on tumor microenvironment remains unclear. Here we investigate the effect of oroxylin A on communication between cancer cells and macrophages in vitro and mouse model. The data shows oroxylin A elicits apoptosis-related extracellular vesicles through caspase 3-mediated ROCK1 activation in HCC cells, which are able to regulate M1-like polarization of macrophage. Moreover, oroxylin A downregulates the population of M2-like macrophage and increase in T cells infiltration in tumor microenvironment, accompanied with suppression of HCC development and enhancement of immune checkpoint inhibitor treatment. Mechanistically, glycolysis proteins enriched in oroxylin A-elicited extracellular vesicles from HCC cells is transferred to macrophages where it contributes to ROS-dependent NLRP3 inflammasome activation, therefore promoting anti-tumor phenotype of macrophage. Taken together, this study highlights oroxylin A promotes metabolic shifts between tumor cells and macrophages, facilitating to inhibit tumor development and improve immunotherapy response in HCC model.

Comprehensive treatment for ROS1-overexpressed pulmonary sarcomatoid carcinoma: a case report

The nucleation mechanism for the ternary cluster of hydrated sulfuric acid with ammonia or alkyl-amines is one of the unsettled questions in atmospheric chemistry. The effects of hydration are not be neglected during nucleation. We have investigated the clusters of [(CH3)mNH3-m]∙(H2SO4)∙(H2O)n with m=0-3 and n=0-14 by molecular dynamics simulation and quantum chemistry. 60 stable conformations were obtained by four different proton-transfer manners at the lever of CAM-B3LYP/6-311G(d,p). Three apparent transitions appeared during non-protonation to single protonation to double protonation with the increasing water. According to binding energy and Gibbs free energy by MP2/6-311++G(d,p), we can conclude that the ability of protonation was related to the alkalinities of ammonia and alkyl-amines in the absence of water. By adding water to enlarge clusters, the dimethylamine was the most favorable to the nucleation due to thermodynamic properties. According to the conformation of clusters, the hydrogen bond was the main interaction during the formation and growth of clusters. When the number of water reached to 5(ammonia), 4(methylamine), 3(dimethylamine), and 4(trimethylamine), the H-bond network began to generate, which indicated the ion-induced interaction between water and HSO4-/SO42- can promote the formations of solvent ion-pair and tri-ions isomers beneficially.

For this study, we focus on the exploration of maritime areas that contain accident-prone points, such as illegal riding, unauthorized boarding, illegal fishing, and smuggling. This exploration is carried out using a cooperative system consisting of an Unmanned Aerial Vehicle (UAV) and an Unmanned Surface Vehicle (USV). The goal is to allow the USV-UAV system to efficiently explore all of the accident-prone points while minimizing the UAV’s energy usage. Specifically, we aim to achieve this objective while keeping travel time as short as possible. The collaborative exploration system leverages the strengths of both the UAV and the USV. The UAV is deployed to explore hazardous areas that are inaccessible by the USV, while the USV doubles as a mobile charging station, resolving the UAV’s energy limitation issue. The proposed algorithm for this subject paper, called the Collaborative Accident Searching Routing Optimization (CASRO) algorithm, utilizes the benefits of both the Lazy Theta* algorithm and the Improved Ant Colony algorithm to optimize the path of a cooperative system between USV and UAV. With CASRO, we aim to address the two key limitations of the USV, namely poor flexibility, and the UAV’s limited energy simultaneously. Finally, the effectiveness and superiority of the proposed planning strategy in target exploration is verified by numerical simulations of randomly distributed maritime areas with accident-prone points.

In this paper, a model predictive control algorithm based on dead-zone time optimal compensation is proposed for permanent magnet synchronous motor. First, the dead-time voltage vectors corresponding to each candidate voltage vectors are analyzed. And a new finite control set is obtained under the minimum dead-zone time. Based on the new control set, the predictive controller is designed to obtain the optimal voltage vector and its dead-time voltage vector. Then the beneficial dead-time voltage vector is judged, and the dead-zone time is optimized. The optimal dead-zone time and the optimal voltage vector are used to achieve speed stability and good performance. Finally, a simulation example is established to verify the feasibility and effectiveness of the proposed algorithm.

Abstract: Influenza-like illness (ILI) outbreaks mainly occurred in schools. And annually reformulated composition of influenza vaccines makes it necessary to estimate the effectiveness of the seasonal influenza vaccine. We aimed to estimate the effectiveness of the seasonal influenza vaccine against influenza outbreaks in schools. Methods This was a matched case-control study estimating the effectiveness of the influenza vaccine in preventing school influenza outbreaks. The laboratory-confirmed cases of influenza in school children were paired by the random sample of asymptomatic classmates by sex and age during the 2019–2020 influenza season. Influenza vaccine effectiveness was estimated using a conditional logistic regression model. Results During the 2019–2020 influenza season, 503 paired samples of laboratory-confirmed influenza cases and asymptomatic controls were enrolled. The influenza vaccination rates for cases and controls were 0.40% and 1.59%, respectively. The vaccine effectiveness against influenza outbreaks in schools was 74.35% (95% CI: 5.39–122.00) during the 2019–2020 season. Conclusions No significant vaccine effectiveness was observed during influenza outbreaks in schools during the 2019–2020 influenza season because of the low vaccination rate. Efforts should be made to increase vaccination coverage among students.

Influenza is associated with significant disease burden in the US. Influenza vaccination effectiveness (VE) is low due to several factors, including egg adaptations. Evidence for a relationship between egg-based manufacturing and influenza VE remains largely disassociated, except for two previous European consensuses. The aim of this study was to observe US expert consensus on the phenomenon. Ten US influenza experts assessed evidence for antigenic drift, egg adaptations, and manufacturing component principles of the research question in a novel two-stage online study design to observe proportional group awareness and consensus, known as the Jandhyala Method. US experts agreed that all component principles had a majority of strong or very strong supporting evidence (52–86%), similar to European results (70-90%). They agreed that global surveillance, WHO candidate vaccine virus selection, and manufacturing stages involving eggs were the most likely to impact influenza VE. There was unanimous agreement for a mechanistic basis for reduced influenza VE due to egg-based manufacturing. There is now US and European expert agreement for the increased risk of reduced influenza VE resulting from egg-based manufacturing techniques. Increasing the use of non-egg-based manufacturing that avoids egg-adaptations is a currently available strategy that may improve influenza VE.

PlzA is a c-di-GMP-binding protein crucial for adaptation of the Lyme disease spirochete Borrelia ( Borreliella) burgdorferi during its enzootic life cycle. Unliganded apo-PlzA is important for vertebrate infection, while liganded holo-PlzA is important for tick acquisition; however, the biological function of PlzA has remained enigmatic. Here we report that PlzA has RNA chaperone activity that is inhibited by c-di-GMP binding. Holo- and apo-PlzA bind RNA and accelerate RNA annealing, while only apo-PlzA can strand displace and unwind double-stranded RNA. Guided by the crystal structure of PlzA, we identified several key aromatic amino acids protruding from the N- and C-terminal domains that are required for RNA binding and unwinding activity. Our findings illuminate c-di-GMP as a switch controlling the RNA chaperone activity of PlzA and we propose that complex RNA-mediated modulatory mechanisms allow PlzA to regulate gene expression during both the vector and host phases of the B. burgdorferi life cycle.

Quantum dot Cellular Automata (QCA) may be viewed as the potential digital logic design alternative to supplant the current CMOS Technology. The logical design is based on the polarization of electrons to transfer information which results in a huge improved performance metric in terms of speed, power & area. This paper demonstrates a Reversible Arithmetic Processor (RAP) architecture design with Reversible Multiplexer (RM) and Reversible Functional Gate (RFG) in QCA. The QCA Designer-E simulation tool has been used to design and verify all the proposed architecture and the energy dissipation has been simulated using a coherent vector energy engine setup. The total and average energy dissipation per cycle of our proposed RAP using QCA are 3 . 9 1 × 1 0 − 1 ev and 3 . 5 6 × 1 0 − 2 ev respectively. Regarding cell count, area, latency, and energy dissipation, the proposed architecture beats out the existing architecture.

Purpose: Optimal adherence to antidiabetics among patients with type 2 diabetes mellitus has been associated with positive health outcomes; however, studies to assess this adherence in Saudi Arabia are scarce. We aimed to evaluate adherence to antidiabetics using a Saudi population. Methods: This was a multicenter, retrospective cohort study of patients (≥ 18 years old) with type 2 diabetes mellitus who received ≥ 1 antidiabetic between 2015 and 2020. Adherence was estimated using the continuous multiple-interval measure of medication availability (CMA7). A CMA7 cutoff point of ≥ 80% was chosen to define optimal adherence, and the odds of not achieving therapeutic annual HbA1c levels (i.e. ≥ 7%) in the optimal vs. suboptimal adherence groups was assessed using a logistic regression model adjusting for the measured confounders. Results: A total of 36,789 patients were included in the study. The most commonly prescribed regimens were metformin single treatment (n=15,025 [41.6%]) and gliclazide-metformin combination treatment (n=5,667 [15.7%]). The median CMA7 was 70.4%, and only 13,552 (36.9%) patients were adherent to their antidiabetics (CMA7 ≥ 80%). The odds of not achieving therapeutic HbA1c levels one year after the index date were comparable in the optimal vs. suboptimal adherence groups (odds ratio = 0.99, 95% confidence interval 0.92 to 1.05). Conclusions: This study showed that a large proportion of a Saudi population with type 2 diabetes mellitus were non-adherent to their antidiabetic treatments. Future Saudi and regional studies are needed to assess the impact of adherence on HbA1c levels and on cardiovascular outcomes.

Preventive algorithm ending up being the ‘Cause’!Anindya Ghosh, MD1 │ Deep Chandh Raja, MD21Department of Cardiac Electrophysiology and Pacing, Arrhythmia Heart Failure Academy, The Madras Medical Mission, Chennai, Tamil Nadu, India2Department of Cardiac Electrophysiology and Pacing, Kauvery Hospital, Chennai, India

Aim: This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with hematologic malignancy, identify factors affecting methotrexate PK, and propose optimal dosage regimen for the Korean population. Methods: Data were retrospectively collected from 188 patients with acute leukemia or non-Hodgkin’s lymphoma who were admitted to Severance Hospital for the period from 2005 to 2015. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. Results: A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.99L for central volume of distribution (V_1), 18.76L for peripheral volume of distribution (V_2), 12.9L/h for clearance (CL) and 0.646L/h for inter-compartmental clearance. Covariate analyses showed that, at the weight of 50kg, CL decreased by 0.11 L/h for each one-year increase in age above 14 years old and decreased to 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (=V_1+V_2) was 0.90L/kg, which was similar to those in the Western or Chinese population. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. Conclusion: The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with hematologic malignancy.

Atrial fibrillation (AF) is mainly initiated by arrhythmogenic triggers originating from the pulmonary veins, and ganglion plexus often plays a crucial role in the induction and maintenance of AF. In this report, we describe a case of successful cryoballoon ablation of focal atrial tachycardia originating from the left inferior pulmonary, in which vagal response was observed, and discuss its tachycardia mechanism.

Today, the most important treatment methods for cancer are chemotherapy, surgical intervention, and radiotherapy. In recent years, many studies on radioimmunotherapy have been carried out. New drugs and treatment strategies are constantly being researched, and targeted cancer therapy is the treatment with the highest efficacy and negligible side effects compared to other methods. Breast cancer is the most common type of cancer in women. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-30% of breast cancer cases. Trastuzumab is a humanized monoclonal antibody of recombinant DNA origin targeting the HER2 protein. In this study, the pharmaceutical part of a new radiopharmaceutical to be used in breast cancer treatment was prepared. For this purpose, molecular insertion studies were conducted to show the binding sites between Trastuzumab and different chelating agents (DOTA, DTPA, EDTA and MAG3) in silico. Then, these chelating agents were complex, and characterization studies were carried out.