Efficacy Advantages Research Articles

Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Acute Myeloid Leukemia Patients with FLT3 Mutation

Background Acute myeloid leukemia (AML) is a heterogenous disease and exhibits a dynamic mutational landscape as the disease progresses. Internal tandem duplication (ITD) of FLT3 is considered an acquired late-event mutation and is associated with a poor prognosis in AML. Emavusertib is a potent oral inhibitor of IRAK4 and FLT3, conferring potential efficacy advantages compared to other IRAK4 and FLT3 inhibitors. IRAK4 is upregulated during anti-FLT3- or other cytotoxic therapies, which could drive a resistance pathway of early relapse and progression (Melgar 2019; Li 2019). Presence of spliceosome mutations U2AF1 or SF3B1 results in excessive IRAK4-L and further enhance toll-like receptor pathway activation (Smith 2019). Methods The safety, clinical activity, and potential biomarkers of emavusertib in relapsed/refractory (R/R) AML and higher-risk myelodysplastic syndrome are being investigated in the ongoing open-label, Phase 1/2a TakeAim Leukemia trial (NCT04278768). Here we present preliminary safety and efficacy data in the subset of enrolled AML patients who carried FLT3 mutation (FLT3m) at baseline and were treated with emavusertib monotherapy. Patients' mutational profiles were documented based on local testing results. Results As of 12 June 2023, 10 R/R AML patients with FLT3m have been treated at initial doses of 200, 300, or 400 mg BID. There was 1 patient with FLT3-TKD and 9 patients with FLT3-ITD, of which 2 carry both FLT3-ITD and U2AF1 mutations, and 1 with both FLT3-TKD and SF3B1 mutations. The median number of prior anti-cancer therapies was 3 (range 1-6) and 7 out of 10 patients had prior exposure to gilteritinib. Two patients with prior gilteritinib exposure also received midostaurin therapy. Treatment-emergent adverse events (TEAEs) Grade ≥ 3 were reported in 7/10 (70%) patients, and the majority of Grade ≥ 3 TEAEs were reversible and manageable. No dose-limiting toxicity was reported in these 10 patients. Five of 9 response evaluable patients demonstrated more than 90% bone marrow blast reduction compared to baseline. Enrollment is being expanded in this trial at the Recommended Phase 2 Dose (RP2D) of 300 mg BID for patients with ≤ 2 prior lines of therapy. Preliminary data for the 3 response evaluable patients in this population (for whom baseline and post-treatment marrow assessments were available) include blast count reductions of 99%, 100%, and 100% and include 2 CRs and 1 morphologic leukemia-free state (MLFS), with on-treatment duration of 213 days, 225 days, and 134 days, respectively. FLT3-ITD became undetectable in both patients achieving CR. Conclusion Emavusertib has a favorable safety profile in heavily pretreated AML patients with FLT3m and demonstrated anti-cancer activity in patients with FLT3m, including patients who have progressed on prior FLT3 inhibitor. No dose-limiting myelosuppression was reported. In addition, mutational profiles are suggestive of disease-modifying activity of emavusertib. Enrollment in this trial is continuing at a dose of 300mg BID (phase 2 expansion cohort) for patients with ≤ 2 prior lines of therapy.

Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.

Apixaban in patients with atrial fibrillation and acute coronary syndrome in elective percutaneous coronary intervention: what did the subanalysis of the AUGUSTUS trial add to our understanding?

The article is devoted to the results of the subanalysis published after release of the AUGUSTUS trial. The most important conclusion of the parent trial is the evidence that weekly aspirin therapy is sufficient to prevent thrombotic complications in the majority of patients with AF and ACS, as well as those undergoing elective PCI, and that aspirin therapy can be extended up to 1 month after PCI only in a part of patients with additional risk factors for ischemic events and a low risk of bleeding. Four years have passed since the publication of the AUGUSTUS trial results, and all subsequent subanalyses of the trial confirmed its results. The safety and efficacy advantages of apixaban over warfarin were shown to be independent of renal function and consistent with the overall trial results. The advantages of apixaban and the association of aspirin with bleeding were similar in both stroke and non-stroke patients with AF and were dose-independent when a dose was reduced to 2.5 mg twice in accordance with the reduction criteria. The advantages of apixaban over warfarin lasted regardless of time spent in the therapeutic range in the warfarin group. The advantages of apixaban over warfarin and the association of long-term intake of aspirin with bleeding rates persisted in patients with high and low baseline risk of bleeding and stroke. All subanalyses of the AUGUSTUS trial confirmed the efficacy and safety of apixaban, as well as the option to discontinue aspirin at the outpatient stage in the majority of patients with AF, who underwent elective PCI or ACS.

Review on emission reduction of VCR system using various nano‐refrigerants

AbstractThe focus of the study is the exploration of the possible efficacy and environmental advantages of nanofluids, including hybrid nanoparticles, concerning the effectiveness of the Vapor Compression Refrigeration System (VCRS). This necessitates a thorough assessment of the stability qualities, synthesis techniques, thermal conductivity, viscosity, and heat transfer efficiency of nanofluids. This research also aims to explore different Nano‐Refrigerant combinations that influence the Coefficient of Performance (COP). According to some research findings, the use of copper nanoparticles improved COP by 8.1%, while the use of alumina nanoparticles raised COP values as high as 6.71%. Moreover, studies have demonstrated that various hybrid nanoparticles like silver‐graphene oxide also greatly improve outcomes concerning amounts used, raising the system's overall performance capabilities. Finally, it can be said that there is a wide range of applications for these fluids because they can function cost‐effectively and environmentally friendly while significantly reducing energy consumption, acting as refrigerants or secondary fluid systems, and having a positive impact on performance when used in deployed VCRS configurations.

Histone crotonylation of peripheral blood mononuclear cells is a potential biomarker for diagnosis of colorectal cancer

BackgroundBlood-based tests have public appeal in screening cancers due to their minimally invasive nature, ability to integrate with other routine blood tests, and high compliance. This study aimed to investigate whether certain epigenetic modulation of peripheral blood mononuclear cells (PBMCs) could be a biomarker of colorectal cancer (CRC).ResultsWestern blotting of histones in the PBMCs from 40 colorectal cancer patients and 40 healthy controls was performed to identify the crotonylation sites of proteins. The correlation of crotonylation with tumor staging and diagnostic efficacy were analyzed. Crotonylation of H2BK12 (H2BK12cr) was identified significantly upregulated in the PBMCs of CRC patients compared to healthy controls, and were closely related to distant metastasis (P = 0.0478) and late TNM stage (P = 0.0201). Receiver operator characteristic curve (ROC) analysis demonstrated that the area under curve (AUC) of H2BK12cr was 0.8488, the sensitivity was 70%, and the specificity was 92.5%. The H2BK12cr parameter significantly increased the diagnostic effectiveness of CRC compared with the commercial carcinoembryonic antigen assays.ConclusionsThe H2BK12cr level in PBMCs of CRC patients has a potential to be a biomarker for distinguishing CRC patients from healthy controls with the advantages of easy operation and high diagnostic efficacy.

The benefits of estetrol addition to drospirenone for contraception

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

Recent advances in upstream process development for production of recombinant adeno-associated virus.

Recombinant adeno-associated virus (rAAV) is rapidly emerging as the preferred delivery vehicle for gene therapies, with promising advantages in safety and efficacy. Key challenges in systemic in-vivo rAAV gene therapy applications are the gap in production capabilities versus potential market demand and complex production process. This review summarizes currentavailable information on rAAV upstream manufacturing processes and proposed optimizations for production. The advancements in rAAV production media were reviewed with proposals to speed up the cell culture process development. Furthermore, major methods for genetic element delivery to host cells were summarized with their advantages, limitations, and future directions for optimization. In addition, culture vessel selection criteria were listed based on production cell system, scale, and development stage. Process control at the production step was also outlined with an in-depth understanding of production kinetics and quality control.

Efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Atezolizumab plus bevacizumab and lenvatinib are the current first-line systematic therapy for unresectable hepatocellular carcinoma (uHCC). However, the selection of initial treatment among the two therapies are controversial. This meta-analysis aims to compare efficacy and safety between atezolizumab plus bevacizumab and lenvatinib. We systematically searched for studies on atezolizumab plus bevacizumab and lenvatinib in the online databases PubMed, Embase, Web of Science and Cochrane Library. The outcome data including overall survival (OS), progression free survival (PFS), tumor response and adverse events (AEs), were independently extracted by two authors in a standardized way. Eight retrospective cohort studies with 3690 patients (atezolizumab plus bevacizumab: 1680, lenvatinib: 2010) were included in the meta-analysis. The atezolizumab plus bevacizumab group had significant longer PFS [hazard ratio (HR) 0.76, 95% confidence intervals (CI) 0.65-0.88; I squared statistic (I2) = 0.0%, p = 0.590], compared with lenvatinib group but no significant difference in OS (HR 0.87, 95% CI 0.75-1.01; I2 = 0.0%, p = 0.597), objective response rate (ORR) [risk ratio (RR) 0.89, 95% CI 0.79-1.02; I2 = 19.3%, p = 0.283] and disease control rate (DCR) (RR 1.03, 95% CI 0.98-1.09; I2 = 0.0%, p = 0.467) among them. Moreover, patients receiving atezolizumab plus bevacizumab exhibited lower incidences of grade 3/4 AEs than those receiving lenvatinib (RR 0.65, 95% CI 0.51-0.83; I2 = 69.3%, p = 0.003). However, in non-viral patients group, lenvatinib delivered favorable outcomes in OS (HR 1.32, 95% CI 1.04-1.67; I2 = 0.0%, p = 0.380) compared with atezolizumab plus bevacizumab. Atezolizumab plus bevacizumab provides potential advantage in efficacy and better safety than lenvatinib in the treatment of uHCC. Lenvatinib is an appropriate effective alternative to atezolizumab plus bevacizumab in patients without viral infecting.

Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity

Since the discovery of imatinib, the first tyrosine kinase inhibitor, in 2001, targeted therapy has become mainstream of cancer therapeutics. Despite the advantages in efficacy and low side effects compared with conventional chemotherapy, the success of the targeted anticancer drugs is still limited by the drug resistance which happens due to the fact that the development of cancer is stimulated by several stimuli and therefore, defeating cancer may occur upon the inhibition of several targets. However, coadministration of multiple drugs always lead to many disadvantages including increased toxicity and less patient compliance. Therefore, the aim of research is to develop anticancer agents with multi-target action based on the modification of the chemical structure of sunitinib, a well-known multi-kinase inhibitor. A series of fifteen compounds comprising pyrrolo[2,3-d]pyrimidine and hydrazone have been designed and successfully synthesized. Among the synthesized compounds, compounds 6f, 6l and 6n inhibited the enzymatic activity of EGFR, Her2, VEGFR-2 and CDK2 kinase enzymes similar to sunitinib and the reference protein kinase inhibitors. Interestingly, remarkable results were revealed by compounds 6j and 6c that demonstrated selective VEGFR-2 inhibition activities and compound 6i that exhibited selective dual inhibition of Her2/VEGFR-2 enzymes. Further analysis revealed that compounds 6f and 6n suppressed cell cycle progression of HepG2 cells and induced early and late apoptosis. Moreover, those two compounds triggered a significant elevation in caspase 3 and Bax proapoptotic proteins and a notable reduction in Bcl-2 anti-apoptotic protein. Finally, molecular docking studies were conducted to predict the possible binding interactions of 6f and 6n with CDK2 and 6f, 6n, 6j and 6c with VEGFR-2.

Degradation of DDT by a Novel Bacterium, Arthrobacter globiformis DC-1: Efficacy, Mechanism and Comparative Advantage

A novel bacterium, Arthrobacter globiformis DC-1, capable of degrading DDT as its sole carbon and energy source, was isolated from DDT-contaminated agricultural soil. The bacterium can degrade up to 76.3% of the DDT at a concentration of 10 mg/L in the mineral salt medium (MSM) within 1 day of incubation. The effects of various environmental conditions, such as the concentration of DDT, temperature, pH and additional carbon sources, on its growth and biodegrading capacity of DDT were investigated in the MSM. The A. globiformis DC-1 strain could efficiently grow and degrade DDT at a wide range of concentrations, with the maximum growth and degradation rate at 10 mg/LDDT, followed by inhibitory effects at higher concentrations (20 and 30 mg/LDDT). Mesophilic temperatures (25–30 °C) and a pH of 7–7.5 were the most suitable conditions for the growth and biodegradation. The presence of carbon sources significantly increased the growth of the DC-1 strain; however, degradation was inhibited in the present of glucose, sucrose and fructose, and peptone was determined to be the most appropriate carbon source for A. globiformis DC-1. The optimal DDT degradation (84.2%) was observed at 10 mg/LDDT, peptone as carbon source in pH 7.5 at 30 °C with 1 day of incubation. This strain could also degrade DDE, DDD and DDT simultaneously as the sole carbon and energy source, with degradation rates reaching 70.61%, 64.43% and 60.24% in 10 days, respectively. The biodegradation pathway by A. globiformis DC-1 revealed that DDT was converted to DDD and DDE via dechlorination and dehydrochlorination, respectively; subsequently, both DDD and DDE transformed to DDMU through further dechlorination, and finally, after ring opening, DDMU was mineralized to carbon dioxide. No intermediate metabolites accumulation was observed during the GC/MS analysis, demonstrating that the A. globiformis DC-1 strain can be used for the bioremediation of DDT residues in the environment.

Vitamin B<sub>12</sub> deficiency and Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease with various clinical manifestations, its origin not always can be explained only by dopamine deficiency. Long-term treatment with levodopa (especially its intraduodenal administration), as well as clinical manifestations of polyneuropathy, cognitive deficits, postural disorders with freezing of gate, REM sleep behavioral disorders, are more often associated with vitamin B12 deficiency. Several reasons for this association and mechanisms of their development are discussed. Early detection of cobalamin deficiency in PD, especially in patients from high-risk groups, makes it possible to stop this pathological condition timely and prevent irreversible changes. Modern data on the use of high-dose (1000 μ g) oral vitamin B12 are presented, it has comparable clinical efficacy and significant advantages, compared with the parenteral form, in terms of the ease of use and the ability to avoid undesirable postinjection reactions.

Plasma-Lyte-148 Versus Normal Saline 0.9% in Diabetic Ketoacidosis Management: A Review.

Diabetic ketoacidosis (DKA) is a critical complication of diabetes mellitus characterized by hyperglycemia, ketonemia, circulatory collapse, hypokalemia, and metabolic acidosis. The therapeutic management of DKA includes vigilant fluid resuscitation to address dehydration and electrolyte imbalances and restore hemodynamic stability. The choice of fluid, either isotonic saline or a balanced electrolyte solution like Plasma-Lyte 148 (PL), is pivotal in the clinical outcomes of DKA patients. Recent studies have compared the effectiveness of these fluid solutions in DKA management, focusing on different clinical outcomes such as the resolution of metabolic acidosis, electrolyte imbalances, the incidence of acute kidney injury, and length of hospital stay. This review examines the literature comparing isotonic saline and balanced electrolyte solutions for fluid resuscitation in DKA, analyzing the associated clinical outcomes. Through synthesizing research findings, this review aims to elucidate the efficacy and potential advantages of utilizing PL as an alternative to traditional isotonic saline for fluid resuscitation in treating DKA. This would further facilitate evidence-based decision-making among healthcare professionals and contribute to optimizing DKA management strategies. Understanding the intricacies and implications of fluid resuscitation is crucial, given its profound impact on patient outcomes in DKA management.

NLRP3 participates in the differentiation and apoptosis of PMA‑treated leukemia cells.

Acute myeloid leukemia (AML) is a clonal malignant proliferative disease. In recent years, with the use of all‑trans retinoic acid to induce cancer cell differentiation in acute promyelocytic leukemia, and its advantages of high efficacy and low toxic side effects, tumor differentiation therapy has become a research hotspot; however, the mechanisms underlying its role remain to be fully established. Nod‑like receptor family pyridine domain containing 3 (NLRP3) is the most extensively studied and well‑characterized inflammasome, is involved in a variety of inflammation‑related diseases, including cancer, and is a very attractive potential target for the study of novel therapeutic agents. Activation of the NLRP3 inflammasome is a double‑edged sword in tumor therapy, with evidence of protective anti‑tumor and pro‑tumor effects in different types of cancer. Whether the NLRP3 inflammasome promotes disease progression or exerts a protective anti‑tumor effect in hematological malignancies remains contested. In the present study, the protective anti‑tumor effects of NLRP3 on leukemia cells during their differentiation and maturation were investigated. It was found that the upregulation of NLRP3 expression induced using Phorbol 12‑Myristate 13‑Acetate played a role in promoting the differentiation and maturation of leukemia cells into monocytes/macrophages, and it was directly involved in the apoptosis of leukemia cells and the differentiation and maturation of CD11b+ cells. These results provide novel theoretical evidence for exploring the mechanism of differentiation therapy in leukemia and improves our understanding of the role of NLRP3 in hematologic tumors.

Efficacy and safety of second-line treatment for advanced gastric cancer: A network meta-analysis of randomized controlled trials.

e16018 Background: To evaluate the difference of curative effect between different treatment regimens in patients with advanced gastric cancer (AGC) who have previously received fluorouracil based first-line chemotherapy. Methods: We searched PubMed, PMC and EMBASE databases for published randomized controlled trials (RCTs). The number of people who reached the objective response rate (ORR) and the hazard ratio (HR) and its 95% confidence interval (CI) of progression-free survival (PFS) and overall survival (OS) were extracted. R (version 4.0.5) and R Studio were used to conduct meta-analysis of relevant data based on the Bayesian framework. Gemtc software package facilitates statistical analysis. To provide a ranking for each treatment regimen, surface under the cumulative ranking curve (SUCRA) was calculated. Survival analysis was conducted based on WinBUGS 14. STATA17.0 was used to draw the network diagram and funnel plot. Results: A total of 17 RCTs were included in this meta-analysis, and a total of 15 treatment regimens were used in the second-line treatment of AGC. There was no publication bias or other bias in the studies. Ramucirumab combined with paclitaxel and nab-paclitaxel weekly regimens have obvious advantages in efficacy and safety. Among them, ramucirumab combined with paclitaxel (83.6%) has great advantages in ORR, while the probability of anemia (36.6%) and anorexia (22.7%) is low, and the probability of leucopenia (66.6%) is high. However, the ORR of nab-paclitaxel weekly regimen (71.4%) is only second to that of ramucirumab combined with paclitaxel, and the probability of anemia (46.3%) and anorexia (44%) is also low, and the probability of leucopenia (53.8%) is high. In terms of OS and PFS, ramucirumab combined with paclitaxel has the best effect according to the probabilistic settlement table. Pembrolizumab and 5-Fu have poor therapeutic effects in terms of PFS. Conclusions: Ramucirumab combined with paclitaxel and nab-paclitaxel can significantly improve the survival outcome of patients with AGC. The effect of ramucirumab combined with paclitaxel is significantly better than that of paclitaxel, and the effect of nab-paclitaxel is only second to that of ramucirumab combined with paclitaxel. The safety of multi-drug combination should also be carefully considered. These findings may help clinicians better choose the second-line treatment strategy for patients with AGC.

Description and Treatment Progress of Postpartum Body Pain in Chinese Medicine

Postpartum body pain is one of the common postpartum diseases, the damage to the patient’s physical and mental health can not be ignored. The recognition and treatment of postpartum body pain in traditional Chinese medicine mainly take qi and blood, Zang-fu organs and ying wei as the main points of syndrome differentiation. Its main etiology and pathogenesis are postpartum deficiency of qi and blood, wind-cold and dampness evil invading human body, the dysfunction of each viscera and the disharmony of camp and health. According to the cause, the treatment can be summarized as supplementing qi and blood, harmonizing Yingwei, dispelling wind and dispersing cold, activating collages and relieving pain, regulating zang fu organs and so on. TCM treatment focuses on the holistic view, and its systematic treatment through early intervention, multiple means and multiple approaches has the advantages of high safety, significant efficacy and low recurrence rate. Clinical syndrome differentiation is not limited to one of the above types, but this article can provide treatment ideas for this disease.

Pulsed field ablation based pulmonary vein isolation utilizing a simplified approach

Abstract Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) is a novel non-thermal energy source with promising safety and efficacy advantages compared to standard ablation technologies. Purpose We aimed to develop a safe, effective and fast pulmonary vein isolation (PVI) utilizing a single shot PFA catheter via a single femoral vein puncture and a venous closure system approach. Methods Forty-eight consecutive AF patients underwent first-time PVI via PFA under deep sedation. A single ultrasound guided femoral vein puncture and a single transseptal puncture was utilized for left atrial access. After pulmonary vein (PV) angiography eight pulse trains (2kV/2.5 sec, bipolar, biphasic, each 4x basket/flower configuration) were delivered to each PV. Extra pulse trains in the flower configuration (8x) were added to the posterior wall for very wide antral circumferential ablation (vWACA). Continuous intraluminal esophageal temperature (TESO) was monitored with a s-shaped esophageal temperature probe. A venous closure system was utilized on the single access site. A Donati suture was performed. The pressure bandage was removed after 1h. Results Patients (mean age: 64 +/-11 years) presented with AF (paroxysmal 58% or persistent AF (42%). A total of 192 PV were identified and isolated via PFA (100%). A mean of 40 pulse trains for PVI and vWACA have been used. The mean procedural time was 27 +/- 7 minutes, the mean catheter dwell time was 14 +/- 6 minutes and the median fluoroscopy time was 6 +/- 2 minutes. No relevant esophagus temperature rise occurred. One patient (2%) experienced a transient phrenic nerve palsy which recovered until the end of the procedure. Two patients (4%) experienced a superficial bleeding which was treated by a figure of eight suture. No severed hematoma, transfusion or intervention was necessary. No pericardial effusion or tamponade occurred. Conclusion The combination of a single vein single transseptal puncture approach resulted in a 100% rate of acute PVI and an extraordinary fast procedure and dwell time. The rate of periprocedural complications was low.

Effects of da Vinci robot versus thoracoscopic surgery on body trauma and lymphocyte subsets in lung cancer patients: A propensity score matching study.

To assess the impact of da Vinci robot versus thoracoscopic surgery on body trauma and lymphocyte subsets in lung cancer patients. Retrospective analysis of 352 patients with lung cancer treated by minimally invasive surgery completed by the same operator in the Department of Thoracic Surgery, Gansu Provincial People's Hospital from October 2019 to October 2022. According to the surgical procedure, the patients were divided into a robotic-assisted thoracic surgery (RATS) group (n = 159) and a video-assisted thoracoscopic surgery group (VATS) (n = 193), respectively. Propensity score matching (PSM) analysis was performed in both groups, and perioperative indicators were recorded. Levels of inflammatory markers (C-reactive protein, CRP; interleukin-6, IL-6) and lymphocyte subsets (CD3+ , CD4+ , CD8+ , andCD4+ /CD8+ ) were measured 1 day before surgery and 1, 3, and 5 days after surgery, respectively. To compare the effects of the two surgical procedures on the trauma and lymphocyte subsets of the patient's organism. One hundred and thirty-eight patients in each group after PSM. Compared with the VATS group, the RATS group had shorter operative time (p < 0.001), less intraoperative bleeding (p < 0.001), less postoperative chest drainage (p = 0.029), shorter postoperative chest drainage time (p = 0.008), and shorter postoperative hospital stay (p = 0.005). The levels of CRP and IL-6 increased in both groups after surgery compared with those before surgery, and the increase was less in the RATS group than that in the VATS group. Postoperative T-lymphocyte levels were lower in both groups compared with preoperative levels, and T-lymphocyte levels were significantly lower in the VATS group compared with the RATS group. Compared with VATS for treating lung cancer, RATS has advantages in short-term efficacy, and smaller surgical trauma to patients, which can reduce the body's inflammatory response. It also has less impact on T lymphocyte subpopulations, which can better protect patients' immune function.

2 Challenges in Breeding and Genetics

Abstract Over the past 50 years tremendous advances were made in reproductive and genetic technologies that are available for beef cow-calf producers. In addition, extensive research has been done to establish the efficacy and economic advantages of adoption of such technologies. Nonetheless, adoption of reproductive and genetic technologies in beef cow-calf operations remain poor, especially when compared with dairy production. The USDA – National Animal Health Monitoring System (NAHMS) performs a survey of cow-calf management practices, with the latest survey performed in 2017. According to the NAHMS survey the majority (58.7%) of cow-calf operations in the U.S. do not have a defined breeding season, with 69.5% of operations in the southeast (SE) failing to adopt a defined breeding season. Reproductive technology adoption is poor, with only 37.5% of all operations utilizing at least one reproductive technology, with 78.1% of larger operations (&amp;gt;200 cows) utilizing at least one reproductive technology, compared with 30.4% of small operations (&amp;lt; 50 cows). Semen evaluation was the leading technology with 19.7% overall adoption, followed by palpation for pregnancy with 19.3%, artificial insemination with 11.6% and estrus synchronization with only 7.3%. The SE is behind the rest of the country on adoption of technology with only 22.1% of the operations adopting at least one reproductive technology, with the North-Central region leading the country with 58.3% of operations adopting at least one reproductive technology. Nationally, most heifers and nearly all cows were exposed only to bulls (76.8 and 92.9 %, respectively), with a greater percentage of heifers (15.1 %) than cows (5.5 %) being artificially inseminated and followed by natural service breeding. A total of 90.7% of all beef females were exposed to natural service only, clearly demonstrating that artificial insemination is not widely adopted by U.S. beef operations. Veterinary consultation also remains below expectations, with only 52.8% of operations consulting a veterinarian every year, and disease diagnosis and treatment being the most common reason (37.3%). The East U.S. remains behind the rest of the country with only 41% of beef operations consulting a veterinarian on a yearly basis. When making decisions about breeding and genetics, 21.5% of producers rated Extension services as slightly useful and 22.6% rated Veterinarians as very useful, with most (23.6) producers consulting other producers. Adoption of reproductive and genetic technologies remains below expectations for the entire U.S. with the East and SE regions lagging behind the rest of the country. Perhaps the fact that the vast majority (84.2% in the U.S., and 89.9% in East) of beef cow-calf producers list their operations as a supplemental source of income remains the most difficult challenge to increase adoption of technologies.

How does traditional chinese medicine treat attention deficit hyperactivity disorder-A different understanding and treatment strategy

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, and the incidence in children is increasing year by year. The modern medical field lacks long-acting drugs for the treatment of ADHD and there is an urgent need to investigate new therapeutic drugs or complementary and alternative therapies. Recent studies have found that Traditional Chinese Medicine (TCM) has the advantages of individualization, precise efficacy and minimal side effects in improving attention deficit hyperactivity disorder. This paper reviews the progress of Chinese medicine in the treatment of ADHD in terms of its understanding of the etiology and pathogenesis of ADHD, treatment according to pattern identification and Chinese medicinal preparations.

Development of a PBPK model to quantitatively understand absorption and disposition mechanism and support future clinical trials for PB-201.

PB-201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB-201 will be broad. Because the liver is the primary organ for PB-201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB-201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB-201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB-201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically-based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB-201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age-induced changes in physiological factors may significantly increase the exposure under fasted state by 36%-158% and 48%-82%, respectively. The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB-201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB-201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results.