Comparison of unilateral versus bilateral central neck dissection for clinically invasive papillary thyroid carcinoma.

BACKGROUND: The American Thyroid Association guidelines primarily recommend central neck dissection for papillary thyroid carcinoma with advanced primary tumors or clinically positive neck nodes. However, the appropriate extent of dissection remains unclear. We aimed to compare the rate of locoregional recurrence between unilateral and bilateral central neck dissection in invasive papillary thyroid carcinoma. METHODS: Among 330 consecutive patients who underwent total thyroidectomy with central neck dissection for advanced papillary thyroid carcinoma, 212 underwent unilateral central neck dissection (UCND group) while 118 underwent bilateral central neck dissection (BCND group). We performed 1:1 propensity score matching, resulting in 99 matched pairs. Surgical outcomes and safety were compared between the two groups. Additionally, the impact of surgery on locoregional recurrence was compared using survival analysis. RESULTS: During a follow-up of 47.8 ± 20.4 months, 29 (8.8%) patients experienced locoregional recurrence within the entire study cohort. Following propensity score matching, no significant difference in recurrence-free survival was observed between the two groups (log-rank p = 0.516). Multivariate analysis revealed that only T4 staging was an independent risk factor for locoregional recurrence (p = 0.006). The mean number of total and metastatic central lymph nodes retrieved were significantly greater in BCND group (14.1 vs. 9.3, p < 0.001 and 6.8 vs. 4.6, p = 0.005, respectively). There was no significant difference in postoperative stimulated thyroglobulin levels between the two groups (0.79 ng/mL vs. 1.44 ng/mL, p = 0.389). CONCLUSION: The present study demonstrates no prognostic benefit in conducting bilateral central neck dissection. Unilateral central neck dissection may be the preferred choice for clinically invasive papillary thyroid carcinoma.

Subcutaneous implantation of nodular goiter after transoral endoscopic thyroidectomy vestibular approach: A case study and review of literature.

BACKGROUND: Extrathyroid implantation or dissemination of thyroid tissue secondary to a thyroid procedure is rare. Most of these belonged to thyroid carcinoma with metastatic potential and uncommon for benign pathologies. METHODS: We report the case of a 31-year-old female who was identified to have multiple subcutaneous implantation of thyroid tissue 5 years after transoral endoscopic thyroidectomy vestibular approach. A comprehensive literature search on implantation of thyroid tissue secondary to thyroid procedures was performed. RESULTS: Accidental tearing of the capsule during previous surgery may lead to the subcutaneous implantation. Through literature review, a total 29 articles with 47 patients were identified. 33.3% were benign lesions, and implantation was mostly secondary to fine needle aspiration biopsy (46.5%). CONCLUSIONS: Subcutaneous or port site implantation after endoscopic thyroid surgery may occur in benign thyroid pathologies and therefore, oncologic principles must be strictly followed during surgery regardless of its histopathological nature.

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common aggressive non-Hodgkin's lymphoma (NHL), accounting for 30%-40% of adult NHLs. This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors (BTKis) in the treatment of elderly patients with DLBCL. CASE SUMMARY: The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed, and the literature was reviewed. The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses. Then, they received rituximab in combination with BTKi. CONCLUSION: The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients, thus providing a new treatment strategy.

Dim and Small Target Detection with a Combined New Norm and Self-Attention Mechanism of Low-Rank Sparse Inversion.

Methods for detecting small infrared targets in complex scenes are widely utilized across various domains. Traditional methods have drawbacks such as a poor clutter suppression ability and a high number of edge residuals in the detection results in complex scenes. To address these issues, we propose a method based on a joint new norm and self-attention mechanism of low-rank sparse inversion. Firstly, we propose a new tensor nuclear norm based on linear transformation, which globally constrains the low-rank characteristics of the image background and makes full use of the structural information among tensor slices to better approximate the rank of the non-convex tensor, thus achieving effective background suppression. Secondly, we construct a self-attention mechanism in order to constrain the sparse characteristics of the target, which further eliminates any edge residuals in the detection results by transforming the local feature information into a weight matrix to further constrain the target component. Finally, we use the alternating direction multiplier method to decompose the newly reconstructed objective function and introduce a reweighted strategy to accelerate the convergence speed of the model. The average values of the three evaluation metrics, SSIM, BSF, and SNR, for the algorithm proposed in this paper are 0.9997, 467.23, and 11.72, respectively. Meanwhile, the proposed detection method obtains a higher detection rate compared with other algorithms under the same false alarm rate.

Fusing Self-Attention and CoordConv to Improve the YOLOv5s Algorithm for Infrared Weak Target Detection.

Convolutional neural networks have achieved good results in target detection in many application scenarios, but convolutional neural networks still face great challenges when facing scenarios with small target sizes and complex background environments. To solve the problem of low accuracy of infrared weak target detection in complex scenes, and considering the real-time requirements of the detection task, we choose the YOLOv5s target detection algorithm for improvement. We add the Bottleneck Transformer structure and CoordConv to the network to optimize the model parameters and improve the performance of the detection network. Meanwhile, a two-dimensional Gaussian distribution is used to describe the importance of pixel points in the target frame, and the normalized Guassian Wasserstein distance (NWD) is used to measure the similarity between the prediction frame and the true frame to characterize the loss function of weak targets, which will help highlight the targets with flat positional deviation transformation and improve the detection accuracy. Finally, through experimental verification, compared with other mainstream detection algorithms, the improved algorithm in this paper significantly improves the target detection accuracy, with the mAP reaching 96.7 percent, which is 2.2 percentage points higher compared with Yolov5s.

[Animal experimental study on the effects of different levels of amputation on cardiovascular system].

Vascular injury resulting from lower limb amputation leads to the redistribution of blood flow and changes in vascular terminal resistance, which can affect the cardiovascular system. However, there was no clear understanding of how different amputation levels affect the cardiovascular system in animal experiments. Therefore, this study established two animal models of above-knee amputation (AKA) and below-knee amputation (BKA) to explore the effects of different amputation levels on the cardiovascular system through blood and histopathological examinations. The results showed that amputation caused pathological changes in the cardiovascular system of animals, including endothelial injury, inflammation, and angiosclerosis. The degree of cardiovascular injury was higher in the AKA group than in the BKA group. This study sheds light on the internal mechanisms of amputation's impact on the cardiovascular system. Based on the amputation level of patients, the findings recommend more comprehensive and targeted monitoring after surgery and necessary interventions to prevent cardiovascular diseases.

To Explore the Mechanism of "Fuzi-Guizhi" for the Treatment of Osteoarthritis on the Basis of Network Pharmacology and Molecular Docking.

OBJECTIVE: The objective of this study is to analyze and verify the main drug components and targets of "Fuzi-Guizhi" in the treatment of osteoarthritis by using the network pharmacology platform. METHODS: The integrated pharmacology of "Fuzi-Guizhi" was analyzed by using the platform of integrated pharmacology of traditional Chinese medicine to explore its mechanism in the treatment of osteoarthritis. By establishing an arthritis model in vitro, the pharmacological effect of "aconitecassia twigs" on articular cartilage was evaluated and conducted for molecular docking. RESULTS: 28 candidate active components, 37 compound targets, and 583 osteoarthritis-related potential targets were screened, and 10 key target processes were screened in the protein interaction network model. Enrichment analysis showed that the 10 core targets involved 958 GO biologic function items and 76 KEGG signal pathways, which were mainly related to apoptosis and mitochondrial functional metabolism and "Fuzi-Guizhi" drug-containing serum inhibited the expression of Caspase-3 mRNA and protein in chondrocytes and promoted the synthesis of ATP. CONCLUSION: Our research is preliminary that the mechanism of action of "Fuzi-Guizhi" may inhibit chondrocyte degeneration by resisting mitochondrial apoptosis, and further experimental research is required to determine.

[Establishment of an animal model to study the effects of amputation on the cardiovascular system].

Lower limb amputation is a significant change in body structure. Loss of muscle, blood vessels, and blood leads to a redistribution of blood flow and changes in resistance at the end of blood vessels. In view of the significant increase in the prevalence of cardiovascular disease after lower limb amputation, the mechanism of which is still unclear, this study aims to establish an animal research model that can verify and explore the effects of amputation on cardiovascular system, and provide the experimental basis for subsequent animal experiments when exploring the effect of different amputation levels on the cardiovascular system. SPF New Zealand rabbits were divided into normal group ( n = 6) and amputation group ( n = 6). The amputation group was treated with above-knee amputation. The changes of low-density liptein cholesterol (LDL-C) and total cholesterol (TC) in serum of all the rabbits were monitored regularly after the surgery. The arterial pathological examination was conducted after the experimental rabbits were executed. The results showed that compared with the normal group, serum LDL-C content and TC content in the amputation group were significantly increased ( P<0.05); The blood vessels of the amputated rabbits had pathological changes such as degeneration and necrosis of smooth muscle cells in the middle membrane layer and rupture of elastic fibers. At the abdominal aorta and aortic arch, the elastic fiber area expression percentage (EFEP) of the experimental group was significantly lower than that of the normal group. The results suggest that the cardiovascular system of rabbits has the tendency of decreased arterial elasticity and lipid deposition in blood after amputation, indicating that the animal research model on the effect of amputation on the cardiovascular system has been successfully established, and can provide an experimental platform for further study on the mechanism of the effect of amputation on the cardiovascular system.

Delayed tracheal rupture following transoral endoscopic thyroidectomy vestibular approach: Case report and review of the literature.

BACKGROUND: Although the transoral endoscopic thyroidectomy vestibular approach (TOETVA) has been proven to be a safe procedure for select patients, as it is a novel approach, all associated complications require adequate attention. METHODS: We presented a 49-year old woman who underwent TOETVA developed delayed tracheal rupture 1 week after surgery. An extensive search of literature was carried out using PubMed, Embase, and Web of Science for studies reporting tracheal injury following endoscopic thyroidectomy. RESULTS: Thirteen cases of endoscopic thyroidectomy were analyzed, including eight cases of TOETVA. Tracheal injury occurred during various procedures, including accidental dissection, surgical needle puncture, Hegar dilation and trocar placement, and thermal injury by the energy device. CONCLUSIONS: Tracheal injury following TOETVA is an underreported complication that can be induced by various factors. Thermal injury to the trachea is more likely to cause a delayed rupture. Careful blunt dissection and standardized use of energy devices are suggested.

[Effect of lower limb amputation level on aortic hemodynamics: a numerical study].

It has been found that the incidence of cardiovascular disease in patients with lower limb amputation is significantly higher than that in normal individuals, but the relationship between lower limb amputation and the episodes of cardiovascular disease has not been studied from the perspective of hemodynamics. In this paper, numerical simulation was used to study the effects of amputation on aortic hemodynamics by changing peripheral impedance and capacitance. The final results showed that after amputation, the aortic blood pressure increased, the time averaged wall shear stress of the infrarenal abdominal aorta decreased and the oscillatory shear index of the left and right sides was asymmetrically distributed, while the time averaged wall shear stress of the iliac artery decreased and the oscillatory shear index increased. The changes above were more significant with the increase of amputation level, which will result in a higher incidence of atherosclerosis and abdominal aortic aneurysm. These findings preliminarily revealed the influence of lower limb amputation on the occurrence of cardiovascular diseases, and provided theoretical guidance for the design of rehabilitation training and the optimization of cardiovascular diseases treatment.

Intraoperative near-infrared autofluorescence imaging for hypocalcemia risk reduction after total thyroidectomy: Evidence from a meta-analysis.

This meta-analysis evaluates whether near-infrared autofluorescence (NIRAF) imaging reduces the risk of hypocalcemia after total thyroidectomy. A systematic literature search in PubMed, EMBASE, Web of Science, and Cochrane Library for studies from June 2011 to January 2021 comparing total thyroidectomy with NIRAF and conventional surgery (naked eye). Six eligible studies involving 2180 patients were included. The prevalence of transient hypocalcemia was 8.11% (40/493) and 25.19% (425/1687) in the NIRAF and naked eye groups (p < 0.0001), respectively. The prevalence of permanent hypocalcemia was 0% (0/493) and 2.19% (37/1687) in the NIRAF and naked eye groups (p = 0.05), respectively. NIRAF reduces the risk of transient hypocalcemia and may possibly lower the rate of permanent hypocalcemia. Nonetheless, further studies are needed to verify our results and evaluate the cost-effectiveness of NIRAF in real-world clinical practice.

Advancing the Understanding of Vitamin D Status in Post-Thyroidectomy Hypocalcemia.

BACKGROUND: Post-thyroidectomy hypocalcemia is the most common complication after total thyroidectomy. Studies to examine the role of low vitamin D in increasing post-thyroidectomy hypocalcemia incidence have produced varying results. This study aimed to assess whether vitamin D deficiency increases the risk of post-thyroidectomy hypocalcemia. METHODS: This retrospective study involved 244 patients who underwent total thyroidectomy between 2014 and 2019. Patients were divided into two groups based on pre-operative vitamin D levels. Group A and Group B had pre-operative vitamin D (25-hydroxyvitamin D) levels of ≥20 ng/ml and <20 ng/ml (reference range for vitamin D is 30-100 ng/dl). The effect of vitamin D, gender, body mass index (BMI), and ethnicity on post-operative calcium and PTH levels was analyzed. RESULTS: Post-operative calcium levels for Group A were not statistically different compared to Group B (8.52 ± 0.64 mg/dl vs. 8.45 ± 0.58 mg/dl (mean ± S.D.; p value = 0.352). The average post-operative PTH of the two groups did not differ significantly (Group A: 32.4 ± 27.5 pg/ml; Group B: 34.4 ± 41.7 pg/ml; p value = 0.761). CONCLUSION: Pre-operative vitamin D levels are not predictive of post-thyroidectomy hypocalcemia.

Novel phenoxy-(trifluoromethyl)pyridine-2-pyrrolidinone-based inhibitors of protoporphyrinogen oxidase: Design, synthesis, and herbicidal activity.

As important chemical pesticides, protoporphyrinogen oxidase (PPO, EC 1.3.3.4) herbicides play a vital role in weed management. Herein, in a search for novel PPO herbicides, a series of phenoxypyridine-2-pyrrolidinone derivatives were synthesized and their herbicidal activities were tested. To confirm the structures of the newly synthesized compounds, a colorless single crystal of compound 9d was obtained and crystallographic data collected. PPO inhibition experiments showed that most compounds have PPO inhibitory effects. The half-maximal inhibitory concentration (IC50) of compound 9d and oxyfluorfen were 0.041 mg/L and 0.043 mg/L, respectively, which showed compound 9d was the most potent compound. Compound 9d reduced the Chlorophyll a (Chl a) and Chlorophyll b (Chl b) contents of Abutilon theophrasti (A. theophrasti), to 0.306 and 0.217 mg/g, respectively. Crop selectivity experiments and field trial indicated that compound 9d can potentially be used to develop post-emergence herbicides for weed control in rice, cotton, and peanut. Molecular docking studies showed that both oxyfluorfen and compound 9d can enter the PPO cavity to occupy the active site and compete with the porphyrin to block the chlorophyll synthesis process, affect photosynthesis, and eventually cause weed death. Compound 9d was found to be a promising lead compound for novel herbicide development.

Utility of Activated Carbon Nanoparticle (CNP) During total Thyroidectomy for Clinically Nodal Positive Papillary Thyroid Carcinoma (PTC).

BACKGROUND: Activated carbon nanoparticle (CNP) is a novel tracer that may facilitate nodal dissection in clinically nodal positive (cN1) papillary thyroid carcinoma (PTC). The present study compared the nodal yield and surgical outcomes between surgery with CNP and without CNP. METHODS: Patients who underwent total thyroidectomy with therapeutic nodal dissection for cN1 PTC were given the option of intraoperative CNP injection. Among those who received CNP, 0.2 mL CNP suspension was injected in both thyroid lobes before dissection. Study endpoints included number of total and metastatic lymph nodes, inadvertently removed parathyroid glands (PGs), postoperative parathyroid hormone, calcium, and post-6-month thyroglobulin (Tg). Biochemical complete response (BCR) was defined as Tg ≤ 1 ng/mL and/or stimulated Tg ≤ 2 ng/mL. RESULTS: One-hundred and twenty patients (58.3%) received CNP, while 86 (41.7%) had surgery without CNP. Demographics, tumor characteristics, and operative time were comparable between the two groups. However, total mean number of normal and metastatic lymph nodes retrieved were significantly greater in CNP group (10.0 vs. 8.1, p = 0.032 and 4.5 vs. 2.7, p = 0.002, respectively). Rate of inadvertently removed PG was significantly less in CNP group (13.3% vs. 23.3%, p = 0.042). Postoperative Tg level and BCR were significantly lower in CNP group (9.9 ng/mL vs. 14.7 ng/mL, p = 0.297 and 82.4% vs. 72.9%, p = 0.002, respectively). However, large-sized ( ≥ 3 cm) PTCs had a significantly lower nodal staining rate than smaller-sized PTCs (10.3% vs. 69.4%, p < 0.001). CONCLUSIONS: CNP injection can facilitate therapeutic central nodal dissection by increasing the nodal yield rates and reducing inadvertent PG removal. To enhance its utility, a greater volume of CNP might be necessary in larger-sized (> 3 cm) PTCs.

Novel Thiazole Phenoxypyridine Derivatives Protect Maize from Residual Pesticide Injury Caused by PPO-Inhibitor Fomesafen.

The herbicide fomesafen has the advantages of low toxicity and high selectivity, and the target of this compound is protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4). However, this herbicide has a long residual period and can have phytotoxic effects on succeeding crops. To protect maize from fomesafen, a series of thiazole phenoxypyridines were designed based on structure-activity relationships, active substructure combinations, and bioisosterism. Bioassays showed that thiazole phenoxypyridines could improve maize tolerance under fomesafen toxicity stress to varying degrees at a dose of 10 mg·kg-1. Compound 4i exhibited the best effects. After being treated by compound 4i, average recovery rates of growth index exceeded 72%, glutathione content markedly increased by 167% and glutathione S-transferase activity was almost 163% of fomesafen-treated group. More importantly, after being treated by compound 4i, the activity of PPO, the main target enzyme of fomesafen, recovered to 93% of the control level. The molecular docking result exhibited that the compound 4i could compete with fomesafen to bind with the herbicide target enzyme, which consequently attained the herbicide detoxification. The present work suggests that compound 4i could be developed as a potential safener to protect maize from fomesafen.

Improvement of thermoelectric performance of copper-deficient compounds Cu2.5+δ In4.5Te8 (δ = 0-0.15) due to a degenerate impurity band and ultralow lattice thermal conductivity.

Cu-In-Te ternary chalcogenides have unique crystal and band structures; hence they have received much attention in thermoelectrics. In this work we have observed an enhancement in Hall carrier concentration (n H) and ultralow lattice thermal conductivity (κ L) when Cu was added to ternary Cu2.5+δ In4.5Te8 (δ = 0-0.15) compounds. The enhancement in n H is attributed to a degenerate impurity band at the G point in the valence band maximum (VBM), while the extremely low κ L results from the increased lattice disorder. We thus obtained the minimum κ L value of only 0.23 W K-1 m-1 in the sample at δ = 0.1 and 820 K, which is in good agreement with the calculation using the Callaway model. The highest thermoelectric figure of merit ZT is 0.84 for the material at δ = 0.1, which is about 0.38 higher than that of the pristine Cu2.5In4.5Te8.

Periprocedural use of tirofiban in elective percutaneous coronary intervention for long coronary lesions in stable patients with overlapping drug-eluting stents--the PETITION study: a prospective, randomized, multicenter study.

BACKGROUND AND PURPOSE: Patients are at risk of developing periprocedural myonecrosis after percutaneous coronary intervention (PCI). We investigated whether the use of the platelet glycoprotein (GP) IIb/IIIa receptor inhibitor tirofiban could reduce periprocedural myocardial infarction (PMI) in patients with stable coronary artery disease undergoing elective PCI with overlapping stent implantation for long lesions. METHODS: A total of 748 stable angina patients with long lesions (≥ 40 mm in length) treated with overlapping stent implantation were randomly assigned to receive tirofiban (tirofiban group; n = 373) or conventional therapy (control group; n = 375). Intravenous tirofiban was initiated before PCI and maintained for 12 hr after the procedure. The primary endpoint was PMI, defined as an elevation in CK-MB > 3 times the upper limit of normal 12 hr after the index procedure. The secondary endpoint was major adverse cardiac events (MACE), including cardiac death, target vessel revascularization, and recurrent MI (re-MI), at one-year of clinical follow-up. The safety end-points included Thrombolysis in Myocardial Infarction (TIMI) major bleeding and stent thrombosis. RESULTS: Despite comparable angiographic and procedural characteristics, in the intention-to-treatment analysis, the primary endpoint was significantly reduced in the tirofiban group (4.0% vs. 11.5%, P < 0.001). Multivariate analysis revealed that the adjunctive use of tirofiban was the only negative predictor of PMI (OR 0.41, 95% CI 0.28-0.81, P < 0.01). At one-year of clinical follow-up, the overall occurrence of MACE was significantly lower in the tirofiban group (13.4% vs. 22.7%, P = 0.001). The rate of TIMI major bleeding and stent thrombosis did not differ significantly between the two groups. CONCLUSION: Our results show that the adjunctive use of tirofiban reduces the occurrence of PMI and MACE at one year in stable coronary artery disease patients undergoing elective PCI for long lesions with overlapping stent implantation.

Can surface EMG be adequately described by digital sampling?

Surface electromyography (SEMG) is a common tool to evaluate muscle function in kinesiological studies, musculoskeletal rehabilitation, prosthetics, clinical research and neurological disease diagnosis. The acquisition of SEMG is a crucially basic issue to gain an insight into musculoskeletal system function. The aim of this study is to investigate if the sampled surface EMG signals can reflect adequately the neural activity of the underlying musculature. The surface EMG signals of four muscles (abductor pollicis muscles and abductor digiti minimi muscles of right hand and left hand) are studied on the amplitude, frequency and nonlinear measure based on symplectic geometry. There are obvious differences in nonlinear measures of the different sampled signals, although there are little significant changes in their amplitude and frequency measures. Meanwhile, surface EMG signals obviously differ from their surrogate data at higher sampling frequencies. The results indicate that surface EMG signals contain nonlinear components. To gather the sufficient information of surface EMG signal, the data acquisition should be required at the higher sampling frequency. Furthermore, the nonlinear measure based on symplectic geometry can be used as a sensitive index for evaluation of the activity of the human muscles.

Effects of Danshen Injection () on inhibiting proliferation and inducing apoptosis through down-regulation of mutant JAK2 gene and its protein phosphorylation in human erythroid leukemic cells.

OBJECTIVE: To explore the effects of Danshen Injection () on inhibition proliferation, inducing apoptosis and its possible mechanisms on human erythroid leukemic (HEL) cells. METHODS: The commercial Chinese patent medicine of Danshen Injection was extracted and isolated from Chinese herb of Salvia miltiorrhiza bung. The inhibition effects of proliferation were assayed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method in HEL cells treated by Danshen Injection at various concentrations for 48 h. The cellular apoptosis was observed in morphology, analyzed by flow cytometry with annexin V and propidium iodide (PI) staining, and examined by DNA degradation ladder on agarose gel electrophoresis. Meanwhile, the expression levels of mutant Janus kinasez (JAK2) gene and phosphorylation-JAK2 (P-JAK2) protein were detected by allele specific-polymerase chain reaction and Western blot. RESULTS: The proliferation of HEL cells was effectively inhibited by Danshen Injection in a dose-dependent manner, with suppression rates from 19.46±2.31% to 50.20±5.21%. Typical apoptosis cells was observed in Danshen Injection treated HEL cells, the rates of annexin V positive cells increased obviously in a dose-dependent manner, as well as the DNA degradation ladder of apoptosis revealed on gel electrophoresis. The expression levels of mutant JAK2 gene and P-JAK2 protein reduced gradually with increasing dosage of Danshen injection. CONCLUSION: Danshen Injection could not only significantly inhibit the proliferation, but also induce apoptosis in HEL cells; down-regulation of the mutant JAK2 gene and P-JAK2 protein expressions are probably one of its molecular mechanisms.

The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model.

INTRODUCTION: In recent years, the anesthetized guinea pig has been used increasingly to evaluate the cardiovascular effects of drug-candidate molecules during lead optimization prior to conducting longer, more resource intensive safety pharmacology and toxicology studies. The aim of these studies was to evaluate the correlations between pharmacologically-induced ECG changes in the anesthetized cardiovascular guinea pig (CVGP) with ECG changes in conscious non-rodent telemetry models, human clinical studies and effects on key cardiac ion channels. METHODS: We compared the effects of 38 agents on ion channel inhibition to their ECG effects in the CVGP. 26 of these agents were also evaluated in non-rodent telemetry and compared to the results in the CVGP. RESULTS: The CVGP was highly sensitive for detecting QTc, PR and QRS interval prolongation mediated by inhibition of hERG, hCav1.2 and hNav1.5, respectively. There were robust correlations between ion channel inhibitory potencies and the free plasma concentrations (Cu) producing prolongation of the QTc, PR or QRS interval. Further evaluation showed that ECG changes in the CVGP were predictive of their effects on the QTc, PR and QRS intervals in non-rodent telemetry models with 92%, 92% and 100% accuracy, respectively. The CVGP proved to be 100% specific and 88%, 75% and 100% sensitive for QTc, PR and QRS interval prolongation, respectively. Similarly, the Cu that prolonged the QTc, PR and QRS in CVGP and humans correlated well. DISCUSSION: The CVGP is a sensitive model for assessing QTc, PR and QRS prolongation elicited by effects on hERG, hCav1.2 and hNav1.5, respectively. ECG changes in the CVGP are predictive of changes in non-rodent telemetry models and in humans (QTc). ECG parameters can be reliably evaluated with the CVGP model which increases the efficiency of CV derisking. Importantly, the design and implementation of this model is consistent with the "3Rs" for animal research.