Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5.

MDA5, a viral double-stranded RNA (dsRNA) receptor, shares sequence similarity and signaling pathways with RIG-I yet plays essential functions in antiviral immunity through distinct specificity for viral RNA. Revealing the molecular basis for the functional divergence, we report here the crystal structure of MDA5 bound to dsRNA, which shows how, using the same domain architecture, MDA5 recognizes the internal duplex structure, whereas RIG-I recognizes the terminus of dsRNA. We further show that MDA5 uses direct protein-protein contacts to stack along dsRNA in a head-to-tail arrangement, and that the signaling domain (tandem CARD), which decorates the outside of the core MDA5 filament, also has an intrinsic propensity to oligomerize into an elongated structure that activates the signaling adaptor, MAVS. These data support a model in which MDA5 uses long dsRNA as a signaling platform to cooperatively assemble the core filament, which in turn promotes stochastic assembly of the tandem CARD oligomers for signaling.

A study on whether deep learning models based on CT images for bone density classification and prediction can be used for opportunistic osteoporosis screening.

This study utilized deep learning to classify osteoporosis and predict bone density using opportunistic CT scans and independently tested the models on data from different hospitals and equipment. Results showed high accuracy and strong correlation with QCT results, showing promise for expanding osteoporosis screening and reducing unnecessary radiation and costs. PURPOSE: To explore the feasibility of using deep learning to establish a model for osteoporosis classification and bone density value prediction based on opportunistic CT scans and to verify its generalization and diagnostic ability using an independent test set. METHODS: A total of 1219 cases of opportunistic CT scans were included in this study, with QCT results as the reference standard. The training set: test set: independent test set ratio was 703: 176: 340, and the independent test set data of 340 cases were from 3 different hospitals and 4 different CT scanners. The VB-Net structure automatic segmentation model was used to segment the trabecular bone, and DenseNet was used to establish a three-classification model and bone density value prediction regression model. The performance parameters of the models were calculated and evaluated. RESULTS: The ROC curves showed that the mean AUCs of the three-category classification model for categorizing cases into "normal," "osteopenia," and "osteoporosis" for the training set, test set, and independent test set were 0.999, 0.970, and 0.933, respectively. The F1 score, accuracy, precision, recall, precision, and specificity of the test set were 0.903, 0.909, 0.899, 0.908, and 0.956, respectively, and those of the independent test set were 0.798, 0.815, 0.792, 0.81, and 0.899, respectively. The MAEs of the bone density prediction regression model in the training set, test set, and independent test set were 3.15, 6.303, and 10.257, respectively, and the RMSEs were 4.127, 8.561, and 13.507, respectively. The R-squared values were 0.991, 0.962, and 0.878, respectively. The Pearson correlation coefficients were 0.996, 0.981, and 0.94, respectively, and the p values were all < 0.001. The predicted values and bone density values were highly positively correlated, and there was a significant linear relationship. CONCLUSION: Using deep learning neural networks to process opportunistic CT scan images of the body can accurately predict bone density values and perform bone density three-classification diagnosis, which can reduce the radiation risk, economic consumption, and time consumption brought by specialized bone density measurement, expand the scope of osteoporosis screening, and have broad application prospects.

[18 F] -FAPI-42 PET/CT assessment of Progressive right ventricle fibrosis under pressure overload.

BACKGROUND: Right heart failure (RHF) is a complication of pulmonary hypertension (PH) and increases the mortality independently of the underlying disease. However, the process of RHF development and progression is not fully understood. We aimed to develop effective approaches for early diagnosis and precise evaluation of RHF. METHODS: Right ventricle (RV) pressure overload was performed via pulmonary artery banding (PAB) surgery in Sprague-Dawley (SD) rats to induce RHF. Echocardiography, right heart catheterization, histological staining, fibroblast activation protein (FAP) immunofluorescence and 18 F-labelled FAP inhibitor-42 ([18 F] -FAPI-42) positron emission tomography/computed tomography (PET/CT) were performed at day 3, week 1, 2, 4 and 8 after PAB. RNA sequencing was performed to explore molecular alterations between PAB and sham group at week 2 and week 4 after PAB respectively. RESULTS: RV hemodynamic disorders were aggravated, and RV function was declined based on right heart catheterization and echocardiography at week 2, 4 and 8 after PAB. Progressive cardiac hypertrophy, fibrosis and capillary rarefaction could be observed in RV from 2 to 8 weeks after PAB. RNA sequencing indicated 80 upregulated genes and 43 downregulated genes in the RV at both week 2 and week 4 after PAB; Gene Ontology (GO) analysis revealed that fibrosis as the most significant biological process in the RV under pressure overload. Immunofluorescence indicated that FAP was upregulated in the RV from week 2 to week 8 after PAB; and [18 F] -FAPI-42 PET/CT revealed FAPI uptake was significantly higher in RV at week 2 and further increased at week 4 and 8 after PAB. CONCLUSION: RV function is progressively declined with fibrosis as the most prominent molecular change after pressure overload, and [18 F] -FAPI-42 PET/CT is as sensitive and accurate as histopathology in RV fibrosis evaluation.

Label-free Aptasensor for the Ultrasensitive Detection of Insulin Via a Synergistic Fluorescent Turn-on Strategy Based on G-quadruplex and AIEgens.

Insulin, the only hormone regulating blood glucose level, is strongly associated with diabetes and its complications. Specific recognition and ultrasensitive detection of insulin are of clinical significance for the early diagnosis and treatment of diabetes. Inspired by aggregation-induced emission, we presented a turn-on label-free fluorescence aptasensor for insulin detection. Quaternized tetraphenylethene salt was synthesized as the fluorescence probe. Guanine-rich aptamer IGA3 was selected as recognition element. Graphene oxide was chosen as the quencher. Under optimized conditions, the fluorescence aptasensor displayed a wide linear range (1.0 pM-1.0 µM) with a low limit of detection (0.42 pM). Furthermore, the aptasensor was successfully applied to detect insulin in human serum. Spiked recoveries were obtained in the range of 96.06%-104.26%. All these results demonstrated that the proposed approach has potential application in the clinical diagnostics of diabetes.

Suppression function against environmental dust exposure after Dermatophagoides pteronyssinus immunotherapy is associated with production of specific and cross-reactive immunoglobulin G4.

BACKGROUND: Whether Dermatophagoides pteronyssinus (Der-p) allergen immunotherapy (AIT) can induce Dermatophagoides farina (Der-f)-specific immunoglobulin (sIg) G4 production, and tolerance to environmental allergens has not been fully investigated. OBJECTIVE: We aimed to determine serum Der-p-sIgG4 and Der-f-sIgG4 levels in asthma and/or rhinitis patients undergoing Der-p AIT and their ability to reduce immune responses triggered by indoor dust extracts. METHODS: We performed a real-world prospective trial and enrolled patients with allergic rhinitis and/or asthma in Guangzhou, China. These patients received either Der-p AIT (SCIT group) or routine medications (non-SCIT group) for 156 weeks. Clinical outcomes were assessed by the combined symptom medication score (SMS) and FEV1 % changes. House dust samples were collected to analyse allergen levels. Serum levels of Der-p-sIgG4 and Der-f-sIgG4, serum inhibitory capacity against Der-p, Der-f and indoor dust extract by sIgE-facilitated allergen binding to B cells (IgE-FAB), and serum blocking indoor dust extract-induced basophil activation inhibition assays (BATI) in peripheral blood monocytes were carried out at weeks 0, 4, 12, 16, 52, 104 and 156 after the initiations of the treatments. RESULTS: Our study enrolled a total of 60 participants, with 30 patients in each group. Patients in the SCIT group had significantly improved SMS when compared with the baseline and the patients in the non-SCIT group. Median levels of Der-p 1 and Der-f 1 in indoor dust extract were 1.86 µg/g and 4.74 µg/g, respectively. Serum Der-p-sIgG4 and Der-f-IgG4 levels in SCIT patients showed a significant increase from weeks 12 to 156. Serum in these SCIT patients could significantly block Der-p, Der-f and indoor dust extract formation of allergen-sIgE complex and reduced the threshold of IgE-FAB from 16 weeks after the initiation of the treatment. The capacity to inhibit Der-p, Der-f and indoor dust extract BATI was observed in SCIT serum after 12 weeks. Der-p-sIgG4 and Der-f-sIgG4 had a significant correlation with IgE-FAB and BATI in SCIT patients at all time points. CONCLUSION: Single Der-p immunotherapy induced both Der-p-sIgG4 and Der-f-sIgG4 production, which might cross-reactively induce tolerance against environmental allergen exposure in patients with asthma and/or rhinitis.

Water treatment sludge conversion to biochar as cementitious material in cement composite.

Water treatment sludge was successfully thermally converted to obtain biochar as a stable material with resource potential. This research explored the application of sludge biochar as a supplementary cementitious material. The cement paste samples incorporating different amounts of sludge biochar were prepared, hardened, and analyzed for performance. The results show an improvement in hydration kinetics and mechanical properties of cement paste incorporating biochar, compared to raw sewage sludge. The mineralogical, thermal and microscopic analyses show evidence of pozzolanic activity of the biochar. The samples with 2% and 5% biochar showed higher heat release than the reference material. Specimens with 1%, 2% and 5% biochar showed a slightly higher compressive strength at 28 days compared to the reference material. Sludge conversion to biochar will incur an estimated cost of US$398.23/ton, which is likely to be offset by the substantial benefits from avoiding landfill and saving valuable cementitious materials. Therefore, this research has demonstrated that through conversion to biochar, water treatment sludge can be promoted as a sustainable and alternative cementitious material for cement with minimum environmental impacts, hence contributing to circular economy.

The IL-6 rs1800795 and rs1800796 polymorphisms are associated with coronary artery disease risk.

Studies examining the associations between the interleukin-6 (IL-6) rs1800795 and rs1800796 gene polymorphisms and risk of coronary artery disease (CAD) remain controversial. Our aim was to evaluate the accurately determine role of these two polymorphisms in CAD risk. PubMed, Embase, VIP, Wan fang and China National Knowledge Infrastructure databases were searched. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The trial sequential analysis (TSA) was conducted, and bioinformatics tools were employed. A total of thirty-seven articles were obtained. For the IL-6 rs1800795 polymorphism, 9411 CAD patients and 3161 controls were included, 4720 patients with CAD, and 5000 controls were included for the IL-6 rs1800796 polymorphism. In the pooled analysis, significant associations were only observed for the rs1800796 polymorphism (allelic: OR [95%CI] = 1.28 [1.13, 1.44], dominant: OR [95%CI] = 1.35 [1.17, 1.57], recessive: OR [95%CI] = 1.35 [1.18, 1.55], heterozygote: OR [95%CI] = 1.26 [1.15, 1.37], homozygote: OR [95%CI] = 1.62 [1.23, 2.13]). Significant associations were detected in the Asian and Mongoloid populations and 'more than 500' subgroup for the rs1800795 polymorphism. TSA confirmed the true-positive results for the rs1800796 polymorphism. The bioinformatics analysis showed that the two polymorphisms played important roles in the gene transcription. The IL-6 rs1800796 polymorphism is associated with an increased susceptibility to CAD and is a risk factor for CAD. The IL-6 rs1800795 polymorphism is associated with an increased risk of CAD in Asians, particularly in Chinese, and a decreased risk of CAD in an African population is remarkably observed.

Cost-Effectiveness Analysis of First-Line FOLFIRI Combined With Cetuximab or Bevacizumab in Patients With RAS Wild-Type Left-Sided Metastatic Colorectal Cancer.

BACKGROUND: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.

Functional and Immunoreactive Levels of IgG4 Correlate with Clinical Responses during the Maintenance Phase of House Dust Mite Immunotherapy.

Allergen-specific immunotherapy for house dust mite allergy is effective, but there are no validated biomarkers reflecting or predicting the clinical efficacy. We aimed to investigate the relationship between clinical outcomes and functional responses of allergen-specific IgG4 (sIgG4) and specific IgE (sIgE) during Dermatophagoides pteronyssinus s.c. allergen immunotherapy (SCIT) in allergic rhinitis and/or asthma patients. Combined symptom medication scores (SMS), D. pteronyssinus-sIgG4 levels, D. pteronyssinus-sIgE levels, and the serum inhibitory capacity against D. pteronyssinus-sIgE facilitated allergen binding to B cells (IgE-FAB) were determined during the updosing (week 0, 4, 12, and 16) and maintenance (week 52, 104, and 156) phase of SCIT. We found that SCIT patients had a significant improvement in SMS from week 52 to 156 compared with medication-treated control subjects (p < 0.05). Levels of D. pteronyssinus-sIgG4 in SCIT patients showed a significant increase from week 12 to 156 (p < 0.05). Serum obtained from SCIT patients significantly inhibited D. pteronyssinus-sIgE binding to B cells after 16 wk (p < 0.01). Significantly lower levels of D. pteronyssinus-sIgE were observed in SCIT patients after 52 wk (p < 0.05). A significant relationship was demonstrated between SMS and IgE-FAB or D. pteronyssinus-sIgG4 during the maintenance phase according to linear regression analysis. In conclusion, D. pteronyssinus-sIgG4 level and D. pteronyssinus IgE-FAB are associated with clinical efficacy in the maintenance phase rather than the updosing phase of SCIT. Immunologic tolerance can be induced with SCIT when maintenance phase is achieved.

First-line atezolizumab in addition to bevacizumab plus chemotherapy for metastatic, nonsquamous non-small cell lung cancer: A United States-based cost-effectiveness analysis.

BACKGROUND: The IMpower150 trial found that adding atezolizumab to the combination of bevacizumab and chemotherapy improved survival for patients with metastatic, nonsquamous non-small cell lung cancer (NSCLC). However, considering the high cost of immunotherapy, there is a need to assess its value by considering both efficacy and cost. The current study evaluated the cost-effectiveness of atezolizumab in the first-line setting for the treatment of patients with metastatic NSCLC from the US payer perspective. METHODS: A Markov model was developed to compare the lifetime cost and effectiveness of the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) with the combination of bevacizumab, carboplatin, and paclitaxel (BCP) and carboplatin and paclitaxel (CP) in the first-line treatment of patients with metastatic NSCLC. Life-years (LYs), quality-adjusted LYs (QALYs), and lifetime costs were estimated. One-way and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Additional subgroup analyses were performed. RESULTS: ABCP provided an additional 0.413 QALYs (0.460 LYs) and 0.738 QALYs (0.956 LYs), respectively, compared with BCP and CP. The corresponding incremental costs were $234,998 and $381,116, respectively. The incremental cost-effectiveness ratio for ABCP was $568,967 per QALY compared with BCP and $516,114 per QALY compared with CP. The subgroup analysis demonstrated that PD-L1 expression of ≥50% on tumor cells (TC3) or ≥10% on immune cells (IC3) decreased the incremental cost-effectiveness ratio to $464,703 per QALY. CONCLUSIONS: From the perspective of the US payer, ABCP is estimated to not be cost-effective compared with BCP or CP in the first-line setting for patients with metastatic, nonsquamous NSCLC at a willingness-to-pay threshold of $100,000 per QALY.

Potential role of sympathetic activity on the pathogenesis of massive pulmonary embolism with circulatory shock in rabbits.

BACKGROUND: We recently showed that intravenous sodium nitroprusside treatment (SNP) could relieve the pulmonary vasospasm of pulmonary embolism (PE) and non-pulmonary embolism (non-PE) regions in a rabbit massive pulmonary embolism (MPE) model associated with shock. The present study explored the potential role of cardiopulmonary sympathetic activity on the pathogenesis and the impact of vasodilators on cardiopulmonary sympathetic activity in this model. METHODS: Rabbits were randomly divided into sham operation group (S group, n = 8), model group (M, equal volume of saline intravenously, n = 11), SNP group (3.5 µg/kg/min intravenously, n = 10) and diltiazem group (DLZ, 6.0 µg/kg/min intravenously, n = 10). RESULTS: MPE resulted in reduced mean arterial pressure and increased mean pulmonary arterial pressure as well as reduced PaO2 in the M, SNP and DLZ groups. Tyrosine hydroxylase (TH), neuropeptide Y (NPY) and endothelin-1 (ET-1) expression levels were significantly increased, while nitric oxide (NO) levels were reduced in both PE and non-PE regions in the M group. Both SNP and DLZ decreased mean pulmonary arterial pressure, reversed shock status, downregulated the expression of TH, NPY and ET-1, and increased NO levels in PE and non-PE regions. CONCLUSION: Present results indicate that upregulation of the sympathetic medium transmitters TH and NPY in whole lung tissues serves one of the pathological features of MPE. The vasodilators SNP and DLZ could relieve pulmonary vasospasm in both embolization and non-embolization regions and reverse circulatory shock, thereby indirectly downregulating the sympathetic activation of the whole lung tissues and breaking a vicious cycle related to sympathetic activation in this model.

[Health economics analysis for 18F-fluorodeoxyglucose positron-emission tomography compared with computed tomography in lung cancer].

Compared with conventional imaging, 18F-fluorodeoxyglucose positron-emission tomography compared with computed tomography (18F-FDG PET/CT) possesses higher sensitivity and specificity in the diagnosis of solitary pulmonary nodule (SPN) and lung cancer. From the perspective of health economics, PET/CT is more suitable strategy for diagnose of SPN with intermediate probability of malignancy, and has good health economics value in preoperative staging diagnosis and follow-up after radiotherapy and chemotherapy of lung cancer. The evaluation method, effect index and comparison method used in the health economics research of PET/CT for lung cancer diagnosis and treatment are cost-effect analysis, life year and incremental cost-effect ratio, respectively. Case tracking and follow-up was a means of early studies on PET/CT health economics, and in recent years mathematical models are used in most studies.

Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA pathway.

This study was designed to investigate the precancerous lesions of gastric carcinoma (PLGC)-reversing mechanisms of astragaloside IV (ASIV) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced PLGC rats. All rats were sacrificed after 10-week treatment. Gastric tissue was analyzed by using histopathology and electron microscope. To be fully evidenced, LDHA, p53, TIGAR, MCT1, MCT4, HIF-1α, CD147, and miRNA-34a were detected by Western blotting and Real-time Quantitative polymerase chain reaction (RT-qPCR). As histopathology and electron microscope showed, it can be clearly observed that the area of dysplasia was reduced in ASIV groups, indicating that MNNG-induced PLGC was markedly reversed by ASIV. Moreover, compared with model group, a significant decrease in gene expressions of LDHA, MCT1, MCT4, HIF-1α, CD147, and TIGAR was observed whereas miRNA-34a level was increased in ASIV groups. A significant up-regulation induced by MNNG in protein levels of LDHA, MCT1, MCT4, HIF-1α, and CD147 was attenuated in rats treated with ASIV. In contrast, the decreased expression of TIGAR was restored by ASIV. Interestingly, up-regulation of p53 expression induced by MNNG was further increased in ASIV groups. In brief, these results implied that abnormal glycolysis was relieved by ASIV via regulation of the expressions of LDHA, p53, TIGAR, MCT1, MCT4, HIF-1α, CD147, and miRNA-34a.

Selective reduction in the expression of UGTs and SULTs, a novel mechanism by which piperine enhances the bioavailability of curcumin in rat.

Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low bioavailability hinders the development of curcumin as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of curcumin, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which piperine enhances the bioavailability of curcumin, the dosage ratio (CUR: PIP) and pre-treatment with piperine were hypothesized as key factors for improving the bioavailability in this combination. Therefore, combining curcumin with piperine at various dose ratios (1:1 to 100:1) and pre-dosing with piperine (0.5-8 h prior to curcumin) were designed to investigate their contributions to the pharmacokinetic parameters of curcumin in rats and their effects on the expression of UGT and SULT isoforms. It was shown that the Cmax and AUC0-t of curcumin were slightly increased by 1.29 and 1.67 fold at a ratio of 20:1, while curcumin exposure was enhanced significantly in all the piperine pre-treated rats (0.5-8 h), peaking at 6 h (a 6.09-fold and 5.97-fold increase in Cmax and AUC0-t , p < 0.01), regardless of the unchanged t1/2 and Tmax . Also observed was a time-dependent inhibition of the hepatic expression of UGT1A6, 1A8, SULT1A1, 1A3, and the colonic expression of UGT1A6 that occurred within 6 h of piperine pre-treatment but was reversed at 8 h, which correlated with the changes in curcumin exposure. Similarly, the inhibitory effect of piperine on most of the UGTs and SULTs are time-dependent in Caco-2 and HepG2 cells. It is concluded that piperine pre-treatment time-dependently improves the bioavailability of curcumin through the reversible and selective inhibition of UGTs and SULTs. Copyright © 2016 John Wiley & Sons, Ltd.

[Development of residual voltage testing equipment].

For the existing measurement methods of residual voltage which can't turn the power off at peak voltage exactly and simultaneously display waveforms, a new residual voltage detection method is put forward in this paper. First, the zero point of the power supply is detected with zero cross detection circuit and is inputted to a single-chip microcomputer in the form of pulse signal. Secend, when the zero point delays to the peak voltage, the single-chip microcomputer sends control signal to power off the relay. At last, the waveform of the residual voltage is displayed on a principal computer or oscilloscope. The experimental results show that the device designed in this paper can turn the power off at peak voltage and is able to accurately display the voltage waveform immediately after power off and the standard deviation of the residual voltage is less than 0.2 V at exactly one second and later.

Comparison Between Sotorasib with Docetaxel for the Treatment of Chinese Patients with Previously Treated NSCLC with KRASG12C Mutation: A Cost-Effectiveness Analysis to Inform Drug Pricing.

INTRODUCTION: This study sought to investigate the affordable price of sotorasib among patients with previously treated advanced KRASG12C-mutant non-small cell lung cancer (NSCLC) through a cost-effectiveness analysis from the perspectives of both the Chinese healthcare system and the patients. METHODS: We developed a Markov model spanning a 20-year time horizon with a cycle length of 21 days. Our data were derived from the CodeBreaK 200 clinical trial, supplemented with published literature, publicly available national databases, and local hospitals. The primary outcomes were the affordable prices of sotorasib which would result in the incremental cost-effectiveness ratios (ICERs) of sotorasib relative to docetaxel below the preset willing-to-pay (WTP) threshold. Sensitivity analyses were performed to evaluate the model's robustness. RESULTS: At the national level, from the perspective of the Chinese healthcare system and patients, the price of sotorasib should be lower than US$0.04673 and $0.03231, respectively, to make it affordable, which is equivalent to $1346 and $931 per box (120 mg × 240 pieces). At the provincial level, the price ceiling of sotorasib/mg fluctuated between $0.04084 to $0.08061 from the Chinese healthcare system's perspective and between $0.02642 to $0.06620 from the patients' perspective. Probabilistic sensitivity analyses revealed that, as the price of sotorasib decreased, its likelihood of being cost-effective increased. CONCLUSION: Sotorasib might be a cost-effective therapy in China. The pharmaco-economic evidence generated from this study has significant implications not only for guiding the drug pricing of the upcoming sotorasib but also for determining the reimbursement ratio for its potential inclusion in the National Reimbursement Drugs List in the future.

First-line treatments for extensive-stage small-cell lung cancer with immune checkpoint inhibitors plus chemotherapy: a China-based cost-effectiveness analysis.

Objective: To determine the cost-effectiveness of imported immune checkpoint inhibitors (ICIs) such as atezolizumab and durvalumab, and domestic ICIs like serplulimab and adebrelimab, in combination with chemotherapy for extensive-stage small cell lung cancer (ES-SCLC) in China. Methods: Using a 21-day cycle length and a 20-year time horizon, a Markov model was established to compare the clinical and economic outcomes of five first-line ICIs plus chemotherapy versus chemotherapy alone, as well as against each other, from the perspective of the Chinese healthcare system. Transition probabilities were estimated by combining the results of the CAPSTONE-1 trial and a published network meta-analysis. Cost and health state utilities were collected from multiple sources. Both cost and effectiveness outcomes were discounted at a rate of 5% annually. The primary model output was incremental cost-effectiveness ratios (ICERs). A series of sensitivity analyses were preformed to assess the robustness of the model. Results: In the base-case analysis, the addition of first-line ICIs to chemotherapy resulted in the ICERs ranged from $80,425.31/QALY to $812,415.46/QALY, which exceeded the willing-to-pay threshold set for the model. When comparing these first-line immunochemotherapy strategies, serplulimab plus chemotherapy had the highest QALYs of 1.51286 and the second lowest costs of $60,519.52, making it is the most cost-effective strategy. Our subgroup-level analysis yielded results that are consistent with the base-case analysis. The sensitivity analysis results confirmed the validity and reliability of the model. Conclusion: In China, the combination of fist-line ICIs plus chemotherapy were not considered cost-effective when compared to chemotherapy alone. However, when these fist-line immunochemotherapy strategies were compared with each other, first-line serplulimab plus chemotherapy consistently demonstrated superiority in terms of cost-effectiveness. Reducing the cost of serplulimab per 4.5 mg/kg would be a realistic step towards making first-line serplulimab plus chemotherapy more accessible and cost-effective.

An accurate calculation method for inductor air gap length in high power DC-DC converters.

High-power inductors are fundamental components in high-power DC-DC converters, with their performance being a crucial metric of converter efficiency. This paper presents an in-depth analysis of a novel calculation method for the air gap length in such inductors. Taking into account the effects of air gap diffusion and the winding magnetic field, an expression for the air gap diffusion radius is derived, focusing on a distributed air gap structure. Furthermore, models for calculating the air gap and winding reluctance are developed, grounded in electromagnetic field theory. An equivalent magnetic circuit model, formulated based on Kirchhoff's second law, facilitates the proposed method for air gap length calculation. This study also involves the development of 3D models for both discrete and decoupled integrated inductors. The comparison between simulation outcomes and calculated air gap lengths indicates a maximum error of less than 8%, with the minimum error being as low as - 0.79%. Compared with traditional methods, the calculation method proposed in this paper has significant advantages. Additionally, the discrepancy between calculated values and experimental measurements is found to be 1.11%. These results validate the accuracy and applicability of the theoretical analysis and calculation method, underscoring their significance in the design and optimization of high-power DC-DC converters.

The complete chloroplast genome and phylogenetic analysis of Christella dentata (Forssk.) Brownsey & Jermy (Thelypteridaceae).

Christella dentata (Forssk.) Brownsey & Jermy (Thelypteridaceae) is endemic to the tropical and subtropical regions of Africa, Asia, and Asia Pacific. In this study, the complete chloroplast genome sequence of C. dentata was assembled using next-generation sequencing data. The complete chloroplast genome was 151,662 bp in length and had a typical quadripartite structure, which consisted of a small single-copy region (21,776 bp) and a large single-copy region (82,624 bp) that were separated by a pair of inverted repeats (23,631 bp each). A total of 131 genes were predicted, including 89 protein coding (CDS), 34 tRNA, and eight rRNA genes. The overall GC content of the chloroplast genome was 42.48%. Based on the concatenated shared unique CDS sequence dataset, phylogenetic analysis using both the maximum-likelihood and the Bayesian inference methods revealed that C. dentata is placed within Thelypteridaceae and is closely related to Christella appendiculata. Such genetic information would be useful for studies on the evolution pattern in ferns. The availability of chloroplast genome sequence for the species also paves the way to resolving the complicated relationship among members of Christella.

GABRP is a Promising Prognostic Biomarker and Associated with Immune Cell Infiltration in Lung Squamous Cell Carcinoma.

Background: GABRP has been reported to play an oncogenic role in various carcinomas. However, no report has been found for its involvement in lung squamous cell carcinoma (LUSC) development yet. We aimed to explore the expression and prognostic roles of GABRP and assessment of its association with tumor microenvironment in LUSC. Methods: The GABRP expression in LUSC was analyzed using TCGA, GEO, and HPA databases. The Kaplan-Meier, Cox regression analysis, and receiver operating characteristic (ROC) curve were applied to assess the prognostic and diagnostic values of GABRP in LUSC. We also performed ESTIMATE and ssGSEA to explore the association between GABRP expression and immune cell infiltrations. GABRP was highly expressed in LUSC patients, and up-regulation of GABRP was associated with shorter overall survival (OS). Cox regression analysis indicated that GABRP was an independent prognostic factor for LUSC patients. KEGG analysis revealed that GABRP may play an important role in starch and sucrose metabolism and nicotine addiction. Specifically, GABRP expression showed significant positive correlations with the infiltration levels of most types of immune cells, as well as immune checkpoint molecules expression. Conclusion: Up-regulation of GABRP in LUSC could be severed as a prognostic marker and a potential target for immunotherapy in LUSC.