Structural and functional prediction, evaluation, and validation in the post-sequencing era.

The surge of genome sequencing data has underlined substantial genetic variants of uncertain significance (VUS). The decryption of VUS discovered by sequencing poses a major challenge in the post-sequencing era. Although experimental assays have progressed in classifying VUS, only a tiny fraction of the human genes have been explored experimentally. Thus, it is urgently needed to generate state-of-the-art functional predictors of VUS in silico. Artificial intelligence (AI) is an invaluable tool to assist in the identification of VUS with high efficiency and accuracy. An increasing number of studies indicate that AI has brought an exciting acceleration in the interpretation of VUS, and our group has already used AI to develop protein structure-based prediction models. In this review, we provide an overview of the previous research on AI-based prediction of missense variants, and elucidate the challenges and opportunities for protein structure-based variant prediction in the post-sequencing era.

[Clinical application of Fastpass Scorpion suture passer for arthroscopic Bankart repair].

Objective: To explore the effectiveness and advantages of using Fastpass Scorpion suture passer to stitch the inferior capsulolabral complex in arthroscopic Bankart repair compared with traditional arthroscopic suture shuttle. Methods: The clinical data of 41 patients with Bankart lesion, who met the selection criteria and were admitted between August 2019 and October 2021, was retrospectively analyzed. Under arthroscopy, the inferior capsulolabral complex was stitched with Fastpass Scorpion suture passer in 27 patients (FS group) and with arthroscopic suture shuttle in 14 patients (ASS group). There was no significant difference between the two groups ( P>0.05) in gender, age, injured side, frequency of shoulder dislocation, time from first dislocation to operation, and preoperative Rowe score of shoulder. Taking successful suture and pull-tightening as the criteria for completion of repair, the number of patients that were repaired at 5∶00 to 6∶00 (<6:00) and 6∶00 to 7∶00 positions of the glenoid in the two groups was compared. The operation time, and the difference of Rowe shoulder score betwee pre- and post-operation, the occurrence of shoulder joint dislocation, the results of apprehension test, and the constituent ratio of recovery to the pre-injury movement level between the two groups at 1 year after operation. Results: Both groups completed the repair at 5∶00 to 6∶00 (<6∶00), and the constituent ratio of patients completed at 6∶00 to 7∶00 was significantly greater in the FS group than in the ASS group ( P<0.05). The operation time was significantly shorter in the FS group than in the ASS group ( P<0.05). All incisions in the two groups healed by first intention. All patients were followed up 12-36 months (mean, 19.1 months). No anchor displacement or neurovascular injury occurred during follow-up. Rowe score of shoulder in the two groups significantly improved at 1 year after operation than preoperative scores ( P<0.05), and there was no significant difference in the difference of Rowe shoulder score between pre- and post-operation between the two groups ( P>0.05). At 1 year after operation, no re-dislocation occurred, and there was no significant difference in the apprehension test and the constituent ratio of recovery to the pre-injury movement level between the two groups ( P>0.05). Conclusion: Compared with the arthroscopic suture shuttle, using Fastpass Scorpion suture passer to stitch the inferior capsulolabral complex in arthroscopic Bankart repair is more convenient, saves operation time, and has good effectiveness.

Artificial intelligence-based recognition for variant pathogenicity of BRCA1 using AlphaFold2-predicted structures.

With the surge of the high-throughput sequencing technologies, many genetic variants have been identified in the past decade. The vast majority of these variants are defined as variants of uncertain significance (VUS), as their significance to the function or health of an organism is not known. It is urgently needed to develop intelligent models for the clinical interpretation of VUS. State-of-the-art artificial intelligence (AI)-based variant effect predictors only learn features from primary amino acid sequences, leaving out information about the most important three-dimensional structure that is more related to its function. Methods: We proposed a deep convolutional neural network model named variant effect recognition network for BRCA1 (vERnet-B) to recognize the clinical pathogenicity of missense single-nucleotide variants in the BRCT domain of BRCA1. vERnet-B learned features associated with the pathogenicity from the tertiary protein structures of variants predicted by AlphaFold2. Results: After performing a series of validation and analyses on vERnet-B, we discovered that it exhibited significant advances over previous works. Recognizing the phenotypic consequences of VUS is one of the most daunting challenges in genetic informatics; however, we achieved 85% accuracy in recognizing disease BRCA1 variants with an ideal balance of false-positive and true-positive detection rates. vERnet-B correctly recognized the pathogenicity of variant A1708E, which was poorly predicted by AlphaFold2 as previously described. The vERnet-B web server is freely available from URL: http://ai-lab.bjrz.org.cn/vERnet. Conclusions: We applied protein tertiary structures to successfully recognize the pathogenic missense SNVs, which were difficult to be addressed by classical approaches based on sequences. Our work demonstrated that AlphaFold2-predicted structures were expected to be used for rich feature learning and revealed unique insights into the clinical interpretation of VUS in disease-related genes, using vERnet-B as a discovery tool.

Flattening Filter-Free Volumetric-Modulated Arc Radiotherapy for Left-Sided Whole-Breast, Partial-Breast, and Postmastectomy Irradiations.

Purpose: Unflattened photon beams exhibit many benefits over traditional flattened beams for radiotherapy (RT), but comprehensive evaluations of dosimetric results and beam-on time using flattening filter-free (FFF) beams for all types of breast irradiations are still lacking. The purpose of this study was to investigate if FFF RT can maintain equal or better dose coverage than standard flattened-beam RT while reducing doses to organs at risk (OARs) and beam-on time for various types of breast cancer irradiations. Methods and Materials: FFF volumetric-modulated arc therapy (FFF-VMAT) and standard VMAT (STD-VMAT) treatment plans were created for 15 whole-breast irradiation (WBI) patients with 50 Gy/25 fractions, 13 partial-breast irradiation (PBI) patients with 38.5 Gy/10 fractions, and 9 postmastectomy irradiation (PMI) patients with 50 Gy/25 fractions. Planning target volume (PTV) coverage and dose to OARs were evaluated. Results: Both techniques produced clinically acceptable plans for all three types of irradiations. For WBI, FFF-VMAT plans exhibited similar PTV and OARs evaluation metrics as STD-VMAT. For PBI, FFF-VMAT plans showed significantly lower mean and maximum doses for ipsilateral and contralateral lungs, contralateral breast, and heart. For PMI, FFF-VMAT plans showed significantly lower mean dose and V5 for contralateral breast but significantly higher Dmean, Dmax, and V20 for ipsilateral lung and significantly higher Dmean, V22.5, and V30 for heart. FFF-VMAT techniques significantly reduced beam-on time than STD-VMAT for all cases. Conclusion: This work has shown that FFF beams are most beneficial for small-field irradiation such as PBI, and breast cancer patients could potentially benefit from the shortened beam-on time.

Association of stress hyperglycemia ratio and in-hospital mortality in patients with coronary artery disease: insights from a large cohort study.

BACKGROUND: Stress hyperglycemia is strongly associated with poor clinical outcomes in patients with acute coronary syndrome (ACS). Recently, the stress hyperglycemia ratio (SHR) has been proposed to represent relative hyperglycemia. Studies regarding the relationship between SHR and mortality in coronary artery disease (CAD) are limited. This study aimed to clarify the association between SHR and in-hospital mortality in patients with CAD. METHODS: A total of 19,929 patients with CAD who were hospitalized in Beijing Hospital were enrolled in this study. Patients with an estimated glomerular filtration rate < 30 ml/min, cancer, or missing blood glucose/HbA1c data were excluded; therefore, 8,196 patients were included in the final analysis. The patients were divided into three groups based on tertiles of SHR: T1 group (SHR < 0.725, n = 2,732), T2 group (0.725 ≤ SHR < 0.832, n = 2,730), and T3 group (SHR ≥ 0.832, n = 2,734). The primary endpoint was in-hospital mortality. RESULTS: The overall in-hospital mortality rate was 0.91% (n = 74). After adjusting for covariates, SHR was significantly associated with in-hospital mortality in patients with CAD [odds ratio (OR) = 17.038; 95% confidence interval (CI) = 9.668-30.027; P < 0.001], and the T3 group had a higher risk of in-hospital mortality (OR = 4.901; 95% CI = 2.583-9.297; P < 0.001) compared with T1 group. In the subgroup analysis, the T3 group had an increased risk of mortality among patients with pre-diabetes mellitus (pre-DM) (OR = 9.670; 95% CI = 1.886-49.571; P = 0.007) and diabetes mellitus (DM) (OR = 5.023; 95% CI = 2.371-10.640; P < 0.001) after adjustments for covariates. The relationship between SHR and in-hospital mortality among patients with ACS and chronic coronary syndrome was consistent with the main finding. SHR and in-hospital mortality exhibited a dose-response relationship, and the risk of in-hospital mortality increased when the SHR index was above 1.20. Moreover, the area under the curve of SHR for predicting in-hospital mortality in patients with CAD was 0.741. CONCLUSION: SHR is significantly associated with in-hospital mortality in patients with CAD. SHR may be an effective predictor of in-hospital mortality in patients with CAD, especially for those with pre-DM and DM.

Association between the triglyceride-glucose index and severity of coronary artery disease.

BACKGROUND: The triglyceride-glucose (TyG) index, which is a reliable surrogate marker of insulin resistance (IR), has been associated with cardiovascular diseases. However, evidence of the impact of the TyG index on the severity of coronary artery disease (CAD) is limited. This study investigated the relationship between the TyG index and CAD severity of individuals with different glucose metabolic statuses. METHODS: This study enrolled 2792 participants with CAD in China between January 1, 2018 and December 31, 2021. All participants were divided into groups according to the tertiles of the TyG index as follows: T1 group, TyG index < 6.87; T2 group, TyG index ≥ 6.87 to < 7.38; and T3 group, TyG index ≥ 7.38. The glucose metabolic status was classified as normal glucose regulation, pre-diabetes mellitus (pre-DM), and diabetes mellitus according to the standards of the American Diabetes Association. CAD severity was determined by the number of stenotic vessels (single-vessel CAD versus multi-vessel CAD). RESULTS: We observed a significant relationship between the TyG index and incidence of multi-vessel CAD. After adjusting for sex, age, body mass index, smoking habits, alcohol consumption, hypertension, estimated glomerular filtration rate, antiplatelet drug use, antilipidemic drug use, and antihypertensive drug use in the logistic regression model, the TyG index was still an independent risk factor for multi-vessel CAD. Additionally, the highest tertile of the TyG group (T3 group) was correlated with a 1.496-fold risk of multi-vessel CAD compared with the lowest tertile of the TyG group (T1 group) (odds ratio [OR], 1.496; 95% confidence interval [CI], 1.183-1.893; P < 0.001) in the multivariable logistic regression model. Furthermore, a dose-response relationship was observed between the TyG index and CAD severity (non-linear P = 0.314). In the subgroup analysis of different glucose metabolic statuses, the T3 group (OR, 1.541; 95% CI 1.013-2.344; P = 0.043) were associated with a significantly higher risk of multi-vessel CAD in individuals with pre-DM. CONCLUSIONS: An increased TyG index was associated with a higher risk of multi-vessel CAD. Our study indicated that TyG as an estimation index for evaluating IR could be a valuable predictor of CAD severity, especially for individuals with pre-DM.

How Duty-Free Policy Influences Travel Intention: Mediating Role of Perceived Value and Moderating Roles of COVID-19 Severity and Counterfactual Thinking.

Counterfactual thinking is presumed to play a preparatory function in promoting people's behavioural intentions. This study specifically addresses the impacts of COVID-19 severity, tourists' counterfactual thinking about the pandemic, and tourists' perceived duty-free consumption value on the effect of a duty-free policy on travel intentions. Four hundred and ten participants took part in this study, which involved a 2 (duty-free policy: absent vs. present) × 2 (COVID-19 severity: high vs. low) design. Results reveal the following patterns: (a) compared to the absence of a duty-free policy in tourist destinations, enactment of a duty-free policy leads to stronger visit intentions through greater perceived value and (b) the effect of a duty-free policy on travel intention is moderated by tourists' counterfactual thinking and COVID-19 severity.

Design of Chopsticks-Shaped Heating Resistors for a Thermal Inkjet: Based on TaN Film.

Efficient printing frequency is critical for thermal bubble inkjet printing, while the difficulty lies in the structural design and material selection of the heating resistors. In this paper, a TaN film was used as the main material of the heating resistors, and two TaN films were placed in parallel to form the chopsticks-shaped structure. The heating time was divided into two sections, in which 0-0.1 µs was the preheating and 1.2-1.8 µs was the primary heating. At 1.8 µs, the maximum temperature of the Si3N4 film could reach about 1100 °C. At the same time, the SiO2 film was added between the TaN film and Si3N4 film as a buffer layer, which effectively avoided the rupture of the Si3N4 film due to excessive thermal stress. Inside the inkjet print head, the maximum temperature of the chamber reached about 680 °C at 2.5 µs. Due to the high power of the heating resistors, the working time was greatly reduced and the frequency of the inkjet printing was effectively increased. At the interface between the back of the chip and the cartridge, the SiO2 film was used to connect to ensure a timely ink supply. Under the condition of 12 V at 40 kHz, the inkjet chip could print efficiently with 10 nozzles at the same time. The inkjet chip proposed in this paper is not limited to only office printing, but also provides a new reference for 3D printing, cell printing, and vegetable and fruit printing.

Extracellular vesicles from bone marrow stromal cells reduce the impact of stroke on glial cell activation and blood brain-barrier permeability via a putative miR-124/PRX1 signalling pathway.

Ischaemic stroke (IS) is a cerebrovascular disease caused by cerebral infarction and cerebral artery occlusion. In this study, we proposed that EVs from bone marrow stromal cells (BMSCs) could reduce the impact of stroke by reducing the resultant glial cell activation and blood-brain barrier (BBB) leak. We furthermore investigated some of the signalling mechanisms. The transient middle cerebral artery occlusion (t-MCAO) mouse model was established. The behavioural deficits and neuronal damage were verified using Bederson's scale and the 28-point neurological score. The area of cerebral infarction was detected. The expressions of astrocytes/microglia markers and BBB permeability were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The internalization of EVs by astrocytes/microglia in the peripheral area was detected by fluorescence labelling. The expressions of astrocyte/microglia markers were measured by RT-qPCR. Levels of TNF-α and IL-1ß in microglia were detected by ELISA. BBB permeability was evaluated. The downstream target genes and pathway of miR-124 were analysed. Microglia/astrocytes were treated by oxygen-glucose deprivation reoxygenation (OGD/R). OGD/R microglia/astrocyte conditioned medium was used to culture bEnd.3 cells. The transendothelial electric resistance (TEER) of bEnd.3 cells was measured, and BBB permeability was characterized. Our results suggested that EVs from BMSCs can indeed reduce the extent of stroke-mediated damage and evidenced that these effects are mediated via expression of the non-coding RNA, miR-124 that may act via the peroxiredoxin 1 (PRX1). Our results provided further motivation to pursue the use of modified EVs as a treatment option for neurological diseases.

The Bidirectional Relation Between Counterfactual Thinking and Closeness, Controllability, and Exceptionality.

In four experiments, we explored the inferences people make when they learn that counterfactual thinking has occurred. Experiment 1 (N = 40) showed that knowing that a protagonist had engaged in counterfactual thinking (compared to no counterfactual thinking) resulted in participants inferring that the past event was closer in time to the protagonist, but there was no difference in inferring how close the past event was between knowing that a protagonist made many or a single counterfactual statement(s). Experiment 2 (N = 80) confirmed that participants were not affected by the number of counterfactual statements they read when inferring temporal closeness. Experiment 3 (N = 49) demonstrated that participants who learned that a protagonist had engaged in counterfactual thinking were more likely to infer that the protagonist experienced the controllable event. Experiment 4 (N = 120) indicated that participants who learned that a protagonist had engaged in counterfactual thinking were more likely to infer that the protagonist experienced the exceptional event. We concluded that the existence (but not the number) of counterfactual thoughts can lead people to infer that events were close, exceptional, and controllable, which suggests that the relations between closeness/controllability/exceptionality and counterfactual thinking are bidirectional. These results showed that as well as making inferences based on facts about the real world, people also make inferences about the real world based on hypothetical worlds.

Magnetic covalent organic framework nanospheres-based miRNA biosensor for sensitive glioma detection.

Sensitive detection and accurate diagnosis/prognosis of glioma remain urgent challenges. Herein, dispersed magnetic covalent organic framework nanospheres (MCOF) with uniformed Fe3O4 nano-assembly as cores and high-crystalline COF as shells were prepared by monomer-mediated in-situ interface growth strategy. Based on the unique interaction between MCOF and hairpin DNA, a fluorescent signal amplified miRNA biosensor was constructed. It could realize the sensitive detection of miRNA-182 in different matrixes, where the detection limit, linearity range and determination coefficient (R2) in real blood samples reached 20 fM, 0.1 pM-10 pM and 0.991, respectively. Also, it possessed good stability and precision as observed from the low intra-day/inter-day RSD and high extraction recovery. As a result, it could quantify miRNA-182 in serum of glioma patients, the concentration of which was significantly higher than that of healthy people and obviously decreased after surgery. Finally, a proof-of-concept capillary chip system using this biosensor was proposed to realize the visualized detection of miRNA-182 in microsample. These findings suggest a robust way for sensitive detection and accurate diagnosis/prognosis of glioma.

Design of H-Shape Chamber in Thermal Bubble Printer.

The utilization rate of ink liquid in the chamber is critical for the thermal bubble inkjet head. The difficult problem faced by the thermal bubble inkjet printing is how to maximize the use of ink in the chamber and increase the printing frequency. In this paper, by adding a flow restrictor and two narrow channels into the chamber, the H-shape flow-limiting structure is formed. At 1.8 µs, the speed of bubble expansion reaches the maximum, and after passing through the narrow channel, the maximum reverse flow rate of ink decreased by 25%. When the vapor bubble disappeared, the ink fills the nozzle slowly. At 20 µs, after passing through the narrow channel, the maximum flow rate of the ink increases by 39%. The inkjet printing frequency is 40 kHz, and the volume of the ink droplet is about 13.1 pL. The structure improves the frequency of thermal bubble inkjet printing and can maximize the use of liquid in the chamber, providing a reference for cell printing, 3D printing, bioprinting, and other fields.

Improved Weighted Non-Local Mean Filtering Algorithm for Laser Image Speckle Suppression.

Laser speckle noise caused by coherence between lasers greatly influences the produced image. In order to suppress the effect of laser speckles on images, in this paper we set up a combination of a laser-structured light module and an infrared camera to acquire laser images, and propose an improved weighted non-local mean (IW-NLM) filtering method that adopts an SSI-based adaptive h-solving method to select the optimal h in the weight function. The analysis shows that the algorithm not only denoises the laser image but also smooths pixel jumps in the image, while preserving the image details. The experimental results show that compared with the original laser image, the equivalent number of looks (ENL) index of the IW-NLM filtered image improved by 0.80%. The speckle suppression index (SSI) of local images dropped from 4.69 to 2.55%. Compared with non-local mean filtering algorithms, the algorithm proposed in this paper is an improvement and provides more accurate data support for subsequent image processing analysis.

Assessing the robustness of artificial intelligence powered planning tools in radiotherapy clinical settings-a phantom simulation approach.

BACKGROUND: Artificial intelligence (AI) based radiotherapy treatment planning tools have gained interest in automating the treatment planning process. It is essential to understand their overall robustness in various clinical scenarios. This is an existing gap between many AI based tools and their actual clinical deployment. This study works to fill the gap for AI based treatment planning by investigating a clinical robustness assessment (CRA) tool for the AI based planning methods using a phantom simulation approach. METHODS: A cylindrical phantom was created in the treatment planning system (TPS) with the axial dimension of 30 cm by 18 cm. Key structures involved in pancreas stereotactic body radiation therapy (SBRT) including PTV25, PTV33, C-Loop, stomach, bowel and liver were created within the phantom. Several simulation scenarios were created to mimic multiple scenarios of anatomical changes, including displacement, expansion, rotation and combination of three. The goal of treatment planning was to deliver 25 Gy to PTV25 and 33 Gy to PTV33 in 5 fractions in simultaneous integral boost (SIB) manner while limiting luminal organ-at-risk (OAR) max dose to be under 29 Gy. A previously developed deep learning based AI treatment planning tool for pancreas SBRT was identified as the validation object. For each scenario, the anatomy information was fed into the AI tool and the final fluence map associated to the plan was generated, which was subsequently sent to TPS for leaf sequencing and dose calculation. The final auto plan's quality was analyzed against the treatment planning constraint. The final plans' quality was further analyzed to evaluate potential correlation with anatomical changes using the Manhattan plot. RESULTS: A total of 32 scenarios were simulated in this study. For all scenarios, the mean PTV25 V25Gy of the AI based auto plans was 96.7% while mean PTV33 V33Gy was 82.2%. Large variation (16.3%) in PTV33 V33Gy was observed due to anatomical variations, a.k.a. proximity of luminal structure to PTV33. Mean max dose was 28.55, 27.68 and 24.63 Gy for C-Loop, bowel and stomach, respectively. Using D0.03cc as max dose surrogate, the value was 28.03, 27.12 and 23.84 Gy for C-Loop, bowel and stomach, respectively. Max dose constraint of 29 Gy was achieved for 81.3% cases for C-Loop and stomach, and 78.1% for bowel. Using D0.03cc as max dose surrogate, the passing rate was 90.6% for C-Loop, and 81.3% for bowel and stomach. Manhattan plot revealed high correlation between the OAR over dose and the minimal distance between the PTV33 and OAR. CONCLUSIONS: The results showed promising robustness of the pancreas SBRT AI tool, providing important evidence of its readiness for clinical implementation. The established workflow could guide the process of assuring clinical readiness of future AI based treatment planning tools.

A Review of Functions of Speculative Thinking.

Speculative thinking refers to thinking about past or future possibilities; it includes counterfactual thinking, prefactual thinking, and other types. In this narrative review, we discuss the traditional function of speculative thinking in improving future performance (i.e., the preparatory function). We also explore several non-preparatory functions of speculative thinking that have not been widely covered, namely the functions of conveying information and of supporting lying. In addition, we address temporal asymmetry; one perspective focuses on psychological distance in speculative thinking about the past and future, while another focuses on temporal asymmetry and reality/hypothetical differences in the preparatory function of speculative thinking. Overall, this review suggests that a broader functional theory is needed to address non-preparatory functions and the traditional preparatory function. Such a theory should cover all speculative thinking about the past and future rather than simply counterfactual thinking.

Development and Validation of an Electronic Frailty Index Using Routine Electronic Health Records: An Observational Study From a General Hospital in China.

Background: This study aimed to develop and validate an electronic frailty index (eFI) based on routine electronic health records (EHR) for older adult inpatients and to analyze the correlations between frailty and hospitalized events and costs. Methods: We created an eFI from routine EHR and validated the effectiveness by the consistency of the comprehensive geriatric assessment-frailty index (CGA-FI) with an independent prospective cohort. Then, we analyzed the correlations between frailty and hospitalized events and costs by regressions. Results: During the study period, 49,226 inpatients were included in the analysis, 42,821 (87.0%) of which had enough data to calculate an eFI. A strong correlation between the CGA-FI and eFI was shown in the validation cohort of 685 subjects (Pearson's r = 0.716, P < 0.001). The sensitivity and specificity for an eFI≥0.15, the upper tertile, to identify frailty, defined as a CGA-FI≥0.25, were 64.8 and 88.7%, respectively. After adjusting for age, sex, and operation, an eFI≥0.15 showed an independent association with long hospital stay (odds ratio [OR] = 2.889, P < 0.001) and death in hospital (OR = 19.97, P < 0.001). Moreover, eFI values (per 0.1) were positively associated with total costs (ß = 0.453, P < 0.001), examination costs (ß = 0.269, P < 0.001), treatment costs (ß = 0.414, P < 0.001), nursing costs (ß = 0.381, P < 0.001), pharmacy costs (ß = 0.524, P < 0.001), and material costs (ß = 0.578, P < 0.001) after adjusting aforementioned factors. Conclusions: We successfully developed an effective eFI from routine EHR from a general hospital in China. Frailty is an independent risk factor for long hospital stay and death in hospital. As the degree of frailty increases, the hospitalized costs increase accordingly.

Cost-effectiveness analysis of radiotherapy techniques for whole breast irradiation.

BACKGROUND: The current standard of care (SOC) for whole breast radiotherapy (WBRT) in the US is conventional tangential photon fields. Advanced WBRT techniques may provide similar tumor control and better normal tissue sparing, but it is controversial whether the medical benefits of an advanced technology are significant enough to justify its higher cost. OBJECTIVE: To analyze the cost-effectiveness of six advanced WBRT techniques compared with SOC. METHODS: We developed a Markov model to simulate health states for one cohort of women (65-year-old) with early-stage breast cancer over 15 years after WBRT. The cost effectiveness analyses of field-in-field (FIF), hybrid intensity modulated radiotherapy (IMRT), full IMRT, standard volumetric modulated arc therapy (STD-VMAT), multiple arc VMAT (MA-VMAT), non-coplanar VMAT (NC-VMAT) compared with SOC were performed with both tumor control and radiogenic side effects considered. Transition probabilities and utilities for each health state were obtained from literature. Costs incurred by payers were adopted from literature and Medicare data. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to evaluate the impact of uncertainties on the final results. RESULTS: FIF has the lowest ICER value of 1,511 $/QALY. The one-way analyses show that the cost-effectiveness of advanced WBRT techniques is most sensitive to the probability of developing contralateral breast cancer. PSAs show that SOC is more cost effective than almost all advanced WBRT techniques at a willingness-to-pay (WTP) threshold of 50,000 $/QALY, while FIF, hybrid IMRT and MA-VMAT are more cost-effective than SOC with a probability of 59.2%, 72.3% and 72.6% at a WTP threshold of 100,000 $/QALY, respectively. CONCLUSIONS: FIF might be the most cost-effective option for WBRT patients at a WTP threshold of 50,000 $/QALY, while hybrid IMRT and MA-VMAT might be the most cost-effective options at a WTP threshold of 100,000 $/QALY.

Effect of CSR contribution timing during COVID-19 pandemic on consumers' prepayment purchase intentions: Evidence from hospitality industry in China.

Corporate social responsibility (CSR) contributions are essential for hospitality companies during the COVID-19 pandemic. However, little is known about how CSR contribution timing during the pandemic might affect consumers' prepayment purchase intentions. This paper takes a hospitality company as an example, using two experiments to explore (a) the effect of CSR contribution timing on consumers' prepayment purchase intentions and (b) the potential roles of psychological contracts and distance to the COVID-19 risk center. Study 1 demonstrated that CSR contributions during the COVID-19 outbreak (vs. after its peak) led consumers to have higher prepayment purchase intentions, revealing the impact of CSR contribution timing. This effect was also driven by psychological contracts between consumers and the hospitality company. Study 2 showed that, when participants were in the peripheral area of a COVID-19 outbreak, CSR contributions during the outbreak (vs. after its peak) increased prepayment purchase intentions whereas the opposite effect occurred when consumers were in the risk center.

Cost-effectiveness analysis of advanced radiotherapy techniques for post-mastectomy breast cancer patients.

BACKGROUND: Prior cost-effectiveness studies of post-mastectomy radiotherapy (PMRT) only compared conventional radiotherapy versus no radiotherapy and only considered tumor control. The goal of this study was to perform cost-effectiveness analyses of standard of care (SOC) and advanced PMRT techniques including intensity-modulated radiotherapy (IMRT), standard volumetric modulated arc therapy (STD-VMAT), non-coplanar VMAT (NC-VMAT), multiple arc VMAT (MA-VMAT), Tomotherapy (TOMO), mixed beam therapy (MIXED), and intensity-modulated proton therapy (IMPT). METHODS: Using a Markov model, we estimated the cost-effectiveness of various techniques over 15 years. A cohort of women (55-year-old) was simulated in the model, and radiogenic side effects were considered. Transition probabilities, utilities, and costs for each health state were obtained from literature and Medicare data. Model outcomes include quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). RESULTS: For the patient cohort, STD-VMAT has an ICER of $32,617/QALY relative to SOC; TOMO is dominated by STD-VMAT; IMRT has an ICER of $19,081/QALY relative to STD-VMAT; NC-VMAT, MA-VMAT, MIXED are dominated by IMRT; IMPT has an ICER of $151,741/QALY relative to IMRT. One-way analysis shows that the probability of cardiac toxicity has the most significant impact on the model outcomes. The probability sensitivity analyses show that all advanced PMRT techniques are more cost-effective than SOC at a willingness-to-pay (WTP) threshold of $100,000/QALY, while almost none of the advanced techniques is more cost-effective than SOC at a WTP threshold of $50,000/QALY. CONCLUSION: Advanced PMRT techniques are more cost-effective for breast cancer patients at a WTP threshold of $100,000/QALY, and IMRT might be a cost-effective option for PMRT patients.

Versatile hollow COF nanospheres via manipulating transferrin corona for precise glioma-targeted drug delivery.

Covalent organic framework (COF) nanoparticles for interference-free targeted drug delivery to glioma remains in its infancy. Herein, hollow COF nanospheres with high crystallinity and uniformed sizes were facilely prepared via heterogeneous nucleation-growth. The prepared COF had large surface area/pore volume and exhibited appropriate degradation behavior under acid environment, where therefore doxorubicin was effectively encapsulated and exhibited a pH-sensitive release. Most charmingly, T10 peptide that has high affinity with transferrin (Tf), was conjugated to endow the hollow COF interesting properties to specifically absorb Tf in vivo as Tf corona. For the first time, multifunctional hollow COF nanospheres (the better one named DCPT-2) were successfully synthesized to achieve interference-free cascade-targeting glioma drug delivery across the blood-brain barrier. Treatment with DCPT-2 brought an improved therapeutic outcome with significantly prolonged median survival time and low side effects. This work promised not only a potential protein corona-mediated COF-based drug delivery platform with good biocompatibility for effective and precise brain tumor therapy, but also an endogenous protein corona-mediated targeting strategy for general cancer therapy.