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BackgroundNivolumab is an effective treatment option for advanced gastric cancer (GC). This study aimed to conduct a systematic review of existing literature to investigate the relationship between immune-related adverse events (irAEs) and the prognosis of patients with GC treated with nivolumab.MethodsWe comprehensively searched four online literature databases: the Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, until 27 March 2024. The outcome measures of interest included: overall survival (OS), progression-free survival (PFS), hazard ratio (HR), median survival ratio (MSR), objective response rate (ORR), and disease control rate (DCR).ResultsA total of six studies, including 393 patients, met the eligibility criteria. The OS (pooled hazard ratio [HR] = 0.4, 95% confidence interval [CI]: 0.3–0.6, p < 0.05) and PFS (pooled HR = 0.5, 95% CI: 0.4–0.6, p < 0.05) of patients with irAEs were significantly superior to individuals without irAEs. The MSR for OS and PFS were 2.5 (95% CI: 1.5-4.1, p < 0.05) and 2.8 (95% CI: 1.9–4.1, p < 0.05), respectively. Regarding the ORR and DCR, we found that the development of irAEs was significantly associated with higher rates: patients with irAEs had an ORR of 24.7% compared to 6.4% in those without irAEs (risk ratio [RR] = 2.6, p < 0.05), and a DCR of 86.0% compared to 30.3% in those without irAEs (RR = 3.2, p < 0.05).ConclusionThere appears to be a significant correlation between the development of irAEs and the better survival benefits with nivolumab in patients with GC.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022341396.

Abstract Recently, there has been great interest in the phenomenon of severe violation of the Wiedemann–Franz law in graphene Dirac fluids around 75 K, due to the strong coupling relativistic plasma near the neutral point, where traditional perturbation theory fails. To explain this phenomenon, this article proposes a holographic dual two-current axion coupling model, describing the interaction between electrons and holes in graphene near the charge neutrality point (CNP) and revealing the related physical mechanism. The study shows that the holographic two-current model aligns with experimental results at 100 $$\upmu $$ μ m $$^{-2}$$ - 2 , and correctly predicts conductivity as temperature increases. Additionally, the article explores the behavior of $$\beta +\gamma $$ β + γ and its impact on conductivity and thermal conductivity. The results suggest a frictional effect between electrons and holes. Consequently, this study provides us with a clearer understanding of the properties of graphene Dirac fluids and further confirms the reliability of the holographic duality method.

Snake venoms, comprising a complex array of protein-rich components, an important part of which are snake venom metalloproteinases (SVMPs). These SVMPs, which are predominantly isolated from viperid venoms, are integral to the pathology of snakebites. However, SVMPs derived from elapid venoms have not been extensively explored, and only a handful of SVMPs have been characterized to date. Atrase A, a nonhemorrhagic P-III class metalloproteinase from Naja atra venom, exhibits weak proteolytic activity against fibrinogen in vitro but has pronounced anticoagulant effects in vivo. This contrast spurred investigations into its anticoagulant mechanisms. Research findings indicate that atrase A notably extends the activated partial thromboplastin time, diminishes fibrinogen levels, and impedes platelet aggregation. The anticoagulant action of atrase A primarily involves inhibiting coagulation factor VIII and activating the endogenous fibrinolytic system, which in turn lowers fibrinogen levels. Additionally, its effect on platelet aggregation further contributes to its anticoagulant profile. This study unveils a novel anticoagulant mechanism of atrase A, significantly enriching the understanding of the roles of cobra venom metalloproteinases in snake venom. Furthermore, these findings underscore the potential of atrase A as a novel anticoagulant drug, offering insights into the functional evolutions of cobra venom metalloproteinases.

Phosphorus (P) is a nonrenewable resource and a critical element for plant growth that plays an important role in improving crop yield. Excessive P fertilizer application is widespread in agricultural production, which not only wastes phosphate resources but also causes P accumulation and groundwater pollution. Here, we hypothesized that the apparent P balance of a crop system could be used as an indicator for identifying the critical P input in order to obtain a high yield with high phosphorus use efficiency (PUE). A 12-year field experiment with P fertilization rates of 0, 45, 90, 135, 180, and 225 kg P2O5 ha−1 was conducted to determine the crop yield, PUE, and soil Olsen-P value response to P balance, and to optimize the P input. Annual yield stagnation occurred when the P fertilizer application exceeded a certain level, and high yield and PUE levels were achieved with annual P fertilizer application rates of 90–135 kg P2O5 ha−1. A critical P balance range of 2.15–4.45 kg P ha−1 was recommended to achieve optimum yield with minimal environmental risk. The critical P input range estimated from the P balance was 95.7–101 kg P2O5 ha−1, which improved relative yield (>90%) and PUE (90.0–94.9%). In addition, the P input–output balance helps in assessing future changes in Olsen-P values, which increased by 4.07 mg kg−1 of P for every 100 kg of P surplus. Overall, the P balance can be used as a critical indicator for P management in agriculture, providing a robust reference for limiting P excess and developing a more productive, efficient and environmentally friendly P fertilizer management strategy.

Abstract Aim The purpose of this study was to provide a comprehensive understanding of the attitudes and experiences of the medical staff regarding the hospital bed‐sharing model. Design The present research was a qualitative study. Methods This qualitative study used in‐depth individual interviews with 7 doctors, 10 clinical nurses and 3 head nurses, which were then transcribed and analysed thematically. Results The study identified six overall themes. Issues were raised about the efficient utilization of hospital bed resources, greater challenges for nursing work, adjustment of doctors' work modes, barriers to communication between doctors, nurses, and patients, potential medical risks, and differentiation of patients' medical experience. Implications for Nursing Management Hospital administrators and nurse managers should work together to solve the challenges that medical staff face, including strengthening nursing training, improving medical–nursing collaboration models, standardizing and effective communication strategies, and improving patient experiences.

In recent decades, with the rapid development of the inorganic synthesis and the increasing discharge of pollutants in the process of industrialization, hollow-structured metal oxides (HSMOs) have taken on a striking role in the field of environmental catalysis. This is all due to their unique structural characteristics compared to solid nanoparticles, such as high loading capacity, superior pore permeability, high specific surface area, abundant inner void space, and low density. Although the HSMOs with different morphologies have been reviewed and prospected in the aspect of synthesis strategies and potential applications, there has been no systematic review focusing on the structures and compositions design of HSMOs in the field of environmental catalysis so far. Therefore, this review will mainly focus on the component dependence and controllable structure of HSMOs in the catalytic elimination of different environmental pollutants, including the automobile and stationary source emissions, volatile organic compounds, greenhouse gases, ozone-depleting substances, and other potential pollutants. Moreover, we comprehensively reviewed the applications of the catalysts with hollow structure that are mainly composed of metal oxides such as CeO2, MnOx, CuOx, Co3O4, ZrO2, ZnO, Al3O4, In2O3, NiO, and Fe3O4 in automobile and stationary source emission control, volatile organic compounds emission control, and the conversion of greenhouse gases and ozone-depleting substances. The structure–activity relationship is also briefly discussed. Finally, further challenges and development trends of HSMO catalysts in environmental catalysis are also prospected.

CeO2 is an outstanding support commonly used for the CuO-based CO oxidation catalysts due to its excellent redox property and oxygen storage–release property. However, the inherently small specific surface area of CeO2 support restricts the further enhancement of its catalytic performance. In this work, the novel mesoporous CeO2 nanosphere with a large specific surface area (~190.4 m2/g) was facilely synthesized by the improved hydrothermal method. The large specific surface area of mesoporous CeO2 nanosphere could be successfully maintained even at high temperatures up to 500 °C, exhibiting excellent thermal stability. Then, a series of CuO-based CO oxidation catalysts were prepared with the mesoporous CeO2 nanosphere as the support. The large surface area of the mesoporous CeO2 nanosphere support could greatly promote the dispersion of CuO active sites. The effects of the CuO loading amount, the calcination temperature, mesostructure, and redox property on the performances of CO oxidation were systematically investigated. It was found that high Cu+ concentration and lattice oxygen content in mesoporous CuO/CeO2 nanosphere catalysts greatly contributed to enhancing the performances of CO oxidation. Therefore, the present mesoporous CeO2 nanosphere with its large specific surface area was considered a promising support for advanced CO oxidation and even other industrial catalysts.

Background: Nivolumab is an effective treatment option for advanced gastric cancer (GC). This study aimed to conduct a systematic review of existing literature to investigate the relationship between immune-related adverse events (irAEs) and the prognosis of patients with GC treated with nivolumab. Methods: We comprehensively searched four online literature databases: the Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, until 27 March 2024. The outcome measures of interest included: overall survival (OS), progression-free survival (PFS), hazard ratio (HR), median survival ratio (MSR), objective response rate (ORR), and disease control rate (DCR). Results: A total of six studies, including 393 patients, met the eligibility criteria. The OS (pooled hazard ratio [HR] = 0.4, 95% confidence interval [CI]: 0.3-0.6, p < 0.05) and PFS (pooled HR = 0.5, 95% CI: 0.4-0.6, p < 0.05) of patients with irAEs were significantly superior to individuals without irAEs. The MSR for OS and PFS were 2.5 (95% CI: 1.5-4.1, p < 0.05) and 2.8 (95% CI: 1.9-4.1, p < 0.05), respectively. Regarding the ORR and DCR, we found that the development of irAEs was significantly associated with higher rates: patients with irAEs had an ORR of 24.7% compared to 6.4% in those without irAEs (risk ratio [RR] = 2.6, p < 0.05), and a DCR of 86.0% compared to 30.3% in those without irAEs (RR = 3.2, p < 0.05). Conclusion: There appears to be a significant correlation between the development of irAEs and the better survival benefits with nivolumab in patients with GC. [ABSTRACT FROM AUTHOR]

As a toxic pollutant, carbon monoxide (CO) usually causes harmful effects on human health. Therefore, the thermally catalytic oxidation of CO has received extensive attention in recent years. The CuO-based catalysts have been widely investigated due to their availability. In this study, a series of transition metal oxides (Fe2O3, Co3O4 and NiO) promoted CuO-based catalysts supported on the α-MnO2 nanowire catalysts were prepared by the deposition precipitation method for catalytic CO oxidation reactions. The effects of the loaded transition metal type, the loading amount, and the calcination temperature on the catalytic performances were systematically investigated. Further catalyst characterization showed that the CuO/α-MnO2 catalyst modified with 3 wt% Co3O4 and calcined at 400 °C performed the highest CO catalytic activity (T90 = 75 °C) among the investigated catalysts. It was supposed that the loading of the Co3O4 dopant not only increased the content of oxygen vacancies in the catalyst but also increased the specific surface area and pore volume of the CuO/α-MnO2 nanowire catalyst, which would further enhance the catalytic activity. The CuO/α-MnO2 catalyst modified with 3 wt% NiO and calcined at 400 °C exhibited the highest surface adsorbed oxygen content and the best normalized reaction rate, but the specific surface area limited its activity. Therefore, the appropriate loading of the Co3O4 modifier could greatly enhance the activity of CuO/α-MnO2. This research could provide a reference method for constructing efficient low-temperature CO oxidation catalysts.

In recent decades, with the rapid development of the inorganic synthesis and the increasing discharge of pollutants in the process of industrialization, hollow-structured metal oxides (HSMOs) have taken on a striking role in the field of environmental catalysis. This is all due to their unique structural characteristics compared to solid nanoparticles, such as high loading capacity, superior pore permeability, high specific surface area, abundant inner void space, and low density. Although the HSMOs with different morphologies have been reviewed and prospected in the aspect of synthesis strategies and potential applications, there has been no systematic review focusing on the structures and compositions design of HSMOs in the field of environmental catalysis so far. Therefore, this review will mainly focus on the component dependence and controllable structure of HSMOs in the catalytic elimination of different environmental pollutants, including the automobile and stationary source emissions, volatile organic compounds, greenhouse gases, ozone-depleting substances, and other potential pollutants. Moreover, we comprehensively reviewed the applications of the catalysts with hollow structure that are mainly composed of metal oxides such as CeO2, MnOx, CuOx, Co3O4, ZrO2, ZnO, Al3O4, In2O3, NiO, and Fe3O4 in automobile and stationary source emission control, volatile organic compounds emission control, and the conversion of greenhouse gases and ozone-depleting substances. The structure–activity relationship is also briefly discussed. Finally, further challenges and development trends of HSMO catalysts in environmental catalysis are also prospected. [ABSTRACT FROM AUTHOR]

The Cycolcarya paliurus (C. paliurus) has a long history of medicinal use as a traditional Chinese medicine to deal with diabetic, hyperlipidemic, inflammatory, and cancer, and triterpenes are one of its main active substances. Current studies on triterpenoids from C. paliurus have shown that different combinations of extraction methods and techniques have been used to isolate triterpenes from the leaves of the tree. The structures of the isolated triterpenoids from C. paliurus have also been elucidated to analyze their biological activities and conformational relationships. This paper presents a comprehensive evaluation of the triterpenes in C. paliurus in terms of extraction and purification methods, chemical structure, active functions and utilization, in order to provide a reference for the further development and utilization of triterpenoids in C. paliurus. [ABSTRACT FROM AUTHOR]

Qing Han,* Quan Zhang,* Feiquan Ying, Zehua Wang, Yifan Zhang, Lanqing Gong, E Cai, Jiaxian Qian, Jing Cai Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Cai; Jiaxian Qian Department of Obstetrics and Gynecology, Union HospitalTongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei 430022, People’s Republic of ChinaTel +86 135 5451 1709; +86 157 1715 6977Fax +86 27 8572 6993Email caijingmmm@hotmail.com; qianjiaxian@hust.edu.cnBackground: Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2)-expressing monocytes (TEMs) are a highly proangiogenic subset of myeloid cells, which are characterized by expressing the angiopoietin receptor Tie2 with pro-tumor activity.Purpose: The present study aimed to determine the clinical value of circulating TEMs (cTEMs) for cervical cancer.Patients and Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 7 healthy volunteers, 17 uterine fibroid patients, 24 cervical intraepithelial neoplasia (CIN) II patients, 31 CIN III patients and 99 patients with cervical cancer. The cTEMs were evaluated by the ratio of Tie2+ CD14+ cells to all CD14+ monocytes in the PBMCs through flow cytometry. The diagnostic value of cTEM was assessed by receiver operating characteristic (ROC) curves and the correlation between cTEM and clinicopathological characters in cervical cancer patients was analyzed.Results: The proportion of cTEMs was gradually increasing from healthy volunteers to patients with non-invasive lesions, then to cervical cancer patients. The area under the ROC curve was 0.913 when the level of cTEMs was used to distinguish cervical cancer from all the other women ranging from healthy volunteers to CIN III patients. In cervical cancer, an increased cTEM fraction was significantly correlated with advanced tumor stage, larger tumor size, lymph node metastasis (LNM), deep stromal infiltration, parametrial involvement and lymph-vascular space invasion and was an independent risk factor for LNM.Conclusion: The cTEM proportion might be a promising biomarker for the malignant transformation of cervical lesions and the progression of cervical cancer.Keywords: cervical cancer, Tie2-expressing monocytes, lymph node metastasis, tumor associated macrophages, biomarker, tumor progression

Objective To investigate the effects of astragalus polysaccharide (APS) on proliferation, apoptosis, migration and invasion of multiple myeloma (MM) cell line U266 and potential mechanisms. Methods U266 cells were incubated with APS at different concentrations (6, 8 and 10 mg/mL) for 24, 48 and 72 h, or 8 mg/mL treated APS on U266 cells transfected with tumor necrosis factor receptor-associated factor 6 (TRAF6) expression plasmid (pcDNA3.1-TRAF6) for 48 h.The proliferation of U266 cells was detected by CCK-8 method. Apoptosis of U266 cells was detected by flow cytometry. Migration and invasion of U266 cells were detected by Transwell. The level of cyclin D1, p21, Bax, Bcl-2, E-cadherin, MMP-2 and TRAF6 protein expression was detected by Western blot. Results Compared with the control, the inhibition rate, apoptosis rate, migration and invasion number of U266 cells in APS group were significantly increased(P＜0.05), and the expression of cyclin D1, Bcl-2, MMP-2 and TRAF6 was significantly decreased(P＜0.05), and the expression of p21, Bax and E-cadherin was significantly elevated(P＜0.05). Compared with the APS+pcDNA3.1 group, the inhibition rate, apoptosis rate, migration and invasion number of U266 cells in APS+pcDNA3.1-TRAF6 group were significantly decreased(P＜0.05), and the expression of cyclin D1, Bcl-2, MMP-2 and TRAF6 was significant elevated(P＜0.05). The expression of p21, Bax and E-cadherin was significantly inhibited(P＜0.05). Conclusions APS may inhibit the proliferation, migration and invasion of U266 cells through down-regulating the expression of TRAF6 protein, and promote the apoptosis of U266 cells.

Abstract Background To investigate the clinical value of heart failure echocardiography index (HFEI) in evaluating the cardiac function and predicting the prognosis of patients with different types of heart failure (HF). Methods Four hundred eighty-nine consecutively admitted HF patients were divided into three groups: HF with reduced ejection (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). The baseline characteristics and ultrasound indexes were compared between the three groups. The correlation between HFEI and one-year risk of adverse events was compared by multivariate logistic regression. The clinical value of HFEI and plasma level of NT-proBNP in assessing the prognosis of patients with chronic heart failure (CHF) was analyzed by the receiver operating characteristic (ROC) curve. Results HFEI in HFrEF was significantly higher than that in HFmrEF and HFpEF. Multivariate regression analysis indicated that HFEI and plasma level of NT-proBNP were independent risk factors for predicting the short-time prognosis of HF patients. The ROC curve indicated that the HFEI cutoff level of 3.5 and the plasma NT-proBNP level of 3000 pg/ml predicted a poor prognosis of CHF patients with a sensitivity of 64% and a specificity of 75% vs. 68 and 65%. Conclusion HFEI can comprehensively evaluate the overall cardiac function of patients with various types of HF, and may prove to be an important index of assessing the prognosis of HF patients.

In this work, a series of Cu2O/S (S = α-MnO2, CeO2, ZSM-5, and Fe2O3) supported catalysts with a Cu2O loading amount of 15% were prepared by the facile liquid-phase reduction deposition–precipitation strategy and investigated as CO oxidation catalysts. It was found that the Cu2O/α-MnO2 catalyst exhibits the best catalytic activity for CO oxidation. Additionally, a series of Cu2O-CuO/α-MnO2 heterojunctions with varied proportion of Cu+/Cu2+ were synthesized by further calcining the pristine Cu2O/α-MnO2 catalyst. The ratio of the Cu+/Cu2+ could be facilely regulated by controlling the calcination temperature. It is worth noting that the Cu2O-CuO/α-MnO2-260 catalyst displays the best catalytic performance. Moreover, the kinetic studies manifest that the apparent activation energy could be greatly reduced owing to the excellent redox property and the Cu2O-CuO interface effect. Therefore, the Cu2O-CuO heterojunction catalysts supported on α-MnO2 nanotubes are believed to be the potential catalyst candidates for CO oxidation with advanced performance.

CeO2 is an outstanding support commonly used for the CuO-based CO oxidation catalysts due to its excellent redox property and oxygen storage–release property. However, the inherently small specific surface area of CeO2 support restricts the further enhancement of its catalytic performance. In this work, the novel mesoporous CeO2 nanosphere with a large specific surface area (~190.4 m2/g) was facilely synthesized by the improved hydrothermal method. The large specific surface area of mesoporous CeO2 nanosphere could be successfully maintained even at high temperatures up to 500 °C, exhibiting excellent thermal stability. Then, a series of CuO-based CO oxidation catalysts were prepared with the mesoporous CeO2 nanosphere as the support. The large surface area of the mesoporous CeO2 nanosphere support could greatly promote the dispersion of CuO active sites. The effects of the CuO loading amount, the calcination temperature, mesostructure, and redox property on the performances of CO oxidation were systematically investigated. It was found that high Cu+ concentration and lattice oxygen content in mesoporous CuO/CeO2 nanosphere catalysts greatly contributed to enhancing the performances of CO oxidation. Therefore, the present mesoporous CeO2 nanosphere with its large specific surface area was considered a promising support for advanced CO oxidation and even other industrial catalysts. [ABSTRACT FROM AUTHOR]

CO2 reforming of methane (CRM) can effectively convert two greenhouse gases (CO2 and CH4) into syngas (CO + H2). This process can achieve the efficient resource utilization of CO2 and CH4 and reduce greenhouse gases. Therefore, CRM has been considered as a significantly promising route to solve environmental problems caused by greenhouse effect. Ni-based catalysts have been widely investigated in CRM reactions due to their various advantages, such as high catalytic activity, low price, and abundant reserves. However, Ni-based catalysts usually suffer from rapid deactivation because of thermal sintering of metallic Ni active sites and surface coke deposition, which restricted the industrialization of Ni-based catalysts toward the CRM process. In order to address these challenges, scientists all around the world have devoted great efforts to investigating various influencing factors, such as the option of appropriate supports and promoters and the construction of strong metal-support interaction. Therefore, we carefully summarized recent development in the design and preparation of Ni-based catalysts with advanced catalytic activity and enhanced anti-coke performance toward CRM reactions in this review. Specifically, recent progresses of Ni-based catalysts with different supports, additives, preparation methods, and so on, have been summarized in detail. Furthermore, recent development of reaction mechanism studies over Ni-based catalysts was also covered by this review. Finally, it is prospected that the Ni-based catalyst supported by an ordered mesoporous framework and the combined reforming of methane will become the future development trend.

With the development and prosperity of the global economy, the emission of carbon dioxide (CO2) has become an increasing concern. Its greenhouse effect will cause serious environmental problems, such as the global warming and climate change. Therefore, the worldwide scientists have devoted great efforts to control CO2 emissions through various strategies, such as capture, resource utilization, sequestration, etc. Among these, the catalytic conversion of CO2 to methane is considered as one of the most efficient routes for resource utilization of CO2 owing to the mild reaction conditions and simple reaction device. Pioneer thermodynamic studies have revealed that low reaction temperature is beneficial to the high catalytic activity and CH4 selectivity. However, the low temperature will be adverse to the enhancement of the reaction rate due to kinetic barrier for the activation of CO2. Therefore, the invention of highly efficient catalysts with promising low temperature activities toward CO2 methanation reaction is the key solution. The Ni based catalysts have been widely investigated as the catalysts toward CO2 methanation due to their low cost and excellent catalytic performances. However, the Ni based catalysts usually perform poor low-temperature activities and stabilities. Therefore, the development of highly efficient Ni based catalysts with excellent low-temperature catalytic performances has become the research focus as well as challenge in this field. Therefore, we summarized the recent research progresses of constructing highly efficient Ni based catalysts toward CO2 methanation in this review. Specifically, the strategies on how to enhance the catalytic performances of the Ni based catalysts have been carefully reviewed, which include various influencing factors, such as catalytic supports, catalytic auxiliaries and dopants, the fabrication methods, reaction conditions, etc. Finally, the future development trend of the Ni based catalysts is also prospected, which will be helpful to the design and fabrication of the Ni catalysts with high efficiency toward CO2 methanation process.

A bioactive glycoprotein (COG2a) was isolated from the seeds of Camellia oleifera Abel by multiple column chromatography and its structure and antioxidant capacity were investigated in vitro and in vivo. Structural analysis of COG2a revealed that it was an O-linked glycoprotein with a molecular mass of 25.9 kDa. The protein and carbohydrate contents of COG2a were 54.28% and 45.29% respectively, and its carbohydrate moieties were mainly rhamnose, arabinose, xylose, mannose, glucose, and galactose at a molar ratio of 1.29:1.65:5.81:1:16.15:14.47. Fourier transform infrared and circular dichroism spectra of COG2a exhibited the typical characteristics of a glycoprotein, that is, 80.3% α-helix, 1.0% β-strand, 6.4% β-turns, and 15.8% unordered residues. COG2a exhibited concentration-dependent free radicals-scavenging capacity in vitro. COG2a also significantly enhanced the SOD and GSH-PX activities and reduced the MDA and total carbonyl contents in blood and liver tissues of D-galactose-induced mice to protect against oxidative stress.