Current management for spinal cord injury aims to reduce secondary damage and recover sensation and movement.Acute spinal cord injury is often accompanied by spinal cord compartment syndrome.Decompression by durotomy ...Current management for spinal cord injury aims to reduce secondary damage and recover sensation and movement.Acute spinal cord injury is often accompanied by spinal cord compartment syndrome.Decompression by durotomy and/or myelotomy attempts to relieve secondary damage by completelyrelieving the compression of the spinal cord,removing the necrotic tissue,decreasing edema,reducing hemorrhage,and improving blood circulation in the spinal cord.However,it is controversial whether durotomy and/or myelotomy after spinal cord injury are beneficial to neurological recovery.This review compares the clinical effects of durotomy with those of myelotomy in the treatment of spinal cord injury.We found that durotomy has been performed more than myelotomy in the clinic,and that durotomy may be safer and more effective than myelotomy.Durotomy performed in humans had positive effects on neurological function in 92.3% of studies in this review,while durotomy in animals had positive effects on neurological function in 83.3% of studies.Myelotomy procedures were effective in 80% of animal studies,but only one clinical study of myelotomy has reported positive results,of motor and sensory improvement,in humans.However,a number of new animal studies have reported that durotomy and myelotomy are ineffective for spinal cord injury.More clinical data,in the form of a randomized controlled study,are needed to understand the effectiveness of durotomy and myelotomy.展开更多
Hot tearing is known as one of the most serious solidification defects commonly encountered during solidification. It is very important to study the solidification path of alloys. In the work, thermal analysis with co...Hot tearing is known as one of the most serious solidification defects commonly encountered during solidification. It is very important to study the solidification path of alloys. In the work, thermal analysis with cooling curve was used for the investigation of microstructure evolution with different Zn contents during solidification process of MgZn_xY_4Zr_(0.5) alloys. Thermal analysis results of MgY_4Zr_(0.5) alloys revealed one distinct phase precipitation: α-Mg. Three different phase peaks were detected in the Zn-containing alloys: α-Mg, Z-phase(Mg_(12)YZn) and W-phase(Mg_3 Y_2Zn_3). In addition, for the present MgZn_xY_4Zr_(0.5) alloys, the freezing ranges of these alloys from large to small were: MgZn_(1.5)Y_4Zr_(0.5)>MgZn)(3.0) Y)4Zr_(0.5)>MgZn0.5 Y4 Zr0.5>MgY_4Zr_(0.5). The effect of different contents of Zn(0, 0.5, 1.5, 3.0 wt.%) on hot tearing behavior of MgY_4Zr_(0.5) alloy was investigated using a constrained rod casting(CRC) apparatus equipped with a load cell and data acquisition system. The experimental results show that the addition of Zn element significantly increases hot tearing susceptibility(HTS) of the MgY_4Zr_(0.5) alloy due to its extended freezing range. Some free dendrite-like bumps and ruptured liquid films on the fracture surfaces were observed in all the fracture surfaces. These phenomena proved the fact that the hot tearing formation was caused by interdendritic separation due to lack of feeding at the end of solidification.展开更多
Constructing new photocatalysts for the photocatalytic reduction of CO_(2)and efficient degradation of Lev-ofloxacin is of great importance to renewable energy.Here,S-scheme Bi_(2)MoO_(6-x)/MoS_(2)heterojunction nanos...Constructing new photocatalysts for the photocatalytic reduction of CO_(2)and efficient degradation of Lev-ofloxacin is of great importance to renewable energy.Here,S-scheme Bi_(2)MoO_(6-x)/MoS_(2)heterojunction nanospheres containing abundant surface defects(oxygen vacancies)were designed and successfully syn-thesized to enhance CO_(2)photoreduction activity in the absence of other sacrificial agents,co-catalysts or photosensitisers.At the same time,it can efficiently degrade organic pollutants(Levofloxacin).This heterogeneous structure with surface defects provides an abundance of reactive sites,accelerates charge separation and improves oxidation capacity.The improved Bi_(2)MoO_(6-x)/MoS_(2)heterogeneous nanospheres show excellent performance under simulated solar light,with the selectivity and yield of 92.45%and 29.01μmol h−1,respectively,for the generation of CO.Under visible light,the degradation efficiency of levofloxacin hydrochloride(LVX)reached 96.3%within 25 min and remained as high as 95%after three cycles.This work provides a new idea for the design of new S-scheme photocatalysts and an important reference for the preparation of photocatalysts for the efficient photocatalytic reduction of CO_(2)and the efficient degradation of organic pollutants at the same time.展开更多
The imbalance of rural parking supply and demand has a great impact on traffic congestion and environmental pollution,which has attracted the attention of many scholars as well as policymakers.However,most of the curr...The imbalance of rural parking supply and demand has a great impact on traffic congestion and environmental pollution,which has attracted the attention of many scholars as well as policymakers.However,most of the current research on parking choice focuses on urban business and residential areas rather than on rural parking choice behaviour,and focuses on the analysis of observable factors,ignoring the internal relationship with potential variables.This study considers the heterogeneity of individuals and uses the random forest(RF)algorithm to construct a model of rural residents’willingness to choose parking with both latent and explicit variables,to explore how much and in what ways individual characteristics and parking characteristics affect rural residents’parking choices,and to explore parking planning programmes and strategies that are truly applicable to rural areas.The results of the study suggest that the safety and convenience of the parking environment are key factors influencing the parking choice behaviour of rural residents,and can greatly improve the predictive accuracy of the parking willingness model.Upon comparison,it is found that the application of the RF algorithm is also significantly better than the logit model in terms of prediction effect,indicating that there is a nonlinear effect among the factors influencing the parking choice behaviour of rural residents and that the RF model with the addition of latent variables provides a better explanatory ability for the study of the parking choice behaviour of rural residents.展开更多
This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who fai...This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled.Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles,followed by the maintenance of toripalimab and pemetrexed.The primary endpoint was objective-response rate(ORR).Integrated biomarker analysis of PD-L1 expression,tumor mutational burden(TMB),CD8+tumor-infiltrating lymphocyte(TIL)density,whole-exome,and transcriptome sequencing on tumor biopsies were also conducted.Forty patients were enrolled with an overall ORR of 50.0%and disease-control rate(DCR)of 87.5%.The median progression free survival(PFS)and overall survival were 7.0 and 23.5 months,respectively.The most common treatment-related adverse effects were leukopenia,neutropenia,anemia,ALT/AST elevation,and nausea.Biomarker analysis showed that none of PD-L1 expression,TMB level,and CD8+TIL density could serve as a predictive biomarker.Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type.Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC.DSPP mutation might serve as a potential biomarker for this combination.A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing(NCT03924050).展开更多
Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have ...Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.展开更多
Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer chemotherapy.However,currently,no ABCB1-inhibitory drugs have been approved to treat MDR...Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer chemotherapy.However,currently,no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically,mainly due to the inhibitor specificity,toxicity,and drug interactions.Here,we reported that three polyoxypregnanes(POPs)as the most abundant constituents of Marsdenia tenacissima(M.tenacissima)were novel ABCB1-modulatory pro-drugs,which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites.The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression,which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity.These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay,and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo.We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance.The results suggested that these POPs had the potential to be developed as safe,potent,and specific pro-drugs to reverse ABCB1-mediated MDR.Our work also provided scientific evidence for the use of M.tenacissima in combinational chemotherapy.展开更多
Outbreak of COVID-19 is ongoing all over the world.Spine trauma is one of the most common types of trauma and will probably be encountered during the fight against COVID-19 and resumption of work and production.Patien...Outbreak of COVID-19 is ongoing all over the world.Spine trauma is one of the most common types of trauma and will probably be encountered during the fight against COVID-19 and resumption of work and production.Patients with unstable spine fractures or continuous deterioration of neurological function require emergency surgery.The COVID-19 epidemic has brought tremendous challenges to the diagnosis and treatment of such patients.To coordinate the diagnosis and treatment of infectious disease prevention and spine trauma so as to formulate a rigorous diagnosis and treatment plan and to reduce the disability and mortality of the disease,multidisciplinary collaboration is needed.This expert consensus is formulated in order to(1)prevent and control the epidemic,(2)diagnose and treat patients with spine trauma reasonably,and(3)reduce the risk of cross-infection between patients and medical personnel during the treatment.展开更多
基金financially supported by the National Key Research and Development Program of China,No.2016YFC1100100(to XDG)
文摘Current management for spinal cord injury aims to reduce secondary damage and recover sensation and movement.Acute spinal cord injury is often accompanied by spinal cord compartment syndrome.Decompression by durotomy and/or myelotomy attempts to relieve secondary damage by completelyrelieving the compression of the spinal cord,removing the necrotic tissue,decreasing edema,reducing hemorrhage,and improving blood circulation in the spinal cord.However,it is controversial whether durotomy and/or myelotomy after spinal cord injury are beneficial to neurological recovery.This review compares the clinical effects of durotomy with those of myelotomy in the treatment of spinal cord injury.We found that durotomy has been performed more than myelotomy in the clinic,and that durotomy may be safer and more effective than myelotomy.Durotomy performed in humans had positive effects on neurological function in 92.3% of studies in this review,while durotomy in animals had positive effects on neurological function in 83.3% of studies.Myelotomy procedures were effective in 80% of animal studies,but only one clinical study of myelotomy has reported positive results,of motor and sensory improvement,in humans.However,a number of new animal studies have reported that durotomy and myelotomy are ineffective for spinal cord injury.More clinical data,in the form of a randomized controlled study,are needed to understand the effectiveness of durotomy and myelotomy.
基金financially supported by the National Natural Sciences Foundation of China(No.51504153,No.51571145)the General Project of Scientific Research of the Education Department of Liaoning Province(No.L2015397)
文摘Hot tearing is known as one of the most serious solidification defects commonly encountered during solidification. It is very important to study the solidification path of alloys. In the work, thermal analysis with cooling curve was used for the investigation of microstructure evolution with different Zn contents during solidification process of MgZn_xY_4Zr_(0.5) alloys. Thermal analysis results of MgY_4Zr_(0.5) alloys revealed one distinct phase precipitation: α-Mg. Three different phase peaks were detected in the Zn-containing alloys: α-Mg, Z-phase(Mg_(12)YZn) and W-phase(Mg_3 Y_2Zn_3). In addition, for the present MgZn_xY_4Zr_(0.5) alloys, the freezing ranges of these alloys from large to small were: MgZn_(1.5)Y_4Zr_(0.5)>MgZn)(3.0) Y)4Zr_(0.5)>MgZn0.5 Y4 Zr0.5>MgY_4Zr_(0.5). The effect of different contents of Zn(0, 0.5, 1.5, 3.0 wt.%) on hot tearing behavior of MgY_4Zr_(0.5) alloy was investigated using a constrained rod casting(CRC) apparatus equipped with a load cell and data acquisition system. The experimental results show that the addition of Zn element significantly increases hot tearing susceptibility(HTS) of the MgY_4Zr_(0.5) alloy due to its extended freezing range. Some free dendrite-like bumps and ruptured liquid films on the fracture surfaces were observed in all the fracture surfaces. These phenomena proved the fact that the hot tearing formation was caused by interdendritic separation due to lack of feeding at the end of solidification.
基金supported by the Anhui Provincial Natural Science Foundation of China(No.1508085SME219).
文摘Constructing new photocatalysts for the photocatalytic reduction of CO_(2)and efficient degradation of Lev-ofloxacin is of great importance to renewable energy.Here,S-scheme Bi_(2)MoO_(6-x)/MoS_(2)heterojunction nanospheres containing abundant surface defects(oxygen vacancies)were designed and successfully syn-thesized to enhance CO_(2)photoreduction activity in the absence of other sacrificial agents,co-catalysts or photosensitisers.At the same time,it can efficiently degrade organic pollutants(Levofloxacin).This heterogeneous structure with surface defects provides an abundance of reactive sites,accelerates charge separation and improves oxidation capacity.The improved Bi_(2)MoO_(6-x)/MoS_(2)heterogeneous nanospheres show excellent performance under simulated solar light,with the selectivity and yield of 92.45%and 29.01μmol h−1,respectively,for the generation of CO.Under visible light,the degradation efficiency of levofloxacin hydrochloride(LVX)reached 96.3%within 25 min and remained as high as 95%after three cycles.This work provides a new idea for the design of new S-scheme photocatalysts and an important reference for the preparation of photocatalysts for the efficient photocatalytic reduction of CO_(2)and the efficient degradation of organic pollutants at the same time.
基金funded by Social Science Foundation Program of Hebei,China(Grant No.HB22YJ040).
文摘The imbalance of rural parking supply and demand has a great impact on traffic congestion and environmental pollution,which has attracted the attention of many scholars as well as policymakers.However,most of the current research on parking choice focuses on urban business and residential areas rather than on rural parking choice behaviour,and focuses on the analysis of observable factors,ignoring the internal relationship with potential variables.This study considers the heterogeneity of individuals and uses the random forest(RF)algorithm to construct a model of rural residents’willingness to choose parking with both latent and explicit variables,to explore how much and in what ways individual characteristics and parking characteristics affect rural residents’parking choices,and to explore parking planning programmes and strategies that are truly applicable to rural areas.The results of the study suggest that the safety and convenience of the parking environment are key factors influencing the parking choice behaviour of rural residents,and can greatly improve the predictive accuracy of the parking willingness model.Upon comparison,it is found that the application of the RF algorithm is also significantly better than the logit model in terms of prediction effect,indicating that there is a nonlinear effect among the factors influencing the parking choice behaviour of rural residents and that the RF model with the addition of latent variables provides a better explanatory ability for the study of the parking choice behaviour of rural residents.
基金This study was also supported in part by grants from the National Natural Science Foundation of China(No.81871865,81874036,81972167,82102859,31930022,31771476,and 12026608)National Science and Technology Major Project(No.2017YFA0505500)+5 种基金the Strategic Priority Project of Chinese Academy of Sciences(No.XDB38040400,XDB38020000)the Backbone Program of Shanghai Pulmonary Hospital(No.FKGG1802)Shanghai Pujiang Talent Plan(No.2019PJD048)Shanghai Science and Technology Committee Foundation(NO.19411950300)Shanghai Key disciplines of Respiratory(No.2017ZZ02012)the Shanghai Sailing Program(No.20YF1407500).
文摘This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled.Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles,followed by the maintenance of toripalimab and pemetrexed.The primary endpoint was objective-response rate(ORR).Integrated biomarker analysis of PD-L1 expression,tumor mutational burden(TMB),CD8+tumor-infiltrating lymphocyte(TIL)density,whole-exome,and transcriptome sequencing on tumor biopsies were also conducted.Forty patients were enrolled with an overall ORR of 50.0%and disease-control rate(DCR)of 87.5%.The median progression free survival(PFS)and overall survival were 7.0 and 23.5 months,respectively.The most common treatment-related adverse effects were leukopenia,neutropenia,anemia,ALT/AST elevation,and nausea.Biomarker analysis showed that none of PD-L1 expression,TMB level,and CD8+TIL density could serve as a predictive biomarker.Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type.Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC.DSPP mutation might serve as a potential biomarker for this combination.A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing(NCT03924050).
基金sponsored by Shanghai Junshi Biosciences Co.,Ltd.and supported,in part,by National Key R&D Program of China(2018YFC1313300)Science and Technology Program of Guangdong(2019B020227002)+5 种基金CAMS Innovation Fund for Medical Sciences(2019-I2M-5-036)National Natural Science Foundation of China(81930065)Natural Science Foundation of Guangdong Province(2014A030312015)Science and Technology Program of Guangdong(2019B020227002)Science and Technology Program of Guangzhou(201904020046,201803040019,201704020228)Guangdong Basic and Applied Basic Research Foundation(2019A1515110171).
文摘Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.
基金supported by Health and Medical Research Fund(HHSRF Project No.08090481,Hong Kong SAR,China)from Food and Health Bureau,HKSAROne-off Funding for Joint Lab/Research collaboration(Project code:3132968,Hong Kong SAR,China)from the Chinese University of Hong KongSeed Fund for Joint Establishments from School of Biomedical Science,the Chinese University of Hong Kong(China)
文摘Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer chemotherapy.However,currently,no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically,mainly due to the inhibitor specificity,toxicity,and drug interactions.Here,we reported that three polyoxypregnanes(POPs)as the most abundant constituents of Marsdenia tenacissima(M.tenacissima)were novel ABCB1-modulatory pro-drugs,which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites.The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression,which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity.These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay,and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo.We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance.The results suggested that these POPs had the potential to be developed as safe,potent,and specific pro-drugs to reverse ABCB1-mediated MDR.Our work also provided scientific evidence for the use of M.tenacissima in combinational chemotherapy.
基金National Natural Science Foundation of China(81873999,81672158)National Key R&D Program of China(2016YFC1100100).These funding agencies had no role in study design,collection/analyses of data,decision to publish,or manuscript preparation.
文摘Outbreak of COVID-19 is ongoing all over the world.Spine trauma is one of the most common types of trauma and will probably be encountered during the fight against COVID-19 and resumption of work and production.Patients with unstable spine fractures or continuous deterioration of neurological function require emergency surgery.The COVID-19 epidemic has brought tremendous challenges to the diagnosis and treatment of such patients.To coordinate the diagnosis and treatment of infectious disease prevention and spine trauma so as to formulate a rigorous diagnosis and treatment plan and to reduce the disability and mortality of the disease,multidisciplinary collaboration is needed.This expert consensus is formulated in order to(1)prevent and control the epidemic,(2)diagnose and treat patients with spine trauma reasonably,and(3)reduce the risk of cross-infection between patients and medical personnel during the treatment.
