Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted pathogenesis.Although NAFLD initially pre...Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted pathogenesis.Although NAFLD initially presents as benign fat accumulation,it may progress to steatosis,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.Mesenchymal stem cells(MSCs)are recognized for their intrinsic self-renewal,superior biocompatibility,and minimal immunogenicity,positioning them as a therapeutic innovation for liver diseases.Therefore,this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways,including glycolipid metabolism,inflammation,oxidative stress,endoplasmic reticulum stress,and fibrosis.The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics,and support the development of MSC-based therapy in the treatment of NAFLD.展开更多
Near-infrared(NIR)transparent inverted all-inorganic perovskite solar cells(PSCs)are excellent top cell candidates in tandem applications.An essential challenge is the replacement of metal contacts with transparent co...Near-infrared(NIR)transparent inverted all-inorganic perovskite solar cells(PSCs)are excellent top cell candidates in tandem applications.An essential challenge is the replacement of metal contacts with transparent conductive oxide(TCO)electrodes,which requires the introduction of a buffer layer to prevent sputtering damage.In this study,we show that the conventional buffers(i.e.,small organic molecules and atomic layer deposited metal oxides)used for organic-inorganic hybrid perovskites are not applicable to all-inorganic perovskites,due to non-uniform coverage of the vulnerable layers underneath,deterioration upon ion bombardment and moisture induced perovskite phase transition,A thin film of metal oxide nanoparticles by the spin-coating method serves as a non-destructive buffer layer for inorganic PSCs.All-inorganic inverted near-infrared-transparent PSCs deliver a PCE of 17.46%and an average transmittance of 73.7%between 780 and 1200 nm.In combination with an 18.56%Cu(In,Ga)Se_(2) bottom cell,we further demonstrate the first all-inorganic perovskite/CIGS 4-T tandem solar cell with a PCE of 24.75%,which exhibits excellent illumination stability by maintaining 86.7%of its initial efficiency after 1400 h.The non-destructive buffer lays the foundation for efficient and stable NIR-transparent inverted inorganic perovskite solar cells and perovskite-based tandems.展开更多
Photocatalysis offers a sustainable means for the oxidative removal of low concentrations of NOx(NO,NO2,N2O,N2O5,etc.)from the atmosphere.Layered double hydroxides(LDHs)are promising candidate photocatalysts owing to ...Photocatalysis offers a sustainable means for the oxidative removal of low concentrations of NOx(NO,NO2,N2O,N2O5,etc.)from the atmosphere.Layered double hydroxides(LDHs)are promising candidate photocatalysts owing to their unique layered and tunable chemical structures and abundant surface hydroxide(OH)moieties,which are hydroxyl radical(OH)precursors.However,the practical applications of LDHs are limited by their poor charge-separation ability and insufficient active sites.Herein,we developed a facile N_(2)H_(4)-driven etching approach to introduce dual Ni^(2+)and OHvacancies(Niv and OHv,respectively)into NiFe-LDH nanosheets(hereafter referred to as NiFe-LDH-et)to facilitate improved charge-carrier separation and active Lewis acidic site(Fe^(3+)and Ni^(2+)exposed at OHv)formation.In contrast to inert pristine LDH,NiFe-LDH-et actively removed NO under visible-light illumination.Specifically,Ni_(76)Fe_(24)-LDH-et etched with 1.50 mmol·L^(-1)N_(2)H_(4)solution removed 32.8%of the NO in continuously flowing air(NO feed concentration:500 parts per billion(ppb))under visible-light illumination,thereby outperforming most reported catalysts.Experimental and theoretical data revealed that the dual vacancies promoted the production of reactive oxygen species(O_(2)·^(-)andOH)and the adsorption of NO on the LDH.In situ spectroscopy demonstrated that NO was preferentially adsorbed at Lewis acidic sites,particularly exposed Fe^(3+)sites,converted into NO+,and subsequently oxidized to NO3without the notable formation of the more toxic intermediate NO2,thereby alleviating risks associated with its production and emission.展开更多
AIM:To develop a deep learning-based model for automatic retinal vascular segmentation,analyzing and comparing parameters under diverse glucose metabolic status(normal,prediabetes,diabetes)and to assess the potential ...AIM:To develop a deep learning-based model for automatic retinal vascular segmentation,analyzing and comparing parameters under diverse glucose metabolic status(normal,prediabetes,diabetes)and to assess the potential of artificial intelligence(AI)in image segmentation and retinal vascular parameters for predicting prediabetes and diabetes.METHODS:Retinal fundus photos from 200 normal individuals,200 prediabetic patients,and 200 diabetic patients(600 eyes in total)were used.The U-Net network served as the foundational architecture for retinal arteryvein segmentation.An automatic segmentation and evaluation system for retinal vascular parameters was trained,encompassing 26 parameters.RESULTS:Significant differences were found in retinal vascular parameters across normal,prediabetes,and diabetes groups,including artery diameter(P=0.008),fractal dimension(P=0.000),vein curvature(P=0.003),C-zone artery branching vessel count(P=0.049),C-zone vein branching vessel count(P=0.041),artery branching angle(P=0.005),vein branching angle(P=0.001),artery angle asymmetry degree(P=0.003),vessel length density(P=0.000),and vessel area density(P=0.000),totaling 10 parameters.CONCLUSION:The deep learning-based model facilitates retinal vascular parameter identification and quantification,revealing significant differences.These parameters exhibit potential as biomarkers for prediabetes and diabetes.展开更多
In this paper,we construct a high-order discontinuous Galerkin(DG)method which can preserve the positivity of the density and the pressure for the viscous and resistive magnetohydrodynamics(VRMHD).To control the diver...In this paper,we construct a high-order discontinuous Galerkin(DG)method which can preserve the positivity of the density and the pressure for the viscous and resistive magnetohydrodynamics(VRMHD).To control the divergence error in the magnetic field,both the local divergence-free basis and the Godunov source term would be employed for the multi-dimensional VRMHD.Rigorous theoretical analyses are presented for one-dimensional and multi-dimensional DG schemes,respectively,showing that the scheme can maintain the positivity-preserving(PP)property under some CFL conditions when combined with the strong-stability-preserving time discretization.Then,general frameworks are established to construct the PP limiter for arbitrary order of accuracy DG schemes.Numerical tests demonstrate the effectiveness of the proposed schemes.展开更多
BACKGROUND Peroral endoscopic myotomy(POEM)has been widely performed as a standard treatment for achalasia;however,its efficacy and safety for treating distal esophageal segmental spasms induced by cancer metastasis r...BACKGROUND Peroral endoscopic myotomy(POEM)has been widely performed as a standard treatment for achalasia;however,its efficacy and safety for treating distal esophageal segmental spasms induced by cancer metastasis remain unknown.CASE SUMMARY A 72-year-old male was referred to our hospital and complained of progressive dysphagia for two years.Endoscopy revealed a 2 cm long segment esophageal stenosis with intact mucosa and normal cardia.Computed tomography showed a right upper lung mass,and pathology of the right pleural effusion confirmed the diagnosis of right upper lung adenocarcinoma with multiple rib and mediastinal lymph node metastases and right malignant pleural effusion.Individualized POEM was performed first to alleviate dysphagia,and the final diagnosis was changed to esophageal muscle metastasis arising from lung adenocarcinoma.After treatment,the patient could eat soft solid food and received multiple rounds of pembrolizumab-combination chemotherapy.The patient’s progression-free survival was approximately 16 months.Long stable disease was obtained during the 24-month follow-up.CONCLUSION The incidence of distal esophageal segmental spasms induced by muscular metastasis arising from lung adenocarcinoma is extremely low.Individualized POEM can effectively improve a patient’s nutritional status before subsequent chemotherapy can be combined with immune checkpoint inhibitors.展开更多
BACKGROUND The functional lumen imaging probe(FLIP)is a Food and Drug Administration approved tool to aid the diagnosis and management of esophageal disorders.However,widespread adoption of FLIP remains limited and it...BACKGROUND The functional lumen imaging probe(FLIP)is a Food and Drug Administration approved tool to aid the diagnosis and management of esophageal disorders.However,widespread adoption of FLIP remains limited and its utility in highvolume practices remains unclear.AIM To analyze large sample data on clinical use of FLIP and provide insight on several technical aspects when performing FLIP.METHODS We conducted a retrospective comparative and descriptive analysis of FLIP procedures performed by a single provider at an academic medical center.There was a total of 398 FLIP procedures identified.Patient medical records were reviewed and data regarding demographics and procedural details were collected.Statistical tests,including chi-squared,t-test,and multivariable logistic and linear regression,were performed.RESULTS There was an increase in FLIP cases with each successive time period of 13 months(n=68,146,184,respectively)with notable rises specifically for indications of dysphagia and gastroesophageal reflux disease.There was a shift toward use of the longer FLIP balloon catheter for diagnostic purposes(overall 70.4%vs 29.6%,P<0.01).Many cases(42.8%)were performed in conjunction with other diagnostics/interventions,such as dilation and wireless pH probe placement.Procedures were nearly equally performed with anesthesia vs moderate sedation(51.4%anesthesia),with no major complications.Patients who had anesthesia were less likely to have recurrent antegrade contractions[odds ratio(OR)=0.4,95%CI:0.3-0.8]and were also more likely to have absent contractility(OR=2.4,95%CI:1.3-CONCLUSION FLIP cases have increased in our practice with expanding indications for its use.Given limited normative data,providers should be aware of several potential technical issues,including the possible impact of sedation choice when assessing esophageal motility patterns.展开更多
Since the age of digital intelligence,the government has introduced policies to actively promote the intelligent transformation of grassroots public cultural services.Based on the investigation and analysis of the dev...Since the age of digital intelligence,the government has introduced policies to actively promote the intelligent transformation of grassroots public cultural services.Based on the investigation and analysis of the development status quo of grassroots libraries in Henan Province,we put forward the path of high-quality development of grassroots libraries in Henan,namely,improving the mechanism and system,leading with digital intelligence technology,empowering by Yellow River culture(the heritage and values rooted in the history and traditions of the Yellow River region),and driven by users’demand.展开更多
BACKGROUND Perihilar cholangiocarcinoma(pCCA)has a poor prognosis and urgently needs a better predictive method.The predictive value of the age-adjusted Charlson comorbidity index(ACCI)for the long-term prognosis of p...BACKGROUND Perihilar cholangiocarcinoma(pCCA)has a poor prognosis and urgently needs a better predictive method.The predictive value of the age-adjusted Charlson comorbidity index(ACCI)for the long-term prognosis of patients with multiple malignancies was recently reported.However,pCCA is one of the most surgically difficult gastrointestinal tumors with the poorest prognosis,and the value of the ACCI for the prognosis of pCCA patients after curative resection is unclear.AIM To evaluate the prognostic value of the ACCI and to design an online clinical model for pCCA patients.METHODS Consecutive pCCA patients after curative resection between 2010 and 2019 were enrolled from a multicenter database.The patients were randomly assigned 3:1 to training and validation cohorts.In the training and validation cohorts,all patients were divided into low-,moderate-,and high-ACCI groups.Kaplan-Meier curves were used to determine the impact of the ACCI on overall survival(OS)for pCCA patients,and multivariate Cox regression analysis was used to determine the independent risk factors affecting OS.An online clinical model based on the ACCI was developed and validated.The concordance index(C-index),calibration curve,and receiver operating characteristic(ROC)curve were used to evaluate the predictive performance and fit of this model.RESULTS A total of 325 patients were included.There were 244 patients in the training cohort and 81 patients in the validation cohort.In the training cohort,116,91 and 37 patients were classified into the low-,moderate-and high-ACCI groups.The Kaplan-Meier curves showed that patients in the moderate-and high-ACCI groups had worse survival rates than those in the low-ACCI group.Multivariable analysis revealed that moderate and high ACCI scores were independently associated with OS in pCCA patients after curative resection.In addition,an online clinical model was developed that had ideal C-indexes of 0.725 and 0.675 for predicting OS in the training and validation cohorts.The calibration curve and ROC curve indicated that the model had a good fit and prediction performance.CONCLUSION A high ACCI score may predict poor long-term survival in pCCA patients after curative resection.High-risk patients screened by the ACCI-based model should be given more clinical attention in terms of the management of comorbidities and postoperative follow-up.展开更多
文摘Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted pathogenesis.Although NAFLD initially presents as benign fat accumulation,it may progress to steatosis,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.Mesenchymal stem cells(MSCs)are recognized for their intrinsic self-renewal,superior biocompatibility,and minimal immunogenicity,positioning them as a therapeutic innovation for liver diseases.Therefore,this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways,including glycolipid metabolism,inflammation,oxidative stress,endoplasmic reticulum stress,and fibrosis.The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics,and support the development of MSC-based therapy in the treatment of NAFLD.
基金financially supported by the National Natural Science Foundation of China (22279083,22109166,52202183)Guangdong Basic and Applied Basic Research Foundation (Grant No.2019A1515011136,2022B1515120006,2023B1515120041,2414050001473)+3 种基金Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded SchemeGuangdong Provincial Key Laboratory Program (2021B1212040001)from the Department of Science and Technology of Guangdong ProvinceBeijing Institute of TechnologySongshan Lake Materials Laboratory。
文摘Near-infrared(NIR)transparent inverted all-inorganic perovskite solar cells(PSCs)are excellent top cell candidates in tandem applications.An essential challenge is the replacement of metal contacts with transparent conductive oxide(TCO)electrodes,which requires the introduction of a buffer layer to prevent sputtering damage.In this study,we show that the conventional buffers(i.e.,small organic molecules and atomic layer deposited metal oxides)used for organic-inorganic hybrid perovskites are not applicable to all-inorganic perovskites,due to non-uniform coverage of the vulnerable layers underneath,deterioration upon ion bombardment and moisture induced perovskite phase transition,A thin film of metal oxide nanoparticles by the spin-coating method serves as a non-destructive buffer layer for inorganic PSCs.All-inorganic inverted near-infrared-transparent PSCs deliver a PCE of 17.46%and an average transmittance of 73.7%between 780 and 1200 nm.In combination with an 18.56%Cu(In,Ga)Se_(2) bottom cell,we further demonstrate the first all-inorganic perovskite/CIGS 4-T tandem solar cell with a PCE of 24.75%,which exhibits excellent illumination stability by maintaining 86.7%of its initial efficiency after 1400 h.The non-destructive buffer lays the foundation for efficient and stable NIR-transparent inverted inorganic perovskite solar cells and perovskite-based tandems.
基金the supports from Debris of the Anthropocene to Resources(DotA2)Lab at NTU.
文摘Photocatalysis offers a sustainable means for the oxidative removal of low concentrations of NOx(NO,NO2,N2O,N2O5,etc.)from the atmosphere.Layered double hydroxides(LDHs)are promising candidate photocatalysts owing to their unique layered and tunable chemical structures and abundant surface hydroxide(OH)moieties,which are hydroxyl radical(OH)precursors.However,the practical applications of LDHs are limited by their poor charge-separation ability and insufficient active sites.Herein,we developed a facile N_(2)H_(4)-driven etching approach to introduce dual Ni^(2+)and OHvacancies(Niv and OHv,respectively)into NiFe-LDH nanosheets(hereafter referred to as NiFe-LDH-et)to facilitate improved charge-carrier separation and active Lewis acidic site(Fe^(3+)and Ni^(2+)exposed at OHv)formation.In contrast to inert pristine LDH,NiFe-LDH-et actively removed NO under visible-light illumination.Specifically,Ni_(76)Fe_(24)-LDH-et etched with 1.50 mmol·L^(-1)N_(2)H_(4)solution removed 32.8%of the NO in continuously flowing air(NO feed concentration:500 parts per billion(ppb))under visible-light illumination,thereby outperforming most reported catalysts.Experimental and theoretical data revealed that the dual vacancies promoted the production of reactive oxygen species(O_(2)·^(-)andOH)and the adsorption of NO on the LDH.In situ spectroscopy demonstrated that NO was preferentially adsorbed at Lewis acidic sites,particularly exposed Fe^(3+)sites,converted into NO+,and subsequently oxidized to NO3without the notable formation of the more toxic intermediate NO2,thereby alleviating risks associated with its production and emission.
基金Supported by Shenzhen Science and Technology Program(No.JCYJ20220530153604010).
文摘AIM:To develop a deep learning-based model for automatic retinal vascular segmentation,analyzing and comparing parameters under diverse glucose metabolic status(normal,prediabetes,diabetes)and to assess the potential of artificial intelligence(AI)in image segmentation and retinal vascular parameters for predicting prediabetes and diabetes.METHODS:Retinal fundus photos from 200 normal individuals,200 prediabetic patients,and 200 diabetic patients(600 eyes in total)were used.The U-Net network served as the foundational architecture for retinal arteryvein segmentation.An automatic segmentation and evaluation system for retinal vascular parameters was trained,encompassing 26 parameters.RESULTS:Significant differences were found in retinal vascular parameters across normal,prediabetes,and diabetes groups,including artery diameter(P=0.008),fractal dimension(P=0.000),vein curvature(P=0.003),C-zone artery branching vessel count(P=0.049),C-zone vein branching vessel count(P=0.041),artery branching angle(P=0.005),vein branching angle(P=0.001),artery angle asymmetry degree(P=0.003),vessel length density(P=0.000),and vessel area density(P=0.000),totaling 10 parameters.CONCLUSION:The deep learning-based model facilitates retinal vascular parameter identification and quantification,revealing significant differences.These parameters exhibit potential as biomarkers for prediabetes and diabetes.
基金supported by the NSFC Grant 11901555,12271499the Cyrus Tang Foundationsupported by the NSFC Grant 11871448 and 12126604.
文摘In this paper,we construct a high-order discontinuous Galerkin(DG)method which can preserve the positivity of the density and the pressure for the viscous and resistive magnetohydrodynamics(VRMHD).To control the divergence error in the magnetic field,both the local divergence-free basis and the Godunov source term would be employed for the multi-dimensional VRMHD.Rigorous theoretical analyses are presented for one-dimensional and multi-dimensional DG schemes,respectively,showing that the scheme can maintain the positivity-preserving(PP)property under some CFL conditions when combined with the strong-stability-preserving time discretization.Then,general frameworks are established to construct the PP limiter for arbitrary order of accuracy DG schemes.Numerical tests demonstrate the effectiveness of the proposed schemes.
基金Supported by The Young and Middle-aged Mainstay Talent Training Program of Fujian Provincial Health System,China,No.2017-ZQN-16The Science and Technology Project of Fujian Province,China,No.2020Y0068The Joint Funds for the Innovation of Science and Technology of Fujian Province,China,No.2023Y9414.
文摘BACKGROUND Peroral endoscopic myotomy(POEM)has been widely performed as a standard treatment for achalasia;however,its efficacy and safety for treating distal esophageal segmental spasms induced by cancer metastasis remain unknown.CASE SUMMARY A 72-year-old male was referred to our hospital and complained of progressive dysphagia for two years.Endoscopy revealed a 2 cm long segment esophageal stenosis with intact mucosa and normal cardia.Computed tomography showed a right upper lung mass,and pathology of the right pleural effusion confirmed the diagnosis of right upper lung adenocarcinoma with multiple rib and mediastinal lymph node metastases and right malignant pleural effusion.Individualized POEM was performed first to alleviate dysphagia,and the final diagnosis was changed to esophageal muscle metastasis arising from lung adenocarcinoma.After treatment,the patient could eat soft solid food and received multiple rounds of pembrolizumab-combination chemotherapy.The patient’s progression-free survival was approximately 16 months.Long stable disease was obtained during the 24-month follow-up.CONCLUSION The incidence of distal esophageal segmental spasms induced by muscular metastasis arising from lung adenocarcinoma is extremely low.Individualized POEM can effectively improve a patient’s nutritional status before subsequent chemotherapy can be combined with immune checkpoint inhibitors.
基金The study was approved by the Stanford University IRB:53329.
文摘BACKGROUND The functional lumen imaging probe(FLIP)is a Food and Drug Administration approved tool to aid the diagnosis and management of esophageal disorders.However,widespread adoption of FLIP remains limited and its utility in highvolume practices remains unclear.AIM To analyze large sample data on clinical use of FLIP and provide insight on several technical aspects when performing FLIP.METHODS We conducted a retrospective comparative and descriptive analysis of FLIP procedures performed by a single provider at an academic medical center.There was a total of 398 FLIP procedures identified.Patient medical records were reviewed and data regarding demographics and procedural details were collected.Statistical tests,including chi-squared,t-test,and multivariable logistic and linear regression,were performed.RESULTS There was an increase in FLIP cases with each successive time period of 13 months(n=68,146,184,respectively)with notable rises specifically for indications of dysphagia and gastroesophageal reflux disease.There was a shift toward use of the longer FLIP balloon catheter for diagnostic purposes(overall 70.4%vs 29.6%,P<0.01).Many cases(42.8%)were performed in conjunction with other diagnostics/interventions,such as dilation and wireless pH probe placement.Procedures were nearly equally performed with anesthesia vs moderate sedation(51.4%anesthesia),with no major complications.Patients who had anesthesia were less likely to have recurrent antegrade contractions[odds ratio(OR)=0.4,95%CI:0.3-0.8]and were also more likely to have absent contractility(OR=2.4,95%CI:1.3-CONCLUSION FLIP cases have increased in our practice with expanding indications for its use.Given limited normative data,providers should be aware of several potential technical issues,including the possible impact of sedation choice when assessing esophageal motility patterns.
文摘Since the age of digital intelligence,the government has introduced policies to actively promote the intelligent transformation of grassroots public cultural services.Based on the investigation and analysis of the development status quo of grassroots libraries in Henan Province,we put forward the path of high-quality development of grassroots libraries in Henan,namely,improving the mechanism and system,leading with digital intelligence technology,empowering by Yellow River culture(the heritage and values rooted in the history and traditions of the Yellow River region),and driven by users’demand.
基金Supported by National Natural Science Foundation of China,No. 81874211Chongqing Technology Innovation and Application Development Special Key Project,No. CSTC2021jscx-gksb-N0009
文摘BACKGROUND Perihilar cholangiocarcinoma(pCCA)has a poor prognosis and urgently needs a better predictive method.The predictive value of the age-adjusted Charlson comorbidity index(ACCI)for the long-term prognosis of patients with multiple malignancies was recently reported.However,pCCA is one of the most surgically difficult gastrointestinal tumors with the poorest prognosis,and the value of the ACCI for the prognosis of pCCA patients after curative resection is unclear.AIM To evaluate the prognostic value of the ACCI and to design an online clinical model for pCCA patients.METHODS Consecutive pCCA patients after curative resection between 2010 and 2019 were enrolled from a multicenter database.The patients were randomly assigned 3:1 to training and validation cohorts.In the training and validation cohorts,all patients were divided into low-,moderate-,and high-ACCI groups.Kaplan-Meier curves were used to determine the impact of the ACCI on overall survival(OS)for pCCA patients,and multivariate Cox regression analysis was used to determine the independent risk factors affecting OS.An online clinical model based on the ACCI was developed and validated.The concordance index(C-index),calibration curve,and receiver operating characteristic(ROC)curve were used to evaluate the predictive performance and fit of this model.RESULTS A total of 325 patients were included.There were 244 patients in the training cohort and 81 patients in the validation cohort.In the training cohort,116,91 and 37 patients were classified into the low-,moderate-and high-ACCI groups.The Kaplan-Meier curves showed that patients in the moderate-and high-ACCI groups had worse survival rates than those in the low-ACCI group.Multivariable analysis revealed that moderate and high ACCI scores were independently associated with OS in pCCA patients after curative resection.In addition,an online clinical model was developed that had ideal C-indexes of 0.725 and 0.675 for predicting OS in the training and validation cohorts.The calibration curve and ROC curve indicated that the model had a good fit and prediction performance.CONCLUSION A high ACCI score may predict poor long-term survival in pCCA patients after curative resection.High-risk patients screened by the ACCI-based model should be given more clinical attention in terms of the management of comorbidities and postoperative follow-up.
