The building sector is the largest consumer of energy in industrial countries. Saving energy in new buildings or building renovations can thus lead to significant global environmental impacts. In this endeavor, buildi...The building sector is the largest consumer of energy in industrial countries. Saving energy in new buildings or building renovations can thus lead to significant global environmental impacts. In this endeavor, building information <span>modeling (BIM) and building energy modeling (BEM) are two important to</span>ols to make the transition to net-zero energy buildings (NZEB). So far, little attention has been devoted, in the literature, to discuss the connection between BIM, BEM, and Life-cycle assessment (LCA), which is the main topic of this article. A literature review of 157 journal articles and conference proceedings published between 1990 and 2020 is presented. This review outlines knowledge gaps concerning BIM, BEM, and environmental impact assessment. It suggests that defining the process with the right technology (at the right time) would result in a more integrated design process (IDP) and bridge current gaps. The most efficient way to improve process and technology is related to the competences of the architects, engineers and constructors (AEC). The review also indicates that the IDP in the early design phases (EDP) is in need of improvement for architects and engineers, where a better connection between design phases, specific levels of development (LOD) and BIM tools is needed. <span>Competences, process and technology are the three main themes addressed in the review. Their relation to design phases and LOD is discussed. The aim </span>is to propose possible solutions to the current hinders in BIM-to-BEM (BIM2BEM) and BIM-for-LCA (BIM4LCA) integration.展开更多
Centuries of forest exploitation have caused significant loss of natural forests in Europe,leading to a decline in populations for many species.To prevent further loss in biodiversity,the Norwegian government has set ...Centuries of forest exploitation have caused significant loss of natural forests in Europe,leading to a decline in populations for many species.To prevent further loss in biodiversity,the Norwegian government has set a target of protecting 10%of the forested area.However,recent data from the National Forest Inventory(NFI)reveals that less than 2%of Norway's forested area consists of natural forests.To identify forests with high conservation value,we used vertical and horizontal variables derived from airborne laser scanning(ALS)data,along with NFI plot measurements.Our study aimed to predict the presence of natural forests across three counties in southeastern Norway,using three different definitions:pristine,near-natural,and semi-natural forests.Natural forests are scarce,and their underrepresentation in field reference data can compromise the accuracy of the predictions.To address this,we assessed the potential gain of including additional field data specifically targeting natural forests to achieve a better balance in the dataset.Additionally,we examined the impact of stratifying the data by dominant tree species on the performance of the models.Our results revealed that semi-natural forests were the most accurately predicted,followed by near-natural and pristine forests,with Matthews correlation coefficient values of 0.32,0.24,and 0.17,respectively.Including additional field data did not improve the predictions.However,stratification by species improved the accuracy of predictions for near-natural and semi-natural forests,while reducing accuracy for pristine forests.The use of horizontal variables did not improve the predictions.Our study demonstrates the potential of ALS data in identifying forests with high conservation value.It provides a basis for further research on the use of ALS data for the detection and conservation of natural forests,offering valuable insights to guide future forest preservation efforts.展开更多
BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric...BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)conditions.Roles of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains unclarified.AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.METHODS CCA cells,KKU-055 and KKU-213A,were cultured in Dulbecco Modified Eagle’s Medium supplemented with 5.6 mmol/L(normal glucose,NG)or 25 mmol/L(HG)glucose and assigned as NG and HG cells,respectively.GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot.Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence.GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry,and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis.Effects of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays.Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment,and the candidate signaling molecules were validated using the public transcriptomic data and western blot.RESULTS GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent manner.CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia(P<0.01).High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors(P<0.05).HG cells of both tested CCA cell lines wer展开更多
AIM To investigate the clinical outcomes of transcatheter aortic valve implantation(TAVI) with the SAPIEN 3 transcatheter heart valve(S3-THV) vs the SAPIEN XT valve(XT-THV).METHODS We retrospectively analyzed 507 pati...AIM To investigate the clinical outcomes of transcatheter aortic valve implantation(TAVI) with the SAPIEN 3 transcatheter heart valve(S3-THV) vs the SAPIEN XT valve(XT-THV).METHODS We retrospectively analyzed 507 patients that underwent TAVI with the XT-THV and 283 patients that received the S3-THV at our institution between March 2010 and December 2015.RESULTS Thirty-day mortality(3.5% vs 8.7%:OR=0.44,P=0.21) and 1-year mortality(25.7% vs 20.1%,P=0.55) were similar in the S3-THV and the XT-THV groups.The rates of both major vascular complication and paravalvular regurgitation(PVR)>1 were almost 4 times lower in the S3-THV group than the XT-THV group(major vascular complication: 2.8% vs 9.9%,P<0.0001:PVR>1: 2.4% vs 9.7%,P<0.0001).However,the rate of new pacemaker implantation was almost twice as high in the S3-THV group(17.3% vs 9.8%,P=0.03).In the S3 group,independent predictors of new permanent pacemaker were pre-procedural RBBB(OR=4.9:P=0.001),pre-procedural PR duration(OR=1.14,P=0.05) and device lack of coaxiality(OR=1.13:P=0.05) during deployment.CONCLUSION The S3-THV is associated to lower rates of major vascular complications and PVR but higher rates of new pacemaker compared to the XT-THV.Sub-optimal visualization of the S3-THV in relation to the aortic valvular complex during deployment is a predictor of new permanent pacemaker.展开更多
The hypoxia inducible factors （Hifs） are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary f...The hypoxia inducible factors （Hifs） are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1a in osteoanabolic signaling, we assessed the effect of Hif-1a loss-of-function on bone formation in response to intermittent parathyroid hormone （PTH）. Mice lacking Hif-1a in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1a protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1a-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1a functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1a function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.展开更多
AIM:To assess the effect of nitric oxide (NO) on the large conductance potassium channel (BKCa) in isolated circular (CM) and sling (SM) muscle cells and muscle strips from the cat lower esophageal sphincter (LES) to ...AIM:To assess the effect of nitric oxide (NO) on the large conductance potassium channel (BKCa) in isolated circular (CM) and sling (SM) muscle cells and muscle strips from the cat lower esophageal sphincter (LES) to determine its regulation of resting tone and relaxation.METHODS:Freshly enzymatically-digested and isolated circular smooth muscle cells were prepared from each LES region.To study outward K + currents,the perforated patch clamp technique was employed.To assess LES resting tone and relaxation,muscle strips were mounted in perfused organ baths.RESULTS:(1) Electrophysiological recordings from isolated cells:(a) CM was more depolarized than SM (-39.7 ± 0.8mV vs-48.1 ± 1.6 mV,P < 0.001),and maximal outward current was similar (27.1 ± 1.5 pA/pF vs 25.7 ± 2.0 pA/pF,P > 0.05);(b) The NO donor sodium nitroprusside (SNP) increased outward currents only in CM (25.9 ± 1.9 to 46.7 ± 4.2 pA/pF,P < 0.001) but not SM (23.2 ± 3.1 to 27.0 ± 3.4 pA/pF,P > 0.05);(c) SNP added in the presence of the BK Ca antagonist iberiotoxin (IbTX) produced no increase in the outward current in CM (17.0 ± 2.8 vs 13.7 ± 2.2,P > 0.05);and (d) L-NNA caused a small insignificant inhibition of outward K + currents in both muscles;and (2) Muscle strip studies:(a) Blockade of the nerves with tetrodotoxin (TTX),or BK Ca with IbTX had no significant effect on resting tone of either muscle;and (b) SNP reduced tone in both muscles,and was unaffected by the presence of TTX or IbTX.CONCLUSION:Exogenous NO activates BK Ca only in CM of the cat.However,as opposed to other species,exogenous NO-induced relaxation is predominantly by a non-BK Ca mechanism,and endogenous NO has minimal effect on resting tone.展开更多
Development of low-resistance electrode/electrolyte interfaces is key for enabling all-solid-state batteries with fast-charging capabilities.Low interfacial resistance and high current density were demonstrated for Na...Development of low-resistance electrode/electrolyte interfaces is key for enabling all-solid-state batteries with fast-charging capabilities.Low interfacial resistance and high current density were demonstrated for Na-β″-alumina/sodium metal interfaces,making Na-β″-alumina a promising solid electrolyte for high-energy all-solid-state batteries.However,integration of Na-β″-alumina with a high-energy sodium-ion intercalation cathode remains challenging.Here,we report a proof-of-concept study that targets the implementation of a Na-β″-alumina ceramic electrolyte with a slurry-casted porous NaCrO_(2) cathode with infiltrated sodium hydroborates as secondary electrolyte.The hydroborate Na4(B_(12)H_(12))(B_(10)H_(10))possesses similar sodium-ion conductivity of 1 mS cm^(-1) at room temperature as Na-β″-alumina and can be fully densified by cold pressing.Using the Na4(B_(12)H_(12))(B_(10)H_(10))secondary electrolyte as interlayer between Na-β″-alumina and NaCrO_(2),we obtain a cathode-electrolyte interfacial resistance of only 25Ωcm^(2) after cold pressing at 70 MPa.Proof-of-concept cells with a sodium metal anode and a NaCrO_(2) cathode feature an initial discharge capacity of 103 mAh g^(-1) at C/10 and 42 mAh g^(-1) at 1 C with an excellent capacity retention of 88%after 100 cycles at 1 C at room temperature.Ion-milled cross-sections of the cathode/electrolyte interface demonstrate that intimate contact is maintained during cycling,proving that the use of hydroborates as secondary electrolyte and as an interlayer is a promising approach for the development of all-solid-state batteries with ceramic electrolytes.展开更多
Growth hormone （GH） exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 （IGF-1） in liver and skeletal tissues. To exa...Growth hormone （GH） exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 （IGF-1） in liver and skeletal tissues. To examine the requirement for the GH receptor （GHR） in osteoblast function in bone, we used Cre-LoxP methods to disrupt the GHR from osteoblasts, both in vitro and in vivo. Disruption of GHR from primary calvarial osteoblasts in vitro abolished GH-induced signaling, as assessed by JAK2/STAT5 phosphorylation, and abrogated GH-induced proliferative and anti-apoptotic actions. Osteoblasts lacking GHR exhibited reduced IGF-l-induced Erk and Akt phosphorylation and attenuated IGF-1-induced proliferation and anti-apoptotic action. In addition, differentiation was modestly impaired in osteoblasts lacking GHR, as demonstrated by reduced alkaline phosphatase staining and calcium deposition. In order to determine the requirement for the GHR in bone in vivo, we generated mice lacking the GHR specifically in osteoblasts （△GHR）, which were born at the expected Mendelian frequency, had a normal life span and were of normal size. Three week-old, female AGHR mice had significantly reduced osteoblast numbers, consistent with the in vitro data. By six weeks of age however, female AGHR mice demonstrated a marked increase in osteoblasts, although mineralization was impaired; a phenotype similar to that observed previously in mice lacking IGF-1R specifically in osteoblasts. The most striking phenotype occurred in male mice however, where disruption of the GHR from osteoblasts resulted in a ＂feminization＂ of bone geometry in 16 week-old mice, as observed by faCT. These results demonstrate that the GHR is required for normal postnatal bone development in both sexes. GH appears to serve a primary function in modulating local IGF-1 action. However, the changes in bone geometry observed in male AGHR mice suggest that, in addition to facilitating IGF-1 action, GH may function to a greater extent than previously ap展开更多
Multimorbidity, defined as 2 or more chronic diseases, is of increasing importance for health professionals. Many factors are at play when it comes to multimorbidity, but we still know very little about how clinicians...Multimorbidity, defined as 2 or more chronic diseases, is of increasing importance for health professionals. Many factors are at play when it comes to multimorbidity, but we still know very little about how clinicians actually weigh up the different factors—medical, social, and psychological—to reach a particular course of action. Further research is therefore required to explore the ways in which clinical reasoning processes are involved in the follow up of patients suffering from multimorbidities, to highlight their potential risks of errors. A better understanding of these clinical processes will also enrich supervision of trainees and collaboration between healthcare professionals involved in primary care.展开更多
Background: In recent years, a number of initiatives aimed at promoting healthy lifestyles in health-friendly environments have been implemented.The purpose of this review is to synthesize initiatives conducted in Can...Background: In recent years, a number of initiatives aimed at promoting healthy lifestyles in health-friendly environments have been implemented.The purpose of this review is to synthesize initiatives conducted in Canada and documented in publications for the period 1995–2015 in order to gain a better understanding of their objectives and impacts.Methods: A systematic review of Canadian initiatives published over the past 20 years was conducted from multiple databases(i.e., Scopus,SPORTDiscus, Pub Med, Academic search complete, Reseausante.com, Cairn, and Erudit). In total, 264 publications were identified and retained for the final analysis based on 5 criteria:(1) publication between 1995 and 2015,(2) online availability,(3) research conducted in Canada,(4) main topic related to environments favorable to healthy lifestyles(EFHL), and(5) publication in French or English.Results: A sharp increase in the number of studies on EFHL was observed between 2010 and 2015(57%). Two major lifestyle components—physical activity and nutrition—and 2 environmental aspects—neighborhood and built environment—were the elements most frequently examined regarding adults(48%), young people(34%), and seniors(9%), using quantitative(60%) and qualitative(18%) methods. Furthermore, the analysis reveals a greater focus on the municipal(53%) than the national or provincial levels(31%).Conclusion: This work is a first map of Canadian studies related to EFHL. It clarifies the definition of EFHL and classifies its components. As well,it documents the issues raised, the research methods employed, and the role of stakeholders, while outlining a new research agenda that includes dimensions of EFHL formerly neglected by researchers, namely, political and sociocultural spheres of action.? 2018 Production and hosting by Elsevier B.V. on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).展开更多
Objectives Despite the high prevalence of patients suffering from multimorbidity,the clinical reasoning processes involved during the longitudinal management are still sparse.This study aimed to investigate what are t...Objectives Despite the high prevalence of patients suffering from multimorbidity,the clinical reasoning processes involved during the longitudinal management are still sparse.This study aimed to investigate what are the different characteristics of the clinical reasoning process clinicians use with patients suffering from multimorbidity,and to what extent this clinical reasoning differs from diagnostic reasoning.Design Given the exploratory nature of this study and the difficulty general practitioners(GPs)have in expressing their reasoning,a qualitative methodology was therefore,chosen.The Clinical reasoning Model described by Charlin et al was used as a framework to describe the multifaceted processes of the clinical reasoning.Setting Semistructured interviews were conducted with nine GPs working in an ambulatory setting in June to September 2018,in Geneva,Switzerland.Participants Participants were GPs who came from public hospital or private practice.The interviews were transcribed verbatim and a thematic analysis was conducted.Results The results highlighted how some cognitive processes seem to be more specific to the management reasoning.Thus,the main goal is not to reach a diagnosis,but rather to consider several possibilities in order to maintain a balance between the evidence-based care options,patient’s priorities and maintaining quality of life.The initial representation of the current problem seems to be more related to the importance of establishing links between the different pre-existing diseases,identifying opportunities for actions and trying to integrate the new elements from the patient’s context,rather than identifying the signs and symptoms that can lead to generating new clinical hypotheses.The multiplicity of options to resolve problems is often perceived as difficult by GPs.Furthermore,longitudinal management does not allow them to achieve a final resolution of problems and that requires continuous review and an ongoing prioritisation process.Conclusion This study contributes to a better展开更多
Objective: We examined what was known about individuals in Canada who were assessed as being at moderate risk for future fracture. Methods: A scoping review was conducted. Eligible articles were Canadian studies publi...Objective: We examined what was known about individuals in Canada who were assessed as being at moderate risk for future fracture. Methods: A scoping review was conducted. Eligible articles were Canadian studies published from 2010 onwards reporting on primary data that included patients at moderate risk for future fracture. We limited the search to Canada as fracture risk categorization is unique to each country. Studies were identified by searching relevant databases. Two reviewers independently reviewed titles and abstracts to determine each study’s eligibility. General information about each study, demographic information about the moderate risk groups (including tool used to determine moderate risk (Fracture Risk Assessment Tool (FRAX), Canadian Association of Radiologists and Osteoporosis Canada (CAROC)), and outcomes (number of patients: recommended treatment, prescribed treatment, initiating treatment, persisting with treatment after six months, who refractured, who died) were documented. Results: We identified 1193 papers which were further screened for eligibility. Of the 1193 identified, 7 were eligible for the review but only 4 articles contained demographic or outcome data on moderate risk patients. In one study, 1.8% of moderate risk patients died over a mean 5.3 years of observation and in three studies, the risk of fracture was 5.9% over a median of 3 years of follow-up, 8.3% over a mean of 5.4 years, and 14.7% over 10 years of follow-up. Conclusion: There is a wide knowledge gap in the literature concerning individuals who are assessed as moderate risk for future fracture in Canada.展开更多
We used reported behavioural data from cisgender men who have sex with men and transgender women(MSM/TGW)in Bangalore,mainly collected from‘hot-spot’locations that attract MSM/TGW,to illustrate a technique to deal w...We used reported behavioural data from cisgender men who have sex with men and transgender women(MSM/TGW)in Bangalore,mainly collected from‘hot-spot’locations that attract MSM/TGW,to illustrate a technique to deal with potential issues with the representativeness of this sample.A deterministic dynamic model of HIV transmission was developed,incorporating three subgroups of MSM/TGW,grouped according to their reported predominant sexual role(insertive,receptive or versatile).Using mathematical modelling and data triangulation for‘balancing’numbers of partners and role preferences,we compared three different approaches to determine if our technique could be useful for inferring characteristics of a more‘hidden’insertive MSM subpopulation,and explored their potential importance for the HIV epidemic.Projections for 2009 across all three approaches suggest that HIV prevalence among insertive MSM was likely to be less than half that recorded in the surveys(4.5e6.5%versus 13.1%),but that the relative size of this subgroup was over four times larger(61e69%of all MSM/TGW versus 15%).We infer that the insertive MSM accounted for 10e20%of all prevalent HIV infections among urban males aged 15e49.Mathematical modelling can be used with data on‘visible’MSM/TGW to provide insights into the characteristics of‘hidden’MSM.A greater understanding of the sexual behaviour of all MSM/TGW is important for effective HIV programming.More broadly,a hidden subgroup with a lower infectious disease prevalence than more visible subgroups,has the potential to contain more infections,if the hidden subgroup is considerably larger in size.展开更多
文摘The building sector is the largest consumer of energy in industrial countries. Saving energy in new buildings or building renovations can thus lead to significant global environmental impacts. In this endeavor, building information <span>modeling (BIM) and building energy modeling (BEM) are two important to</span>ols to make the transition to net-zero energy buildings (NZEB). So far, little attention has been devoted, in the literature, to discuss the connection between BIM, BEM, and Life-cycle assessment (LCA), which is the main topic of this article. A literature review of 157 journal articles and conference proceedings published between 1990 and 2020 is presented. This review outlines knowledge gaps concerning BIM, BEM, and environmental impact assessment. It suggests that defining the process with the right technology (at the right time) would result in a more integrated design process (IDP) and bridge current gaps. The most efficient way to improve process and technology is related to the competences of the architects, engineers and constructors (AEC). The review also indicates that the IDP in the early design phases (EDP) is in need of improvement for architects and engineers, where a better connection between design phases, specific levels of development (LOD) and BIM tools is needed. <span>Competences, process and technology are the three main themes addressed in the review. Their relation to design phases and LOD is discussed. The aim </span>is to propose possible solutions to the current hinders in BIM-to-BEM (BIM2BEM) and BIM-for-LCA (BIM4LCA) integration.
基金funding under the umbrella of ERA-NET Cofund ForestValue project NOBEL,“Novel business models and mechanisms for the sustainable supply of and payment for forest ecosystem services”ForestValue was funded by the European Union's Horizon 2020 research and innovation program(grant number 773324)+1 种基金Furthermore,the Norwegian Environment Agency funded the collection of the additional plots as a part of the project“Remote sensing-based mapping and monitoring of the forest ecosystem”(grant number 18087221)supported by the Norwegian Research Council(project number 297883).
文摘Centuries of forest exploitation have caused significant loss of natural forests in Europe,leading to a decline in populations for many species.To prevent further loss in biodiversity,the Norwegian government has set a target of protecting 10%of the forested area.However,recent data from the National Forest Inventory(NFI)reveals that less than 2%of Norway's forested area consists of natural forests.To identify forests with high conservation value,we used vertical and horizontal variables derived from airborne laser scanning(ALS)data,along with NFI plot measurements.Our study aimed to predict the presence of natural forests across three counties in southeastern Norway,using three different definitions:pristine,near-natural,and semi-natural forests.Natural forests are scarce,and their underrepresentation in field reference data can compromise the accuracy of the predictions.To address this,we assessed the potential gain of including additional field data specifically targeting natural forests to achieve a better balance in the dataset.Additionally,we examined the impact of stratifying the data by dominant tree species on the performance of the models.Our results revealed that semi-natural forests were the most accurately predicted,followed by near-natural and pristine forests,with Matthews correlation coefficient values of 0.32,0.24,and 0.17,respectively.Including additional field data did not improve the predictions.However,stratification by species improved the accuracy of predictions for near-natural and semi-natural forests,while reducing accuracy for pristine forests.The use of horizontal variables did not improve the predictions.Our study demonstrates the potential of ALS data in identifying forests with high conservation value.It provides a basis for further research on the use of ALS data for the detection and conservation of natural forests,offering valuable insights to guide future forest preservation efforts.
基金the Research Grant for Young Talented Scholars,National Research Council of Thailand,No.N41A640108.
文摘BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)conditions.Roles of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains unclarified.AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.METHODS CCA cells,KKU-055 and KKU-213A,were cultured in Dulbecco Modified Eagle’s Medium supplemented with 5.6 mmol/L(normal glucose,NG)or 25 mmol/L(HG)glucose and assigned as NG and HG cells,respectively.GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot.Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence.GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry,and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis.Effects of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays.Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment,and the candidate signaling molecules were validated using the public transcriptomic data and western blot.RESULTS GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent manner.CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia(P<0.01).High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors(P<0.05).HG cells of both tested CCA cell lines wer
文摘AIM To investigate the clinical outcomes of transcatheter aortic valve implantation(TAVI) with the SAPIEN 3 transcatheter heart valve(S3-THV) vs the SAPIEN XT valve(XT-THV).METHODS We retrospectively analyzed 507 patients that underwent TAVI with the XT-THV and 283 patients that received the S3-THV at our institution between March 2010 and December 2015.RESULTS Thirty-day mortality(3.5% vs 8.7%:OR=0.44,P=0.21) and 1-year mortality(25.7% vs 20.1%,P=0.55) were similar in the S3-THV and the XT-THV groups.The rates of both major vascular complication and paravalvular regurgitation(PVR)>1 were almost 4 times lower in the S3-THV group than the XT-THV group(major vascular complication: 2.8% vs 9.9%,P<0.0001:PVR>1: 2.4% vs 9.7%,P<0.0001).However,the rate of new pacemaker implantation was almost twice as high in the S3-THV group(17.3% vs 9.8%,P=0.03).In the S3 group,independent predictors of new permanent pacemaker were pre-procedural RBBB(OR=4.9:P=0.001),pre-procedural PR duration(OR=1.14,P=0.05) and device lack of coaxiality(OR=1.13:P=0.05) during deployment.CONCLUSION The S3-THV is associated to lower rates of major vascular complications and PVR but higher rates of new pacemaker compared to the XT-THV.Sub-optimal visualization of the S3-THV in relation to the aortic valvular complex during deployment is a predictor of new permanent pacemaker.
基金Support was provided by a Career Development Award (RCR, BX001284) from the Veterans Administration
文摘The hypoxia inducible factors （Hifs） are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1a in osteoanabolic signaling, we assessed the effect of Hif-1a loss-of-function on bone formation in response to intermittent parathyroid hormone （PTH）. Mice lacking Hif-1a in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1a protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1a-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1a functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1a function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.
基金Supported by A Postgraduate Fellowship Award to L'Heureux MC from the Department of Medicine,University of Torontoa doctoral research studentship and an Operating Grant from the Canadian Institutes of Health Research(Gaisano HY and Diamant NE)
文摘AIM:To assess the effect of nitric oxide (NO) on the large conductance potassium channel (BKCa) in isolated circular (CM) and sling (SM) muscle cells and muscle strips from the cat lower esophageal sphincter (LES) to determine its regulation of resting tone and relaxation.METHODS:Freshly enzymatically-digested and isolated circular smooth muscle cells were prepared from each LES region.To study outward K + currents,the perforated patch clamp technique was employed.To assess LES resting tone and relaxation,muscle strips were mounted in perfused organ baths.RESULTS:(1) Electrophysiological recordings from isolated cells:(a) CM was more depolarized than SM (-39.7 ± 0.8mV vs-48.1 ± 1.6 mV,P < 0.001),and maximal outward current was similar (27.1 ± 1.5 pA/pF vs 25.7 ± 2.0 pA/pF,P > 0.05);(b) The NO donor sodium nitroprusside (SNP) increased outward currents only in CM (25.9 ± 1.9 to 46.7 ± 4.2 pA/pF,P < 0.001) but not SM (23.2 ± 3.1 to 27.0 ± 3.4 pA/pF,P > 0.05);(c) SNP added in the presence of the BK Ca antagonist iberiotoxin (IbTX) produced no increase in the outward current in CM (17.0 ± 2.8 vs 13.7 ± 2.2,P > 0.05);and (d) L-NNA caused a small insignificant inhibition of outward K + currents in both muscles;and (2) Muscle strip studies:(a) Blockade of the nerves with tetrodotoxin (TTX),or BK Ca with IbTX had no significant effect on resting tone of either muscle;and (b) SNP reduced tone in both muscles,and was unaffected by the presence of TTX or IbTX.CONCLUSION:Exogenous NO activates BK Ca only in CM of the cat.However,as opposed to other species,exogenous NO-induced relaxation is predominantly by a non-BK Ca mechanism,and endogenous NO has minimal effect on resting tone.
基金support from the BRIDGE Proof-of-Concept program under contract number 40B1-0_198678/2.
文摘Development of low-resistance electrode/electrolyte interfaces is key for enabling all-solid-state batteries with fast-charging capabilities.Low interfacial resistance and high current density were demonstrated for Na-β″-alumina/sodium metal interfaces,making Na-β″-alumina a promising solid electrolyte for high-energy all-solid-state batteries.However,integration of Na-β″-alumina with a high-energy sodium-ion intercalation cathode remains challenging.Here,we report a proof-of-concept study that targets the implementation of a Na-β″-alumina ceramic electrolyte with a slurry-casted porous NaCrO_(2) cathode with infiltrated sodium hydroborates as secondary electrolyte.The hydroborate Na4(B_(12)H_(12))(B_(10)H_(10))possesses similar sodium-ion conductivity of 1 mS cm^(-1) at room temperature as Na-β″-alumina and can be fully densified by cold pressing.Using the Na4(B_(12)H_(12))(B_(10)H_(10))secondary electrolyte as interlayer between Na-β″-alumina and NaCrO_(2),we obtain a cathode-electrolyte interfacial resistance of only 25Ωcm^(2) after cold pressing at 70 MPa.Proof-of-concept cells with a sodium metal anode and a NaCrO_(2) cathode feature an initial discharge capacity of 103 mAh g^(-1) at C/10 and 42 mAh g^(-1) at 1 C with an excellent capacity retention of 88%after 100 cycles at 1 C at room temperature.Ion-milled cross-sections of the cathode/electrolyte interface demonstrate that intimate contact is maintained during cycling,proving that the use of hydroborates as secondary electrolyte and as an interlayer is a promising approach for the development of all-solid-state batteries with ceramic electrolytes.
基金supported by grants from the NIH: R01 AR052746 to TLC and R01 AR062074 to DJD
文摘Growth hormone （GH） exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 （IGF-1） in liver and skeletal tissues. To examine the requirement for the GH receptor （GHR） in osteoblast function in bone, we used Cre-LoxP methods to disrupt the GHR from osteoblasts, both in vitro and in vivo. Disruption of GHR from primary calvarial osteoblasts in vitro abolished GH-induced signaling, as assessed by JAK2/STAT5 phosphorylation, and abrogated GH-induced proliferative and anti-apoptotic actions. Osteoblasts lacking GHR exhibited reduced IGF-l-induced Erk and Akt phosphorylation and attenuated IGF-1-induced proliferation and anti-apoptotic action. In addition, differentiation was modestly impaired in osteoblasts lacking GHR, as demonstrated by reduced alkaline phosphatase staining and calcium deposition. In order to determine the requirement for the GHR in bone in vivo, we generated mice lacking the GHR specifically in osteoblasts （△GHR）, which were born at the expected Mendelian frequency, had a normal life span and were of normal size. Three week-old, female AGHR mice had significantly reduced osteoblast numbers, consistent with the in vitro data. By six weeks of age however, female AGHR mice demonstrated a marked increase in osteoblasts, although mineralization was impaired; a phenotype similar to that observed previously in mice lacking IGF-1R specifically in osteoblasts. The most striking phenotype occurred in male mice however, where disruption of the GHR from osteoblasts resulted in a ＂feminization＂ of bone geometry in 16 week-old mice, as observed by faCT. These results demonstrate that the GHR is required for normal postnatal bone development in both sexes. GH appears to serve a primary function in modulating local IGF-1 action. However, the changes in bone geometry observed in male AGHR mice suggest that, in addition to facilitating IGF-1 action, GH may function to a greater extent than previously ap
文摘Multimorbidity, defined as 2 or more chronic diseases, is of increasing importance for health professionals. Many factors are at play when it comes to multimorbidity, but we still know very little about how clinicians actually weigh up the different factors—medical, social, and psychological—to reach a particular course of action. Further research is therefore required to explore the ways in which clinical reasoning processes are involved in the follow up of patients suffering from multimorbidities, to highlight their potential risks of errors. A better understanding of these clinical processes will also enrich supervision of trainees and collaboration between healthcare professionals involved in primary care.
文摘Background: In recent years, a number of initiatives aimed at promoting healthy lifestyles in health-friendly environments have been implemented.The purpose of this review is to synthesize initiatives conducted in Canada and documented in publications for the period 1995–2015 in order to gain a better understanding of their objectives and impacts.Methods: A systematic review of Canadian initiatives published over the past 20 years was conducted from multiple databases(i.e., Scopus,SPORTDiscus, Pub Med, Academic search complete, Reseausante.com, Cairn, and Erudit). In total, 264 publications were identified and retained for the final analysis based on 5 criteria:(1) publication between 1995 and 2015,(2) online availability,(3) research conducted in Canada,(4) main topic related to environments favorable to healthy lifestyles(EFHL), and(5) publication in French or English.Results: A sharp increase in the number of studies on EFHL was observed between 2010 and 2015(57%). Two major lifestyle components—physical activity and nutrition—and 2 environmental aspects—neighborhood and built environment—were the elements most frequently examined regarding adults(48%), young people(34%), and seniors(9%), using quantitative(60%) and qualitative(18%) methods. Furthermore, the analysis reveals a greater focus on the municipal(53%) than the national or provincial levels(31%).Conclusion: This work is a first map of Canadian studies related to EFHL. It clarifies the definition of EFHL and classifies its components. As well,it documents the issues raised, the research methods employed, and the role of stakeholders, while outlining a new research agenda that includes dimensions of EFHL formerly neglected by researchers, namely, political and sociocultural spheres of action.? 2018 Production and hosting by Elsevier B.V. on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
基金The study received financial support(CHF50000)from the SGAIM Foundation(Foundation of the Swiss Society of General Internal Medicine),in the context of a call for research projects on multimorbidity(Project title:Understanding the clinical reasoning processes involved in managing multimorbid patients:a key to face future challenges in primary care.
文摘Objectives Despite the high prevalence of patients suffering from multimorbidity,the clinical reasoning processes involved during the longitudinal management are still sparse.This study aimed to investigate what are the different characteristics of the clinical reasoning process clinicians use with patients suffering from multimorbidity,and to what extent this clinical reasoning differs from diagnostic reasoning.Design Given the exploratory nature of this study and the difficulty general practitioners(GPs)have in expressing their reasoning,a qualitative methodology was therefore,chosen.The Clinical reasoning Model described by Charlin et al was used as a framework to describe the multifaceted processes of the clinical reasoning.Setting Semistructured interviews were conducted with nine GPs working in an ambulatory setting in June to September 2018,in Geneva,Switzerland.Participants Participants were GPs who came from public hospital or private practice.The interviews were transcribed verbatim and a thematic analysis was conducted.Results The results highlighted how some cognitive processes seem to be more specific to the management reasoning.Thus,the main goal is not to reach a diagnosis,but rather to consider several possibilities in order to maintain a balance between the evidence-based care options,patient’s priorities and maintaining quality of life.The initial representation of the current problem seems to be more related to the importance of establishing links between the different pre-existing diseases,identifying opportunities for actions and trying to integrate the new elements from the patient’s context,rather than identifying the signs and symptoms that can lead to generating new clinical hypotheses.The multiplicity of options to resolve problems is often perceived as difficult by GPs.Furthermore,longitudinal management does not allow them to achieve a final resolution of problems and that requires continuous review and an ongoing prioritisation process.Conclusion This study contributes to a better
文摘Objective: We examined what was known about individuals in Canada who were assessed as being at moderate risk for future fracture. Methods: A scoping review was conducted. Eligible articles were Canadian studies published from 2010 onwards reporting on primary data that included patients at moderate risk for future fracture. We limited the search to Canada as fracture risk categorization is unique to each country. Studies were identified by searching relevant databases. Two reviewers independently reviewed titles and abstracts to determine each study’s eligibility. General information about each study, demographic information about the moderate risk groups (including tool used to determine moderate risk (Fracture Risk Assessment Tool (FRAX), Canadian Association of Radiologists and Osteoporosis Canada (CAROC)), and outcomes (number of patients: recommended treatment, prescribed treatment, initiating treatment, persisting with treatment after six months, who refractured, who died) were documented. Results: We identified 1193 papers which were further screened for eligibility. Of the 1193 identified, 7 were eligible for the review but only 4 articles contained demographic or outcome data on moderate risk patients. In one study, 1.8% of moderate risk patients died over a mean 5.3 years of observation and in three studies, the risk of fracture was 5.9% over a median of 3 years of follow-up, 8.3% over a mean of 5.4 years, and 14.7% over 10 years of follow-up. Conclusion: There is a wide knowledge gap in the literature concerning individuals who are assessed as moderate risk for future fracture in Canada.
文摘We used reported behavioural data from cisgender men who have sex with men and transgender women(MSM/TGW)in Bangalore,mainly collected from‘hot-spot’locations that attract MSM/TGW,to illustrate a technique to deal with potential issues with the representativeness of this sample.A deterministic dynamic model of HIV transmission was developed,incorporating three subgroups of MSM/TGW,grouped according to their reported predominant sexual role(insertive,receptive or versatile).Using mathematical modelling and data triangulation for‘balancing’numbers of partners and role preferences,we compared three different approaches to determine if our technique could be useful for inferring characteristics of a more‘hidden’insertive MSM subpopulation,and explored their potential importance for the HIV epidemic.Projections for 2009 across all three approaches suggest that HIV prevalence among insertive MSM was likely to be less than half that recorded in the surveys(4.5e6.5%versus 13.1%),but that the relative size of this subgroup was over four times larger(61e69%of all MSM/TGW versus 15%).We infer that the insertive MSM accounted for 10e20%of all prevalent HIV infections among urban males aged 15e49.Mathematical modelling can be used with data on‘visible’MSM/TGW to provide insights into the characteristics of‘hidden’MSM.A greater understanding of the sexual behaviour of all MSM/TGW is important for effective HIV programming.More broadly,a hidden subgroup with a lower infectious disease prevalence than more visible subgroups,has the potential to contain more infections,if the hidden subgroup is considerably larger in size.
