The mucosal immune system serves as our front-line defense against pathogens. It also tightly maintains immune tolerance to self-symbiotic bacteria, which are usually called commensals. Sensing both types of microorga...The mucosal immune system serves as our front-line defense against pathogens. It also tightly maintains immune tolerance to self-symbiotic bacteria, which are usually called commensals. Sensing both types of microorganisms is modulated by signalling primarily through various pattern-recognition receptors （PRRs） on barrier epithelial cells or immune cells. After sensing, proinflammatory molecules such as cytokines are released by these cells to mediate either defensive or tolerant responses. The interleukin-17 （IL-17） family members belong to a newly characterized cytokine subset that is critical for the maintenance of mucosal homeostasis. In this review, we will summarize recent progress on the diverse functions and signals of this family of cytokines at different mucosal edges.展开更多
Aim:To evaluate the hearing of children with congenital hypothyroidism(CH)and to analyze the knowledge that parents’have on the possible auditory impacts of the disease.Methods:A total of 263 parents/guardians were i...Aim:To evaluate the hearing of children with congenital hypothyroidism(CH)and to analyze the knowledge that parents’have on the possible auditory impacts of the disease.Methods:A total of 263 parents/guardians were interviewed about aspects of CH and hearing.Audiological evaluation was performed on 80 participants,divided into two groups:with CH(n?50)and without CH(n紏30).Clinical and laboratory CH data were obtained from medical records,pure tone auditory thresholds and acoustic reflexes were analyzed.The auditory data was compared between groups.Student’s t-test and Chi-square were used for statistical analysis at a significance level of 5%(p<0.05).Results:The majority(78%),of the parents were unaware that CH when not treated early is a potential risk to hearing.There was no correlation between socioeconomic class and level of information about CH and hearing(p>0,05;p=0.026).There was a statistically significant difference between the auditory tone thresholds of the groups and between the levels of intensity necessary for the triggering of the acoustic reflex.The group with CH presented the worst results(p<0.05)and absence of acoustic reflex in a normal tympanometric condition.Conclusions:Children with CH are more likely to develop damage to the auditory system involving retrocochlear structures when compared to healthy children,and that the disease may have been a risk factor for functional deficits without deteriorating hearing sensitivity.The possible impacts of CH on hearing,when not treated early,should be more publicized among the parents/guardians of this population.展开更多
Under the acceptable hypothesis that cardiac rhythm is an approximately deterministic process with a small scale noise component, an available way is provided to construct a model that can reflect its prominent dynami...Under the acceptable hypothesis that cardiac rhythm is an approximately deterministic process with a small scale noise component, an available way is provided to construct a model that can reflect its prominent dynamics of the deterministic component. When applied to the analysis of 19 heart rate data sets, three main findings are stated. The obtained model can reflect prominent dynamics of the deterministic component of cardiac rhythm; cardiac chaos is stated in a reliable way; dynamical noise plays an important role in the generation of complex cardiac rhythm.展开更多
Importance:Critically ill children with pre-existing mental health conditions may have an increased risk of poor health outcomes.Objective:We aimed to evaluate if pre-existing mental health conditions in critically il...Importance:Critically ill children with pre-existing mental health conditions may have an increased risk of poor health outcomes.Objective:We aimed to evaluate if pre-existing mental health conditions in critically ill pediatric patients would be associated with worse clinical outcomes,compared to children with no documented mental health conditions.Methods:This retrospective observational cohort study utilized the TriNetX electronic health record database of critically ill subjects aged 12-18 years.Data were analyzed for demographics,pre-existing conditions,diagnostic,medication,procedural codes,and mortality.Results:From a dataset of 102027 critically ill children,we analyzed 1999 subjects(284[14.2%]with a pre-existing mental health condition and 1715[85.8%]with no pre-existing mental health condition).Multivariable analysis demonstrated that death within one year was associated with the presence of pre-existing mental health conditions(odds ratio 8.97[3.48-23.15],P<0.001),even after controlling for the presence of a complex chronic condition.Interpretation:The present study demonstrates that the presence of pre-existing mental health conditions was associated with higher odds of death within 1 year after receiving critical care.However,the confidence interval was wide and hence,the findings are inconclusive.Future studies with a larger sample size may be necessary to evaluate the true long-term impact of children with pre-existing mental health conditions who require critical care services.展开更多
Dear Sir,My name is Manjool M.Shah,from the Casey Eye Institute at Oregon Health&Science University in Portland,Oregon,USA.I wish to write to you with regards to an interesting presentation of a rare eyelid malign...Dear Sir,My name is Manjool M.Shah,from the Casey Eye Institute at Oregon Health&Science University in Portland,Oregon,USA.I wish to write to you with regards to an interesting presentation of a rare eyelid malignancy.A 41-year old Caucasian female was referred to the oculoplastic service by her comprehensive ophthalmologist展开更多
Objective The objective of this research was to examine how different measurements of poverty(household-level and neighborhood-level)were associated with asthma care utilisation outcomes in a community health centre s...Objective The objective of this research was to examine how different measurements of poverty(household-level and neighborhood-level)were associated with asthma care utilisation outcomes in a community health centre setting among Latino,non-Latino black and non-Latino white children.Design,setting and participants We used 2012–2017 electronic health record data of an open cohort of children aged<18 years with asthma from the OCHIN,Inc.network.Independent variables included household-level and neighborhood-level poverty using income as a percent of federal poverty level(FPL).Covariate-adjusted generalised estimating equations logistic and negative binomial regression were used to model three outcomes:(1)≥2 asthma visits/year,(2)albuterol prescription orders and(3)prescription of inhaled corticosteroids over the total study period.Results The full sample(n=30196)was 46%Latino,26%non-Latino black,31%aged 6–10 years at first clinic visit.Most patients had household FPL<100%(78%),yet more than half lived in a neighbourhood with>200%FPL(55%).Overall,neighbourhood poverty(<100%FPL)was associated with more asthma visits(covariate-adjusted OR 1.26,95%CI 1.12 to 1.41),and living in a low-income neighbourhood(≥100%to<200%FPL)was associated with more albuterol prescriptions(covariate-adjusted rate ratio 1.07,95%CI 1.02 to 1.13).When stratified by race/ethnicity,we saw differences in both directions in associations of household/neighbourhood income and care outcomes between groups.Conclusions This study enhances understanding of measurements of race/ethnicity differences in asthma care utilisation by income,revealing different associations of living in low-income neighbourhoods and households for Latino,non-Latino white and non-Latino black children with asthma.This implies that markers of family and community poverty may both need to be considered when evaluating the association between economic status and healthcare utilisation.Tools to measure both kinds of poverty(family and community)may already exist within clin展开更多
Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge,unbiased chemoproteomi...Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge,unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.展开更多
The success and safety seen in treating complement-mediated hemolysis conditions has sparked the development of targeted therapies for rare autoimmune diseases,with expansion to more common autoimmune conditions.Vario...The success and safety seen in treating complement-mediated hemolysis conditions has sparked the development of targeted therapies for rare autoimmune diseases,with expansion to more common autoimmune conditions.Various classes of drugs,including small molecules,peptides,monoclonal antibodies,and small interfering RNA(siRNA),are undergoing development to specifically address complement activity.A dual approach targeting both complement and other immune components may be required for autoimmune diseases characterized by inflammation and complex pathogenic mechanisms.siRNA,which suppresses complement production,is emerging as a potent therapeutic tool.Combining a complement-blocking siRNA drug with a treatment that reduces autoantibodies could prove clinically feasible and impactful in managing these conditions.展开更多
Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transana...Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.展开更多
It is widely recognized that treatment intervention in patients with rheumatoid arthritis(RA)at early stages is associated with improved outcomes.1 Hence,research efforts have been devoted to investigation of whether ...It is widely recognized that treatment intervention in patients with rheumatoid arthritis(RA)at early stages is associated with improved outcomes.1 Hence,research efforts have been devoted to investigation of whether intervention starting at the preclinical stage will prevent the clinical onset of RA.2-5 In these studies,individuals at risk for RA were identified mainly by the detection of anti-citrullinated protein antibodies(ACPAs)and/or the rheumatoid factor(RF),which may precede the clinical symptoms of RA patients.展开更多
Objective:Nasal obstruction is a very common problem often addressed by functional nasal surgery.Increasingly,these procedures are being performed in the office setting secondary to decreased down time,cost,and obviat...Objective:Nasal obstruction is a very common problem often addressed by functional nasal surgery.Increasingly,these procedures are being performed in the office setting secondary to decreased down time,cost,and obviation of general anesthesia.Our goal with this review is to discuss how to appropriately select patients for office-based procedures,what procedures may be considered,and current outcomes with in-office functional nasal surgery.Data Sources:PubMed,Scopus,Google Scholar.Methods:Research databases were searched for articles discussing techniques for performing functional nasal surgery in an office setting,and outcomes of various in-office functional nasal procedures.Results:Studies found and included in this review discuss many aspects of office-based functional nasal surgery,including practical points on patient selection and office set-up,what procedures can safely be performed,and outcomes of different techniques to address specific problems.Broadly,procedures amenable to performance in the office address the internal and external nasal valves,the nasal septum,and the inferior turbinates.Conclusion:A wide range of techniques to aaddress the nasal valves,septum,and inferior turbinates can be performed in a safe and effective manner without the need for an operative suite.展开更多
The transcription factor c-MYC(MYC thereafter)controls diverse transcription programs and plays a key role in the development of many human cancers.Cells develop multiple mechanisms to ensure that MYC levels and activ...The transcription factor c-MYC(MYC thereafter)controls diverse transcription programs and plays a key role in the development of many human cancers.Cells develop multiple mechanisms to ensure that MYC levels and activity are precisely controlled in normal physiological context.As a short half-lived protein,MYC protein levels are tightly regulated by the ubiquitin proteasome system.Over a dozen of ubiquitin ligases have been found to ubiquitinate MYC whereas a number of deubiquitinating enzymes counteract this process.Recent studies show that SUMOylation and deSUMOylation can also regulate MYC protein stability and activity.Interestingly,evidence suggests an intriguing crosstalk between MYC ubiquitination and SUMOylation.Deregulation of the MYC ubiquitination-SUMOylation regulatory network may contribute to tumorigenesis.This review is intended to provide the current understanding of the complex regulation of the MYC biology by dynamic ubiquitination and SUMOylation and their crosstalk.展开更多
Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthrit...Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis(RA)due to recently discovered neutrophil extracellular trap(NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.展开更多
Background and Aims:In the REALM (Randomized, Obser-vational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Pa-tients with Chronic HBV Infection) study, 12,378 pa...Background and Aims:In the REALM (Randomized, Obser-vational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Pa-tients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progres-sion events, and deaths. An external event adjudication com-mittee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize poten-tial adverse effects of the large cohort, interdisciplinary out-come assessments, geographic scope, and long duration. Methods:The EAC comprised an international group of hep-atologists and oncologists with expertise in diagnosis of tar-geted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria cap-tured in the EAC charter. Operational processes, including da-ta collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%;hepatocellular carcino-ma (HCC), 83.3%;non-HCC malignancies, 88.0%;non-HCC HBV disease progression, 68.2%. Reasons for lack of con-cordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consis-tency;EAC performance was facilitated by well-defined diag-nostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.展开更多
When compared with maintenance dialysis,renal transplantation affords patients with end-stage renal disease better long-term survival and a better quality of life.Approximately 9% of patients will develop a major urol...When compared with maintenance dialysis,renal transplantation affords patients with end-stage renal disease better long-term survival and a better quality of life.Approximately 9% of patients will develop a major urologic complication following kidney transplantation.Ureteral complications are most common and include obstruction(intrinsic and extrinsic),urine leak and vesicoureteral reflux.Ureterovesical anastomotic strictures result from technical error or ureteral ischemia.Balloon dilation or endoureterotomy may be considered for short,low-grade strictures,but open reconstruction is associated with higher success rates.Urine leak usually occurs in the early postoperative period.Nearly 60% of patients can be successfully managed with a pelvic drain and urinary decompression(nephrostomy tube,ureteral stent,and indwelling bladder catheter).Proximal,large-volume,or leaks that persist despite urinary diversion,require open repair.Vesicoureteral reflux is common following transplantation.Patients with recurrent pyelonephritis despite antimicrobial prophylaxis require surgical treatment.Deflux injection may be considered in recipients with low-grade disease.Grade IV and V reflux are best managed with open reconstruction.展开更多
PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),P...PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),PARPi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to treatment.In this review,we discuss the role of PARPi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and PARP inhibitors.展开更多
Objective To assess the Affordable Care Act(ACA)Medicaid expansion’s impact on new hypertension and diabetes diagnoses in community health centres(CHCs).Design Rates of new hypertension and diabetes diagnoses were co...Objective To assess the Affordable Care Act(ACA)Medicaid expansion’s impact on new hypertension and diabetes diagnoses in community health centres(CHCs).Design Rates of new hypertension and diabetes diagnoses were computed using generalised estimating equation Poisson models and we tested the difference-in difference(DID)pre-ACA versus post-ACA in states that expanded Medicaid compared with those that did not.Setting We used electronic health record data(pre-ACA:1 January 2012-31 December 2013-post-ACA:1 January 2014-31 December 2016)from the Accelerating Data Value Across a National Community Health Center Network clinical data network.We included clinics with≥50 patients contributing to person-time at risk in each study year.Participants Patients aged 19-64 with≥1 ambulatory visit in the study period were included.We then excluded patients who were pregnant during the study period(N=127530).For the hypertension outcome,we excluded individuals with a diagnosis of hypertension prior to the start of the study period,those who had a hypertension diagnosis on their first visit to a clinic or their first visit after 3 years without a visit,and those who had a diagnosis more than 3 years after their last visit(pre-ACA non-expansion N=130973;expansion N=193198;post-ACA non-expansion N=186341;expansion N=251015).For the diabetes analysis,we excluded patients with a diabetes diagnosis prior to study start,on their first visit or first visit after inactive patient status,and diagnosis while not an active patient(pre-ACA non-expansion N=145435;expansion N=198558;post-ACA non-expansion N=215039;expansion N=264644).Results In non-expansion states,adjusted hypertension diagnosis rates saw a relative decrease of 6%,while in expansion states,the adjusted rates saw a relative increase of 7%(DID 1.14,95%CI 1.11 to 1.18).For diabetes diagnosis,adjusted rates in non-expansion states experienced a significant relative increase of 28%and in expansion states the relative increase was 25%;yet these differences were not significan展开更多
基金This work was supported by grants from the National Natural Science Foundation of China （81430036, 81230075, 91429307, 31329002, 91329301 and 91542119）, the 973 Program （2013CB944904）, and the Science and Technology Commission of Shanghai Municipality （131C1408900）.
文摘The mucosal immune system serves as our front-line defense against pathogens. It also tightly maintains immune tolerance to self-symbiotic bacteria, which are usually called commensals. Sensing both types of microorganisms is modulated by signalling primarily through various pattern-recognition receptors （PRRs） on barrier epithelial cells or immune cells. After sensing, proinflammatory molecules such as cytokines are released by these cells to mediate either defensive or tolerant responses. The interleukin-17 （IL-17） family members belong to a newly characterized cytokine subset that is critical for the maintenance of mucosal homeostasis. In this review, we will summarize recent progress on the diverse functions and signals of this family of cytokines at different mucosal edges.
文摘Aim:To evaluate the hearing of children with congenital hypothyroidism(CH)and to analyze the knowledge that parents’have on the possible auditory impacts of the disease.Methods:A total of 263 parents/guardians were interviewed about aspects of CH and hearing.Audiological evaluation was performed on 80 participants,divided into two groups:with CH(n?50)and without CH(n紏30).Clinical and laboratory CH data were obtained from medical records,pure tone auditory thresholds and acoustic reflexes were analyzed.The auditory data was compared between groups.Student’s t-test and Chi-square were used for statistical analysis at a significance level of 5%(p<0.05).Results:The majority(78%),of the parents were unaware that CH when not treated early is a potential risk to hearing.There was no correlation between socioeconomic class and level of information about CH and hearing(p>0,05;p=0.026).There was a statistically significant difference between the auditory tone thresholds of the groups and between the levels of intensity necessary for the triggering of the acoustic reflex.The group with CH presented the worst results(p<0.05)and absence of acoustic reflex in a normal tympanometric condition.Conclusions:Children with CH are more likely to develop damage to the auditory system involving retrocochlear structures when compared to healthy children,and that the disease may have been a risk factor for functional deficits without deteriorating hearing sensitivity.The possible impacts of CH on hearing,when not treated early,should be more publicized among the parents/guardians of this population.
基金This work was supported by the National Natural Science Foundation of China (Grant Nos. 69735101 and 69872009).
文摘Under the acceptable hypothesis that cardiac rhythm is an approximately deterministic process with a small scale noise component, an available way is provided to construct a model that can reflect its prominent dynamics of the deterministic component. When applied to the analysis of 19 heart rate data sets, three main findings are stated. The obtained model can reflect prominent dynamics of the deterministic component of cardiac rhythm; cardiac chaos is stated in a reliable way; dynamical noise plays an important role in the generation of complex cardiac rhythm.
基金National Center for Advancing Translational Sciences,National Institutes of Health,Grant/Award Number:UL1 TR002014。
文摘Importance:Critically ill children with pre-existing mental health conditions may have an increased risk of poor health outcomes.Objective:We aimed to evaluate if pre-existing mental health conditions in critically ill pediatric patients would be associated with worse clinical outcomes,compared to children with no documented mental health conditions.Methods:This retrospective observational cohort study utilized the TriNetX electronic health record database of critically ill subjects aged 12-18 years.Data were analyzed for demographics,pre-existing conditions,diagnostic,medication,procedural codes,and mortality.Results:From a dataset of 102027 critically ill children,we analyzed 1999 subjects(284[14.2%]with a pre-existing mental health condition and 1715[85.8%]with no pre-existing mental health condition).Multivariable analysis demonstrated that death within one year was associated with the presence of pre-existing mental health conditions(odds ratio 8.97[3.48-23.15],P<0.001),even after controlling for the presence of a complex chronic condition.Interpretation:The present study demonstrates that the presence of pre-existing mental health conditions was associated with higher odds of death within 1 year after receiving critical care.However,the confidence interval was wide and hence,the findings are inconclusive.Future studies with a larger sample size may be necessary to evaluate the true long-term impact of children with pre-existing mental health conditions who require critical care services.
基金Partially supported by an unrestricted educational grant to the Casey Eye Institute from Research to Prevent Blindness,645 Madison Ave,Floor 21,New York,New York 10022-1010,USA
文摘Dear Sir,My name is Manjool M.Shah,from the Casey Eye Institute at Oregon Health&Science University in Portland,Oregon,USA.I wish to write to you with regards to an interesting presentation of a rare eyelid malignancy.A 41-year old Caucasian female was referred to the oculoplastic service by her comprehensive ophthalmologist
基金supported by an NIH National Institute on Minority Health and Health Disparities grant(R01MD011404background study,principal investigator:JH).The funder/sponsor did not participate in the work.
文摘Objective The objective of this research was to examine how different measurements of poverty(household-level and neighborhood-level)were associated with asthma care utilisation outcomes in a community health centre setting among Latino,non-Latino black and non-Latino white children.Design,setting and participants We used 2012–2017 electronic health record data of an open cohort of children aged<18 years with asthma from the OCHIN,Inc.network.Independent variables included household-level and neighborhood-level poverty using income as a percent of federal poverty level(FPL).Covariate-adjusted generalised estimating equations logistic and negative binomial regression were used to model three outcomes:(1)≥2 asthma visits/year,(2)albuterol prescription orders and(3)prescription of inhaled corticosteroids over the total study period.Results The full sample(n=30196)was 46%Latino,26%non-Latino black,31%aged 6–10 years at first clinic visit.Most patients had household FPL<100%(78%),yet more than half lived in a neighbourhood with>200%FPL(55%).Overall,neighbourhood poverty(<100%FPL)was associated with more asthma visits(covariate-adjusted OR 1.26,95%CI 1.12 to 1.41),and living in a low-income neighbourhood(≥100%to<200%FPL)was associated with more albuterol prescriptions(covariate-adjusted rate ratio 1.07,95%CI 1.02 to 1.13).When stratified by race/ethnicity,we saw differences in both directions in associations of household/neighbourhood income and care outcomes between groups.Conclusions This study enhances understanding of measurements of race/ethnicity differences in asthma care utilisation by income,revealing different associations of living in low-income neighbourhoods and households for Latino,non-Latino white and non-Latino black children with asthma.This implies that markers of family and community poverty may both need to be considered when evaluating the association between economic status and healthcare utilisation.Tools to measure both kinds of poverty(family and community)may already exist within clin
基金partially by the financial supports from the National Institutes of Health R01 CA197513 (XX),R01GM122820 (XX) and R21EB028425 (BXL),USAperformed by the OHSU Proteomics Shared Resource with partial support from NIH core grants P30EY010572,P30CA069533,and S10RR025571,USA。
文摘Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge,unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.
基金supported by an Innovative Research Award from Rheumatology Research Foundation and by a VA Merit Review grant(I01BX005195).
文摘The success and safety seen in treating complement-mediated hemolysis conditions has sparked the development of targeted therapies for rare autoimmune diseases,with expansion to more common autoimmune conditions.Various classes of drugs,including small molecules,peptides,monoclonal antibodies,and small interfering RNA(siRNA),are undergoing development to specifically address complement activity.A dual approach targeting both complement and other immune components may be required for autoimmune diseases characterized by inflammation and complex pathogenic mechanisms.siRNA,which suppresses complement production,is emerging as a potent therapeutic tool.Combining a complement-blocking siRNA drug with a treatment that reduces autoantibodies could prove clinically feasible and impactful in managing these conditions.
基金This work was supported by the National Institutes of Health grants[NIH R01HL130274 and R01HL144113]NSERC-CREATE Training in Global Biomedical Technology Research and Innovation at the University of Waterloo[CREATE-509950-2018]+2 种基金Canada Foundation for Innovation(CFI35573)NSERC Research Tools and Instruments Fund(RTI-2018-00220)the Oregon National Primate Research Center NIH grant award[P51OD011092].
文摘Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.
基金supported by an Innovative Research Award by Rheumatology Research Foundation and by VA Merit Review grant(I01BX005195).
文摘It is widely recognized that treatment intervention in patients with rheumatoid arthritis(RA)at early stages is associated with improved outcomes.1 Hence,research efforts have been devoted to investigation of whether intervention starting at the preclinical stage will prevent the clinical onset of RA.2-5 In these studies,individuals at risk for RA were identified mainly by the detection of anti-citrullinated protein antibodies(ACPAs)and/or the rheumatoid factor(RF),which may precede the clinical symptoms of RA patients.
文摘Objective:Nasal obstruction is a very common problem often addressed by functional nasal surgery.Increasingly,these procedures are being performed in the office setting secondary to decreased down time,cost,and obviation of general anesthesia.Our goal with this review is to discuss how to appropriately select patients for office-based procedures,what procedures may be considered,and current outcomes with in-office functional nasal surgery.Data Sources:PubMed,Scopus,Google Scholar.Methods:Research databases were searched for articles discussing techniques for performing functional nasal surgery in an office setting,and outcomes of various in-office functional nasal procedures.Results:Studies found and included in this review discuss many aspects of office-based functional nasal surgery,including practical points on patient selection and office set-up,what procedures can safely be performed,and outcomes of different techniques to address specific problems.Broadly,procedures amenable to performance in the office address the internal and external nasal valves,the nasal septum,and the inferior turbinates.Conclusion:A wide range of techniques to aaddress the nasal valves,septum,and inferior turbinates can be performed in a safe and effective manner without the need for an operative suite.
基金We thank members of the Dai and Sears laboratories for active discussion.This work was supported by NIH/NCI grant R01 CA186241 to M-S.D.and R.S.
文摘The transcription factor c-MYC(MYC thereafter)controls diverse transcription programs and plays a key role in the development of many human cancers.Cells develop multiple mechanisms to ensure that MYC levels and activity are precisely controlled in normal physiological context.As a short half-lived protein,MYC protein levels are tightly regulated by the ubiquitin proteasome system.Over a dozen of ubiquitin ligases have been found to ubiquitinate MYC whereas a number of deubiquitinating enzymes counteract this process.Recent studies show that SUMOylation and deSUMOylation can also regulate MYC protein stability and activity.Interestingly,evidence suggests an intriguing crosstalk between MYC ubiquitination and SUMOylation.Deregulation of the MYC ubiquitination-SUMOylation regulatory network may contribute to tumorigenesis.This review is intended to provide the current understanding of the complex regulation of the MYC biology by dynamic ubiquitination and SUMOylation and their crosstalk.
基金supported by Rheumatology Research Foundation Innovative and Pilot grants and VA Merit Review grant(BX002858).
文摘Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis(RA)due to recently discovered neutrophil extracellular trap(NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.
基金This study was funded by Bristol-Myers Squibb,which designed the study,conducted statistical analyses,and provided financial support for the study.
文摘Background and Aims:In the REALM (Randomized, Obser-vational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Pa-tients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progres-sion events, and deaths. An external event adjudication com-mittee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize poten-tial adverse effects of the large cohort, interdisciplinary out-come assessments, geographic scope, and long duration. Methods:The EAC comprised an international group of hep-atologists and oncologists with expertise in diagnosis of tar-geted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria cap-tured in the EAC charter. Operational processes, including da-ta collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%;hepatocellular carcino-ma (HCC), 83.3%;non-HCC malignancies, 88.0%;non-HCC HBV disease progression, 68.2%. Reasons for lack of con-cordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consis-tency;EAC performance was facilitated by well-defined diag-nostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.
文摘When compared with maintenance dialysis,renal transplantation affords patients with end-stage renal disease better long-term survival and a better quality of life.Approximately 9% of patients will develop a major urologic complication following kidney transplantation.Ureteral complications are most common and include obstruction(intrinsic and extrinsic),urine leak and vesicoureteral reflux.Ureterovesical anastomotic strictures result from technical error or ureteral ischemia.Balloon dilation or endoureterotomy may be considered for short,low-grade strictures,but open reconstruction is associated with higher success rates.Urine leak usually occurs in the early postoperative period.Nearly 60% of patients can be successfully managed with a pelvic drain and urinary decompression(nephrostomy tube,ureteral stent,and indwelling bladder catheter).Proximal,large-volume,or leaks that persist despite urinary diversion,require open repair.Vesicoureteral reflux is common following transplantation.Patients with recurrent pyelonephritis despite antimicrobial prophylaxis require surgical treatment.Deflux injection may be considered in recipients with low-grade disease.Grade IV and V reflux are best managed with open reconstruction.
文摘PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),PARPi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to treatment.In this review,we discuss the role of PARPi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and PARP inhibitors.
基金CDC/NIDDK grant#U18DP006116 and NHLBI grant#R01HL136575.
文摘Objective To assess the Affordable Care Act(ACA)Medicaid expansion’s impact on new hypertension and diabetes diagnoses in community health centres(CHCs).Design Rates of new hypertension and diabetes diagnoses were computed using generalised estimating equation Poisson models and we tested the difference-in difference(DID)pre-ACA versus post-ACA in states that expanded Medicaid compared with those that did not.Setting We used electronic health record data(pre-ACA:1 January 2012-31 December 2013-post-ACA:1 January 2014-31 December 2016)from the Accelerating Data Value Across a National Community Health Center Network clinical data network.We included clinics with≥50 patients contributing to person-time at risk in each study year.Participants Patients aged 19-64 with≥1 ambulatory visit in the study period were included.We then excluded patients who were pregnant during the study period(N=127530).For the hypertension outcome,we excluded individuals with a diagnosis of hypertension prior to the start of the study period,those who had a hypertension diagnosis on their first visit to a clinic or their first visit after 3 years without a visit,and those who had a diagnosis more than 3 years after their last visit(pre-ACA non-expansion N=130973;expansion N=193198;post-ACA non-expansion N=186341;expansion N=251015).For the diabetes analysis,we excluded patients with a diabetes diagnosis prior to study start,on their first visit or first visit after inactive patient status,and diagnosis while not an active patient(pre-ACA non-expansion N=145435;expansion N=198558;post-ACA non-expansion N=215039;expansion N=264644).Results In non-expansion states,adjusted hypertension diagnosis rates saw a relative decrease of 6%,while in expansion states,the adjusted rates saw a relative increase of 7%(DID 1.14,95%CI 1.11 to 1.18).For diabetes diagnosis,adjusted rates in non-expansion states experienced a significant relative increase of 28%and in expansion states the relative increase was 25%;yet these differences were not significan
