Background:This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines,named Scientific,Transparent and Applicable Rankings tool(STAR),and test its reliability,validi...Background:This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines,named Scientific,Transparent and Applicable Rankings tool(STAR),and test its reliability,validity,and usability.Methods:This study set up a multidisciplinary working group including guideline methodologists,statisticians,journal editors,clinicians,and other experts.Scoping review,Delphi methods,and hierarchical analysis were used to develop the STAR tool.We evaluated the instrument’s intrinsic and interrater reliability,content and criterion validity,and usability.Results:STAR contained 39 items grouped into 11 domains.The mean intrinsic reliability of the domains,indicated by Cronbach’sαcoefficient,was 0.588(95%confidence interval[CI]:0.414,0.762).Interrater reliability as assessed with Cohen’s kappa coefficient was 0.774(95%CI:0.740,0.807)for methodological evaluators and 0.618(95%CI:0.587,0.648)for clinical evaluators.The overall content validity index was 0.905.Pearson’s r correlation for criterion validity was 0.885(95%CI:0.804,0.932).The mean usability score of the items was 4.6 and the median time spent to evaluate each guideline was 20 min.Conclusion:The instrument performed well in terms of reliability,validity,and efficiency,and can be used for comprehensively evaluating and ranking guidelines.展开更多
Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because ...Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].展开更多
BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the...BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.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
Negotiating a resource package as a potential new department chair is common practice in academic medicine.The foundations for this negotiation include the historical presence of the department in relation to the broa...Negotiating a resource package as a potential new department chair is common practice in academic medicine.The foundations for this negotiation include the historical presence of the department in relation to the broader institution,projections for future growth,accounting for mission/vision,resource needs(space,personnel,finances,etc),faculty and staff development,and external partnerships within and outside the institution.Despite similarities in this process across departments,many nuances influence the development of a specific new chair package,such as,department size;desires,perspectives and talents of the incoming chair,the department faculty,the medical school and dean;prevailing agendas and mission imperatives;and the overall priorities of the institution.With strategy and forethought,a new chair package can promote a successful chair tenure and departmental growth.Assembled through the Association of Departments of Family Medicine with input from several dozen department chairs and senior leaders,this is intended to serve as a practical guide to new chair packages for chair candidates.展开更多
Objectives:Prior research on olfactory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role.The pu...Objectives:Prior research on olfactory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role.The purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens,comparing normosmic and dysosmic CRS patients without polyps(CRSsNP).Methods:Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus surgery.Samples subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic(n=7)and normosmic(n=4)patients.Results:Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 genes.Using stringent criteria for multiple comparisons,one upregulated gene(Immediate Early Response 3[IER3])had an false discovery rate(FDR)correction adjustedP value considered statistically significant(P<0.001,fold change 2.69).Reactome functional analysis revealed eight biological pathways significantly different between dysosmic and normosmic patients(P<0.05,FDR correction)including IL-4 and IL-13 signaling,IL-10 signaling,and rhodopsin-like receptors.Conclusions:RNA sequencing of the superior turbinates in patients with CRSsNP can provide valuable information regarding biological pathways and genes involved in olfactory dysfunction.This study supports literature suggesting that Type 2 inflammation may play a role in olfactory dysfunction in at least some patients with CRSsNP.This study also prompts questions regarding the role of IL-10,rhodopsin-like receptors,andIER3 in the pathogenesis of olfactory dysfunction.展开更多
Introduction Country of birth/nativity information may be crucial to understanding health equity in Latino populations and is routinely called for in health services literature assessing cardiovascular disease and ris...Introduction Country of birth/nativity information may be crucial to understanding health equity in Latino populations and is routinely called for in health services literature assessing cardiovascular disease and risk,but is not thought to co-occur with longitudinal,objective health information such as that found in electronic health records(EHRs).Methods We used a multistate network of community health centres to describe the extent to which country of birth is recorded in EHRs in Latinos,and to describe demographic features and cardiovascular risk profiles by country of birth.We compared geographical/demographic/clinical characteristics,from 2012 to 2020(9 years of data),of 914495 Latinos recorded as US-born,non-US-born and without a country of birth recorded.We also described the state in which these data were collected.Results Country of birth was collected for 127138 Latinos in 782 clinics in 22 states.Compared with those with a country of birth recorded,Latinos without this record were more often uninsured and less often preferred Spanish.While covariate adjusted prevalence of heart disease and risk factors were similar between the three groups,when results were disaggregated to five specific Latin countries(Mexico,Guatemala,Dominican Republic,Cuba,El Salvador),significant variation was observed,especially in diabetes,hypertension and hyperlipidaemia.Conclusions In a multistate network,thousands of non-US-born,US-born and patients without a country of birth recorded had differing demographic characteristics,but clinical variation was not observed until data was disaggregated into specific country of origin.State policies that enhance the safety of immigrant populations may enhance the collection of health equity related data.Rigorous and effective health equity research using Latino country of birth information paired with longitudinal healthcare information found in EHRs might have significant potential for aiding clinical and public health practice,but it depends on increased,widespread and accurate avai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
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
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
Objective:To explore the possible neuroprotective activities of Humulus japonicus extract against Parkinson's disease(PD)in a cellular model.Methods:PD was modeled in PC12 cells using 6-hydroxydopamine(6-OHDA).The...Objective:To explore the possible neuroprotective activities of Humulus japonicus extract against Parkinson's disease(PD)in a cellular model.Methods:PD was modeled in PC12 cells using 6-hydroxydopamine(6-OHDA).The cell activity,intracellular levels of reactive oxygen species(ROS),anti-oxidative and anti-apoptotic effects,and other related indicators and related signaling pathways were evaluated to elucidate the neuroprotective effects of Humulus japonicus extract.Results:Humulus japonicus extract exhibited anti-oxidative and anti-apoptotic effects in 6-OHDA-stimulated PC12 cells.It also reduced oxidative stress-induced ROS accumulation;upregulated antioxidant enzymes,such as glutathione,catalase,heme oxidase-1,and 8-oxguanine glycosylase 1;promoted cell survival by decreasing BAX and increasing Bcl-2 and sirtuin 1 expression via the MAPK and/or Nrf2 signaling pathways.Conclusions:Humulus japonicus extract has antioxidative and anti-apoptotic effects and could be developed as a promising candidate for preventing and treating oxidative stress-related neurodegenerative diseases.展开更多
There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie th...There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.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
Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metab...Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.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
基金funded by China Scholarship Council(Grant No.202206180007)funded by China Scholarship Council(Grant No.202206180006).
文摘Background:This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines,named Scientific,Transparent and Applicable Rankings tool(STAR),and test its reliability,validity,and usability.Methods:This study set up a multidisciplinary working group including guideline methodologists,statisticians,journal editors,clinicians,and other experts.Scoping review,Delphi methods,and hierarchical analysis were used to develop the STAR tool.We evaluated the instrument’s intrinsic and interrater reliability,content and criterion validity,and usability.Results:STAR contained 39 items grouped into 11 domains.The mean intrinsic reliability of the domains,indicated by Cronbach’sαcoefficient,was 0.588(95%confidence interval[CI]:0.414,0.762).Interrater reliability as assessed with Cohen’s kappa coefficient was 0.774(95%CI:0.740,0.807)for methodological evaluators and 0.618(95%CI:0.587,0.648)for clinical evaluators.The overall content validity index was 0.905.Pearson’s r correlation for criterion validity was 0.885(95%CI:0.804,0.932).The mean usability score of the items was 4.6 and the median time spent to evaluate each guideline was 20 min.Conclusion:The instrument performed well in terms of reliability,validity,and efficiency,and can be used for comprehensively evaluating and ranking guidelines.
基金the National Natural Science Foundation of China(81520108016,81661148045,and 31471084 to Yu-Feng Zang81671774 and 81630031 to Chao-Gan Yan+11 种基金81571228 to Tao Wu61571047 to Xia Wu81701664 to Jian Wang,81471654 to Biao Huang81701671 to Wei-Guo Liu82001898 to Xi-Ze Jia81771820,81371519 and 81571654 to Wei Luo)Henry G Leong Endowed Professorship in Neurology to Shu-Leong Ho and Shirley YY Pang,BRC for Mental Health at South London and Maudsley NHS Foundation Trust and by the Sackler Institute to Grainne McAlonan,NIH(2R01AG006457 to Fay B.Horak1RC4NS073008-01 and P50NS062684 to Tara Madhyastha)NINDS Intramural Research Program to Mark HallettStart-up Funds for Leading Talents at Beijing Normal UniversityNational Basic Science Data Center‘‘Chinese Data-sharing Warehouse for In-vivo Imaging Brain”(NBSDC-DB-15)to Xi-Nian ZuoGrant NU20-04-00294 of the Agency for Health Research,Czech Republic to Lenka Krajcovicova and Irena Rektorova。
文摘Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].
基金Supported by the Oregon Health&Sciences(OHSU)Institutional Review Board,No.STUDY00026428.
文摘BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.
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
文摘Negotiating a resource package as a potential new department chair is common practice in academic medicine.The foundations for this negotiation include the historical presence of the department in relation to the broader institution,projections for future growth,accounting for mission/vision,resource needs(space,personnel,finances,etc),faculty and staff development,and external partnerships within and outside the institution.Despite similarities in this process across departments,many nuances influence the development of a specific new chair package,such as,department size;desires,perspectives and talents of the incoming chair,the department faculty,the medical school and dean;prevailing agendas and mission imperatives;and the overall priorities of the institution.With strategy and forethought,a new chair package can promote a successful chair tenure and departmental growth.Assembled through the Association of Departments of Family Medicine with input from several dozen department chairs and senior leaders,this is intended to serve as a practical guide to new chair packages for chair candidates.
基金National Institute of General Medical Sciences,Grant/Award Number:NIGMS GM103499MUSC's Office of the Vice President for Research。
文摘Objectives:Prior research on olfactory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role.The purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens,comparing normosmic and dysosmic CRS patients without polyps(CRSsNP).Methods:Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus surgery.Samples subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic(n=7)and normosmic(n=4)patients.Results:Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 genes.Using stringent criteria for multiple comparisons,one upregulated gene(Immediate Early Response 3[IER3])had an false discovery rate(FDR)correction adjustedP value considered statistically significant(P<0.001,fold change 2.69).Reactome functional analysis revealed eight biological pathways significantly different between dysosmic and normosmic patients(P<0.05,FDR correction)including IL-4 and IL-13 signaling,IL-10 signaling,and rhodopsin-like receptors.Conclusions:RNA sequencing of the superior turbinates in patients with CRSsNP can provide valuable information regarding biological pathways and genes involved in olfactory dysfunction.This study supports literature suggesting that Type 2 inflammation may play a role in olfactory dysfunction in at least some patients with CRSsNP.This study also prompts questions regarding the role of IL-10,rhodopsin-like receptors,andIER3 in the pathogenesis of olfactory dysfunction.
基金This work was funded by the NIH National Institute for Minority Health and Health Disparities(grant number R01MD014120 awarded to JH)(grant number K23MD015267 awarded to EB)DMC was in part supported by the Robert Wood Johnson Foundation.
文摘Introduction Country of birth/nativity information may be crucial to understanding health equity in Latino populations and is routinely called for in health services literature assessing cardiovascular disease and risk,but is not thought to co-occur with longitudinal,objective health information such as that found in electronic health records(EHRs).Methods We used a multistate network of community health centres to describe the extent to which country of birth is recorded in EHRs in Latinos,and to describe demographic features and cardiovascular risk profiles by country of birth.We compared geographical/demographic/clinical characteristics,from 2012 to 2020(9 years of data),of 914495 Latinos recorded as US-born,non-US-born and without a country of birth recorded.We also described the state in which these data were collected.Results Country of birth was collected for 127138 Latinos in 782 clinics in 22 states.Compared with those with a country of birth recorded,Latinos without this record were more often uninsured and less often preferred Spanish.While covariate adjusted prevalence of heart disease and risk factors were similar between the three groups,when results were disaggregated to five specific Latin countries(Mexico,Guatemala,Dominican Republic,Cuba,El Salvador),significant variation was observed,especially in diabetes,hypertension and hyperlipidaemia.Conclusions In a multistate network,thousands of non-US-born,US-born and patients without a country of birth recorded had differing demographic characteristics,but clinical variation was not observed until data was disaggregated into specific country of origin.State policies that enhance the safety of immigrant populations may enhance the collection of health equity related data.Rigorous and effective health equity research using Latino country of birth information paired with longitudinal healthcare information found in EHRs might have significant potential for aiding clinical and public health practice,but it depends on increased,widespread and accurate avai
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.
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.
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financially supported by the Ministry of Small and Medium Enterprise and Startups (MSS),Korea,under the Social Economy Innovation Growth Project (R&D)(Project number P0013037)
文摘Objective:To explore the possible neuroprotective activities of Humulus japonicus extract against Parkinson's disease(PD)in a cellular model.Methods:PD was modeled in PC12 cells using 6-hydroxydopamine(6-OHDA).The cell activity,intracellular levels of reactive oxygen species(ROS),anti-oxidative and anti-apoptotic effects,and other related indicators and related signaling pathways were evaluated to elucidate the neuroprotective effects of Humulus japonicus extract.Results:Humulus japonicus extract exhibited anti-oxidative and anti-apoptotic effects in 6-OHDA-stimulated PC12 cells.It also reduced oxidative stress-induced ROS accumulation;upregulated antioxidant enzymes,such as glutathione,catalase,heme oxidase-1,and 8-oxguanine glycosylase 1;promoted cell survival by decreasing BAX and increasing Bcl-2 and sirtuin 1 expression via the MAPK and/or Nrf2 signaling pathways.Conclusions:Humulus japonicus extract has antioxidative and anti-apoptotic effects and could be developed as a promising candidate for preventing and treating oxidative stress-related neurodegenerative diseases.
基金a National Health and Medical Research Council Leadership Fellowship(1195830)has received research funding from The Michael J.Fox Foundation and the Australian Research Council.S.A.F.was supported by The Sartain Lanier Family Foundation.He has been a consultant for Lundbeck,Sunovion,Biogen,Impel,Acorda,and CereSpir.He has received education and research grants from Medtronic,Boston Scientific,Sun Pharmaceuticals Advanced Research Company,Biohaven,Impax,Lilly,US World Meds,Sunovion Therapeutics,Neurocrine,Vaccinex,Voyager,Jazz Pharmaceuticals,CHDI Foundation,The Michael J.Fox Foundation,National Institutes of Health(NIH),and Parkinson’s Foundation.He receives royalties from Demos,Blackwell Futura,Springer for textbooks,and UpToDate.Other support was from Signant(Bracket Global LLC)and CNS Ratings LLC.N.G.serves as consultant to Sionara,NeuroDerm,Pharma2B,Denali,Neuron23,Sanofi-Genzyme,Biogen,and AbbVie.He receives royalties from Lysosomal Therapeutics(LTI)and payment for lectures at AbbVie,Sanofi-Genzyme,and Movement Disorder Society.He received research support from The Michael J.Fox Foundation,the National Parkinson Foundation,European Union,and Israel Science Foundation,as well as from Teva NNE program,Biogen,and Ionis.He receives support from the Sieratzki Family Foundation and the Aufzien Academic Center in Tel-Aviv University.A.N.received funding from the European Commission,Research Foundation Flanders,King Baudouin Foundation,The Michael J.Fox Foundation,Jacques and Gloria Gossweiler Foundation,and KU Leuven Internal Research Funds.M.H.is an inventor of patents held by the NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulationin relation to the latter,he has received license-fee payments from the NIH(from Brainsway).He is on the Medical Advisory Boards of CALA Health and Brainsway(both unpaid positions).He is on the editorial board of approximately 15 journals and receives royalties and/or honoraria from publishing from Cambridge University Press,Ox
文摘There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.
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.
基金This study is partially supported by NIH R01CA235622(to MK).
文摘Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.
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.
