Serum ferritin and the risk of early-onset colorectal cancer

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.

大鼠小脑脑脊液自体输入减少其大脑皮层和海马区的Aβ沉积

目的探讨大鼠小脑脑脊液自体输入对其大脑皮层和海马区β淀粉样蛋白(Aβ)含量的影响及作用机制。方法脑立体定位仪第四脑室抽取脑脊液并注射到同一只大鼠的侧脑室内,饲养1周后,断头法处死大鼠取海马及皮层组织,通过免疫组织化学和酶联免疫吸附试验检测大鼠大脑皮层和海马区Aβ含量,并用Western blot的方法检测胰岛素降解酶(IDE)的表达情况。结果实验组大鼠小脑脑脊液自体输入可以减少自体大脑皮层和海马区Aβ含量,包括可溶性Aβ(P<0.05)和不可溶性Aβ(P<0.05)的含量。同时,IDE的表达较对照组明显增加(P<0.05)。结论大鼠小脑脑脊液自体输入可以降低自体大脑皮层和海马区内的Aβ含量及其造成的病理损伤,这种作用可能是通过上调IDE的表达来实现的。该研究为阿尔茨海默病的临床治疗提供了一个新思路。

Contribution of neutrophils in the pathogenesis of rheumatoid arthritis

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.

Diagnosis and management of ureteral complications following renal transplantation

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.

SPECTRAL IMAGING AND ANALYSIS TO YIELD TISSUE OPTICAL PROPERTIES

An introduction to the basics of spectral imaging as applied to biological tissues is presented.An example of a spectral image of a face is used to demonstrate the data and spectral analysis that specify the melanin content(M),blood content(B),tissue oxygen saturation(S),water content(W),fraction of scattering due to Rayleigh scattering(f)and due to Mie scattering(1−f),and the reduced scattering coefficient at 500-nm wavelength(µ
s 500 nm).The sensitivity of reflectance spectra to variation in the various parameters is illustrated.

Tunneling nanotubes and actin cytoskeleton dynamics in glaucoma

Glaucoma and the actin cytoskeleton:Glaucoma is an optic neuropathy,with pathophysiological changes affecting anterior and posterior tissues of the eye.The trabecular meshwork(TM)in the anterior segment regulates intraocular pressure(IOP),while photoreceptors in the posterior retina convert light into signals that retinal ganglion cells(RGC)transmit to the brain.The TM is a small,fenestrated tissue located in the anterior chamber angle,between the iris and cornea(Figure 1A1).In humans,the majority of aqueous humor fluid drains through the TM into Schlemm’s canal.If the outflow channels become blocked,as in glaucoma,IOP starts to increase,pushing the lens and vitreous back onto the optic disk.Pressure-induced damage to the optic nerve head causes a progressive loss of RGCs and their axons,which leads to irreversible blindness.Surgical or pharmacological management of IOP prevents RGC damage in glaucoma patients.Standard pharmacological therapies either reduce production of aqueous humor fluid,or increase aqueous drainage via the TM or the uveoscleral outflow pathways.Recently,a new class of glaucoma therapies targeting the actin cytoskeleton were approved by the Food and Drug Administration.These are known as the Rho kinase inhibitors,and they act on the Rho/Rho-associated protein kinase signaling pathway to disassemble actin stress fibers in TM and Schlemm’s canal cells(Rao et al.,2017;Lin et al.,2018).While the molecular details are only partially understood,perturbing the actomyosin system can alter cell shape,volume,contractility,and adhesion of cells to extracellular matrix(Tian et al.,2009),which in turn allows greater aqueous outflow and a reduction in IOP.In addition to forming stress fibers,filamentous actin assembles into actin bundles,which are a major component of filopodia,long finger-like projections that emanate from the cell surface,as well as the related cellular protrusions known as tunneling nanotubes(TNTs).

Syringoid eccrine carcinoma of the eyelid presenting as cicatricial entropion

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

Altering the intestinal microbiota for therapeutic benefit in uveitis

An intestinal dysbiosis is connected to a number of inflammatory diseases through various mechanisms relating to its effect on immune cell function and differentiation.This is a review of the literature summarizing our current understanding of intestinal microbial contributions to non-infectious uveitis and strategies to target the intestinal microbiome to treat uveitis.Several groups have demonstrated an intestinal dysbiosis associated with certain types of non-infectious uveitis.Additionally,approaches to treat uveitis by modifying the intestinal microbiota,such as oral antibiotics or administration of oral short chain fatty acids(SCFAs),which are intestinal bacterial metabolites produced by fermentation of dietary fiber,can successfully treat uveitis in mouse models.This reduction in severity of ocular inflammation occurs via the following mechanisms:enhancement of regulatory T cells,decreasing intestinal permeability,and/or affecting T cell trafficking between the intestines and the spleen.Other strategies that are directed at the intestinal microbiota that might be effective to treat uveitis include dietary changes,probiotics,or fecal microbial transplantation.The commensal gut bacteria are influential in systemic and intestinal mucosal immunity and thus contribute to the development of extraintestinal inflammation like uveitis.Targeting the intestinal microbiome thus has the potential to be a successful strategy to treat non-infectious uveitis.

Biologics in non-infectious uveitis past,present and future

Our increase in knowledge of the pathophysiology of non-infectious uveitis(NIU)and other immune-mediated diseases has been mirrored over the last two decades by the expansion of therapeutic options in the realm of immunosuppressive medications.Principal among these advances is the emergence of biologics,which offer the promise of targeted therapy and the hope of reduced toxicity when compared to corticosteroids and“standard”immunosuppression.Among the biologics,monoclonal antibodies blocking tumor necrosis factor alpha(TNF-α)have been shown to be a very effective therapeutic target for uveitis and many associated systemic inflammatory diseases.Multiple TNF blockers have shown benefit for uveitis,and in 2016,adalimumab became the first biologic and non-corticosteroid immunosuppressive to obtain Food and Drug Administration(FDA)approval in the treatment of NIU.Although effective,TNF blockers are not universally so,and safety concerns such as infection and demyelinating disease must be carefully considered and ruled out prior to their use,especially in patients with intermediate uveitis with which multiple sclerosis is a known association.Ongoing study has identified novel targets for regulation in the treatment of immune-mediated and inflammatory diseases.Interferons,interleukin and Janus kinase inhibitors in addition to antibodies targeting T cell and B cell activation highlight the expanding field of treatment modalities in NIU.Ongoing study will be required to better determine the safety and efficacy of biologics in the armamentarium of immunosuppressive treatments for NIU.

The good doctor:more than medical knowledge & surgical skill

Introduction You have worked hard in school over many years to excel in academic and extracurricular activities.You submitted a strong application for successful entry into medical school during which time you doubled up on your academic productivity and soaked in everything that you could possibly learn about medicine.You feel that your academic productivity paid off since you were able to obtain a residency in your favorite field:ophthalmology.You are excited about becoming the best ophthalmic physician and surgeon that you can be.You already know what it takes to tackle large amounts of medical information and you have a feeling that you have the proper kinesthetic skills to become a competent surgeon.So how come this is not enough to be a good doctor?

LABEL-FREE 3D OPTICAL MICROANGIOGRAPHY IMAGING OF FUNCTIONAL VASA NERVORUM AND PERIPHERAL MICROVASCULAR TREE IN THE HIND LIMB OF DIABETIC MICE

Diabetic neuropathy(DN)is,at least in part,associated with the functional attenuation of vasa nervorum,the microvascular structure of peripheral nerves.Microvascular imaging options for vasa nervorum still remain limited.In this work,optical microangiography(OMAG),a volumetric,label-free imaging technique,is utilized for characterizing,with high resolution,blood perfusion of peripheral nerve in diabetic mice.We demonstrate that OMAG is able to visualize the structure of microvasculature and to quantify the changes of dynamic blood flow and vessel diameters during administration of vessel stimulant in both diabetic and normal mice.The results indicate the potential of OMAG to assess the blood supply of nerve involved in the pathology and treatment of DN.

Entropy and enthalpy for triggering cutaneous erythema

The molar entropy(OS)and molar enthalpy(△H)for the denaturation event that triggers cutaneous erythema was determined to be △S=190J/(mole K)and△H=146.9×10^(3) J/mole.The experiment involved placing heated water against the skin of the forearm,for a range of termperatures and exposure times.Exposing the skin to 45℃ for 22 s was at the threshold for producing erythema,which was similar to the threshold for a slight degree of pain.

The Dynamic Relationship of Brain Networks Across Time Windows During Product-Based Creative Thinking

Consensus of creativity research suggests that the measurement of both originality and valuableness is necessary when designing creativity tasks.However,few studies have emphasized valuableness when exploring underlying neural substrates of creative thinking.The present study employs product-based creativity tasks that measure both originality and valuableness in an exploration of the dynamic relationship between the default mode(DMN),executive control(ECN),and salience(SN)networks through time windows.This methodology highlights relevance,or valuableness,in creativity evaluation as opposed to divergent thinking tasks solely measuring originality.The researchers identified seven brain regions belonging to the ECN,DMN,and SN as regions of interest(ROIs),as well as four representative seeds to analyze functional connectivity in 25 college student participants.Results showed that all of the identified ROIs were involved during the creative task.The insula,precuneus,and ventrolateral prefrontal cortex(vlPFC)remained active across all stages of product-based creative thinking.Moreover,the connectivity analyses revealed varied interaction patterns of DMN,ECN,and SN at different thinking stages.The integrated findings of the whole brain,ROI,and connectivity analyses suggest a trend that the DMN and SN(which relate to bottom-up thinking)attenuate as time proceeds,whereas the vlPFC(which relates to top-down thinking)gets stronger at later stages;these findings reflect the nature of our creativity tasks and decision-making of valuableness in later stages.Based on brain region activation throughout execution of the task,we propose that product-based creative process may include three stages:exploration and association,incubation and insight,and finally,evaluation and decision making.This model provides a thinking frame for further research and classroom instruction.

FTY720,a sphingosine analog,altered placentome histoarchitecture in ewes

Background:The lysosphingolipid,sphingosine-1-phosphate,is a well-described and potent pro-angiogenic factor.Receptors,as well as the sphingosine phosphorylating enzyme sphingosine kinase 1,are expressed in the placentomes of sheep and the decidua of rodents;however,a function for this signaling pathway during pregnancy has not been established.The objective of this study was to investigate whether sphingosine-1-phosphate promoted angiogenesis within the placentomes of pregnant ewes.Ewes were given daily jugular injections of FTY720(2-amino-2[2-(−4-octylphenyl)ethyl]propate-1,3-diol hydrochloride),an S1P analog.Results:FTY720 infusion from days 30 to 60 of pregnancy did not alter maternal organ weights nor total number or mass of placentomes,but did alter placentome histoarchitecture.Interdigitation of caruncular crypts and cotyledonary villi was decreased,as was the relative area of cotyledonary tissue within placentomes.Also,the percentage of area occupied by cotyledonary villi per unit of placentome was increased,while the thickness of the caruncular capsule was decreased in ewes treated with FTY720.Further,FTY720 infusion decreased the number and density of blood vessels within caruncular tissue near the placentome capsule where the crypts emerge from the capsule.Finally,FTY720 infusion decreased asparagine and glutamine in amniotic fluid and methionine in allantoic fluid,and decreased the crown rump length of day 60 fetuses.Conclusions:While members of the sphingosine-1-phosphate signaling pathway have been characterized within the uteri and placentae of sheep and mice,the present study uses FTY720 to address the influence of S1P signaling on placental development.We present evidence that modulation of the S1P signaling pathway results in the alteration of caruncular vasculature,placentome architecture,abundance of amino acids in allantoic and amniotic fluids,and fetal growth during pregnancy in sheep.The marked morphological changes in placentome histoarchitecture,including alteration in the vasculature,may be relevant to fetal growth and survival.It is somewhat surprising that fetal length was reduced as early as day 60,because fetal growth in sheep is greatest after day 60.The subtle changes observed in the fetuses of ewes exposed to FTY720 may indicate an adaptive response of the fetuses to cope with altered placental morphology.

Practice patterns and outcomes of equivocal bone scans for patients with castration-resistant prostate cancer: Results from SEARCH

Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-up imaging.Methods:We identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis,of whom 99(15%)had equivocal scans.Men with equivocal scans were segregated into“high-risk”and“low-risk”subcategories based upon wording in the bone scan report.All follow-up imaging(bone scans,computed tomography[CT],magnetic resonance imaging[MRI],and X-rays)in the 3 months after the equivocal scan were reviewed.Variables were compared between patients with a positive vs.negative follow-up imaging after an equivocal bone scan.Results:Of 99 men with an equivocal bone scan,43(43%)received at least one follow-up imaging test,including 32/82(39%)with low-risk scans and 11/17(65%)with high-risk scans(p=0.052).Of follow-up tests,67%were negative,14%were equivocal,and 19%were positive.Among those who underwent follow-up imaging,3/32(9%)low-risk men had metastases vs.5/11(45%)high-risk men(p=0.015).Conclusion:While 19%of all men who received follow-up imaging had positive follow-up imaging,only 9%of those with a low-risk equivocal bone scan had metastases versus 45%of those with high-risk.These preliminary findings,if confirmed in larger studies,suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging.

Comparison of associations of household-level and neighbourhood-level poverty markers with paediatric asthma care utilisation by race/ethnicity in an open cohort of community health centre patients

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 clinics,and can both be used to better tailor asthma care and reduce disparities in primary care safety net settings.

Answering calls for rigorous health equity research:a cross-sectional study leveraging electronic health records for data disaggregation in Latinos

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 availability of this information,co-occurring with other robust demographic and clinical data nativity.

Utilization of RNA sequencing to investigate olfactory dysfunction in chronic rhinosinusitis without nasal polyps:A pilot study

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.

Storylines of family medicine Ⅴ:ways of thinking—honing the therapeutic self

Storylines of Family Medicine is a 12-part series of thematically linked essays with accompanying illustrations that explore the many dimensions of family medicine,as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world.In‘Ⅴ:ways of thinking—honing the therapeutic self’,authors present the following sections:‘Reflective practice in action’,‘The doctor as drug—Balint groups’,‘Cultivating compassion’,‘Towards a humanistic approach to doctoring’,‘Intimacy in family medicine’,‘The many faces of suffering’,‘Transcending suffering’and‘The power of listening to stories.’May readers feel a deeper sense of their own therapeutic agency by reflecting on these essays.