Elderly patients with ST‐elevation myocardial infarction (STEMI) who undergo percutaneous coronary intervention (PCI) are usually excluded from major trials.This study sought to assess 1‐year clinical outcomes following PCI with a drug‐eluting stent in patients older than 80 years old with STEMI.The large all‐comer, multicontinental e‐ULTIMASTER registry included 7507 patients with STEMI who underwent PCI using the Ultimaster stent. The primary clinical endpoint was 1‐year target lesion failure, a composite of cardiac death (CD), target vessel‐related myocardial infarction (TV‐MI), or clinically driven target lesion revascularization (CD‐TLR).p < .001). All‐cause mortality was significantly higher among the elderly group compared to the younger group , as well as CD , but not TV‐MI  or CD‐TLR .There were 457 (6.1%) patients in the elderly group (≥80 years old) that were compared to 7050 (93.9%) patients <80 years. The elderly patients included more female patients and had significantly more comorbidities and had more complex coronary anatomy. The primary endpoint occurred in 7.2% of the elderly, compared to 3.1% of the younger group (Elderly patients with STEMI presentation had a higher incidence of the composite endpoint than younger patients. All‐cause and CD were higher for elderly patients compared to patients younger than 80 years old. However, there was no difference in the incidence of TV‐MI or target lesion revascularizations. These findings suggest that PCI for STEMI in elderly patients is relatively safe. CABGcoronary artery bypass graftingCADcoronary artery diseaseCD‐TLRclinically driven target lesion revascularizationCIconfidence intervalDESdrug‐eluting stentIPSWinverse propensity score weightingMImyocardial infarctionORodds ratioPCIpercutaneous coronary interventionPOCEpatient‐oriented composite endpointSTEMIST‐elevation myocardial infarctionTLFtarget lesion failureTV‐MItarget vessel‐related myocardial infarction1Coronary artery disease (CAD) is the most common cause of death worldwide and is a leading cause of mortality and morbidity in the elderly.Older studies have suggested that age is an independent predictor of adverse outcomes following PCI.Therefore, knowledge regarding the outcome of the elderly referred for PCI in the current era of improved techniques, devices, and pharmacotherapy is limited. Prior studies have shown clear clinical benefits when performing PCI over medical therapy in the elderly group presenting with STEMI.2d,l‐lactic acid polycaprolactone) that is fully metabolized through dl‐lactide and caprolactone into carbon dioxide and water in 3–4 months. This coating is applied on the abluminal side of the struts only; after resorption, a bare‐metal stent (BMS) remains.The e‐ULTIMASTER registry enrolled 37, 198 patients with an indication for PCI. Very few inclusion and exclusion criteria were applied to evaluate the Ultimaster stent outcomes in an all‐comer patient population.clinicaltrial.gov identifier is NCT02188355.The primary endpoint was 1‐year target lesion failure (TLF) defined as the composite of cardiac death, target vessel‐related myocardial infarction (TV‐MI), and clinically driven target lesion revascularization (CD‐TLR). Patient‐oriented composite endpoint (POCE) was defined as all death, any MI, and any revascularization. For myocardial infarction (MI), the extended historical MI definition was applied which primarily uses creatine kinase myocardial band, or if not available troponin, as cardiac biomarker criterion. All primary endpoint‐related events were adjudicated by an independent clinical events committee. The study was approved by the ethical committees of the participating sites and all patients provided written informed consent. The Follow‐up has been performed 3 months and 1‐year postindex procedure. Patients were contacted by telephone or by a visit to the outpatient clinic. Relevant information on adverse events, that is, death, MI, re‐PCI, coronary artery bypass grafting (CABG), bleeding, vascular complication, or stent thrombosis were collected.2.1t‐test. Categorial variables are presented as frequencies (percentage) and compared using the χ2 test or Fischer's exact test, as appropriate. The cumulative events rates were estimated by the Kaplan–Meir method and compared by the logrank test. Hazard ratios and 95% confidence intervals (CIs) were calculated with Cox hazards regression analysis. An inverse propensity score weighting (IPSW) analysis was performed to address differences in baseline patient and lesion characteristics including 22 variables: current smoker, male gender, renal impairment, family history of heart disease, hypertension, severe/moderate calcification, number of lesions identified, balloon predilatation, left main, previous CABG, thrombus aspiration, previous percutaneous transluminal coronary angioplasty, ostial lesion, bifurcation lesion, chronic total occlusion, intravascular imaging, hypercholesterolemia, in‐stent restenosis, acute coronary syndrome (ACS), diabetes mellitus, balloon postdilatation, and radial arterial access .Continuous variables are presented as the mean ± standard deviation and compared using the Student's s Figure . After a3p < .0001). Patients in the elderly group were more likely to be females , and to have more hypertension and renal disease compared to the younger patients , while they were less smokers .A total of 7507 STEMI patients who underwent PCI were included in our analysis Figure , of whicp < .0001), with higher rates of the left main coronary artery treatment , calcified lesions , ostial lesions , and number of stents implanted . The radial artery approach was used more in the elderly group .The angiographic characteristics were different between the groups. The elderly group had more lesions treated during the index procedure compared to the younger patients . All‐cause mortality was significantly higher among the elderly group compared to the younger group , as well as death from cardiac causes , POCE , and bleeding . There was no significant differences in the rates of all MI , TV‐MI , CD‐TLR , or stent thrombosis . At 1 year, 66.4% (261/393) in the elderly group were taking dual antiplatelet therapy and 73.2% (4717/6442) in the nonelderly group, p = .23. More patients were using oral anticoagulation in the elderly group: 8.7% (34/393) versus 3.7% (237/6442), p < .0001.There were 7060 (94.0%) patients with 1‐year follow‐up Figure . The cru3.1p < .001), renal impairment , previous PCI , left main treatment , and the number of lesions treated  emerged as independent predictors for TLF at 1 year , POCE , all death , CD , and bleeding  was higher for the elderly patients . This finding is mainly driven by the CD rate in the elderly group (6.1%), which is higher than the rates reported in the DES arm of the randomized XIMA, SENIOR, and TWENTE trials,In our study, the unadjusted rate of the primary endpoint of 1‐year TLF was significantly higher in the older age group  had more favorable baseline risk factors, fewer prior cardiovascular events, and less severe coronary disease, but lower ejection fraction. At a median follow‐up of 12 months, 51 (8.6%) STEMI patients had died, versus 39 (4.6%) of non‐ST‐elevation ACS patients. After adjusting for sex, age, and previous myocardial infarction, elderly STEMI patients had worse survival and a higher risk of stroke compared with non‐ST‐elevation ACS patients after PCI. The mortality rates are similar to those reported in our current study.The elderly ACS‐2 multicenter trial included 1443 ACS patients aged >75 years (median age 80 years).The After Eighty study was an open‐label randomized controlled multicenter trial, that randomized 457 patients aged 80 years or older with NSTEMI or unstable angina to an invasive strategy or to a conservative strategy in Norway between 2010 and 2014.Among the 229 patients in the After Eighty study invasive group, the procedure was performed via the radial artery in 90%, 48% had three‐vessel disease or left main stenosis. Six patients (3%) underwent coronary artery bypass graft and PCI was performed in 107 patients (49%), with 57% treated with BMS, 37% DES, and 6% balloon angioplasty. Complications included one major PCI‐related bleeding (successfully treated) and 11 periprocedural myocardial infarctions.As the results of our study show, the elderly group who underwent PCI had a more complex procedure with more interventions to the left main, smaller vessels, ostial lesions, and more often calcified lesions. Nonetheless, the transradial artery intervention (TRI) rates were high (>80%) both in the elderly and in the younger groups despite the higher complexity of PCI and higher comorbidities burden in the elderly group, a finding which is consistent with previous studies.Safety is a major concern in elderly patients. Bleeding complications were more frequent in the elderly group compared to the younger group, with similar rates reported in studies using the new generation DES in the elderly.Stent thrombosis is another aspect of postprocedural safety. The low rates of stent thrombosis in our trial are consistent with previous randomized trials with a polymer‐free, drug‐coated stent in patients at high bleeding risk and with a DES in patients in their eighties,Life expectancy in any age group is different. A comparison of the 1‐year mortality rate between the groups has limitations, and the baseline life expectancy must be taken into consideration. The 1‐year mortality rate of 83‐year‐old adults (the mean age of patients in the elderly group) ranges between 4% and 5.7% for females and 6%–7.5% for males in the UK, France, and the USA, while the 1‐year mortality rate among 59‐year‐old adults is 0.5%–0.8% for females and 0.9%–1% for males.In patients presenting with ACS, an invasive approach appears to demonstrate a better benefit–risk ratio compared to a conservative one, across different clinical patient complexity and multiple comorbidities. More powerful strategies of antithrombotic therapy for secondary prevention have been associated with increased bleeding events and have no benefit in terms of mortality reduction.4.1Several potential limitations of this study should be noted. First, its observational nature may affect the way these results are translated into clinical grounds. Baseline characteristics were balanced by IPSW but unmeasured variables with a potential impact on outcomes could not be included. Second, the younger group included patients of a wide range of ages, some of them are close to the age of the elderly ≥80 years old. In addition, indices of frailty were not collected in this trial, as these parameters may vary widely among the elderly population, and, therefore, may affect the clinical outcomes. The findings of this study apply to a specific DES platform and cannot, therefore, be extrapolated to other bioabsorbable or durable polymer DES platforms.5In those presenting with STEMI, elderly patients had more comorbidities and a higher incidence of the composite endpoint TLF than younger patients. The all‐cause death, cardiac mortality, and bleeding rates at 1‐year were higher for elderly patients compared to patients younger than 80 years old. There was no difference in the incidence of PCI‐related outcomes such as recurrent revascularizations, MI, or stent thrombosis. These findings suggest that PCI in the elderly is relatively safe in the era of contemporary DES using this thin‐strut cobalt–chromium sirolimus‐eluting stent. However, even with contemporary DES technology and similar PCI‐related outcomes, elderly patients are still a higher risk population with higher rates of adverse events. This should also be taken into consideration before the decision regarding treatment strategies and the need for post‐STEMI follow‐up, in this age group.The authors declare no conflict of interest.


Postoperative acute kidney injury (AKI) and the requirement for renal replacement therapy (RRT) remain common and significant complications of both transcatheter valve‐in‐valve aortic valve replacement (ViV‐TAVR) and redo surgical aortic valve replacement (SAVR). Nevertheless, the understanding of renal outcomes in the population undergoing either redo SAVR or ViV‐TAVR remains controversial.A systematic database search with meta‐analysis was conducted of comparative original articles of ViV‐TAVR versus redo SAVR in EMBASE, MEDLINE, Cochrane database, and Google Scholar, from inception to September 2021. Primary outcomes were AKI and RRT. Secondary outcomes were stroke, major bleeding, pacemaker implantation rate, operative mortality, and 30‐day mortality.Our search yielded 5435 relevant studies. Eighteen studies met the inclusion criteria with a total of 11,198 patients. We found ViV‐TAVR to be associated with lower rates of AKI, postoperative RRT, major bleeding, pacemaker implantation, operative mortality, and 30‐day mortality. No significant difference was observed in terms of stroke rate. The mean incidence of AKI in ViV‐TAVR was 6.95% (±6%) and in redo SAVR was 15.2% (±9.6%). For RRT, our data showed that VIV‐TAVR to be 1.48% (±1.46%) and redo SAVR to be 8.54% (±8.06%).Renoprotective strategies should be put into place to prevent and reduce AKI incidence regardless of the treatment modality. Patients undergoing re‐intervention for the aortic valve constitute a high‐risk and frail population in which ViV‐TAVR demonstrated it might be a feasible option for carefully selected patients. Long‐term follow‐up data and randomized control trials will be needed to evaluate mortality and morbidity outcomes between these 2 treatments. Over the last decade, a significant drive toward the utilization of bioprosthetic aortic valves has been observed, especially among younger patients prioritizing the avoidance of lifelong anticoagulation and the associated increased quality of life.Postoperative acute kidney injury (AKI) and the requirement for renal replacement therapy (RRT) remain common and significant complications of both treatment modalities.Recently, various meta‐analyses comparing ViV‐TAVR to redo SAVR have been published in the literature. Nevertheless, all of them fell short of reporting renal outcomes, except for Ahmed et al.22.1A systematic review and meta‐analysis were conducted in accordance with the Cochrane Collaboration published guidelines and the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. A literature search was conducted of EMBASE, MEDLINE, Cochrane, PubMed, and Google Scholar from inception to September 2021  inconsistencies in the data precluded valid extraction; (2) the study was performed in an animal model; (3) studies did not have a comparison group; (4) the size of the study population was small (<10 patients). Case reports, reviews, abstracts from meetings, and preclinical studies were excluded. By using the following criteria two reviewers (A. A. R. and R. V.) independently selected articles for further assessment after the title and abstract review. Disagreements between the two reviewers were resolved by a third independent reviewer (V. N.). Potentially eligible studies were then retrieved for full‐text assessment. Studies presenting overlapping data from the same databases were also excluded  and inclusion or exclusion of studies were decided unanimously. When there was disagreement, a third reviewer (V. N.) made the final decision. Using a pre‐established protocol, the following data were extracted: first author, study type and characteristics, number of patients, population demographics, AKI rate, renal replacement rate, operative mortality, 30‐day mortality, stroke, major bleeding, and pacemaker implantation rate. For this review, a data extraction sheet was developed, and pilot‐tested on three randomly selected included studies, whereupon the sheet was refined accordingly. Data extraction was performed by two review authors (A. A. R. and R. V.). A third author (V. N.) validated the correctness of the tabulated data. Potential inter‐reviewer disagreements were resolved by consensus. The primary outcomes were AKI and RRT. Secondary outcomes were hospital stroke, pacemaker implantation rate, major bleeding, operative mortality, and in‐hospital mortality.2.4p‐values for 30‐day mortality, operative mortality, AKI, postoperative dialysis, stroke, major bleeding, and pacemaker implantation rates were calculated. Forest plots were created to represent the clinical outcomes. χ2 test and I2 test were executed for the assessment of statistical heterogeneity. By using a Mantel‐Haenszel random‐effects model, the OR were combined across the studies. Funnel plots were constructed to assess publication bias. All analyses were completed through “metafor” package of R Statistical Software . A two‐tailed p‐value <.05 was considered statistically significant. Meta‐regression analyses were performed to investigate the effects of covariates  on the occurrence of AKI, dialysis, major bleeding, stroke, and operative mortality. Statistical analyses were conducted using the Stata 13.0 software (Stata Corp.).Odds ratios (OR) with 95% confidence interval (CI) and 2.5The influence of a single study on the overall effect of VIV‐TAVR versus redo SAVR on the main outcome was assessed by sequentially removing one study (the “leave‐one‐out” method). This sensitivity analysis was carried out to test the consistency of these results to investigate if individual studies had an excessive impact on the results.33.1The literature search identified 5435 articles. Of these, 115 relevant articles were read in full and assessed according to our inclusion and exclusion criteria. Following the critical appraisal, a total of 18 studies3.2Baseline characteristics of the patients included in the studies are summarized in Table 3.33.3.1p < .001). There was evidence of low heterogeneity among studies reporting on AKI.ViV‐TAVR was compared to redo SAVR with 11 studies3.3.2p = .03). There was evidence of low heterogeneity among studies reporting on postoperative RRT.ViV‐TAVR was compared to redo SAVR with 10 studies3.43.4.1p = .26). There was evidence of high heterogeneity among studies reporting on major bleeding.ViV‐TAVR was compared to redo SAVR in 10 studies3.4.2p = .85). There was evidence of low heterogeneity among studies reporting on stroke.ViV‐TAVR was compared to redo SAVR in 15 studies3.4.3p = .13) among 15 studies.The overall OR for pacemaker implantation rate Figure  demonstr3.4.4p < .001).p = .78).The overall OR for operative mortality , PAD  and preoperative CKD   Table .3.7The sensitivity analysis performed on all outcomes by removing each individual study from the meta‐analysis demonstrated that no single study significantly impacted the OR for AKI, operative mortality, and stroke rate.3.7.1p = .005)  Figure , also re3.7.2p = .005)  Figure , also re3.7.3p = .002)  Figure , also re3.7.4p < .001)  Figure , also re44.1To our knowledge, this is the largest meta‐analysis of comparative studies performed to date focussing on ViV‐TAVR versus redo SAVR and the first with a particular focus on postoperative renal outcomes.In the following meta‐analysis of 18 studies , we found ViV‐TAVR to be associated with lower rates of AKI, postoperative RRT, major bleeding, pacemaker implantation, operative mortality, and 30‐day mortality. No significant difference between ViV‐TAVR and redo SAVR was observed in terms of stroke rate. Metaregression of covariates  did not identify a statistically significant influence of covariates on AKI and postoperative dialysis Table . It is i4.2AKI represents a well‐recognized complication in both SAVR and TAVR. Indeed, irrespective of the treatment modality chosen AKI has been found to be a strong predictor for both worsened short‐ and long‐term mortality and morbidity.Although ViV‐TAVR has been shown to present with lower AKI rates relative to redo SAVR, it must be noted that the incidence of these complications remains of serious concern in ViV‐TAVR as well. The rates of AKI in TAVR remain comparable with the rate found by our analysis in ViV‐TAVR, with a recent major nationwide study of 1,07,814 TAVR patients showing the AKI incidence to be 10.7%.Our analysis also found postoperative RRT requirement to be lower with ViV‐TAVR than with redo SAVR. Data regarding the rates of RRT post‐VIV‐TAVR or redo SAVR remain unclear and vary greatly among studies, our data showed RRT with VIV‐TAVR to be 1.48% (±1.46%) and with redo SAVR to be 8.54% (±8.06%). RRT often constitutes the end spectrum of AKI and has also been associated with poorer short‐ and long‐term mortality, morbidity, and quality of life outcomes. However, it is important to note that patients with CKD often form part of the exclusion criteria for studies. Indeed, Hirji et al.4.3The implications of developing AKI following either ViV‐TAVR or redo SAVR comprise not only a serious issue for patients but could also translate into increased costs and burden for healthcare systems. An analysis4.4Renal Guard System, ensuring Furosemide induced diuresis matched with intravenous isotonic hydration.Reducing the incidence of AKI in patients undergoing ViV‐TAVR or redo SAVR remains of utmost importance. The identification of the numerous procedural and patient‐related risk factors will lead to careful procedural planning and patient selection. Indeed, action to address AKI should take place on multiple fronts. Initially, optimizing renal perfusion preoperatively through adequate patient hydration, inotrope usage, and thorough hemodynamic monitoring should take place, especially for patients with CKD. Nephrotoxic medications discontinuation should also be considered following careful discussion with the Heart Team. Usage of diuretics such as Furosemide, to improve urine output could also be considered. For patients undergoing redo SAVR, although outcomes remain scarce and controversial, Fenoldopam Mesylate (a selective agonist of DA‐1 receptors) could be considered as it has been shown to reduce postoperative AKI incidence.Contrast has been extensively reported to be a known risk factor for AKI, especially in patients with previously diagnosed renal impairment, therefore, the use of noncontract imaging represents another renoprotective avenue. The following is particularly true for patients with an already implanted aortic valve prosthesis, where noncontrast CT scan and angiographic studies could be facilitated by the presence of the prosthesis or the amount of calcium in the aortic annulus.4.5When the study by Majmundar et al.In the present study, the stroke rate was also analyzed, demonstrating no statistically significant difference between ViV‐TAVR and redo SAVR. Contrarily, ViV‐TAVR was associated with lower pacemaker implantation rates when compared to redo SAVR. Deharo et al.4.6Hereby, we found that ViV‐TAVR was associated with better operative mortality outcomes when compared to redo SAVR. Redo aortic valve surgery is known to be related to an increased risk of complications and mortality mainly due to the high risk and frail patients who undergo the operation, which often entails a redo‐sternotomy. The results of Majmundar et al.4.7Although our study provides considerable evidence with regard to both short‐term clinical outcomes and renal outcomes comparing ViV‐TAVR to redo SAVR, there are several limitations in both our study design and reporting of outcomes which impact the interpretation of our results. First, it was not possible to carry out a cluster analysis taking into consideration the different types of valves deployed in both redo SAVR and ViV‐TAVR. Similarly, due to the lack of individual patient data, a comparison based on the pathology of the aortic valve and the grade of AKI was not possible. Heterogeneity remains a further issue of consideration, as patients assigned to ViV‐TAVR tend to be older and have more comorbidities than their redo SAVR counterpart. Even in larger retrospective multicentre studies, the lack of long‐term follow‐up data limits our ability to understand the long‐term performance of the two treatments. Lastly, due to a lack of patient data, it was not possible whether renoprotective strategies were put into place or not.5AKI and the need for RRT both constitute a serious and prevalent complication in both ViV‐TAVR and redo SAVR. Therefore, renoprotective strategies should be put into place to prevent and reduce AKI incidence regardless of the treatment modality. Patients undergoing re‐intervention for the aortic valve constitute a high‐risk and frail population in which ViV‐TAVR demonstrated a lower incidence of AKI, RRT, major bleeding, pacemaker implantation, operative mortality, and 30‐day mortality. Stroke rates remain unchanged between ViV‐TAVR and redo SAVR, demonstrating that ViV‐TAVR might be a feasible option for carefully selected patients. Long‐term follow‐up data and randomized control trials will be needed to evaluate mortality and morbidity outcomes between these two treatments.The authors declare no conflict of interest.Supporting information.Click here for additional data file.


The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Recent evidence indicates that RNA‐dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in tumor formation in a telomere‐independent manner. Non‐canonical function of hTERT has been considered as a therapeutic target for cancer therapy. We have previously shown that hTERT phosphorylation at threonine 249 (p‐hTERT), which promotes RdRP activity, is an indicator of an aggressive phenotype and poor prognosis in liver and pancreatic cancers, using two cohorts with small sample sizes with polyclonal p‐hTERT antibody. To clarify the clinical relevance of p‐hTERT, we developed a specific monoclonal antibody and determined the diagnostic and prognostic value of p‐hTERT in cancer specimens using a large cohort. A monoclonal antibody for phosphorylated hTERT (p‐hTERT) at threonine 249 was developed and validated. The antibody was used for the immunohistochemical staining of formalin‐fixed, paraffin‐embedded specimens from 1523 cases of lung, colon, stomach, pancreatic, liver, breast, and kidney cancers. We detected elevated p‐hTERT expression levels in cases with a high mitotic activity, high pathological grade, and high nuclear pleomorphism. Elevated p‐hTERT expression was an independent prognostic factor for lung, pancreatic, and liver cancers. Furthermore, p‐hTERT expression was associated with immature and aggressive features, such as adenosquamous carcinoma (lung and pancreas), invasive type of cancer (lung), high serum alpha‐fetoprotein level (liver), and triple‐negative status (breast). In conclusion, RdRP activity indicated by p‐hTERT expression predicts aggressive cancer phenotypes in various types of cancer. Thus, p‐hTERT is a novel biomarker for the diagnosis of aggressive cancers with a poor prognosis. © 2022 The Authors.  Cancer causes about one in six deaths worldwide and its incidence is increasing . The inchTERT (TERT) expression levels in cancer remains elusive  and incubated at 30 °C for 30 min.Details are provided in Supplementary materials and methods. Anti‐hTERT mouse monoclonal antibodies (clones 10E9‐2 and 2E4‐2) were generated, and the specificity was evaluated as reported previously . Anti‐hTDetails are provided in Supplementary materials and methods. hTERT was immunoprecipitated from human cell lines as described previously with an anti‐hTERT mAb (clone 10E9‐2) , 16, 21.Total RNA was isolated from human cell lines using the RNeasy Mini Kit  and treated with the RNase‐Free DNase Set (Qiagen). cDNAs were synthesized from total RNA using SuperScript IV VILO Master Mix (Thermo Fisher Scientific Inc), amplified by PCR using the TaqMan Gene Expression Assay , and analyzed with the StepOnePlus Real‐Time PCR System (Thermo Fisher Scientific).http://cohort.umin.jp/english/index.html) . All tumors were taken at diagnosis. We adhered to the REMARK criteria /[median value of telomere/centromere ratio of control HFL‐1 cells]. Patients were divided into two groups based on [normalized telomere length of cancer cells]/[normalized telomere length of fibroblasts], with a cut‐off value of 1.2 to obtain cases with short telomeres (under 1.2) and cases with long telomere lengths (over 1.2).t‐test, χ2 test, and Fisher's exact test. Three or more groups were compared by an analysis of variance (ANOVA) and Tukey's test. Correlations were assessed by Pearson's and Spearman correlation coefficients. Survival was analyzed by Kaplan–Meier curves and a Cox proportional hazard model. Univariate and multivariate analyses were performed using sex, age , p‐hTERT expression , and TNM stage. The level of significance was set at p < 0.05 for all analyses. Statistical analyses were performed using JMP Pro 14  and Statistical Package for the Social Sciences version 22 .Two groups were compared by the unpaired in vitro kinase assay reconstituted by CDK1–cyclin B proteins with two different versions of recombinant hTERT proteins [hTERT amino acids 191–306 [hTERT [hTERT [in vitro  directed against hTERT phosphorylated at Thr249. In combination with validated monoclonal antibodies specific for total hTERT proteins (clones 10E9‐2 and 2E4‐2) , we comp 191–306   was detected in cancer cell nuclei Figure . The frep < 0.0001), colon (p = 0.0068), stomach (p < 0.0001), pancreas (p = 0.0010), and liver (p < 0.0001)  Figure . We confp < 0.0001), pancreas (p < 0.0001), and liver  and liver , and liver  0.58, 95% confidence interval (CI) 0.36–0.93, p = 0.0223; p = 0.0866), pancreas , and liver  mitotic activity in lung, colon, stomach, pancreatic, and liver cancers; (2) pathological grade (differentiation) in lung, pancreatic, and liver cancers; (3) nuclear score (nuclear pleomorphism) in lung and liver cancers; (4) squamous differentiation in lung and pancreas cancers; and (5) aggressive immature features in lung, pancreatic, liver, and breast cancers, as summarized in supplementary material, Table hTERT canonically regulates telomere lengthening via hTERT recruitment to telomeres at the S‐phase. However, we have previously demonstrated that it exhibits RdRP activity at the M‐phase , and thiWe found that p‐hTERT expression has prognostic value in lung, pancreatic, and liver cancers but not in colon and stomach cancers. Interestingly, although p‐hTERT expression increased as the mitosis score increased in all of these cancers, p‐hTERT expression decreased as the pathological grade increased in colon and stomach cancers. It is unclear why the relationships between p‐hTERT expression, mitosis scores, and pathological scores differed according to the cancer origin. We found that cancer cells in the mucosal layer showed higher expression levels of p‐hTERT than those in the muscular or subserosal layer in colon and stomach cancers (unpublished data). It is possible that additional mechanisms regulate p‐hTERT expression, potentially related to the tumor microenvironment, in the mucosal layer of cancer originating in luminal organs.Although p‐hTERT expression is associated with immature and aggressive pathological/clinical features in several cancers, correlation with poor prognostic outcome was only shown in lung, pancreatic, and liver cancers. One possibility to explain the different clinical impacts of p‐hTERT expression on prognosis in distinct cancer subtypes would be the surgical procedures and curability. Curative surgical resection is generally achieved in limited cases of lung, liver, and pancreatic cancers, potentially due to the microscopic tumor dissemination at the time of surgery, resulting in early recurrence with poor prognosis. In contrast, radical resection could be technically achieved irrespective of immature and aggressive features in some colon and stomach cancers. In these cancers, the value of p‐hTERT expression evaluation might be limited. Another possibility is that more impactful genetic alteration or molecular abnormality, in addition to p‐hTERT phosphorylation, might exist and determine the patients' prognosis in colon, stomach, and breast cancers. To clarify the prognostic utility of p‐hTERT in low‐risk patients, therefore, we have analyzed p‐hTERT expression in pancreatic neuroendocrine tumor and found an association between p‐hTERT expression and large tumor size and high mitotic activity, suggesting that p‐hTERT might be a marker of cancers with aggressive features even in low‐risk localized disease (unpublished data).We have also analyzed the intensity and H‐score of phosphorylation of hTERT 249T of most of the cases . However, only high H‐score was correlated with poor prognosis in lung cancer but not in other cancers. The percentage of phosphorylation of hTERT showed the most significant correlation with prognosis in lung, pancreas, and liver cancers as compared with the intensity and H‐score. Evaluation of the percentage of p‐hTERT might be the best approach in a clinical setting.Our results indicate that the evaluation of p‐hTERT could be utilized for prognostic stratification in clinical settings. Furthermore, our monoclonal antibody can detect p‐hTERT in formalin‐fixed, paraffin‐embedded samples using an automatic immunostaining system, thus providing a basis for the development of a novel clinical diagnostic tool to identify patients with aggressive cancer.YMa, JY and NM curated the data. YMa, YK and KM acquired funding. JY, MY, KY, YMu, MM, SY, JT and MKa carried out the investigation. YMa, TYa, YK and KM were responsible for methodology, and YD, YMi, TYo, TO, HI, SM, TK, TM, MKo, SK, TM, MH, RH, KK, NK and KO for resources. YMa was responsible for software. YMa, TYa and KM supervised the study. YMa wrote the original draft, and YMa, TYa and KM reviewed and edited the final manuscript.Supplementary materials and methods Figure S1. p‐hTERT expression is not associated with TNM stageFigure S2. p‐hTERT expression is not associated with ageFigure S3. p‐hTERT expression is not associated with sexFigure S4. Positivity of Ki67 was associated with mitosisFigure S5. p‐hTERT and survivalFigure S6. p‐hTERT and survival of liver cancer cohortsFigure S7. (A) Noguchi classification and p‐hTERT in lung cancer. (B) Serum AFP levels and p‐hTERT in liver cancer. (C) Triple‐negative breast cancer and p‐hTERTFigure S8. Mitosis score and survivalFigure S9. Telomere length and survivalFigure S10. Non‐telomeric and telomeric function of hTERTTable S1. Human cell lines usedTable S2. Clinicopathological characteristics of patients with high and low hTERT phosphorylationTable S3. Clinicopathological factors related to high levels of p‐hTERTClick here for additional data file.


The treatment of bone defects by stem cells (MSCs) has achieved limited success over the recent few decades. The emergence of exosomes provides a new strategy for bone regeneration. Here, we aimed to investigate the effect and mechanisms of exosomes combined with dental pulp stem cells (DPSCs) on bone regeneration.We isolated exosomes from stem cells from human exfoliated deciduous teeth (SHED) aggregates and evaluated the efficacy of exosomes combined with DPSCs in a cranial bone defect model. The potential mechanisms were further investigated.The effect of exosomes combined with DPSCs was remarkable on bone regeneration in vivo and exosomes promoted osteogenic differentiation of DPSCs in vitro. Mechanistically, exosomes increased the expression of mitochondrial transcription factor A (TFAM) in DPSCs by transferring TFAM mRNA. Moreover, highly expressed TFAM in DPSCs enhanced glutamate metabolism and oxidative phosphorylation (OXPHOS) activity.Consequently, exosomes strengthened bone regeneration of DPSCs through the activation of mitochondrial aerobic metabolism. Our study provides a new potential strategy to improve DPSC‐based bone regenerative treatment. Exosomes increase mitochondrial transcription factor A (TFAM) expression in DPSCs by transferring TFAM mRNA. Moreover, highly expressed TFAM in DPSCs enhances GDH expression and OXPHOS activity. Meanwhile, glutamate metabolism provides amounts of NADH to OXPHOS. Consequently, exosomes strengthen osteogenic differentiation of DPSCs through the activation of mitochondrial aerobic metabolism. Due to the complexity of the local environment, the lack of autologous bone sources and the difficulties with the blood supply, treatment based on autologous bone grafting is still unable to meet clinical needs. Dental pulp stem cells (DPSCs) located in the pulp tissue of adults have great advantages in bone regeneration, including excellent biological properties, facile obtainment and no serious ethical problems. DPSCs have widely been used in the regeneration of various tissues, including the spinal cord,Due to the ability of efficient ATP production to sustain cell function, mitochondria are often considered the “powerhouses of the cell.”As a newly recognized mechanism of bone formation and bone homeostasis, exosomes shuttle selective proteins, lipids, nucleic acids and glycoconjugates,In the present study, we investigated the effects of DPSCs combined with exosomes derived from SHED aggregates on bone regeneration in a cranial bone defect model in mice and a mandibular bone defect model in rats. Mechanistically, exosomes transferred TFAM mRNA and increased TFAM expression in DPSCs, which activated mitochondrial OXPHOS and osteogenic differentiation. Our research revealed the unrecognized role of exosomes in transferring the mtDNA regulator TFAM to enhance osteogenic differentiation, which provides a novel strategy for the treatment of bone loss.22.1Tissue‐specific MSCs in the dental pulp were successfully isolated from healthy adults (DPSCs) and children (SHED) and detected by flow cytometry Figure A–D. ThenWe performed a functional assay to assess whether exosomes derived from SHED aggregates contribute to the osteogenic differentiation of DPSCs. First, the osteogenic effects of exosomes at different concentrations  were assessed by quantitative real‐time reverse transcriptase–polymerase chain reaction (qRT‐PCR). In comparison with groups with other exosomes' concentrations , the expression of Runt‐related transcription factor 2 (Runx2) was significantly increased in the 90 μg/ml exosomes group Figure . DPSCs t2.2To investigate the in vivo bone regeneration capacity of DPSCs with exosomes, we implanted DPSCs combined with exosomes on a model of cranial bone defects in mice. Micro‐computed tomography (micro‐CT) showed bone repair of each group in three dimensions Figure . QuantitIn addition, we adopted a rat model of mandibular bone defect. As shown by micro‐CT, there was obvious bone regeneration in the EXO + DPSCs + HA group compared with the Control, HA and DPSCs + HA groups Figure . HE stai2.3Based on our observation of colocalization between exosomes and mitochondria in DPSCs Figure , we assul‐glutamate to α‐ketoglutarate (α‐KG) into the TCA cycle.As exosomes significantly heightened the OCR of DPSCs, DPSCs might consume a certain nutrient increase, such as glucose, amino acids and fatty acids. However, the extracellular acidification rate (ECAR) of glucose metabolism did not differ between the EXO group and the PBS group Figure , as indi2.4As we observed the augmentation of TFAM mediated by exosomes, we examined whether this effect would enhance mitochondrial OXPHOS to promote osteogenic differentiation of DPSCs. The qRT‐PCR assay and western blot showed that exosomes partly restored TFAM expression in TFAM‐KD DPSCs Figure . Next, wFurthermore, there was a significant decrease in protein expression of GDH, and mitochondrial complexes I–V in TFAM‐KD DPSCs, but the addition of exosomes increased the expression of these proteins Figure . Interes2.5We then investigated the underlying mechanism by which exosomes increase the TFAM expression of DPSCs. Exosomes contained more TFAM mRNA than DPSCs Figure  but had In conclusion, TFAM mRNA was shuttled by exosomes and then expressed in DPSCs. TFAM directly enhanced the expression of mitochondrial OXPHOS complexes and supported glutamate metabolism to enhance mitochondrial OXPHOS. Aerobic metabolism mediated by TFAM promoted osteogenic differentiation of DPSCs Figure .3In this study, we found that the combination of DPSCs and exosomes repaired defective cranial bone in mice and mandibular bone in rats. Our study revealed a previously unrecognized mechanism of exosomes in transferring TFAM mRNA to regulate mtDNA and GDH expression, which enhances mitochondrial OXPHOS and osteogenic differentiation of DPSCs.Bone tissue engineering offers a promising alternative of generating constructs composed of instructive biomaterials, including MSCs and exosomes, which could enhance the outcome of reconstructive treatments.Exosomes prompted the rise of TFAM, which aroused our interest. TFAM binds to mtDNA to regulate the transcription of subunits of the mitochondrial electronic respiration chain so as to affect aerobic respiration of mitochondria,Mitochondrial metabolism is emerging as an instructive signal for cell fate programs,We found that TFAM was necessary for osteogenesis differentiation in DPSCs. It has been reported that probiotic treatment increases TFAM expression in osteoblasts by promoting Kdm6b/Jmjd3 histone demethylase, which inhibits H3K27me3 epigenetic methylation at the TFAM promoter.44.1l‐glutamine , 100 units/ml penicillin and 100 mg/ml streptomycin  at 37°C in 5% CO2, cultured for 2 weeks and the medium was changed every 3 days. To further purify the stem cells, single‐cell‐derived colonies were obtained using the limiting dilution technique.The experimental protocols were approved by the Hospital Ethics Committee (No. IRB‐REV‐2018020). Consent forms were obtained before conducting this research project. Tooth samples from healthy adults and kids were collected from 7 adults, aged 20–30 years and 3 kids, aged 8–10 years. Donor information is listed in Tables SHED was isolated and cultivated under the protocol previously described. SHED used for each experiment was at passage 2nd–5th.4.2Enriched exosomes were labelled with PKH67  in accordance with the manufacturer's protocol. DPSCs were seeded in confocal dishes  and incubated with the labelled exosomes for 24 h. 4′,6‐diamidino‐2‐phenylindole  was used for staining nuclei, and MitoTracker  was used for staining mitochondria. The uptake of exosomes was visualized by a confocal fluorescence microscope .4.3Total RNA was extracted with TRIzol reagent  and converted to cDNA using PrimeScript™ RT Master Mix Kit . Then, qRT‐PCR was conducted with TB Green® Premix Ex Taq™ II  using the quantitative PCR System . The primers are shown in Table 4.4For osteogenic experiments, the osteogenic medium containing 90 μg/ml exosomes or PBS was changed every 48 h. For metabolism experiments, exosomes were added to the growth medium every 48 h for a total of 2 times.Primary antibodies employed in this study included β‐actin , ALP , Runx2 , BMP2 , TFAM , total OXPHOS cocktail , Glut1 , GDH , and CPT1A . The secondary antibody was HRP‐conjugated to antibodies in rabbits and mice. The amount of protein was semiquantified by grey‐scale analysis using ImageJ 1.53c  and normalized to β‐actin as an internal standard.4.5Alizarin red staining  was used to assess calcium deposits, and 10% cetylpyridinium chloride was added for quantitative analysis. The absorbance values were measured at 562 nm.4.6Six‐week‐old male C57BL/6J mice for the cranial bone defect model were purchased from the Animal Center of the Fourth Military Medical University, China. All animal experiments were approved by the Animal Ethics Committee of the Fourth Military Medical University, Xi'an, China (No. 2022030).n = 6); (2) a group with 20 mg HA powder only ; (3) a group treated with DPSC aggregates  wrapping 20 mg HA powder ; and (4) a group treated with the combination of DPSC aggregates and exosomes (90 μg/ml exosomes were added into DPSCs every 48 h during the aggregates' induction), wrapping 20 mg HA powder . After 8 weeks, the samples were harvested from the mice and fixed with 4% paraformaldehyde for 12 h.The cranial bone defect model used was modified based on the previous research.4.7Bone samples were scanned using a Micron X‐ray three‐dimensional (3D) Imaging System  with 9 μm resolution. 3D images were reconstructed and analysed by the VG Studio 3.4 . For measurement, a region of interest (ROI) of approximately 2.5 mm in diameter was defined in the cranial bone. The BV/TV, the ratio of new bone area to the defect area, Tb.N and Tb.Sp were calculated.4.8After micro‐CT analysis, the mandibles were decalcified with 17% ethylenediaminetetraacetic acid (EDTA)  for 1 month and then embedded in paraffin. Paraffin sections (3‐mm‐thick) were stained using HE, as described previously.4.9The paraffin sections were stained with Masson trichrome staining  in accordance with the manufacturer's instructions. Photographs were taken using a microscope (OLYMPUS).4.104/well) were seeded in XF24‐cell culture plates  and treated with exosomes for 24 h under the growth conditions. The OCR and ECAR were measured in an XF24 Flux Analyser . In the OCR assay, cells were first measured under basal conditions and then stimulated with oligomycin (1 μM), FCCP (2 μM), rotenone (2 μM) and antimycin A (2 μM) to determine different parameters of mitochondrial functions. In the ECAR assay, glucose (10 mM), oligomycin (1 μM) and 2‐DG (50 mM) were subsequently added into the medium.DPSCs (2 × 104.116/well) treated with exosomes at 0, 24, 48 and 72 h were detected by NADH/NAD assay kit  in line with the instructions.DPSCs , and transferred to a 96‐well plate. The 96‐well plate was placed on a micro‐shaker for 2 min, incubated at room temperature while avoiding light for 10 min, and its chemiluminescence value was detected.A total of 104.13For the shRNA knockdown experiments, DPSCs and SHED were treated with lentivirus, which carried TFAM shRNAs, in line with the manufacturer's protocol . Briefly, DPSCs and SHED were infected with shTFAM lentivirus at a multiplicity of infection (MOI) of 10. At 48 h after the shRNA induction, the cells were analysed for expression levels of TFAM and were used for the following experiments.4.14t tests. Comparisons among three or four groups were evaluated by one‐way ANOVA followed by an LSD post hoc test. A p‐value less than 0.05 was considered statistically significant.All results were presented as the mean ± SD of at least three independent experiments. Two‐group comparisons were analysed by Student's 5Exosomes derived from SHED aggregates promote DPSCs osteogenic differentiation, which contribute to cranial bone defect reparation. Moreover, the exosomes transfer TFAM mRNA to DPSCs and might activate mitochondrial OXPHOS to increase osteogenic differentiation. Our study provides a new potential strategy to improve the clinical therapy with DPSCs in bone regenerative medicine.Jia Guo contributed to the study design, execution, data acquisition, and interpretation. Feng Zhou and Yuan Cao performed the animal experiments. Zhi Liu and Qiming Zhai helped in cell collection and data analysis. Wanming Zhao contributed to study design and interpretation. Zheru Zhang drew the picture. Bei Li, Fang Jin and Yan Jin designed the experiments, oversaw the collection of results and data interpretation, and drafted the reports. All authors have seen and approved the final version.The authors have declared that no competing interest exists.Appendix S1 Supporting Information.Click here for additional data file.


A 67‐year‐old female was hospitalized due to right‐sided hemiparesis and neck pain with rapid deterioration to a deep coma. She had received the Sinopharm vaccine 2 days earlier. MRI showed extensive cervicothoracic hematomyelia. She received intensive medical care for 2 months and was discharged. An 18‐month follow‐up showed significant neurological recovery. COVID‐19 vaccines are relatively safe, but serious complications are expected regarding their emergency approval. Hematomyelia, such as other spinal cord lesions, can be expected in the post‐vaccination period, emphasizing higher healthcare providers' awareness. Headache, peripheral neuropathy, intracerebral hemorrhage, stroke, encephalitis, and Guillain–Barré syndrome are the most common nervous system manifestations of SARS‐CoV‐2.SARS‐CoV‐2 vaccines are generally safe and effective in preventing COVID‐19 pneumonia in emergency global SARS‐CoV‐2 situation.In this case, we report a rare coincidence of spontaneous intramedullary hematoma following the Sinopharm anti‐COVID‐19 vaccine.2A 67‐year‐old female known case of hypothyroidism was admitted to the emergency department due to right‐sided hemiparesis and neck pain in March 2021. She was agitated but fully conscious and cooperative. According to her history, she had received her first Sinopharm vaccine shot 2 days earlier and, after 24 h, started to feel weak and painful on her right side. The pain was radiating from the right side of the neck to her right extremities. The pain quality was burning in nature and accompanied by a tingling sensation in pain distribution areas. The weakness was more severe in her right hand and elbow than in her right knee and ankle. Her vital signs were stable in physical examination, and her Glasgow coma scale (GCS) score was 15 with normal reactive pupils. Incidental right‐sided mild facial paresis was detected. The rest of the cranial examination showed no specific abnormality. Her manual muscle strength testing (MMT) showed right‐sided hemiparesis and hypoesthesia–dysesthesia, right upper extremity force 3/5, and right lower extremity 4/5. She had controlled long‐standing hypothyroidism and was receiving 100 μ grams of Levothyroxine daily. She was not receiving any anticoagulants or anti‐platelets. Her PT, PTT, INR, D‐dimer, and platelet counts were in normal range. Her daughter mentioned she had a benign skin melanoma that was excised 6 years ago and was under regular dermatologist follow‐up. There was no history of autoimmune diseases. The rest of the medical history and laboratory data were negligible.2.1Routine blood tests were obtained. According to her presentations, an ongoing stroke or carotid dissection was suspected for her. Unfortunately, 10 min after admission, she experienced a rapid onset of abdominal pain, seizure‐like movements, loss of consciousness, and bradycardia. Rapid endotracheal intubation, hemodynamic support, and 3 min of resuscitation were performed, and she was stabilized. Serial EKG and troponin tests showed no acute cardiologic problems. Brain CT scan showed no acute intracranial process, so she was transferred to the neurological ICU. After further stabilization, a brain MRI was obtained to rule out stroke within an hour. Brain MRI sequences showed no acute stroke or other intracranial lesions Figure . Due to 2.2In follow‐up appointments, her modified Rankin Scale (mRS) was 3, and facial paresis was slightly improved. Right‐sided upper extremity MMT was 3/5, and right lower extremity force was 4/5. She was able to walk with walker assistance. Two months later, she took SARS‐CoV‐2 pneumonia and recovered in 2 weeks. After 8 months, she had a ground‐level falling during daily activities that caused a type A3 burst fracture in the L3 vertebral body and underwent cement kyphoplasty , cytokine storming, immune complex‐mediated reactions, angiotensin‐converting enzyme‐2 (ACE‐2) mediated virus invasion, and thrombotic microangiopathy are the most accepted theories.The pathophysiology associated with nervous system manifestations of COVID‐19 vaccines is not clearly understood. It is rational to presume that virus and vaccines share common pathways in immunologic responses. The degree of virus inactivation–reactivation, immune complex‐mediated reactions, cytokine‐mediated systemic response, and vector‐associated complications are suggested.Lu et al.Finstere and Scorza narrated on Lu's review, disagreed with their safety concepts, and tried to disclose post‐vaccination strokes, neuropathy, myelitis, and acute disseminated encephalomyelitis (ADEM) neuropathogenesis.Fan et al.The Sinopharm vaccine is based on inactivated SARS‐CoV‐2 virus administered in multiple doses via intramuscular injection. Kaabi et al. conducted an extensive study on the safety and side effects of the Sinopharm vaccine on approximately 11,000 personnel. They reported 153 SARS‐CoV‐2 PCR‐positive individuals after two doses of vaccination, 92 people with mild COVID‐19 pneumonia, and two cases requiring hospitalization for their post‐vaccination COVID‐19 pneumonia.Spontaneous intramedullary hematoma or hematomyelia is an ominous neurological event. Although predisposing factors such as tumors, vascular malformations, and coagulopathic conditions are associated with hematomyelia, most reports delineate no specific reason.Arman Sourani: Conceptualization; investigation; project administration; validation; writing – original draft; writing review and editing. Majid Rezvani: Investigation; project administration; supervision; validation; writing – review and editing. Mina Foroughi: Conceptualization; data curation; supervision; validation; visualization; writing – original draft; writing – review and editing. Sadegh Baradaran Mahdavi: Data curation; investigation; methodology; supervision; validation; visualization; writing – original draft; writing – review and editing.Not applicable.The authors declare no conflict of interest.All procedures performed were under the institutional and/or national research committee's ethical standards and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This report was supervised and approved by Isfahan University neurosurgery department board members on behalf of the Ethical Committee of Isfahan University of medical sciences.Informed consent was obtained from all individual participants included in the Study.


Anti‐PD1 checkpoint inhibitors (ICI) represent an established standard‐of‐care for patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥2; the benefit of ICI in this population is therefore unknown.We retrospectively reviewed RMHNSCC patients who received 1+ dose of ICI at our institution between 2013 and 2019. Demographic and clinical data were obtained; the latter included objective response (ORR), toxicity, and any unplanned hospitalization (UH). Associations were explored using uni‐ and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, toxicity, and UH were evaluated with logistic regression.p < 0.001; HR = 3.30, CI = 2.01–5.41). An association between OS and former (vs. never) smoking was also seen ; current smoking did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR  and increased UH . There was no significant association between toxicity and any patient characteristic.Of the 152 patients, 29 (19%) had an ECOG PS ≥2. Sixty‐six (44%) experienced toxicity; 54 (36%) had a UH. A multivariate model for OS containing PS, smoking status, and HPV status demonstrated a strong association between ECOG ≥2 and shorter OS (We observed inferior OS, ORR, and rates of UH among ICI‐treated RMHNSCC patients with ECOG 2/3. Our findings help frame discussion of therapeutic options in this poor‐risk population. Relative to those with a performance status of 0‐1, patients with an Eastern Cooperative Oncology Group performance status 2 who received immune checkpoint inhibitors for recurrent/metastatic head and neck cancer have poorer response rates and overall survival as well as increased rates of unplanned hospitalization; no significant difference in toxicity was seen. These agents confer a survival benefit in the first and second line settingAppropriate patient selection when utilizing ICI in RMHNSCC can be a challenging clinical dilemma.We examined the pattern of ICI use among RMHNSCC patients at our institution with specific focus on patients with poor PS. We sought to explore the relationship between ECOG PS and oncologic outcomes in addition to obtaining data on the toxicity and unplanned hospitalization (UH) in this group of patients.2We identified a cohort of RMHNSCC patients who were treated with at least one dose of ICI at our institution. Demographic and oncologic data obtained from electronic medical records were recorded in an IRB‐approved database. This project was reviewed and approved by the Fred Hutchinson Cancer Research Center institutional review board.Performance status was evaluated using the Eastern Cooperative Oncology Group (ECOG) scale and was documented by the patients' oncology team on the day of ICI administration. We defined “poor performance status” as an ECOG PS greater than or equal to 2. Four other patient variables , prior lines of therapy (which included systemic therapy given in the curative‐intent setting), and patient‐reported race) were also collected for association testing.Unplanned hospitalization (UH) referred to any unscheduled inpatient admission that occurred between the first dose of ICI and 100 days after the last dose of ICI. Objective response (ORR) was determined both radiographically, as guided by RECIST 1.1 criteria, and clinically, as determined and documented by the patient's primary oncologist; formal RECIST response confirmation was not performed routinely outside of a clinical trial. Treatment‐related toxicity, as graded/reported by the treating physician following initiation of ICI therapy, was also recorded.2.1Overall survival (OS) was defined as time from initiation of ICI to death from any cause.. OS was estimated using the Kaplan–Meier method; p‐values were from the log‐rank test. A multivariate analysis was performed using Cox regression to explore the relationship between survival, ECOG PS, and other patient factors as noted above. The software “R” was used for all analysis.Hospitalization, toxicity, and objective response were evaluated using logistic regression models3n = 124; 81.6%) and White . The most common primary sites were the oropharynx  and the oral cavity . Fifty‐four (35.5%) had p16+ cancers; seven (4.6%) were EBV+. Sixty‐nine (45.4%) were never‐smokers, while 66 (43.4%) were former smokers and the remaining 17 (11.2%) currently smoked. Sixty‐six (43.4%) had a pack‐year history (PYH) >10 years (Table We identified 152 patients treated with ICI at our institution between 2013 and 2019. The average age was 61 (range = 25–90) years. The majority of patients were male  had an ECOG performance status score of 0, 75 (51.4%) had a PS score of 1, 27 (18.5%) had a PS score of 2, and 2 (1.4%) had a PS score of 3. Six individuals did not have a score recorded and were excluded from our analysis.Although PD‐L1 expression testing was not routinely performed at the time of study, ten patients (6.6%) did have an available Tumor Proportion Score (TPS) or a Combined Positive Score (CPS); of these, nine (5.9%) had a score ≥1.n = 144; 94.7%) had received prior therapy; the median number of treatment lines was 1 (range = 0–5). Thirty‐two (21.1%) received XRT within 3 months of ICI. Patients typically received ICI monotherapy ; the remainder received combination therapy, most commonly with ICI + vorinostat while on a clinical trial. Additional treatment characteristics can be seen in Table The majority of patients (irty‐two 1.1% recep = 0.001). Neither smoking, race, number of prior lines of therapy, nor viral association appeared to affect this variable in our cohort (Table Unplanned inpatient admission occurred in 57 38.3%) patients. Patients with poor ECOG PS (2/3 vs. 0/1) experienced higher rates of UH  was achieved in 10 patients (6.7%). Partial response (PR) was seen in 33 (22%) and stable disease (SD) was seen 32 (21.3%). The remaining 75 (50%) experienced progressive disease (PD) as best response; these patients were more likely to have higher ECOG PS at the time of ICI initiation  and smoking status (p = 0.005) were significantly associated with OS. Neither viral association (p = 0.136) nor number of prior lines of therapy (p = 0.54) appeared to correlate with OS in our cohort of ICI‐treated RMHNSCC  had documented disease progression and 101 (69.7%) patients had died. ECOG , as well as smoking status  were independently associated with inferior survival outcomes , while p16+ (HPV‐related) RMHNSCC was associated with improved OS  relative to p16‐ malignancy.On multivariable analysis for overall survival, ECOG PS  in patients with poor PS. Although the reasons for hospitalization were not captured within our dataset, Correa et al. observed an association between higher PS and worsening dysphagia and large tumor burden in the RMHNSCC population. Admissions may therefore reflect challenges with symptom management  that are well documented in advanced disease.Although the current body of evidence is small, our results suggest that survival outcomes from landmark trials evaluating ICI efficacy in RMHNSCC may not be generalizable among patients with poor PS. Further study must be done to evaluate this issue as, at present, it is challenging for clinicians to appropriately counsel patients in this population on anticipated outcomes. While largely regarded to be tolerable, ICI is not without risk; 66 (44%) of the patients in our study experienced grade II/III physician‐reported treatment‐related toxicity; in addition, continuing with therapy can be both costlyOur single‐center, retrospective study had several limitations. The sample size was small and predominantly involved White males; our results may not be generalizable to the broader community of RMHNSCC patients. This was a heterogeneous population reflecting a high‐volume, real‐world clinical practice and included less common and biologically diverse subsets such as EBV‐related nasopharyngeal carcinomas, head and neck cutaneous squamous cell carcinomas, and paranasal sinus squamous cell carcinomas. Oncologic therapy and outcomes that occurred outside our system were not captured in this dataset. In addition, PD‐L1 expression (TPS/CPS score) was not consistently captured and could not be evaluated; as TPS/CPS is known to predict response to therapy/survival,In conclusion, our results suggest that overall survival, response to therapy, and the incidence of unplanned hospitalizations are inferior among patients with initiating ICI with a poor PS indicating an urgent need to prospectively evaluate interventions in this poor‐risk population.No conflict of interest or disclosure to report.All authors certify that they have participated in this work. The manuscript was conceptualized and supervised by Rodriguez, with data curation, original draft writing, and review and editing by Chalker. Voutsinas and Wu contributed to methodology and formal analysis. Hwang assisted with data curation. Santana‐Davila, Baik, Lee, Barber, Futran, Houlton, Laramore, Liao, Parvathaneni, Martins, and Eaton all participated in review and editing. This work has been submitted solely to this journal and is not published or under review elsewhere.This project was approved by our institutional review board.


We identified differentially expressed tRFs in gastric cancer (GC) and the biological properties of tRFs in predicting the malignancy status of GCs as possible biomarkers. Until 15 February 2022, two independent reviewers did a thorough search in electronic databases of Scopus, EMBASE and PubMed. The QUADAS scale was used for quality assessment of the included studies. Ten articles investigating the clinical significance of tRFs, including 928 patients, were analysed. In 10 GC studies, seven tRFs were considerably upregulated and five tRFs were significantly downregulated when compared to controls. Risk of bias was rated low for index test, and flow as well as timing domains in relation to the review question. The applicability of the index test, flow and timing and patient selection for 10 studies was deemed low. In this study, we review the advances in the study of tRFs in GC and describe their functions in gene expression regulation, such as suppression of translation, cell differentiation, proliferation and the related signal transduction pathways associated with them. Our findings may offer researchers new ideas for cancer treatment as well as potential biomarkers for further research in GC. Human diseases, including metabolic diseases and disorders, cancer, have been linked to abnormal expression of tRFs/tiRNAs.tRFs regulate cancer progression via competitive binding of RNA binding proteins.Differentially expressed tRFs have been reported in GC clinical samples.Zhu et al. reported that tRF‐5026a suppressed GC cell proliferation, migration, and cycle progression by regulating the PTEN/PI3K/AKT signalling pathway,Gu et al. reported that hsa_tsr016141 is a potential tumour marker. Relative to normal controls, serum and tissue hsa_tsr016141 expressions in GC patients were elevated. These expressions increased with increasing lymph node metastasis as well as tumour grade, implying a good diagnostic efficacy for GC patients.Shen et al. reported markedly low plasma tRF‐33‐P4R8YP9LON4VDP levels in GC patients, relative to healthy individuals. Moreover, tRF‐33‐ P4R8YP9LON4VDP suppressed GC cell proliferation and was established to be a potential tumour biomarkers.Shen et al. found that tRF‐19‐3L7L73JD suppresses cell proliferation as well as migration, induces apoptosis, and arrests cells at the G0/G1 phases, implying inhibitory roles in GC development.Dong et al. discovered that levels of tRF‐24‐V29K9UV3IU and its target genes  in GC cells and tissues were suppressed, implying that tRF‐24‐V29K9UV3IU inhibits GC progression by suppressing cell migration, proliferation, as well as invasion, while enhancing cell apoptosis via regulation of the Wnt pathway.Huang et al. reported varying serum tRF‐31‐U5YKFN8DYDZDD levels in para‐cancerous and tumour tissues from GC patients and healthy people as well as from GC patients prior to and after surgery. Thus, tRF‐31‐U5YKFN8DYDZDD is a diagnostic and a prognostic marker for poor outcomes in GC patients.In another study, Lin et al. found elevated plasma exosomal tRF‐25, tRF‐18, tRF‐38 levels in GC, relative to controls, implying a potential diagnostic role in GC.Xu et al. established markedly low tRF‐Glu‐TTC‐027 levels in GC samples, which was also shown to regulate the MAPK pathway. Thus, as a tumour suppressor, tRF‐Glu‐TTC‐027 is a potential treatment target for GC.Zhang et al. found that tRF‐3019a‐induced FBXO47 suppression enhances GC cell malignant activities, implying that tRF‐3019a has vital roles in GC by targeting FBXO47. Thus, tRF‐273019a regulates GC cell migration, proliferation as well as invasion via targeting FBXO47, and maybe a diagnostic marker22.1Scopus, EMBASE and PubMed/Medline were extensively searched up to the 15th of February 2022. In our literature search, three keywords were applied: “GC tRFs”, “tRNA‐derived fragments”, and “GC”. In addition, the reference lists of approved publications were carefully examined for supplemental sources.2.2Studies needed to report dysregulated tRFs in GC patients, as well as tRF profiling with GC patients.Using this method to determine levels of tRFs in GC serum or plasma and tissue, the study was conducted with QRT‐PCR.The following criteria were used to determine inclusion:Studies with limited or incomplete data.Non‐human and non‐English subject researches.Abstracts, reviews, comments, and letters.The following was the list of exclusion criteria:2.3The first author's name, sample size, tRFs profiles, specimen source, publication year, expression levels were all collected from the included literature. Two investigators  assessed the quality of enrolled studies using the Quality Assessment of Diagnostic Accuracy Studies‐2 (QUADAS‐2) method, which is based on 4 dimensions  in 2 groups (“Applicability Concerns” and “Risk of Bias”).3Using our search method, a total of 38 studies in PubMed/Medline, EMBASE and Scopus was retrieved. All studies were screened according to role of tRFs in GC. A final total of 10 articles, including tRFs studies for comparing the levels of tRFs in GC patients and normal controls were used for the paper review. Figure 3.1Because all studies used a case–control design and patients were not enrolled consecutively or randomly, the bias risk was high in patient selection domains and unclear for the reference standard domains using the QUADAS‐2 instrument. Furthermore, it is unclear how findings of the reference standard may be understood without establishing the index test results. The tRFs expression levels of all enrolled patients were compared with a normal control group.Risk of bias was rated low for the flow, timing and index test domains in relation to the review question. The applicability of the index test, flow and timing and patient selection for ten studies was considered low. Finally, Figure 3.2A total of 928 GC patients were studied in ten investigations. tRFs' utility in distinguishing GC patients from normal controls. The earliest study was published in 2020, and the majority of them were published last year (2021). All these studies were completed in Chinese population. The number of GC patients investigated in each study ranged from 33 to 193. Did not have a known history of other medical conditions that could potentially interfere with their performance GC patients. Among the 10 studies, tRFs were extracted from tissue (four studies), both serum and tissue (three studies), plasma (two studies) and one study examined tRFs extracted from blood exosomes.All studies examined pre‐selected candidate tRFs using real‐time quantitative PCR, and the number of tRFs examined in each study ranged from one to five. Seven studies3.3Dysregulated tRFs that were found to have different expression levels between GC patients and normal controls are shown in Table 4With the highest death rate, GC is a prevalent global malignant tumour. Early‐stage GC patients usually have no discomfort symptoms. Subsequently, the majority of them are diagnosed in late or middle stages of disease.This study was obtained through a review of 10 articles. These studies support the hypothesis that tRFs may be useful biomarkers for GC. In light of the newly published studies, we gain a better understanding of the current scenario and the prognosis of GC patients. Hence, we chose studies published until February 2022. This is the first review summarizing the discoveries and current research on tRFs in GC. We hypothesize that tRFs may be used in the prognosis of GC patients. We discovered that 12 different tRFs from both the up‐ and down‐regulated tRFs groups were involved in GC. Seven tRFs were upregulated and 5 tRFs were downregulated  revealed that hsa_tsr016141, which was markedly elevated in GC patients, is a potential GC marker.Tong et al. (2020) found that tRF‐3017A inhibited NELL2, a tumour suppressor, at two levels: in vitro and in vivo.GC. In ovarian cancer, tRFleu‐CAG regulates downstream target genes.Aurka levels were suppressed when tRFLeu‐CAG was inhibited. In high‐grade serous ovarian cancer, tRF‐03357 downregulated HMBOX1, a hepatocyte nuclear factor family member.In GC, Shen et al. (2021) revealed that tRF‐33‐P4R8YP9LON4VDP, as a tRF, is involved in cell proliferation stimulation and apoptosis inhibition.The involvement of tRF‐31 U5YKFN8DYDZDD in triggering the GC cell, regulation of transcription, cell division and signal transduction have recently been discovered by Huang (2021).Val suppresses tumours by suppressing the FZD3/Wnt/β‐Catenin pathway. Therefore, tRF has key roles in tumorigenesis and is a potential diagnostic as well as prognostic marker or even a treatment target for tumours.According to the findings of a recent study, tRF‐24‐V29K9UV3IU, a mitochondrial 5‐tRF, by downregulating the Wnt/β‐catenin signalling pathwaysZhu et al. (2021) in their next study found that tRF‐5026a (tRF‐18‐79MP9P04), which was suppressed in GC, downregulated the migration, proliferation, as well as GC cell cycle progression in vitro and ex vivo via regulation of the PTEN/PI3K/AKT pathway.Recent achieved evidence from an investigation by Xu et al. (2021) has disclosed, through inhibiting MAPK signalling, tRF‐Glu‐TTC‐027 could inhibit GC cell progression.It is possible that overexpression of tRF‐Glu‐TTC‐027 in vitro and in vivo, inhibited gastric malignancy. On the contrary, tumour size and histological grade are significantly associated with upregulated tRF‐Glu‐TTC‐027 in GC. Various studies reported consistent findings with regards to functions of tsRNAs. tsRNAs are associated with various tumours.Lin et al. (2020) discovered that the levels of tRF25 (tRF‐25‐R9ODMJ6B26), tRF18 (tRF‐18‐BS68BFD2) and tRF38 (tRF‐38‐QB1MK8YUBS68BFD2) in plasma exosomes from GC patients were considerably greater than those in healthy controls.Zhang et al. (2020) indicated that tRF‐3019a which is 73 derived from the 3′ end of mature tRNA‐Ala‐AGC‐1‐1, with cleavage site at the T‐loop, and is located at chr6: 28763741–3 to 75 28763755, induced GC cell invasion, proliferation and migration by targeting F‐box protein 47 (FBXO47) a member of F‐box family and as functions as a 78 tumour suppressor gene. According to the findings, tRF‐3019a upregulates the cancer suppressor gene FBXO47 in GC.4.1In this review, there were three shortcomings: Firstly, all of the included studies involved patients from China. Second, there is a severe lack of high‐quality clinical studies on tRFs indicators in GC. Finally, potential publication bias and confounders which could not be avoided, because all of the studies examined had observational designs.Maryam Kohansal: Data curation ; software ; visualization . Ali Ghanbariasad: Data curation ; software ; writing – original draft . Reza Tabrizi: Conceptualization ; data curation ; resources . Abdolreza Daraei: Investigation ; software ; validation . Mojtaba Kashfi: Formal analysis ; software ; supervision . Hailin Tang: Conceptualization ; project administration ; writing – review and editing . Cailu Song: Conceptualization ; project administration ; writing – review and editing . yongming Chen: Conceptualization ; project administration ; resources .The authors confirm that there are no conflicts of interest.


On univariate analysis, increasing patient age negatively correlated with a larger number of granulomas (p = .011). Granuloma presence was associated with finding intact and motile sperm from the vasal stump intraoperatively (p = .001), and vasoepididymostomy anastomosis (p < .001). However, granuloma presence (and quantity) did not correlate with obstructive interval or maximum TMC. Tobacco use and body mass index (BMI) were not associated with granuloma presence. On multivariate analysis, granuloma quantity was not associated with TMC. Obstructive interval and vasovasostomy anastomosis were associated with higher TMC, while BMI was negatively associated with TMC. In conclusion, increasing age was negatively correlated with granuloma formation. Granuloma presence was associated with more favourable intraoperative fluid findings and anastomosis type, but not post‐VR TMC, suggesting men with and without granulomas undergoing skilled microsurgery will have similar patency rates. Heavier men should be encouraged for weight loss prior to vasectomy reversal as increasing BMI was associated with lower TMC.The objective of this study was to identify factors that predict for sperm granuloma formation and the impact of sperm granuloma presence and quantity on vasectomy reversal (VR) outcomes. A cross sectional retrospective review of prospectively collected data, on the impact of granuloma on VR outcomes from a single academic center was performed. The impact of age, obstructive interval, intraoperative vasal fluid findings, anastomosis type, body mass index, tobacco use and total motile count (TMC) was determined. A total of 1550 men underwent VR between January 2000 and August 2019. Granulomas were present unilaterally in 23.3% ( No difference in pregnancy rate with or without granulomas were seen  and tobacco use. We also seek to understand the impact of sperm granuloma presence and quantity on factors known to impact post‐VR total motile sperm count (TMC), including intraoperative vasal fluid composition, obstructive interval, male age and anastomosis type.2Institutional review board approval was obtained. A retrospective review of VRs performed between January 2000 and August 2019 by one of two high‐volume microsurgeons (SFM or PJB), at a single institution. All VR were being performed for fertility restoration. Men were advised to undergo post‐VR semen analysis (SA) within four months of VR. Men were excluded if they did not have postoperative SA testing or were using exogenous testosterone.All vasovasostomies (VVs) were performed using a mini‐incision two‐layer microsurgical technique, with six equally spaced 10.0 nylon sutures on the mucosa, and six equally spaced 9.0 nylon sutures on the muscularis. All vasoepididymostomies (VEs) were performed using the end‐to‐side intussusception technique, using four equally spaced 10.0 nylon sutures on the mucosa and four 9.0 nylon sutures on the muscularis. VV was performed if the vasal stump fluid was clear, thin, copious and if sperm or sperm parts were seen at intraoperative bench microscopic evaluation. VE was performed if the fluid obtained was pasty, thick and no sperm or sperm parts were seen.The impact of one or more sperm granulomas on post‐VR outcomes were analysed, including male age, anastomosis type , post‐VR TMC and the vasal obstructive interval. The impact of patient factors on granuloma presence and quantity was also analysed, including age, patient‐reported tobacco usage , and BMI.t‐test and one‐way ANOVA, or their non‐parametric equivalent, were used to test for differences in continuous variables and Pearson's chi‐squared or Fisher's Exact test were used to test for associations in categorical variables. Multivariable logistic and ordinal logistic regression were used to evaluate the associations between independent variables of interest with granuloma presence, while controlling for patient age. Multivariable negative binomial regression was performed to evaluate the association between independent variables of interest and maximum TMC, while controlling for age. All statistical analyses were performed using R version 4.0.2. All tests were two‐sided and a p‐value <.05 was considered statistically significant.Descriptive statistics were presented using median (IQR) or mean (SD), dependent upon distribution, for continuous variables, and frequency (percent) for categorical. Two‐sample 36 sperm.During the study period, 4817 men underwent VR, and after excluding those that did not meet criteria, 1550 were included in analysis. The mean ± SD male age was 39.9 ± 6.8 years. The mean ± SD male BMI was 27.9 ± 4.8. The mean obstructive interval was 8.6 ± 5.6 years. The majority, 1466 (94.6%) of men underwent VV/VV, 71 (4.6%) underwent VV/VE and 13 (0.8%) underwent VE/VE. The mean post‐VR TMC was 58.2 ± 79.0 × 10p‐.011). Patients with two granulomas were younger than patients with zero or one granuloma. Granulomas were present on one side in 23.3% (n = 361) and both sides in 14.2% (n = 220). Granuloma presence was associated with intraoperative vasal fluid findings, including the presence of both complete motile sperm (p = .001) and complete non‐motile sperm (p = .001). Likewise, the presence of granuloma was associated with the type of anastomosis performed (VV or VE), with granuloma presence being more likely to undergo VV anastomosis. However, the presence of granuloma did not correlate with post‐VR maximum TMC or obstructive interval.Univariate analysis of the impact of granuloma presence and quantity is summarized in Table p = .005). Obstructive interval was significantly negatively associated with maximum TMC. For every year increase in obstructive interval there was a 4% decrease in TMC . Anastomosis type was also significantly associated with TMC. Patients that had VE had, on average, a 71% lower TMC when compared to patients that had VV anastomosis .A multivariate negative binomial regression, with TMC as the primary outcome was performed. After adjusting for age and smoking status, number of granulomas was not associated with TMC Table . BMI was4The impact of granuloma presence on post VR patency and pregnancy rates remains unclear. Prior series have been limited by patient number, as well as data on anastomosis type. In addition, all prior series report the presence of granuloma, but do not record laterality, or correlate this with the laterality of intraoperative vasal fluid quality, or anastomosis type. Our series represent the largest series of men undergoing VR for restoration of fertility, nearly 5000 men, of which nearly one‐fourth had granulomas.Prior data has shown that granuloma presence has been associated with better quality intraoperative vasal fluid .


Traditional anthropometric measures, including body mass index (BMI), are insufficient for evaluating the risk of diabetes. This study aimed to evaluate the performance of new anthropometric measures and a combination of anthropometric measures for identifying diabetes.A total of 46 979 participants in the National Health and Nutrition Examination Survey program were included in this study. Anthropometric measures, including weight, BMI, waist circumference (WC), waist‐to‐height ratio (WtHR), conicity index (CI), and A Body Shape Index (ABSI), were calculated. Logistic regression analysis and restricted cubic splines were used to evaluate the association between the anthropometric indices and diabetes. The receiver operating characteristic (ROC) curve analysis was performed to compare the discrimination of different anthropometric measures.2, an elevated level of another metric increased the risk of having diabetes (P < .001). Similarly, at low levels of weight, CI, and ABSI, an elevated BMI increased diabetes risk (P < .001).All anthropometric measures were positively and independently associated with the risk of diabetes. After adjusting for covariates, the per SD increment in WC, WtHR, and CI increased the risk of diabetes by 81%, 83%, and 81%, respectively. In the ROC analysis, CI showed superior discriminative ability for diabetes (area under the curve 0.714), and its optimum cutoff value was 1.31. Results of the combined use of BMI and other anthropometric measures showed that among participants with BMI <30 kg/mWtHR and CI had the best ability to identify diabetes when applied to the US noninstitutionalized population. Anthropometric measures containing WC information could improve the discrimination ability. HighlightsOur study retrospectively analyzed 46 979 members of the noninstitutionalized US population and found that anthropometric parameters, including weight, body mass index, waist circumference (WC), waist‐to‐height ratio (WtHR), A Body Shape Index, and conicity index (CI), had a significant positive correlation with diabetes.CI, a novel central‐obesity index based on WC, weight, and height, showed the strongest discriminatory power among these six indices.WtHR is the second‐best anthropometric index after CI; with the advantages of being robust and straightforward, WtHR may be a good alternative for identifying diabetes. Anthropometric measures can provide a convenient and effective prescreening tool for identifying individuals with obesity because they are noninvasive, cost‐effective, valid, and easy to implement. The body mass index (BMI) is the most common measure of general obesity. However, increasing evidence has proven that BMI cannot sufficiently represent the actual obesity status since it cannot accurately reflect body composition and fat location.Over the past few decades, several novel anthropometric indices have been proposed to estimate obesity, particularly central obesity. In 2012, a new composite anthropometric index, the A Body Shape Index (ABSI), calculated by normalizing WC to weight and height, was developed by Krakauer et al and appeared to be a satisfactory predictor of mortality independent of BMI.This study aimed to determine and compare the discriminatory performance of six anthropometric indices  as instruments for screening diabetes risk in a large multiracial cohort. The optimal cutoff values of these indices were also defined to help health care professionals and health policy makers assess diabetes risk; subsequently, risk‐reducing interventions could be targeted at participants at high risk, thus reducing the risk of developing diabetes.22.1http://www.cdc.gov/nchs/nhanes.htm. The study procedures were approved by the Institutional Review Board of the Centers for Disease Control and Prevention, and all participants provided written informed consent. We included all participants aged ≥18 years. The exclusion criteria included pregnancy and missing anthropometric data. In addition, as the effects of glucose‐lowering therapy may affect the participants' body weight, individuals taking oral hypoglycemic agents or insulin were also excluded from the main analysis. Therefore, the final sample size of the main analysis was 46 979 individuals . The NHANES is a multistage, cross‐sectional, and probability sample survey research program designed to obtain a representative sample of the noninstitutionalized US population. The methods used in this study are described in detail in s Figure S1.2.2Anthropometric data were collected by trained health technicians at the Mobile Examination Center (MEC).Given the statistical independence of ABSI and BMI (as indicated in subsequent results), the Anthropometric risk index (ARI) was computed as followed: 2.3Diabetes was the dependent variable in this study. The criteria for diagnosis were based on the American Diabetes Association Standards of Medical Care in Diabetes 2018.2.4Demographic characteristics and medical history were obtained using a structured questionnaire. Age (years) was used as a continuous variable. Sex was classified as male or female. Race was classified as Mexican American, non‐Hispanic White, non‐Hispanic Black, other Hispanic, and others. Smoking status was categorized as yes or no. Education was divided into two levels: less than high school and high school or above. Marital status was categorized into married and other groups. Blood pressure measures were repeated three times after resting quietly for 5 minutes, and the average value was recorded. The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration creatinine equation.2.5t tests, and Mann‐Whitney U test were performed to compare the differences between participants with and without diabetes. The association between the different anthropometric measures and diabetes was estimated using univariate and multivariate logistic regression analyses. All anthropometric variables were z‐standardized when treated as continuous variables. In multivariate logistic regression analysis, two sets of models were established, among which covariates were selected according to clinical importance: model I, adjusted for age, sex, and race, and model II, further adjusted for study cycle, smoking, educational level, marital status, physical activity, systolic blood pressure, diastolic blood pressure, eGFR, and hypertension. We used restricted cubic splines with three knots  to evaluate the nonlinear association between different anthropometric measures and diabetes, and the median value of each anthropometric measure was used as a reference. Odds ratios (ORs) were logarithm‐transformed to represent the rate of increase. The distribution of the variables is also presented using histograms. Subgroup analyses were performed to explore the effect of heterogeneity. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to compare the discriminative power of different anthropometric indices to identify participants with diabetes. Delong's test was used to assess statistical differences between the AUCs. We further examined whether integrating BMI with other anthropometric measures could better assess the risk of diabetes. BMI and WC were dichotomized according to the World Health Organization (WHO) guidelines2, whereas abdominal obesity was defined as WC ≥ 102 cm in men or WC ≥ 88 cm in women. Other anthropometric indices were dichotomized according to the cutoff point in the ROC analysis. Correlation analysis between the two anthropometric indices was performed using Person's correlation analysis. Sensitivity analyses were conducted including diabetes patients with glucose‐lowering therapy. The sample size in sensitivity analyses was 51 438. All data in this study were analyzed using R software . Two‐sided P values <.05 were considered statistically significant.For descriptive statistics, continuous variables are presented as mean with SD, and categorical variables are described as counts with percentages. Pearson's chi‐square test, independent 33.1P < .01). Compared with participants without diabetes, eGFR (87.7 vs 98.7 mg/min/1.73m2) were significantly lower, and systolic blood pressure (132.2 vs 122.7 mm Hg) was significantly higher in participants with diabetes . In addition, all six anthropometric parameters  involved in this study were significantly elevated in participants with diabetes . The baseline characteristics grouped by sex are shown in Table P < .001). In contrast, BMI (27.9 vs 28.7 kg/m2) and WtHR (0.57 vs 0.59) were significantly higher in women than in men (P < .001).The study sample consisted of 46 979 individuals, of whom 3517 (7.49%) had diabetes. The participants were 49.8% male and 43.6% non‐Hispanic White, with a mean age of 46.15 years. Demographic and clinical data at baseline are shown in Table 3.2P < .001). After adjustment in multivariate logistic analysis, WC , WtHR , and CI  were associated with the highest OR per SD increment. Moreover, restricted cubic spline analysis was performed to evaluate whether nonlinear associations existed between anthropometric measures and diabetes. As presented in Figure The distribution of the six anthropometric measures is shown in Figure 2), and race . The results showed that most anthropometric measures were more strongly associated with diabetes in younger individuals  and those with a BMI less than 30 kg/m2 . Compared with men, the increases in WC were more highly correlated with diabetes in women. (Pinteraction < .05). The non‐Hispanic White population was more sensitive to traditional anthropometric measures  than the non‐Hispanic Black and other populations . However, there was no interaction effect between race and CI (Pinteraction >.05).In the subgroup analysis Table S2, part3.3P < .05). The optimal cutoff value of CI with the highest Youden index was 1.31, which had a sensitivity of 0.72 and a specificity of 0.60. Moreover, the AUCs for weight, BMI, WC, WtHR, and ABSI were 0.620 , 0.656 , 0.695 , 0.707 , and 0.658 , respectively. Separate ROC curve analyses were also performed on the subgroups of participants with and without a BMI ≥ 30 kg/m2 , WC , WtHR , CI , and ABSI  were all positively correlated with diabetes. Similarly, in participants with normal weight, CI, and ASBI, an elevated BMI increased diabetes risk (P < .001). However, participants with a BMI ≥ 30 kg/m2 but normal WC or WtHR did not have an increased risk of diabetes (both P > .05). Additionally, participants with a BMI ≥ 30 kg/m2 along with other abnormal anthropometric measures were associated with the highest risk of diabetes.The correlation analysis of the different anthropometric measures is shown in Table 3.5P < .05), and the optimal cutoff points with the highest Youden index were also close to the main results.As shown in Table 4The present large cross‐sectional study revealed that all six anthropometric indices examined  were positively correlated with diabetes risk, supporting that weight and WC reduction will reduce the population incidence of diabetes. Among these six indices, CI showed the strongest discriminatory power. WtHR has a similarly discriminative ability next to CI with a simpler calculation.Obesity is an established risk factor for diabetes.Although central‐obesity indices are generally considered better than BMI in screening for diabetes, controversy still exists regarding which central‐obesity measures perform the best.x/Weighty. For CI, x = 0.5 and y = 0.5, while for ABSI, x = 5/6 and y = 2/3, whereas the correlations with BMI are 0.50 and 0.01, respectively. We found that CI performed significantly better in screening diabetes than other indices, regardless of whether the individuals had obesity or not. Previous studies have found that CI was superior to BMI for identifying visceral adiposity,We further analyzed CI and ABSI, which incorporate height and weight with WC. The basic formula is given by WC × HeightABSI shows a lower OR in screening for diabetes compared to other central‐obesity indices. However, ABSI was negligibly correlated with BMI, establishing statistical independence and therefore applicability of ABSI to the present cohort. This finding implies that after correction for BMI, the association of WC with DM incidence is attenuated, findings that were compatible with a Chinese study of insulin resistance.This study has several merits and implications. First, our study was based on a large‐sample multicenter study; the sample size was adequate to provide sufficient statistical power. Second, we used restricted cubic splines to reveal the nonlinear associations between different measures and diabetes and intuitively showed the OR for different levels of obesity. Third, the central‐obesity indices based on WC have better discriminatory power for screening diabetes than BMI. It is strongly recommended that WC should be part of a participant's medical history in addition to BMI. Fourth, from the point of view of public health, using CI as a noninvasive, simple screening tool could offer a practical approach for screening the risk of diabetes. However, our study has some limitations. First, this was a cross‐sectional study; thus, causal associations could not be determined. Second, the fat content and distribution data were unavailable in this study. Therefore, we cannot directly assess the association of anthropometric measures with body fat and visceral fat. Third, the NHANES data were not able to distinguish between type 1 and 2 diabetes. Fourth, some variables in this study were self‐reported and may have experienced subjective bias. Fifth, the NHANES study was based on the US noninstitutionalized population. Consequently, the results of this study may not be applicable to other populations.5In this study, we retrospectively analyzed 46 979 members of the US noninstitutionalized population and found that anthropometric parameters, including weight, BMI, WC, WtHR, ABSI, and CI, had a significant positive correlation with diabetes. Measuring BMI alone is insufficient for assessing the risk of diabetes. The CI and WtHR are the strongest discriminators of diabetes and may be used as good indicators for screening diabetes.The authors have no conflicts of interest to disclose.Figure S1. Study flowchart.Figure S2. Sensitivity analysis of different anthropometric measures for discriminating diabetes .Table S1. Baseline characteristics grouped by sexTable S2. Subgroups analysisTable S3. ROC analyses in BMI subgroupTable S4. Pearson correlation analysis among different Anthropometric Measures.Table S5. Comparison of baseline characteristics among participants without diabetes, diabetes patients without any treatments, and diabetes patients with glucose‐lowering therapy.Table S6. Sensitivity analysis of Anthropometric Measures and Diabetes .Click here for additional data file.