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SARS-CoV-2 infection is often associated with severe inflammation, oxidative stress, hypoxia and impaired physical activity. These factors all together contribute to muscle wasting and fatigue. In addition, there is evidence of a direct SARS-CoV-2 viral infiltration into skeletal muscle. Aging is often characterized by sarcopenia or sarcopenic obesity These conditions are risk factors for severe acute COVID-19 and long-COVID-19 syndrome. From these observations we may predict a strong association between COVID-19 and decreased muscle mass and functions. While the relationship between physical inactivity, chronic inflammation, oxidative stress and muscle dysfunction is well-known, the effects on muscle mass of COVID-19-related hypoxemia are inadequately investigated. The aim of this review is to highlight metabolic, immunity-related and redox biomarkers potentially affected by reduced oxygen availability and/or muscle fatigue in order to shed light on the negative impact of COVID-19 on muscle mass and function. Possible countermeasures are also reviewed.

GIORN ARTERIOSCL

A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC’s form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC’s form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.

OBJECTIVE: The optimal protein intake for elderly individuals who exercise regularly has not yet been clearly defined. The aim of this study was to test the hypothesis that protein intake level is associated with muscle strength in elderly elite athletes. METHODS: We evaluated 50 elite senior athletes (38 men and 12 women) participating in the European Master Games 2011 in an observational cross-sectional study. Participants were divided into two groups-lower (LPI) or higher (HPI) protein intake-according to the median value of their ratio of urinary urea nitrogen to urinary creatinine (i.e., 8.8 g/L), as a marker of protein intake. A dietary interview confirmed differences in protein consumption between the LPI and HPI groups. We also evaluated body composition (bioimpedance), muscle strength, and hematochemical indices. RESULTS: LPI and HPI groups were homogeneous for age (72 [68-74] and 71 [68-74] y, respectively), fat-free mass index (18.4 [17-19.4] and 18.2 [17-19.1] kg/m2), body fat (18.3% [12.3-20.7%] and 16.6% [13.6-21.2%]), and glomerular filtration rate (57.7 [53.8-64.9] and 62.7 [56.1-69.3] mL/min/1.73 m2). The HPI group showed greater leg and trunk muscle strength (N) compared with the LPI group (left leg extension, 339 [238-369] versus 454 [273-561], respectively, P < 0.05; right leg extension, 319 [249-417] versus 432 [334-635], P ≤ 0.05; trunk extension, 435 [370-467] versus 464 [390-568], P ≤ 0.05). CONCLUSIONS: Higher protein intake in elite senior athletes is associated with a greater muscle strength.

Comment on Redox status alterations during the competitive season in élite soccer players: focus on peripheral leukocyte-derived ROS.

The RNA interference (RNAi) is a biological process by which a double stranded RNA (dsRNA also called small interfering RNA - siRNA) triggers the sequence-dependent degradation of a target RNA within the cellular environment. Thus siRNAs can be used to combat the expression of deleterious gene(s) causing disease or to destroy invading pathogen RNAs. Despite their enormous therapeutic potential, the use of siRNA as drugs presents two major problems: the difficulties to identify optimal delivery systems and the possible induction of different unwanted side effects. In this review, after presenting an overview about the mechanisms ruling the process of RNAi, we focus the attention on the description of the strategies developed to optimise systemic siRNA delivery; in this sense, considerations about the attempts to improve siRNA stability in the biological environment, the development of synthetic vectors for siRNA delivery, the siRNA bio-distribution and pharmacokinetics together with the selection of siRNA targeted delivery systems, are discussed. Since in the optimisation of the siRNA delivery systems the minimization of siRNA side effects should not be neglected, in the last part of the review we consider the problems related to the possible induction of siRNA mediated side effects focusing on the so called microRNA like off-targeting.

The prevalence of atrial fibrillation (AF) is related to age and is projected to rise exponentially as the populationages and the prevalence of cardiovascular risk factors increases. The risk of ischemic stroke is significantly increasedin AF patients, and there is evidence of a graded increased risk of stroke associated with advancingage. Oral anticoagulation (OAC) is far more effective than antiplatelet agents at reducing stroke risk in patientswith AF. Therefore, increasing numbers of elderly patients are candidates for, and could benefit from, the use ofanticoagulants. However, elderly people with AF are less likely to receive OAC therapy. This is mainly due to concernsabout a higher risk of OAC-associated hemorrhage in the elderly population. Until recently, older patientswere under-represented in randomized controlled trials of OAC versus placebo or antiplatelet therapy, and thereforethe evidence base for the value of OAC in the elderly population was not known. However, analyses of theavailable trial data indicate that the expected net clinical benefit of warfarin therapy is highest among patientswith the highest untreated risk for stroke, which includes the oldest age category. An important caveat with warfarintreatment is maintenance of a therapeutic international normalized ratio, regardless of the age of the patient,where time in therapeutic range should be 65%. Therefore, age alone should not prevent prescription ofOAC in elderly patients, given an appropriate stroke and bleeding risk stratification. (J Am Coll Cardiol 2010;56:827–37) © 2010 by the American College of Cardiology Foundation

Purpose: To assess if a polymorphism (PM) of the microsatellite (CA13–27) in the promoter region of Matrix Metalloproteinase 9 (MMP-9) was associated with the exudative form of age-related macular degeneration (AMD) and to its risk factors. Methods: In 107 patients with AMD (AMD Group) and 223 age- and gender-matched controls (Control Group) with cataract, demographic, clinical data, and MMP-9 PM have been compared. Results: The comparison of allelic frequencies showed a different pattern of CA repeats between AMD and Control Group (P < 0.00005), in particular the prevalence of longer microsatellites (≥ 22 CA repeats) was higher in AMD than in Control Group (O.R. 2.49, 95% CI 1.71 - 3.37, P < 0.001). Analyses of genetic frequencies gave similar results. Logistic regression confirmed that 22 or more CA repeats are associated to AMD. The only association between MMP-9 PM and other risk factors for AMD was with BMI (Spearman’s R = 0.298, P < 0.00005): all patients with both microsatellites ≥ 22 CA repeats were overweight or obese (χ2 test P < 0.0005, compared to other genotypes). Conclusions: Longer microsatellites in the promoter of MMP-9 are associated to the exudative form of AMD and to body mass index, a well-known risk factor for the disease.

A polymorphism (PM) in the microsatellite of the promoter region of matrix metalloproteinase 9 (MMP-9), modulating its expression, could play a role in susceptibility to multiple sclerosis (MS). MMP-9 PM was determined in 95 patients with MS (MS Group) and 95 ageand sex-matched controls (Control Group). Comparison of allelic frequencies showed that a higher number of CA repeats characterized the MS group ( P < 0.0001) and prevalence of carriers of z22 CA repeats was higher in the MS than in the Control Group (OR 3.4, 95% CI: 1.7–6.8, P < 0.0001). An earlier age at disease onset was a characteristic of patients with >22 CA repeats (33F10 vs. 28F10, P= 0.027). No differences were found in the main MRI parameters.

A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination.In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method.Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with non-infective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (pIn MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.

The objective of the study was to determine the accuracy of phospholipase A2 group II (PLA2-II), interferon-gamma-inducible protein 10 (IP-10), angiopoietin-2 (Ang-2), and procalcitonin (PCT) plasma levels in early ruling in/out of sepsis among systemic inflammatory response syndrome (SIRS) patients. Biomarker levels were determined in 80 SIRS patients during the first 4 h of admission to the medical ward. The final diagnosis of sepsis or non-infective SIRS was issued according to good clinical practice. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for sepsis diagnosis were assessed. The optimal biomarker combinations with clinical variables were investigated by logistic regression and decision tree (CART). PLA2-II, IP-10 and PCT, but not Ang-2, were significantly higher in septic (n = 60) than in non-infective SIRS (n = 20) patients (P ≤ 0.001, 0.027, and 0.002, respectively). PLA2-II PPV and NPV were 88 and 86 %, respectively. The corresponding figures were 100 and 31 % for IP-10, and 93 and 35 % for PCT. Binary logistic regression model had 100 % PPV and NPV, while manual and software-generated CART reached an overall accuracy of 95 and 98 %, respectively, both with 100 % NPV. PLA2-II and IP-10 associated with clinical variables in regression or decision tree heterogeneous models may be valuable biomarkers for sepsis diagnosis in SIRS patients admitted to medical ward (MW). Further studies are needed to introduce them into clinical practice.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Because of the fast growth, early hepatic metastasis and the multidrug resistance, the five-year survival rate is very low. Thus, the understanding of its biology can significantly contribute in identifying valuable targets for novel therapeutic approaches. In this regard, E2F1 may represent an interesting candidate. E2F1 is a transcription factor implicated in the regulation of many cellular processes including cell proliferation and apoptosis. Whereas the involvement of E2F1 in HCC has been recognized, its ability to act as a proliferative and/or apoptotic factor in HCC has not yet been clarified and, in this regard, an active debate is ongoing. The definition of E2F1 role in HCC is not a trivial aspect as it can have significant consequences for the development of novel therapeutic options with E2F1 as target. In this review, we present data about the reported proliferative/apoptotic effects as well as the dual (combined proliferation and apoptosis) functions of E2F1 in HCC discussing the molecular basis for this behavior. The data available so far indicate that the proliferative and apoptotic functions of E2F1 in HCC may coexist but the proliferative effect seems to be more pronounced than the apoptotic one.

Therapy with Vitamin K antagonists (VKA) effectively reduces the thrombosis risk in many clinical conditions. Genetic variants of vitamin K epoxide reductase (VKORC-1) are associated with increased VKA effect and bleeding risk. It is unknown whether these variants could also affect the long-term outcome in patients with high-dosage oral anticoagulation and/or more difficult adherence to the therapeutic INR range. Hundred and twenty-four patients with mechanical heart valve replacement assuming VKA were genotyped for VKORC-1 −1639G>A (Rs9923231) polymorphism. Hemorrhage, venous thrombosis and atherothrombotic events were retrospectively assessed for a 6-year period. Furthermore, stability of their INR in relationship with the VKORC-1 genotype was investigated day-by-day for 3 months. No differences were observed in hemorrhage and venous thrombosis events according to rs 9923231. GG genotype carriers (n = 41) had no atherothrombotic events, while 4 strokes, 4 TIA and 3 AMI were diagnosed in A carriers (n = 83; P = 0.0008). During the daily observation period, A allele carriers had lower VKA requirements (4.7, 3.7, 2.2 mg/day for GG/GA/AA genotype respectively; P = 0.00001), higher mean INR (2.7, 2.8, 2.9; P = 0.05) and a higher number of examinations above the therapeutic range than GG carriers (17 % vs. 0 % in GG genotype, P = 0.036). Conversely, patients with GG genotype had a more stable dosage of VKA (P = 0.006) and a higher percentage of examinations under the therapeutic range (51, 43 and 36 % in GG, GA and AA genotype, respectively, P = 0.040). In patients with high dosage VKA, VKORC-1 polymorphism is associated to a different warfarin dosage, anticoagulation level, time spent outside the therapeutic range and, in the long-term, a different incidence of atherothrombotic events.

Hammerhead ribozymes (HRz), catalytic RNA molecules capable of inducing the site-specific cleavage of a phosphodiester bond within an RNA molecule, are typically introduced into target cells by specific constructs (such as viral vectors) able to drive their expression from defined expression cassettes (promoter). This strategy implies the presence of promoter-derived sequences bound to the hammerhead ribozyme structure, a fact which can unpredictably affect HRz cleavage efficiency and eventually the biological effect. We explored the effects of promoter-derived sequences on the cleavage kinetics of an HRz targeted against a relevant cell cycle regulator, i.e. cyclin E1, implicated in the pathogenesis of several human diseases including in-stent restenosis and hepatocellular carcinoma. Sequences derived form the most commonly used promoters (CMV, T7, Pol I and Pol III promoters) were added to the minimal HRz structure and their effects on the cleavage kinetic constants k(cat) and K(m) evaluated in vitro under single turn-over conditions, using a mathematical model we recently developed. The different promoter derived sequences variably affected HRz cleavage efficiency (k(cat)/K(m)) with those derived from the pol III and from a truncated form of T7 promoter (T7-S), impairing maximally and minimally k(cat)/K(m), respectively. Additionally, the extra sequences tend to increase K(m) and to reduce k(cat). The extent of this effect depends both on the secondary RNA structure and on the length of the added sequences. In conclusion, these data, together with further work in cultured cells, can lead to the selection of optimal expression cassettes thus contributing to improve HRz efficacy, bringing these molecules closer to practical applications.

Objective— The aims of this study were to compare a microsatellite polymorphism (PM) of matrix metalloproteinase (MMP)-9 in patients with carotid atherosclerosis and control population, and to assess the relationship between this PM and plaque structure. Methods and Results— One hundred fifty patients referring to vascular diagnostic centers for suspected carotid atherosclerosis (at ultrasound examination: 110 positive, 40 negative) and controls (n=110) have been genotyped for MMP-9 PM. After controlling for risk factors, allelic and genotype frequencies were significantly different among the groups, with significant prevalence of long microsatellites in patients with carotid atherosclerosis. Long microsatellites (settled as 22 to 27 repeats) were associated with carotid atherosclerosis (odds ratio [OR], 5.2; 95% confidence interval [CI], 2.9 to 9.2), compared with controls; an independent case control study on patients with coronary atherosclerosis confirmed such result. Binary logistic regression showed that hypertension, long microsatellites in MMP-9 PM and smoking habits were variables accounting for the difference between ultrasound-positive patients and controls. Long microsatellites were also associated to plaques with thin fibrous cap and echolucent core (OR, 13.1; 95% CI, 1.6 to 100). These alleles were slightly more represented in female patients (χ 2 test=0.019; OR, 2.7; 95% CI, 1.2 to 6) but not associated with other risk factors. Plasma MMP-9 levels were related neither to MMP-9 PM nor to plaque type, and were related to gender and extension of atherosclerosis in carotid arteries. Conclusions— The number of repeats (≥22 CA) in the microsatellite of MMP-9 promoter, but not MMP-9 plasma levels, is associated to carotid atherosclerosis and particularly to plaques with a thin fibrous cap.

Background Matrix metalloproteinase (MMP)-12 levels are increased in the abdominal aortic aneurysm (AAA), implicating this protease in AAA pathogenesis. The purpose of this study was to assess the role of MMP-12 in aneurysm formation. Methods A murine aneurysm model was generated by periaortic application of 0.25 mol/L calcium chloride (CaCl 2 ) for 15 minutes. Aortic diameters were measured and compared before and 10 weeks after aneurysm induction. Aortic diameter changes for wild type (WT) and MMP-12 knockout (MMP-12 −/− ) mice were determined. MMP-12 production in mouse aorta was analyzed by casein zymography. MMP-2 and MMP-9 expressions were examined by gelatin zymography. Immunohistochemical study was used to measure macrophage infiltration into the aorta. Results There is an increase of 63 ± 5% (mean ± SEM) in aortic diameters of WT mice after CaCl 2 inductions, while MMP-12 −/− mice increased only 26 ± 14%. Connective tissue staining of aortic sections from WT mice showed disruption and fragmentation of medial elastic fibers, while MMP-12 −/− mice showed only focal elastic lamellae breakdown. MMP-12 levels in WT mice were significantly increased after CaCl 2 treatment, whereas no MMP-12 was detected in MMP-12 −/− mice. There was no difference in the MMP-2 and MMP-9 productions between WT and MMP-12 −/− mice. Immunohistochemical analysis demonstrated that infiltrating macrophages in the aorta of MMP-12 −/− mice were significantly less than WT controls. Conclusions MMP-12 deficiency attenuates aneurysm growth, possibly by decreasing macrophage recruitment.

Objective. To determine the fatal and non-fatal cardiovascular event rate in patients with intermittent claudication treated with antiplatelet agents.Methods and design. Patients with PAD-II stage Fontaine (n=223) and sex and age matched controls (n=446) were followed up from 1974 to 1998. All patients were treated with antiplatelet agents (aspirin, 325 mg once daily or ticlopidine, 250 mg twice daily) and for risk factors, if present. The end points were death for any cause (vascular event, cancer, and others) and non-fatal vascular events (myocardial infarction, ischemic/hemorrhagic stroke, and leg amputation).Results. PAD patients had a significantly higher mortality rate than controls (3.99 vs. 2.53 deaths for 100 patients per year, respectively), cancer (mostly lung, stomach and colon) and vascular mortality accounted for such difference. The incidence of non-fatal vascular events was three times higher in patients than in controls (1.7 vs. 0.56, 100 patients per year, respectively, p

AIM To evaluate the effects of the proteasome inhibitor Bortezomib (BZB) on E2Fs and related genes in Hepatocellular carcinoma (HCC) cells. METHODS The mRNA levels of the E2F family members (pro-proliferative: E2F1-3 and anti-proliferative: E2F4-8) and of their related genes cyclins and cyclin-dependent kinases (cdks) were evaluated in two HCC cell lines following a single BZB administration. mRNA levels of the epithelial-mesenchymal transition (EMT) genes were also measured in both cell lines after BZB treatment. The BZB concentration (40 nM) used was chosen to stay well below the maximal amount/cm2 recommended for in vivo application, and two days incubation was chosen as this time point has been found optimal to detect BZB effects in our previous studies. The HCC cell lines, HepG2 and JHH6, were chosen as they display different phenotypes, hepatocyte-like for HepG2 and undifferentiated for JHH6, thus representing an in vitro model of low and high aggressive forms of HCC, respectively. The mRNA levels of the target genes were measured by two-color microarray-based gene expression analysis, performed according to Agilent Technologies protocol and using an Agilent Scan B. For the E2F family members, mRNA levels were quantified by RT-PCR. Using small interfering RNA’s, the effects of E2F8 depletion on cell number was also evaluated. RESULTS After BZB treatment, microarray analysis of the undifferentiated JHH6 revealed a significant decrease in the expression of the pro-proliferative E2F member E2F2. Quantitative RT-PCR data were in keeping with the microarray analysis, and showed a significant increase and decrease in E2F8 and E2F2 mRNA levels, respectively. In contrast, BZB treatment of the hepatocyte-like HCC cell line HepG2 had a significant impact on mRNA levels of 5 of the 8 E2F members. In particular, mRNA levels of the pro-proliferative E2F members E2F1, E2F2, and of the anti-proliferative member E2F8, decreased over 80%. Notably, a reduction in E2F8 expression in HepG2 and JHH6 cells following siRNA treatment had no impact on cell proliferation. As observed with JHH6, BZB treatment of HepG2 cells induced a significant increase in mRNA levels of an anti-proliferative E2F member, E2F6 in this case. As was observed with E2F’s, more dramatic changes in mRNA levels of the E2F related genes cyclins and Cdks and the epithelial-mesenchymal transition (EMT) genes were observed after BTZ treatment of HepG2 compared to JHH6 . CONCLUSION The differential expression of E2Fs and related genes induced by BZB in diverse HCC cell phenotypes contribute to bortezomib’s mechanism of action in hepatocellular carcinoma.

Matrix metalloproteinases are involved in the development of acute coronary syndromes, but they are not reliable clinical markers of the occurrence or the outcome of this syndrome. Many limitations in their assessment account for such failure. Functional genetic polymorphisms, as alternatives to plasma levels, might be an interesting alternative.

Remodeling of skeletal muscles is regulated by matrix metalloproteinases (MMPs). Functional genetic polymorphism (PM), modulating the expression of some MMPs, might be associated to different body composition and muscular strength improvement after exercise. Genetic PM of MMP-1 (G+/- at -1607), MMP-3 (5A/6A at -1171) and MMP-9 (Cytosine- Adenine microsatellite = 13-27CA) repeats, around -90), body cell mass (BCM), extracellular water (ECW) and isometric maximal extensor strength (MES) of both legs were determined in 17 old sedentary women at the beginning and at the end of a 24 week physical exercise program. A 12 and 72% increase in BCM and MES, respectively, and 11% reduction in ECW were observed at the end of the program. Carriers of G-insertion in MMP-1, PM increased their BCM (7 kg vs. -1.5, P = 0.007) and lost ECW (9% of total body water vs. 0.1%, P = 0.004) more than the non-carriers; homozygote for 21 or less CA repeats/allele in MMP-9 PM gained more MES (115 N, interquartile range = IQR = 63-132) than carriers of longer microsatellites (63 N, IQR = 40-86, P = 0.028). MMP-3 did not show any association with body composition and exercise-related strength changes. Exercise in elderly women increases BCM and strength, these changes are associate to specific MMP genotypes.

BACKGROUND AND OBJECTIVE To compare the effects of panretinal photocoagulation (PRP) and photodynamic therapy (PDT) for anterior segment neovascularization secondary to ischemic central retinal vein occlusion (CRVO). PATIENTS AND METHODS Fifty-seven eyes were randomized to receive standard PRP (19 eyes), selective PRP (20 eyes), or PDT (17 eyes). Selective PRP was performed only when iris neovascularization and/or angle neovascularization showed progression on weekly follow-up. Primary outcome measures were the extension of anterior segment neovascularization and the rate of neovascular glaucoma development. Secondary outcome measures included visual acuity results. RESULTS After 12 months of follow-up, iris neovascularization extension was 0.52, 2.55, and 2.27 in the PRP, selective PRP, and PDT groups, respectively. Anterior segment neovascularization extension was 0.57, 1.50, and 1.27 in the PRP, selective PRP, and PDT groups, respectively. Both showed a statistically significant difference in the PRP group. The rate of neovascular glaucoma development was similar in the three groups. CONCLUSIONS Although PRP was better at determining iris neovascularization and anterior segment neovascularization regression, the similar rate of neovascular glaucoma development found in the three groups indicates that anterior segment neovascularization secondary to ischemic CRVO can also be safely managed using selective PRP or PDT. [Ophthalmic Surg Lasers Imaging 2007;38:94-99.] AUTHORS From the Eye Clinic (MBP, MP, GD, GR), Azienda Ospedaliero-Universitaria di Trieste, Trieste, Italy; the Department of Ophthalmology/Eye & Ear Institute (TRF), University of Pittsburgh, Pittsburgh, Pennsylvania; and the Dipartimento Scienze Ciniche Morfologiche e Tecnologiche (NF), Azienda Ospedaliero-Universitaria, Trieste, Italy. Accepted for publication January 8, 2007. Presented in part as a poster at the annual meeting of the American Academy of Ophthalmology, Chicago, Illinois, October 15-18, 2005. Address correspondence to Maurizio Battaglia Parodi, MD, Azienda Ospedaliero-Universitaria di Trieste, Ospedale Maggiore, Piazza Ospedale 1, 34129, Trieste, Italy.

Background: The prognostic value of quick sepsis-related organ failure assessment (qSOFA) outside intensive care units has been criticized. Therefore, we aimed to improve its ability in predicting 30-day all-cause mortality, and in ruling out the cases at high risk of death among patients with suspected or confirmed sepsis at emergency department (ED) admission. Methods: This study is a secondary analysis of a prospective multicenter study. We built three predictive models combining qSOFA with the clinical variables and serum biomarkers that resulted in an independent association with 30-day mortality, in both 848 undifferentiated patients (Group 1) and in 545 patients definitively diagnosed with sepsis (Group 2). The models reaching the highest negative predictive value (NPV) with the minimum expenditure of biomarkers in Group 1 and in Group 2 were validated in two cohorts of patients initially held out due to missing data. Results: In terms of the area under the receiver-operating characteristic curve, all six models significantly exceeded qSOFA in predicting prognosis. An &ldquo, extended&rdquo, qSOFA (eqSOFA1) in Group 1 and an eqSOFA2 integrated with C-reactive protein and mid-regional proadrenomedullin (eqSOFA2+CRP+MR-proADM) in Group 2 reached the best NPV (0.94 and 0.93, respectively) and ease of use. eqSOFA1 and eqSOFA2+CRP+MR-proADM performed equally well in both the inception and validation cohorts. Conclusions: We have derived and validated two prognostic models that outweigh qSOFA in predicting mortality and in identifying the low risk of death among patients with suspected or confirmed sepsis at ED admission.