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Xu-Min Zhang

and 4 more

Background Ventricular tachycardia (VT) and ventricular fibrillation are the most causes of early death in patients with myocardial infarction (MI). This study was aimed to explore whether LRP6 and its upstream genes circRNA1615 and miR-152-3p modulated the phosphorylation of Connexin-43 (Cx43) via Gαs in VT of MI. Method we constructed the hypoxia cardiomyocyte model and AMI mice, and explored the modulation relationship of LRP6 and its upstream genes circRNA1615 and miR-152-3p. In addition, the immunoblot analysis with monoclonal and polyclonal antibodies were used to detect whether LRP6 and Cx43 were phosphorylated, further investigated that the LRP6 regulated the phosphorylation of its downstream target Cx43 via G-protein alpha subunit Gαs by using cell transfection, FISH assay, HE staining, RTqPCR, and Western blot techniques. Result LRP6 mRNA expression was significantly reduced in AMI group compared with the control group. Hypoxia could inhibit the protein and phosphorylation levels of LRP6 and Cx43. The expression of circRNA1615 in AMI mice was significantly decreased, but overexpression of circRNA1615 significantly reversed the inhibitory effect of AMI. Also overexpression of circRNA1615 could weaken the effect of miR-152-3p mimic, and the miR-152-3p mimic increased the hypoxia injury of LRP6 and Cx43, further LRP6 interference fragments could aggravate hypoxia injury of Cx43. The overexpression of LRP6 could significantly increase the protein level and phosphorylation level of Cx43, but the interference with LRP6 showed the opposite trend. Noticeably, the interference with Gαs weakened the protein and phosphorylation levels of Cx43, however, the interference with LRP6 and Gαs further inhibited the protein and phosphorylation levels of Cx43. Finally, the transcriptions of circRNA1615 and LRP6 were inhibited in AMI, but the transcription of miR-152-3p was promoted, and the overexpression of circRNA1615 could weaken the damage effect and VT of AMI. Conclusion LRP6 and its upstream genes circRNA1615 and miR-152-3p modulated the phosphorylation of Cx43 via Gαs in VT of MI.

Abu Sadat Sayem

and 3 more

Background: The health sector is one of the outstanding performers through remarkable digitalization in health. Maternal and Perinatal Death Surveillance and Response (MPDSR) was implemented in Bangladesh to investigate the causes of maternal and perinatal deaths in community and health facilities. Objectives: The purpose was to explore information systems available to assess the MPDSR program status, the planning process, gaps and barriers and actions developed using real-time information. Data Collection and Analysis: This study included both primary and secondary data analysis. Six key informant interviews and MPDSR action plans were reviewed from seven districts. Secondary collected from 27 districts. Results: This study revealed that the government health information systems could notify 62% of the maternal deaths and 29% of the neonatal deaths. Despite the challenges in data quality, the health managers developed action plans. The death and service data showed positive changes in most of the districts despite COVID 19 pandemic. Information systems like the MPDSR dashboard and RMNCAH scorecard could is used as tools to assess the impact of actions in a real-time manner. Major gaps are weak monitoring, non-functional MPDSR committees and incoordination, IT issues, blaming culture, and lack of capacity in analyzing data. Conclusion: The outcome of the MPDSR program depends upon how the data is converted to action and measuring the impact. Innovative data visualization tools like health dashboards, scorecards, and administrative data can play a pivotal role in measuring and evidence-based planning. The major challenge remains with capturing all deaths and weak data analysis capacity.

Laura Jones

and 12 more

Objective: To explore the views of female genital mutilation (FGM) survivors, men, and healthcare professionals (HCPs) on the timing of deinfibulation surgery and NHS service provision. Design: Qualitative study informed by the sound of silence framework. Setting: Survivors and men were recruited from three FGM prevalent areas of England. HCPs and stakeholders were from across the UK. Sample: 44 survivors, 13 men and 44 HCPs. 10 participants at two community workshops and 30 stakeholders at a national workshop. Methods: Hybrid framework analysis of 101 interviews and three workshops. Results: There was no consensus across groups on the optimal timing of deinfibulation for survivors who wished to be deinfibulated. Within group, survivors expressed a preference for deinfibulation pre-pregnancy and HCPs antenatal deinfibulation. There was no consensus for men. Participants reported that deinfibulation should take place in a hospital setting and be undertaken by a suitable HCP. Decision making around deinfibulation was complex but for those who underwent surgery it helped to mitigate FGM impacts. Whilst there were examples of good practice, in general, FGM service provision was sub-optimal. Conclusion: Deinfibulation services need to be widely advertised. Information should highlight that the procedure can be carried out at different time points, according to preference, and in a hospital by suitable HCPs. Future services should ideally be developed with survivors, to ensure that they are clinically and culturally appropriate. Guidelines would benefit from being updated to reflect the needs of survivors and to ensure consistency in provision. Study registration number ISRCTN 14710507

Chunlin Chen

and 11 more

Objective To compare long-term survival outcomes between laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) in early-stage cervical adenocarcinoma under the new FIGO 2018 staging guideline. Design Retrospective study Setting and population Early-stage cervical adenocarcinoma received LRH and ORH; 47 Chinese hospitals. Methods We matched patients with early-stage cervical adenocarcinoma in the new FIGO 2018 staging guideline with known risk factors for recurrence who underwent ORH and LRH. Main Outcome Measures 5-year overall survival and 5-year disease-free survival rates Results In total, 549 patients were enrolled in our study, including 235 patients in LRH group and 314 in ORH group. After matching some factors that may affect the prognosis, each group had 223 patients. There was no difference in DFS between LRH and ORH in risk-adjusted analysis (HR1.258, 95% CI: 0.507-3.125, P=0.621). There was no difference in OS between LRH and ORH in risk-adjusted analysis (HR1.961, 95% CI: 0.536-7.183, P=0.309). LRH resulted in significantly lower estimated blood loss (361.2 versus 165.3 ml, P < 0.001) and shorter postoperative anal exhaust time (2.8 versus 2.5 days, P = 0.003) . Intraoperative complication ( 2.7% versus 5.8%,P=0.101) and postoperative complication ( 5.8% versus 6.3%, P=0.843) rates were similar in the two groups. Conclusions LRH has comparable survival outcomes with ORH and was associated with earlier recovery in early-stage adenocarcinoma of the uterine cervix. LRH may be an appropriate option for early-stage cervical adenocarcinoma compared with ORH.

Zihou Liu

and 9 more

Objectives: This study aimed to evaluate the early and rapid diagnostic value and the cut-off value of Heart-type fatty acid-binding protein (H-FABP) for the perioperative myocardial infarction (PMI) diagnosis after off-pump coronary artery bypass grafting (OPCABG) surgery. Method: 109 patients scheduled for first-time, elective, and isolated OPCABG surgery were erolled in this single-center, prospective and consecutive study. Serial samples for measurement of H-FABP at pre-anesthesia induction (T0, baseline), completion of last distal anastomosis (T1), on ICU admission (T2), and at 2h (T3), 4h (T4), 8h (T5), 24h (T6), and 48h (T7) were taken to analyze for H-FABP. CK-MB and cTnI were taken at T4, T5, T6, and T7. Patients were first divided into three groups according to the level of cTnI and ECG changes within the early 24 hours. Results: 44 patients served as a control group, 52 patients identified as myocardial injury group, and 13 patients defined as myocardial infarction group. The level of H-FABP released was significantly higher in the myocardial infarction group than another two groups. Using a cut-off value of 20.53 ng/ml for H-FABP, the sensitivity was 84.62%, 92.31%, and 76.92% immediately, 2 hours, and 4 hours after entering the ICU. The sensitivity of combined H-FABP and cTnI was 92.31% and 84.62% at 4 and 8 hours after entering the ICU. Conclusions: With an optimal H-FABP cut-off level of 20.53 ng/ml, H-FABP was the early and reliable biomarker for PMI diagnosis after OPCABG.

Adam Zemła

and 3 more

Background Despite substantial literature that addresses preoperative anxiety, identifying effective anxiety-management interventions is still recommended. Identifying factors related to preoperative anxiety is essential for intervention planning. Aim To explore patient-reported factors contributing to decreased anxiety among patients scheduled for coronary artery by-pass grafting (CABG). Methods This mixed-methods observational study involved 75 patients aged 40-83 (70.7% men; mean age 65.4±9.41). Qualitative analysis involved 25 randomly selected patients (focus group) and asked to specify factors they believed were helpful in reducing their anxiety. Visual Analogue Scale (VAS-Anxiety) was used at the moment of diagnosis and decision making (Time1, retrospectively), and on the day preceding CABG (Time2). Focus group responses were explored with the use of Interpretative Phenomenological Analysis (IPA). The Pearson’s chi -squared and the Mann-Whitney-U tests were calculated to explore differences between the study groups. Significance level α≤0.05 was used in all analyses. Results VAS-Anxiety scores reduced from 5 points at Time1 to 3 points at Time 2 (p<0.01). Fifty patients (66.7%) reported decreased anxiety between Time1 and Time2, 21 (28%) reported a stable level and 4 (5.3%) reported an increase. Employment status was the only significant factor differentiating “relief’ and “no relief” groups among socio-demographic and clinical variables. IPA yielded five main themes: conversations with health care providers, perceived inevitability of surgery, family support, other patients’ experience, and religion/faith. Conclusions Individual patient-centered interview in conjunction with emotional support are vital for managing preoperative anxiety. Providing contact with family members and paying attention to spiritual needs are also important.

Cinzia Trumello

and 1 more

t’s time for a fivesome. Commentary to: “The predictive value of five glomerular filtration rate formulas for long-term mortality in patients undergoing coronary artery bypass grafting” Coronary artery disease is an extremely common condition and coronary artery bypass-grafting is still one of the most important therapeutic strategy to treat it. Chronic kidney disease is often affecting patients with CAD. Nevertheless, the literature is still debating what formula estimate the best the glomerular filtration rate in patients undergoing CABG. Indeed, the formulas used in clinical practice have some differences some are more accurate in patients with diabetes, while there are some bias given by age and body mass index. In cardiac surgery, the choice of the most fitting formula to evaluate GFR has important clinical implication and, up to now, three formulas have been compared at most. Eilon Ram et al. present a retrospective study which compares the 5 most used formulas (CG, MDRD, CKD-EPI, Mayo, and IB) to derive GFR to evaluate the one with the best accuracy in predicting long-term mortality. In order to do so, they divided 3744 patients in three groups according to the estimated GFR by means of all 5 formulas: significant CKD according to all formulas, non-significant CKD according to all formulas and discordant results (meaning that at least one formula gave normal GFR and at least one formula gave abnormal GFR). Patients with the highest mortality were the ones with significant CKD according to all formulas.

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Yuval Shafir

and 8 more

INTRODUCTION: Transvenous Lead Extraction (TLE) is usually performed via a superior approach. Predictors and outcomes of TLE requiring femoral vein bailout are poorly defined. We aimed to analyze predictors and consequences of TLE requiring femoral bailout. METHODS: A single tertiary center cohort of 421 consecutive patients who underwent TLE between May 2010 and February 2020 were analyzed. Venography was routinely performed before system upgrade to identify occluded veins. Patients were divided into 2 groups according to their need for femoral bailout extraction. RESULTS: A total of 928 leads were extracted with femoral bailout approach was needed in 71 leads(7.7%) among 49 patients(11.6%). A higher proportion of right ventricular(RV) leads required femoral bailout approach compared with right atrial(RA) leads[51/499(10.2%) vs 18/326(5.5%);p=0.02]. Femoral bailout was more common among younger patients, longer lead dwell time, more pocket entries, higher number of extracted leads, presence of abandoned leads and among patients with vascular occlusion. Following multivariate analysis, presence of abandoned leads, vascular occlusion and younger age remained a significant predictor for femoral bailout. Femoral bailout resulted in higher rates of major complications [5/49(10.2%) vs 12/372(3.2%);p=0.05] without intra-procedural mortality and no additional 30-day mortality[2/49(4.1%) vs 33/377(8.8%);p=0.39]. CONCLUSION: TLE of abandoned leads, occluded veins and younger age were found to be predictors of femoral bailout requirement. Despite higher rates of major complications in femoral TLE bailout, mortality was not increased. Venography prior to TLE should be considered for procedure planning.

Manuel E. Izquierdo

and 21 more

Background:  Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic  CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods: We analyzed sequencing data spanning a 190.5Kb region of  CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare  CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) ( Regression-based models tested for association between  CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic  CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic  CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic  CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for  CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

Hanan Al-Abboh

and 2 more

A Novel MECOM Variant Associated with Congenital Amegakaryocytic Thrombocytopenia and Radioulnar Synostosis Hanan Al-Abboh1, Akmal Zahra1 and Adekunle Adekile1,2Pediatric Hematology Unit, Mubarak Hospital1 and Department of Pediatrics, Faculty of Medicine, Kuwait University2, Kuwait Address Correspondence to: Professor Adekunle Adekile Department of Pediatrics Faculty of Medicine Kuwait University PO Box 24923 Safat 13110 Kuwait Email: Tel: +96525319486To the EditorCongenital radioulnar synostosis (RUS) is a rare developmental anomaly of proximal fusion of the radius and ulna, resulting in limited pronation and supination of the forearm. It may accompany other abnormalities in the skeleton, kidney, heart and aneuploidy syndromes1,2. A subset of patients with RUS present with bone marrow failure (BMF) syndromes, characterized by amegakaryocytic thrombocytopenia (RUSAT), progressing to myelodysplasia and pancytopenia2,3. The hematological manifestations are quite variable, with some presenting with severe BMF in childhood, while others are mild and may not present until adulthood.Heterozygous germline variants in the homeobox A11 (HOXA11) gene were the first to be associated with RUS and designated RUSAT14, but lately, several families have been described with variants in the MDS1 and EVI1 complex (MECOM) locus, and referred to as RUSAT22,5,6. Many of these variants appear de novo , while others follow an autosomal dominant inheritance. We, hereby, report the case of a Kuwaiti patient who presented with congenital amegakaryocytic thrombocytopenia (CAMT) in the neonatal period and later noticed to have RUS. Whole exome sequencing revealed a novel MECOM variant.A.A. is a male Kuwaiti, the first child of consanguineous parents and was first seen at the age of 36 days, following antenatal ultrasound diagnosis of bilateral hydronephrosis and right renal cyst. He was a product of induced vaginal delivery with a birth weight of 2.3 kg. After delivery, he was kept under observation in the neonatal intensive care unit. His CBC showed isolated thrombocytopenia (Plt 34 x109/L). He received several platelet transfusions, as well as IVIG twice. Postnatal abdominal ultrasound showed multicystic right kidney, in addition to bilateral hydronephrosis. The mother had no history of thrombocytopenia during pregnancy and there was no other pertinent family history.Physical examination at presentation showed 2 café-au-lait spots, one on the back, measuring 1x2 cm and another over the left leg, that was less than 0.6 cm. There were no obvious dysmorphic features and other systems were unremarkable. CBC showed WBC 11.2 x109/L Hb 10.4 g/dL, MCV 83fl, Plt 49 x109/L, ANC 1.8 x109/L. Renal function tests were normal. Blood film showed no abnormal cells; there was true thrombocytopenia with giant forms. Antiplatelet antibody was negative. Abdominal ultrasound at age 1 month showed complete replacement of the right kidney by cystic changes with left moderate hydronephrosis. Skeletal survey was reportedly normal.Bone marrow biopsy showed normal distribution of granulocytic and erythroid precursors, with severe suppression of megakaryocytosis, consistent with a bone marrow failure syndrome. Chromosomal breakage study was normal. The patient was diagnosed with right undescended testis, as well as right inguinal hernia that were operated at age 1 year and 10 months. At the age 2 and a half years, A.A. was noticed to have limited bilateral arm movement supination and pronation. The mother volunteered that she has a similar defect. X-rays confirmed that the child had bilateral radioulnar synostosis. Whole exome sequencing showed that the patient is heterozygous for a previously-unreported MECOM gene, c.2282A>G mutation. Unfortunately, the parents have not been screened for these mutations.The patient has been under follow up for 4 years, his platelet count has been stable, ranging between 40-50 x109/L, with no bleeding tendency. In spite of his limited arm rotation, he currently functions normally in his daily activities, however, his hand writing skills and ability to engage in sports are yet to be observed since he is still pre-school age. Platelet transfusion is reserved only for severe bleeding, which he has not had. Bone marrow transplant may be considered in future if his bone marrow failure worsens and/or his marrow shows dysplastic changes.Dokal et al3 were the first to report an association between RUS and late-onset BMF, while Thompson et al described its association with CAMT and linked it to the c.872delA ,p.Asn291Thrfs3 variant of the HOXA11gene4,7. More recently, several germline mutations in the MECOM locus have been reported and appear to be the more common cause of RUSAT. Indeed, no other cases of HOXA11 mutations linked to RUSAT have been described since the initial report. Niihori et al8 reported the first 3 heterozygous MECOMmutations in 3 sporadic patients. These variants and those subsequently reported by Walne et al2 are in a highly conserved cluster within 10 amino acids (aa750-760) and impact on either the highly conserved Cys2His2 zinc finger motif (zinc finger 8, aa733-755) or the adjacent linker motif (aa756-760). It has been shown that removal of the 8th zinc finger causes granulopoiesis arrest while mutations and deletions in other parts of the complex, outside the 8th and 9th fingers, are associated with hematological disorders without RUS9.MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis and is involved in the regulation of embryonic development and hematopoietic stem-cell renewal. Hence the phenotype in individuals with these mutations is very variable ranging from BMF to different skeletal, cardiac, renal malformations, B cell deficiency and sensorineural deafness.Our patient showed a previously unreported variant in the region of the 8th zinc finger of the MECOM locus. This c.2282A>G missense variant results in the tyrosine to cysteine substitution at codon 761 (p.Tyr761Cys). The amino acid is in the Zinc finger, C2H2 and Zinc finger, C2H2-like protein domains and is highly evolutionarily conserved. Unfortunately, the parents were not screened for the mutation, however, the mother shows RUS, with normal blood counts. This is consistent with the marked variability in the clinical phenotype. The father is also physically and hematologically normal.Apart from thrombocytopenia, our patient also had renal abnormalities – hydronephrosis and multicystic kidney disease. The natural history of his condition is that he may develop pancytopenia and/or myelodysplasia in the future. He is under close follow up and will be considered for bone marrow transplantation if his condition worsens. In the meantime, he remains hypomegakaryocytic with a platelet count at 30 – 50 x 109/l while other blood cellular elements are normal. His renal function and hearing are being monitored, but still remain normal.AcknowledgementsWe thank the patient’s family for allowing us to report this case. The whole exome sequencing was done at the Laboratory of Genetics and Genomics, Cincinnati Children’s Hospital, Cincinnati, Ohio.References1. Rizzo R, Pavone V, Corsello G, Sorge G, Neri G, Opitz JM. Autosomal dominant and sporadic radio-ulnar synostosis. Am J Med Genet.1997;68(2):127-134.2. Walne A, Tummala H, Ellison A, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103(7):e284-e287.3. Dokal I, Ganly P, Riebero I, et al. Late onset bone marrow failure associated with proximal fusion of radius and ulna: a new syndrome.Br J Haematol. 1989;71(2):277-280.4. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397-398.5. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596.6. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58.7. Thompson AA, Woodruff K, Feig SA, Nguyen LT, Schanen NC. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.Br J Haematol. 2001;113(4):866-870.8. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet.2015;97(6):848-854.9. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet.2012;49(9):598-600.

Hoda Abdelgawad

and 2 more

57-years old man presented with exertional dyspnea. An early systolic murmur was heard over the aortic areas 2D and 3D Echocardiography revealed unicuspid , unicommissural aortic valve (UAV) with a characteristic “teardrop” lateral orifice (Figure A) and moderate valve stenosis (3D planimetered aortic valve area (AVA) is 1.1cm2) (Figure B) Continuous wave Doppler across aortic valve (AV) showed high peak and mean systolic gradients of 85 and 60mmHg respectively.(Figure C). 2D /3D Transesophageal Echocardiography (TOE) revealed a subaortic ridge attached to the posterior annulus (Arrow) (Figure D) Further En-face viewing of the aortic valve from the left ventricular outflow tract (LVOT) perspective showed a shelf-like ridge extending from the commissure to the cusp (Arrow) (Figure E) Zoomed mode of the aortic- LVOT junction confirmed the presence of the subaortic ridge seen attached to the posterior aortic annulus near the commissural opening (Figure F) The patient was referred for surgical consultation .. Unicupid aortic valve (UAV) is a rare congenital anomaly that has.2 subtypes ; unicomissural and acommissural subtypes. Both can present with variable degrees of the aortic stenosis (AS) and/or aortic valve regurgitation (AR).UAV has more early, accelerated and severe valvular degeneration in addition to smaller orifice in comparison with bicuspid and tricuspid aortic valve. Echocardiography is the gold standard for diagnosis and evaluation of the AV morphology and function and the associated disorders such as ventricular septal defect , aortopathy and subaortic obstruction.. Surgical aortic valve replacement (AVR) and repair of the associated anomalies are the most common treatment modality .

Esin Isik

and 7 more

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