Device-detected atrial sensing amplitudes as a marker of increased risk for new onset and progression of atrial high-rate episodes.

BACKGROUND: Atrial high-rate episodes (AHREs) are frequent in patients with cardiac implantable electronic devices. A decrease in device-detected P-wave amplitude may be an indicator of periods of increased risk of AHRE. OBJECTIVE: The objective of this study was to assess the association between P-wave amplitude and AHRE incidence. METHODS: Remote monitoring data from 2579 patients with no history of atrial fibrillation (23% pacemakers and 77% implantable cardioverter-defibrillators, of which 40% provided cardiac resynchronization therapy) were used to calculate the mean P-wave amplitude during 1 month after implantation. The association with AHRE incidence according to 4 strata of daily burden duration (≥15 minutes, ≥6 hours, ≥24 hours, ≥7 days) was investigated by adjusting the hazard ratio with the CHA2DS2-VASc score. RESULTS: The adjusted hazard ratio for 1-mV lower mean P-wave amplitude during the first month increased from 1.10 (95% confidence interval [CI], 1.05-1.15; P < .001) to 1.18 (CI, 1.09-1.28; P < .001) with AHRE duration strata from ≥15 minutes to ≥7 days independent of the CHA2DS2-VASc score. Of 871 patients with AHREs, those with 1-month P-wave amplitude <2.45 mV had an adjusted hazard ratio of 1.51 (CI, 1.19-1.91; P = .001) for progression of AHREs from ≥15 minutes to ≥7 days compared with those with 1-month P-wave amplitude ≥2.45 mV. Device-detected P-wave amplitudes decreased linearly during the 1 year before the first AHRE by 7.3% (CI, 5.1%-9.5%; P < .001 vs patients without AHRE). CONCLUSION: Device-detected P-wave amplitudes <2.45 mV were associated with an increased risk of AHRE onset and progression to persistent forms of AHRE independent of the patient's risk profile.

Long-term clinical outcomes of patients with drug-induced type 1 Brugada electrocardiographic pattern: A nationwide cohort registry study.

BACKGROUND: There are limited real-world data on the extended prognosis of patients with drug-induced type 1 Brugada electrocardiogram (ECG). OBJECTIVE: We assessed the clinical outcomes and predictors of life-threatening arrhythmias in patients with drug-induced type 1 Brugada ECG. METHODS: This multicenter retrospective study, conducted at 21 Italian and Swiss hospitals from July 1997 to May 2021, included consecutive patients with drug-induced type 1 ECG. The primary outcome, a composite of appropriate ICD therapies and sudden cardiac death, was assessed along with the clinical predictors of these events. RESULTS: A total of 606 patients (mean age 49.7 ± 14.7 years; 423 [69.8%] men) were followed for a median of 60.3 months (interquartile range 23.0-122.4 months). Nineteen patients (3.1%) experienced life-threatening arrhythmias, with a median annual event rate of 0.5% over 5 years and 0.25% over 10 years. The SCN5A mutation was the only predictor of the primary outcome (hazard ratio 4.54; P = .002), whereas a trend was observed for unexplained syncope (hazard ratio 3.85; P = .05). In patients who were asymptomatic at presentation, the median annual rate of life-threatening arrhythmias is 0.24% over 5 years and increases to 1.2% if they have inducible ventricular fibrillation during programmed ventricular stimulation. CONCLUSION: In patients with drug-induced type 1 Brugada ECG, the annual risk of life-threatening arrhythmias is low, with the SCN5A mutation as the only independent predictor. Unexplained syncope correlated with worse clinical outcomes. Ventricular fibrillation inducibility at programmed ventricular stimulation significantly increases the median annual rate of life-threatening arrhythmias from 0.24% to 1.2% over 5 years.

Impact of dexmedetomidine on electrophysiological properties and arrhythmia inducibility in adult patients referred for reentrant supraventricular tachycardia ablation.

BACKGROUND: Drugs used for sedation/analgesia may affect the basic cardiac electrophysiologic properties or even supraventricular tachycardia (SVT) inducibility. Dexmedetomidine (DEX) is a selective alpha-2 adrenergic agonist with sedative and analgesic properties. A comprehensive evaluation on use of DEX for reentrant SVT ablation in adults is lacking. The present study aims to systematically assess the impact of DEX on cardiac electrophysiology and SVT inducibility. METHODS: Hemodynamic, electrocardiographic, and electrophysiological parameters and SVT inducibility were assessed before and after DEX infusion in patients scheduled for ablation of reentrant SVT. RESULTS: The population of this prospective observational study included 55 patients (mean age of 58.7 ± 14 years, 29 males [52.7%]). A decrease in systolic and diastolic blood pressure and in heart rate was observed after DEX infusion (p = 0.001 for all). DEX increased corrected sinus node refractory time, atrial effective refractory period, AH interval, AV Wenckebach cycle length, and AV node effective refractory period without affecting the His-Purkinje conduction or ventricular myocardium refractoriness. No AV blocks or sinus arrests occurred during DEX infusion. Globally, there was no difference in SVT inducibility in basal condition or after DEX infusion (46/55 [83.6%] vs. 43/55 [78.1%] patients; p = 0.55), without a difference in isoprenaline use (p = 1.0). In 4 (7.3%) cases, the SVT was inducible only after DEX infusion. In 34.5% of cases, DEX infusion unmasked the presence of an obstructive sleeping respiratory pattern, represented mainly by snoring. CONCLUSIONS: DEX depresses sinus node function and prolongs atrioventricular refractoriness without significantly affecting the rate of SVT inducibility in patients scheduled for reentrant SVT ablation.

The role of fibrosis, inflammation, and congestion biomarkers for outcome prediction in candidates to cardiac resynchronization therapy: is "response" the right answer?

Background: Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods: Consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results: Among the 86 patients enrolled, 44% experienced the primary outcome. In this group, the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p < 0.001, HR 8.33 (1.88-33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p < 0.001, HR 333 (250-1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood. Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08-1.22), p < 0.001; HR: 0.84 (0.74-0.91), p = 0.04; HR: 1.26 (1.10-1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion: In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long-term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

Subcutaneous versus transvenous implantable cardioverter-defibrillator among drug-induced type-1 ECG pattern Brugada syndrome: a propensity score matching analysis from IBRYD study.

No real-world data are available about the complications rate in drug-induced type 1 Brugada Syndrome (BrS) patients with an implantable cardioverter-defibrillator (ICD). Aim of our study is to compare the device-related complications, infections, and inappropriate therapies among drug-induced type 1 BrS patients with transvenous- ICD (TV-ICD) versus subcutaneous-ICD (S-ICD). Data for this study were sourced from the IBRYD (Italian BRugada sYnDrome) registry which includes 619 drug-induced type-1 BrS patients followed at 20 Italian tertiary referral hospitals. For the present analysis, we selected 258 consecutive BrS patients implanted with ICD. 198 patients (76.7%) received a TV-ICD, while 60 a S-ICD (23.4%). And were followed-up for a median time of 84.3 [46.5-147] months. ICD inappropriate therapies were experienced by 16 patients (6.2%). 14 patients (7.1%) in the TVICD group and 2 patients (3.3%) in S-ICD group (log-rank P = 0.64). ICD-related complications occurred in 31 patients (12%); 29 (14.6%) in TV-ICD group and 2 (3.3%) in S-ICD group (log-rank P = 0.41). ICD-related infections occurred in 10 patients (3.88%); 9 (4.5%) in TV-ICD group and 1 (1.8%) in S-ICD group (log-rank P = 0.80). After balancing for potential confounders using the propensity score matching technique, no differences were found in terms of clinical outcomes between the two groups. In a real-world setting of drug-induced type-1 BrS patients with ICD, no significant differences in inappropriate ICD therapies, device-related complications, and infections were shown among S-ICD vs TV-ICD. However, a reduction in lead-related complications was observed in the S-ICD group. In conclusion, our evidence suggests that S-ICD is at least non-inferior to TV-ICD in this population and may also reduce the risk of lead-related complications which can expose the patients to the necessity of lead extractions.

The bone lid technique in lateral sinus lift: a systematic review and meta-analysis.

OBJECTIVE: This systematic review aimed at assessing the effect of the repositioned bone lid on bone augmentation in lateral sinus lift in pre-clinical in vivo and clinical studies. Secondary aims were to report on the healing of the bone window and to assess the implant survival rate. MATERIAL AND METHODS: Animal and human studies comparing lateral maxillary sinus floor elevation in combination or not with the repositioned bone lid were retrieved from MEDLINE (PubMed), Web of Science and Cochrane online library. Studies published in English up to April 2022 and reporting on histological and/or radiographic outcomes were considered. Case reports, case series and reviews were excluded. A hand search was also conducted. Risk of bias was assessed and meta-analysis performed to investigate the effect of the bone lid on new bone formation. RESULTS: After screening, 5 animal studies (4 in rabbits, 1 in sheep) and 2 clinical studies (1 RCT, 1 case-control) were included. Meta-analysis confirmed a higher new bone formation in rabbits at 2 and 8 weeks using the bone lid. The two clinical studies investigated lateral sinus lift with concomitant implant placement and reported similar results and high short-term implant success rate in both test and control groups. CONCLUSIONS: The meta-analysis provided moderate evidence that the repositioned bone lid favored the formation of new bone to a higher extent as compared to resorbable membranes in animal studies. Implant success seems not to be influenced by the technique in the short term.

Four atypical cases of misdiagnosed facial cutaneous sinuses of dental origin.

BACKGROUND: Odontogenic cutaneous sinus tracts are frequently misdiagnosed as cutaneous non-dental related pathologies, due to their lack of a typical morphology, their extraoral location, and the frequent absence of concomitant dental symptoms. An erroneous diagnosis may lead to long-lasting, invasive, and not resolutive surgical and medical treatments. METHODS: Four patients referred to our department lamenting the presence of a recurrent facial cutaneous sinus tract. They all had already had different wrong diagnoses and were treated with not resolutive therapies or surgeries. After a clinical and radiographical oral examination, the cutaneous fistulas were found to have a dental etiology, and the extraction of the compromised tooth was performed. RESULTS: One week after the tooth extraction, all the patients presented good healing of the intraoral mucosa. At the long-term follow-up in all four cases, the definitive closure of the extraoral sinus tract and a reduction of the scar was found. CONCLUSIONS: If a facial sinus tract is present, the odontogenic etiology should always be considered, since it can easily bring to the correct diagnosis, leading to a rapid resolution of the fistula. Once the dental origin has been confirmed, the suggested treatment for a conclusive resolution of the cutaneous sinus tract is the endodontic treatment or the extraction of the affected tooth.

Incidence of ventricular arrhythmias after biventricular defibrillator replacement: impact on safety of downgrading from CRT-D to CRT-P.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces mortality and hospitalizations. It is debated whether CRT alone (CRT-P) or CRT plus defibrillator (CRT-D) is preferable, and still guidelines are not exhaustive. The aim of the study was to investigate whether to implant CRT-P or CRT-D in CRT-D patients who did not experience malignant arrhythmias at the moment of replacement. METHODS: Out of 451 heart failure patients undergoing CRT-D according to guidelines, 103 (67±10 years, 80% men) underwent device replacement with CRT-D. Every 6 months patients underwent to clinical evaluation and device interrogation and episodes of ventricular arrhythmias (VA) stored. At baseline and before replacement echocardiogram was performed. Patients were defined responders if left ventricular (LV) end-systolic volume decreased ≥15% and super-responders if LV ejection fraction increased ≥40% or ≥50%. RESULTS: Mean follow-up was 75±24 months after implantation and 26±10 months after replacement. First VAs incidence per year did not decrease over time (P=0.619). Before replacement, 27 patients (26.2%, 15 responders/12 non-responders) experienced VA. After replacement, 8 patients (7.7%, 4 responders/4 non-responders) experienced VA for the first time. Super-responder condition was not associated with lower VA incidence before (0.499) and after (P=0.339) replacement. At multivariate analysis, age was the only independent predictor of electrical appropriate therapy after substitution (ORper year=1.17; 95% CI: 1.03-1.34; P=0.003). CONCLUSIONS: Freedom from VA before device replacement does not correlate with freedom from VA after replacement, so downgrade from CRT-D to CRT-P is not feasible at replacement, in particular in the elderlies, independently of responder and super-responder condition.

Influence of the Use of a Collagen Membrane Placed on the Bone Window after Sinus Floor Augmentation-An Experimental Study in Rabbits.

BACKGROUND: We studied the influence on healing of a resorbable membrane covering the osteotomy site after maxillary sinus grafting, evaluated in different regions of the augmented area. METHODS: Maxillary sinus augmentation was performed in 24 New Zealand rabbits. Osteotomy, 4 × 6 mm, were performed bilaterally. A collagenated cortico-cancellous porcine bone was used to fill the elevated region. A collagen membrane was randomly placed over the osteotomy site on one side (MG), and the other side was left uncovered (NMG). The animals were euthanized after 2, 4, and 8 weeks; and histomorphometric analysis was performed in eight different regions. RESULTS: New bone percentages were similar in both groups. There were no statistically significant differences. In MG, the overall percentages were 15.6 ± 7.3%, 22.9 ± 6.1%, and 24.9 ± 12.0% after 2, 4, and 8 weeks, respectively. In NMG, the percentages were 11.2 ± 4.5%, 24.1 ± 5.7%, and 24.5 ± 15.7%, respectively. The proportions of new bone in the various regions after 8 weeks were 31 ± 8.9% and 29.9 ± 9.1% in the bone walls region, 25 ± 10.1% and 32.8 ± 9.1% in the submucosa region, 22.6 ± 21.6% and 10.9 ± 11.5 in the middle region, 17.3 ± 14% and 13.4 ± 9.8% in the close-to-window region, and 21.8 ± 11.6%, 19.1 ± 6.4% in the osteotomy region-for MG and NMG, respectively. CONCLUSIONS: In both groups the greatest amounts of bone formation occurred near to the pre-existing bone walls, followed by the sub-mucosa region. The smallest amounts were found in the close-to-window region, followed by the central region. The placement of a collagen membrane to cover the osteotomy site did not influence the amount of new bone formation after sinus grafting.

Radiation awareness in an Italian multispecialist sample assessed with a web-based survey.

INTRODUCTION: The awareness of radiation doses and risks, also during interventional cardiology procedures, is essential today in order to apply the risk-benefit assessment and to reinforce the principles of justification and optimisation in clinical practice. METHODS: A voluntary survey with 10 questions and multiple-choice answers was run on a popular cardiology website (www.cardiolink.it) independently by a scientific publisher, in order to evaluate the contemporary level of radiation awareness in a multi-speciality sample of physicians in Italy. RESULTS: One thousand eight hundred and sixty-one physicians completed the test. The survey showed good results since both prescribers and practitioners (mostly cardiologists) working in Italy are largely aware of the cancer and non-cancer risks of medical radiation use, regardless of their subspecialty background. CONCLUSION: Physicians are largely aware of the cancer and non-cancer risks of medical radiation use, regardless of their subspecialty background. However, there is still broad space for improvement; in the future, the awareness of radiation risk is a prerequisite to create a culture of respect for radiation hazard and a commitment to minimise exposure and maximise protection.

Myocardial Scar on Surface ECG: Selvester Score, but Not Fragmentation, Predicts Response to CRT.

PURPOSE: Myocardial scar is directly related to the response to CRT after implantation. The extent of myocardial scar can be detected not only by cardiac magnetic resonance but also by two electrocardiographic scores: fragmented QRS (fQRS) and Selvester score (SSc). The aim of our study is to compare the role of baseline SSc and fQRS in predicting response to CRT in a cohort of heart failure patients with true left bundle branch block (LBBB). As a secondary endpoint, we assessed the association of both scores with overall and cardiac mortality, heart failure hospitalizations, ventricular arrhythmias requiring ICD intervention, and major adverse cardiovascular event (MACE). METHODS: We evaluated fQRS and SSc of 178 consecutive HF patients with severe systolic dysfunction (LVEF ≤ 35%), NYHA class II-III despite optimal medical treatment, and true-LBBB. Response to CRT was defined as the improvement of LVEF of at least 10% or as the reduction of LVESV of at least 15% at a 6-month follow-up. Each endpoint was related to fQRS and SSc. RESULTS: SSc ≥7 was significantly associated with the absence of echocardiographic response to CRT (OR: 0.327; 95% C.I. 0.155-0.689; p=0.003), while the presence of fQRS at baseline ECG was not (OR: 1.133; 95% C.I. 0.539-2.381; p=0.742). No correlation was found between SSc and overall mortality, cardiac death, ventricular arrhythmias, hospitalizations due to heart failure, or for MACE. Similar results were observed between fQRS and all secondary endpoints. CONCLUSION: In HF patients with true-LBBB and LVEF ≤35% eligible for CRT, myocardial scar assessed by calculating the SSc on preimplant ECG is an independent predictor of nonresponse after multiple adjustments. Neither SSc nor fQRS is associated with overall and cardiac death, ventricular arrhythmias, or hospitalization for heart failure at a 24-month follow-up.

Bone plate repositioned over the antrostomy after sinus floor elevation: an experimental study in sheep.

The objective of this study was to compare the healing of the augmented sinus at which the antrostomy was covered with a membrane or the repositioned bone plate.Eight sheep underwent bilateral maxillary sinus floor augmentation. The control site was covered with a resorbable membrane, while at the experimental site the bone plate was repositioned, and both were secured with cyanoacrylate. Animals were euthanised after 4 months and histomorphometric analysis was performed.A large amount of the graft appeared to be partially interpenetrated by the newly formed bone. Statistical analysis demonstrated different percentages of the new bone and bone interpenetrated to the graft between test and control site in the close-to-window area respectively 22.1 ± 12.6 vs 7.5 ± 4.5 (P = 0.028) and 66.1 ± 14.7 vs 44.2 ± 15.1 (P = 0.046). Other areas showed no difference in the bone and graft amount. More bone was found at the edges of the antrostomy in the experimental site, without statistical significance. In the centre of the antrostomy, the replaced bony window appeared bonded to the newly formed bone. No remnants and no biological response to cyanoacrylate were observed.The repositioning of the bony window after sinus floor elevation in sheep led to a larger amount of newly formed bone in the close-to-window zone of the grafted area. The bony window appeared partially bonded to the new bone. Newly formed bone was found interpenetrating the graft granules.

Sleep-disordered breathing and effectiveness of cardiac resynchronization therapy in heart failure patients: gender differences?

OBJECTIVES: This study evaluated heart failure (HF) patients who underwent cardiac resynchronization therapy (CRT) and who had device-documented sleep-disordered breathing (SDB). We found gender differences in acute changes in SDB due to CRT impact. BACKGROUND: SDB typically occurs in HF patients. However, the role of SDB and its response to CRT in HF patients, as well as the relation with gender are currently not fully researched. METHODS: Among 63 consecutive patients who received CRT with an SDB algorithm, 23 patients documented SDB at one-month cardiac device interrogation and represented our population. We defined a Sleep apnoea Severity SCore(SSSC), and consequently, patients were categorized to have mild, moderate, and severe sleep apnoea syndrome divided into two groups: Group-1: 18 males (78%); Group-2: 5 females (22%). We evaluated the variation of apnoea burden and CRT response based on gender differences. RESULTS: A significantly higher proportion of patients in the male group were non-responders to CRT at 12-months follow-up (p = 0.076) while in the female population 5/5 patients (100%) were responders to CRT at the same follow-up time (p = 0.021). Among Group-2 subjects, we documented a significant linear decrease in SSSC(p > 0,01) while in Group-1 the CRT effect on SSSC was variable. At 12-months follow-up, the difference in SSSC between the two groups was statistically significant (p < 0.001). CONCLUSIONS: Our study reports a correlation between CRT response and sleep apnoea burden considering gender differences. In particular, HF-women responders to CRT demonstrate a significant linear decrease in sleep apnoea burden determined through a device algorithm, when compared to a similar male population. Further research is needed to confirm these findings.

Prophylactic protocol for dental care in ligneous gingivitis due to severe plasminogen deficiency: Case report and review of literature.

INTRODUCTION: Severe plasminogen (PLG) deficiency causes ligneous conjunctivitis, a rare disease characterized by the growth of fibrin-rich pseudomembranes on mucosal surfaces; gums involvement leads to ligneous gingivitis (LG). Specific therapy for LG is not available yet. We report a prophylactic treatment with enoxaparin and fresh frozen plasma (FFP) for invasive dental procedures in a patient with LG, and a review of literature on LG treatment. METHODS: A 43-year-old female with LG was studied. In order to prevent LG recurrence after dental care, FFP before and the day after the procedure, and enoxaparin were administered in addition to proper minimally invasive dentistry techniques and implant surgery. RESULTS: Plasminogen deficiency was confirmed by reduced PLG antigen (25 µg/mL) and activity (20%) levels, and genetic analysis. PLG levels rose to 46% after FFP transfusion and returned to baseline after 48 hours. Minimally invasive dental procedures and implants were performed. Small gingival pseudomembranes developed soon thereafter in some cases but disappeared within a few weeks; no bleeding complications were observed. CONCLUSIONS: In our patient with LG, the adoption of combined haematological and dentistry protocols appeared to be safe and effective in preventing abnormal gingival pseudomembranes growth after dental interventions, maintaining a healthy periodontal condition.

Long-term outcomes after "Zero X-ray" arrhythmia ablation.

PURPOSE: Radiation exposure related to conventional tachyarrhythmia radiofrequency catheter ablation (RFCA) carries small but definite risk for both patients and operators. Today, non-fluoroscopic mapping systems enable to perform catheter ablation with minimal or zero fluoroscopy. The purpose of this study was to evaluate the long-term outcome of patients who had undergone "Zero X-ray" ablation, since no information is available on the very long-term benefits. METHODS: A total of 272 arrhythmias in 266 patients have been treated with catheter ablation by means of a zero-ray approach guided only by a nonconventional mapping system (EnSite NavX™, Ensite™ Velocity™ mapping system; subsequently Ensite™ Precision™ Abbott, St. Paul, MN). Fluoroscopy was never used. RESULTS: Over a period of 6 years, patients were followed up for an average of 2.9 ± 1.6 years. A 100% rate of acute success was observed in the study population, with a complication rate of 0.8%. Chronic success was achieved in 90.8% of the total number of procedures (272). Patients in whom the same arrhythmia recurred during follow-up underwent to a redo catheter ablation procedure in 60.0% of cases, while the remaining 40.0% underwent pharmacological treatment. A new post-ablation arrhythmia occurred in 7.7% of the sample. CONCLUSIONS: The non-fluoroscopic approach is a feasible and safe alternative to fluoroscopy for arrhythmias ablation. This method ensures low complications rates, high acute procedural success rates, and comparable long-term outcomes with clinical benefits for both patients and physicians. The complete elimination of fluoroscopy during catheter ablation is advantageous and does not reduce patient safety.

Ablation of recurrent malignant idiopathic ventricular tachycardia: When proper diagnosis and success is a matter of contact.

Effective and stable contact between the catheter tip and the tissue is crucial for both mapping and lesion formation during cardiac ablation procedures. Contact force catheter may be not only a therapeutic approach to arrhythmias, but also a tool for achieving accurate characterization of the arrhythmic substrate.