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Objective: To investigate the efficacy and safety of idarucizumab in the treatment of perioperative cardiac tamponade and thromboembolic events during catheter ablation in atrial fibrillation (AF) patients under dabigatran therapy. Methods: This study was a retrospective analysis enrolling patients under dabigatran therapy, who underwent catheter ablation for AF at Beijing Anzhen Hospital from January 2019 to December 2020 and developed perioperative cardiac tamponade or acute ischemic stroke (AIS) and received idarucizumab to reverse the anticoagulant effect of dabigatran. Patients' age, sex, renal function, coagulation test and safety events at 30 d after idarucizumab administration were collected and analyzed. The clinical presentation and prognosis were also analyzed. Results: A total of 7 patients were included, 2 (2/7) were male, mean age was (66.3±11.2) years, serum creatinine level was (66.3±13.6) μmol/L, estimated glomerular filtration rate was (89.4±11.2) ml·min -1 ·1.73 m -2 , CHA 2 DS 2 -VASc and HAS-BLED scores were (3.2±1.9) and (1.3±1.3), respectively. Five patients (5/7) developed cardiac tamponade during the perioperative period and the time interval to the last dose of dabigatran was (6.3±2.6) h. Idarucizumab was given at (36.4±16.7) min after the definitive diagnosis of cardiac tamponade. A significant decrease of activated partial thromboplastin time was achieved after idarucizumab administration in all five cases. Pericardial puncture and drainage were applied to all patients (5/5) with cardiac tamponade, the drainage volume was (1 037.0±846.9) ml, the retention time of pericardial drainage catheter was (27.9±13.9) h, and the recovery time of anticoagulation was (28.4±13.2) h. One patient (1/5) underwent thoracotomy for hemostasis due to excessive blood loss with the aim of ensuring complete hemostasis. Bleeding occurred in 1 patient (1/5) after the first restart of anticoagulation. AIS occurred in 2 patients (2/7) after operation. One case (1/2) received intravenous thrombolysis after receiving 5.0 g idarucizumab, no hemorrhagic transformation was observed, and the recovery process was satisfactory. Another patient in this group experienced significantly prolonged onset time and 5.0 g idarucizumab was applied before intravascular thrombectomy, there was no bleeding complication in this patient after thrombectomy. At the time of discharge, the consciousness was not significantly improved, and the muscle strength of the right lower limb was recovered somehow compared with that before operation. No hypersensitivity reactions or thrombotic events occurred in these patients within 30 days of the administration of idarucizumab. Conclusion: In AF catheter ablation-associated cardiac tamponade and AIS, idarucizumab is safe and effective in rapidly reversing the anticoagulant effect of dabigatran, use of thrombectomy saves valuable time for timely hemostasis and improvement of cerebral blood circulation.

Objective  Anticoagulation management in patients with atrial fibrillation (AF) and impaired renal function is challenging. This study aimed to evaluate anticoagulation prescription patterns in relation to renal function and to describe 2-year clinical outcomes among dabigatran users. Methods  Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international, prospective, and observational study program involving patients with newly diagnosed AF at risk for stroke. Prescription patterns were assessed by creatinine clearance (CrCl) at enrollment. Dabigatran users were followed for 2 years. Clinical outcomes were standardized for stroke and bleeding risk, based on CHA 2 DS 2 -VASc and HAS-BLED scores, with missing values imputed. Results  Baseline CrCl values were available for 12,056 of 15,308 eligible patients (79%). With declining renal function, prescriptions increased for vitamin K antagonists (VKAs) and decreased for dabigatran (30-47% and 34-12%, respectively). The prescription of other non-vitamin K antagonists remained similar across CrCl groups (14-19%). In 4,873 dabigatran users, standardized stroke rates were low across all CrCl groups; 0.58/100 patient-years (95% confidence interval [CI]: 0.30-0.90) in CrCl ≥80 mL/min, 0.85 (95% CI: 0.48-1.21) in CrCl 50 to 79 mL/min, and 0.33 (95% CI: 0.06-1.11) in CrCl 30 to 49 mL/min. Similarly, major bleeding rates were low and numerically increased with declining renal function (0.68/100 patient-years, 95% CI: 0.39-1.03; 0.92, 95% CI: 0.58-1.32; and 1.26, 95% CI: 0.66-1.97, respectively). Conclusion  In patients with AF, VKA prescriptions increased and dabigatran prescriptions decreased with declining renal function. Rates of stroke and major bleeding in dabigatran patients remained low across the categories of renal impairment., Competing Interests: Conflict of Interest S.J.V declares no conflict of interest. H.C.D. has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Daiichi-Sankyo, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Merck Sharp & Dohme, Medtronic, Novartis, Pfizer, Sanofi-Aventis, Servier, St Jude, and WebMD Global. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), the German Ministry of Education and Research (BMBF), the European Union, the National Institutes of Health (NIH), the Bertelsmann Foundation, and the Heinz-Nixdorf Foundation. S.J.D. has received consultancy fees for serving as a steering committee member for Boehringer Ingelheim. He also holds research grants from Abbott (St Jude Medical). J.H. is currently conducting research sponsored by Boehringer Ingelheim as a member of the Executive Steering Committee for the GLORIA-AF Registry, and has received consulting fees from Bayer HealthCare, Janssen-Ortho-McNeil, and Pfizer for advisory activities involving the development of anticoagulant drugs. C.H.M. has received honoraria for presentations, as well as research grants from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer. K.J.R. is an employee of RTI Health Solutions, an independent nonprofit research organization that works with government agencies and pharmaceutical companies. C.T., M.P., K.Z., L.R.F., and S.L. are employees of Boehringer Ingelheim. G.Y.H.L. has been a consultant for Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Medtronic, Novartis, and Verseon; and speaker for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and Medtronic. M.V.H. has received honoraria for presentations and research grants from Actelion Pharmaceuticals, Bayer HealthCare, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.

Introduction: Catheter ablation for atrial fibrillation (AF-CA) in patients with situs inversus dextrocardia (SID) can be challenging because of the contrary anatomy and associated anomalies. Cases and literature regarding AF-CA in SID are rare and provide little information. Our study aims to present an improved procedure, ablation strategies, and evaluate the safety and outcomes of AF-CA in patients with AF and SID., Methods: A total of 10 patients with AF-SID (mean age, 60.4 ± 15.7 years; six paroxysmal AF, four persistent atrial fibrillation [PeAF]) were enrolled. For the improved procedure, images obtained by preacquired computed tomography and three-dimensional electroanatomical mapping, integrating intracardiac echocardiography, and x-ray imaging data are necessary to optimize the transseptal puncture and ablation procedure., Results: All patients successfully underwent 13 AF-CA procedures without complications, including three patients received repeat procedures. However, two PeAF patients presented sick sinus syndrome (SSS) after the AF-CA procedure, and one underwent permanent pacemaker implantation therapy during hospitalization. During the follow-up period (6-72 months), the outcomes were not favorable: three patients (30%) maintained sinus rhythm (SR) after the initial procedure; after repeated procedures, the overall SR rate was 40% (four patients)., Conclusion: With the improved strategy, AF-CA can be safely and effectively performed with low radiation exposure in patients with SID. However, the long-term outcomes were not favorable, even when managed at a tertiary center by a team of specialists. Moreover, patients with PeAF might also have masked SSS, which should be carefully considered., (© 2020 Wiley Periodicals LLC.)

Background: An understanding of the risk factors for atrial fibrillation (AF) progression and the associated impacts on clinical prognosis are important for the future management of this common arrhythmia. We aimed to investigate the rate of progression from paroxysmal (PAF) to more sustained subtypes of AF (SAF), the associated risk factors for this progression, and its impact on adverse clinical outcomes., Methods and Results: Using data from the Chinese trial Fibrillation Registry study, we included 8290 PAF patients. Half of them underwent initial AF ablation at enrollment. The main outcomes were ischemic stroke/systemic embolism (IS/SE), cardiovascular hospitalization, cardiovascular death, and all-cause mortality. The median follow-up duration was 1091 (704, 1634) days, and progression from PAF to SAF occurred in 881 (22.5%) nonablated patients, while 130 (3.0%) ablated patients had AF recurrence and developed SAF. The incidence rate of AF progression for the cohort was 3.87 (95% confidence interval [CI] = 3.64-4.12) per 100 patient-years, being higher in nonablated compared to ablated patients. Older age, longer AF history, heart failure, hypertension, coronary artery disease, respiratory diseases, and larger atrial diameter were associated with a higher incidence of AF progression, while antiarrhythmic drug use and AF ablation were inversely related to it. For nonablated patients, AF progression was independently associated with an increased risk of IS/SE (hazard ratio [HR] = 1.52, 95% CI = 1.15-2.01) and cardiovascular hospitalizations (HR = 1.40, 95% CI = 1.23-1.58)., Conclusion: AF progression was common in its natural course. It was related to comorbidities and whether rhythm control strategies were used, and was associated with an increased risk of IS/SE and cardiovascular hospitalization., (© 2020 Wiley Periodicals LLC.)

Objective: To evaluate the safety and efficacy of catheter ablation in patients with new-onset atrial arrhythmia after surgical excision of left atrial myxoma. Methods: Nine patients with new onset atrial arrhythmia and a prior history of left atrial myxoma, who received surgical myxoma excision and catheter ablation between September 2014 and November 2019, were included in the present study. Baseline characteristics, procedural parameters during catheter ablation, severe perioperative adverse events, recurrence rate of arrhythmia and clinical prognosis were analyzed. Kaplan Meier survival analysis was used to define the maintenance rate of sinus rhythm after catheter ablation in this patient cohort. Results: Nine patients were included. The average age was (55.8 ± 9.1) years old (3 male), there were 3 patients (3/9) with paroxysmal atrial fibrillation (PAF) and 6 patients (6/9) with atrial flutter or atrial tachycardia (AFL or AT). Ablation was successful in all patients, there were no perioperative complications such as stroke, pericardial effusion, cardiac tamponade, vascular complications or massive hemorrhage. During a mean follow-up time of 40.0 (27.5, 55.5) months, sinus rhythm was maintained in six patients (6/9) after the initial catheter ablation. The overall sinus rhythm maintenance rate was 2/3. In addition, 1 out of the 3 AF patients (1/3) developed recurrence of AF at 3 month after ablation, and 2 out of the 6 AFL or AT patients (2/6) developed late recurrence of AF or AFL (19 months and 29 months after ablation), two out of three patients with recurrent AFs or AFL received repeated catheter ablation and one patient remained sinus rhythm post repeat ablation. Meanwhile, there was no recurrence of atrial myxoma, no death, stroke, acute myocardial infarction and other events during the entire follow-up period. Conclusions: Catheter ablation is a safe and feasible therapeutic option for patients with new-onset atrial arrhythmia after surgical excision of left atrial myxoma.

Global change includes a substantial increase in the frequency and intensity of extreme high temperatures (EHTs), which influence insects at almost all levels. The number of studies showing the ecological importance of EHTs has risen in recent years, but the knowledge is rather dispersed in the contemporary literature. In this article, we review the biological and ecological effects of EHTs actually experienced in the field, i.e., when coupled to fluctuating thermal regimes. First, we characterize EHTs in the field. Then, we summarize the impacts of EHTs on insects at various levels and the processes allowing insects to buffer EHTs. Finally, we argue that the mechanisms leading to positive or negative impacts of EHTs on insects can only be resolved from integrative approaches considering natural thermal regimes. Thermal extremes, perhaps more than the gradual increase in mean temperature, drive insect responses to climate change, with crucial impacts on pest management and biodiversity conservation.

Background: It is unclear whether catheter ablation (CA) for atrial fibrillation (AF) affects the long-term prognosis in the elderly. This study aims to evaluate the relationship between CA and long-term outcomes in elderly patients with AF., Methods: Patients more than 75 years old with non-valvular AF were prospectively enrolled between August 2011 and December 2017 in the Chinese Atrial Fibrillation Registry Study. Participants who underwent CA at baseline were propensity score matched (1:1) with those who did not receive CA. The outcome events included all-cause mortality, cardiovascular mortality, stroke/transient ischemic attack (TIA), and cardiovascular hospitalization., Results: Overall, this cohort included 571 ablated patients and 571 non-ablated patients with similar characteristics on 18 dimensions. During a mean follow-up of 39.75 ± 19.98 months (minimum six months), 24 patients died in the ablation group, compared with 60 deaths in the non-ablation group [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.30-0.79, P = 0.0024]. Besides, 6 ablated and 29 non-ablated subjects died of cardiovascular disease (HR = 0.25, 95% CI: 0.11-0.61, P = 0.0022). A total of 27 ablated and 40 non-ablated patients suffered stroke/TIA (HR = 0.79, 95% CI: 0.48-1.28, P = 0.3431). In addition, 140 ablated and 194 non-ablated participants suffered cardiovascular hospitalization (HR = 0.84, 95% CI: 0.67-1.04, P = 0.1084). Subgroup analyses according to gender, type of AF, time since onset of AF, and anticoagulants exposure in initiation did not show significant heterogeneity., Conclusions: In elderly patients with AF, CA may be associated with a lower incidence of all-cause and cardiovascular mortality., (Copyright and License information: Journal of Geriatric Cardiology 2020.)

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 + γδ T lymphocytes, and of Mycobacterium-non reactive classic T H 1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 + αβ T and non-classic CD4 + αβ T H 1 ∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 + γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 + αβ T, and CD4 + αβ T H 1 ∗ cells unable to compensate for this deficit., Competing Interests: Declaration of Interests L.H.G. serves on the Board of Directors of GlaxoSmithKline Pharmaceutical Company and the Analog Device Corporation and formerly served on the Boards of Bristol Myers Squibb Pharmaceutical Company and the Waters Corporation. She is also on the Scientific Advisory Boards of Abpro, Kaleido, and Repare biotechnology companies. J.-L.C. serves on the Scientific Advisory Boards of ADMA Biologics Inc., Celgene, and Kymera Therapeutics, Inc. He also consults for Elixiron Immunotherapeutics. Other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

Background: Post hoc analysis of the landmark atrial fibrillation follow-up investigation of rhythm management trial revealed that amiodarone was associated with higher risks of mortality, intensive care unit admission, and non-cardiovascular death. We aim to evaluate the association between amiodarone use and patient survival under updated medical mode and level using data from the China Atrial Fibrillation (China-AF) Registry study., Methods: Clinical data of 8161 non-valvular atrial fibrillation (NVAF) patients who were antiarrhythmic drug (AAD)-naive before enrollment into the China-AF Registry, recruited between August 2011 and February 2017, were collected. The primary outcome was all-cause mortality. A Cox proportional hazard regression model was used to evaluate the association between amiodarone use and the outcome. We also calculated the rate of sinus rhythm maintenance at the penultimate follow-up., Results: Compared with 6167 patients of non-AAD group, 689 patients of the amiodarone group were younger (mean age 65.6 vs. 68.6 years), more frequently completed high school education, had fewer comorbidities such as chronic heart failure, prior bleeding, and stroke, and were more likely to be treated in tertiary hospitals while less hospitalization. The proportion of persistent AF was much lower among users of amiodarone, who were also less likely to be taking oral anticoagulants. The patients in the amiodarone group had a statistically insignificant lower incidence of all-cause mortality (2.44 vs. 3.91 per 100 person-years) over a mean follow-up duration of 300.6 ± 77.5 days. After adjusting for potential confounders, amiodarone use was not significantly associated with a lower risk of all-cause mortality (adjusted hazard ratio, 0.79; 95% confidence interval, 0.42-1.49). Sub-group analysis revealed the consistent results. The rate of sinus rhythm maintenance at the penultimate follow-up in the amiodarone group was significantly higher than in the non-AAD group., Conclusions: Our study indicated that amiodarone use was not significantly associated with a lower risk of 1-year all-cause mortality compared with a non-AAD strategy in "real-world" patients with NVAF., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Atrial fibrillation (AF) is common in abdominal solid organ transplant recipients and a cause of morbidity and mortality in this population. However, the outcomes of catheter ablation (CA) in transplant recipients with AF remain unclear. This study aimed to elucidate the outcomes of CA in renal and hepatic transplant recipients., Methods and Results: Between 2015 and 2019, 14 transplant recipients (nine with kidney transplantation and five with liver transplantation) were enrolled from among 10,741 AF patients and underwent CA at Anzhen Hospital. Another 56 patients matched by age, sex, and AF type were selected as the control group (four controls for each transplant recipient). During a mean follow-up of 30.0 ± 13.3 months after the initial procedure, 10 (71.4%) of the transplant patients, compared to 41 (73.2%) of the control patients, remained free from AF recurrence (p = 1.000). A repeated procedure was performed in one transplant patient and in six control subjects. Consequently, 11 (78.6%) of the transplant patients, compared to 46 (82.1%) of controls, were in sinus rhythm after the repeated ablation (p = .715). Notably, Kaplan-Meier analysis did not demonstrate any significant differences in the atrial arrhythmia-free rate after the initial and repeated procedure between the two groups. Vascular complications were identified in one transplant patient and two control subjects, while no life-threatening complications were observed in either group. There was no transient allograft dysfunction in transplant recipients after CA., Conclusion: CA is safe and effective in abdominal solid transplant recipients, and maybe an optimal therapeutic strategy for this group., (© 2020 Wiley Periodicals LLC.)

This study aimed to verify the reliability of ablation index (AI) for ablation lesion estimating with different settings for radiofrequency (RF) parameters: power, impedance, contact angles, irrigation rate, temperature of irrigation saline, and irrigation solution. RF ablations (N = 66) were performed on ex vivo porcine left ventricle submerged in 37 °C saline. The aforementioned ablation parameters were changed to measure whether the size of the ablation lesion was consistent at a fixed AI value of 500. The maximum lesion diameter (r = - 0.631, P = 0.028), depth (r = - 0.896, P < 0.001), and volume (r = - 0.745, P < 0.005) were significantly reduced with an increase of the impedance. The lesion depth (P < 0.05) and the lesion volume (P < 0.05) were significantly larger with glucose irrigation than saline irrigation. In conclusion, at a fixed AI value, impedance and irrigation solution have impact on the ablation lesions, which could affect the accuracy of AI formula to estimate ablation lesion size. Graphical abstract.

Objective: To investigate the characteristics of left ventricular longitudinal strain (LS) in myocardial amyloidosis (CA), hypertrophic cardiomyopathy (HCM) and Fabry disease (FD), as well as the correlation between left ventricular LS and these diseases. Methods: A total of 14 CA patients, 28 HCM patients and 5 FD patients who visited the Department of Cardiology of the First Affiliated Hospital of Suzhou University from June 2017 to November 2019 were retrospectively included. EchoPAC software was used to analyze left ventricular LS, and univariate logistic regression analysis was used to analyze the correlation between echocardiographic LS indexes and various myocardial hypertrophy diseases. The receiver operating characteristic (ROC) curve was used to assess the sensitivity and specificity of echocardiograph LS indexes in the diagnosis of various myocardial hypertrophy diseases. Results: There were significant differences in LS of left ventricular basal segment, inferior wall, posterior wall, lateral wall and posterior septum among the three groups ( P <0.05). The absolute value of LS in the left ventricular basal segment decreased in the CA group; the absolute value of LS in left ventricular posterior wall and lateral wall decreased significantly in the FD group ( P <0.05); the absolute values of LS in left ventricular basal segment, inferior wall, posterior septum, lateral wall and posterior wall increased significantly in the HCM group ( P <0.05). The absolute value of LS < 7.9% in the left ventricular basal segment, or > 13.2% in the inferior wall and > 9.2% in the basal segment, or < 8.3% in the lateral wall and < 7.9% in the posterior wall were the indicators of high sensitivity and specificity in the diagnosis of CA, HCM and FD, respectively. Conclusions: Left ventricular LS was an important index to differentiate myocardial hypertrophy. Combined with their respective clinical characteristics, it could provide certain reference value for clinical practice.

Objective: To explore the differences of adherence, lipid reduction and cost-effectiveness between brand-name and generic statins. Methods: Statins prescription records of adult patients aged 18 years and above with the first prescription of statins between January 2015 to December 2017, were collected from community health information system of Chaoyang district of Beijing. Medication compliancy after first prescription was compared between group only taking brand-name statins (41 496 records) and group only taking generic statins (60 491 records). Lipid reduction and cost-effectiveness were also compared between two groups. Results: The medication compliancy of generic statins was worse than brand-name statins (28.2 % vs. 36.2 % , P <0.001). After excluding the influence of age, sex, history of hypertension and diabetes, and community correlation, generic atorvastatin (20 mg/day) showed better total cholesterol reduction effect [(0.86±0.07) mmol/L] and better low density lipid-cholesterol reduction effect [(0.67±0.07) mmol/L] one year later in 199 patients who consistently used it compared with brand-name atorvastatin at same dosage in 232 patients [(0.40±0.10) mmol/L and (0.42±0.08) mmol/L] ( P <0.001, P =0.003). From the perspective of cost effectiveness, generic atorvastatin (20 mg/day) can reduce more than 50 % of medical expenses at the same cholesterol reduction level. Conclusions: Generic statins might replace brand-name statins with similar treatment effect but lower medical expenses although its compliancy needs improvement. However, the data of adverse reactions of generic statins are lacking, it is necessary to carry out high-quality clinical research to improve and promote the development of generic statins.

Atrial fibrillation (AF) can be secondary to acute pulmonary embolism (PE). This study aimed to investigate the prognostic impact of new-onset AF on patients with acute PE. In this study, 4,288 consecutive patients who were diagnosed with acute PE were retrospectively screened. In total, 77 patients with acute PE and new-onset AF were analyzed. Another 154 acute PE patients without AF were selected as the age- and sex-matched control group. Adverse in-hospital outcome comprised one of the following conditions: all-cause death, endotracheal intubation, cardiopulmonary resuscitation, and intravenous catecholamine therapy. The patients with new-onset AF had higher prevalence of congestive heart failure, higher simplified PE severity index (sPESI), higher creatinine, and larger left atrium diameter. The incidences of adverse in-hospital outcomes were 10.4 and 2.6% in patients with new-onset AF and no AF, respectively ( p  = 0.02). Patients with sPESI ≥ 1 had higher incidence of adverse in-hospital outcomes than those with sPESI = 0 (9.4 vs. 0.9%, p  < 0.01). The area under the receiver operating characteristic curve of sPESI and sPESI + AF (adding 1 point for new-onset AF) scores in assessing the adverse in-hospital outcome were 0.80 (95% confidence interval [CI]: 0.68-0.93) and 0.84 (95% CI: 0.72-0.96), respectively. In multivariable analysis, sPESI ≥ 1 (odds ratio, 8.88; 95% CI: 1.10-72.07; p  = 0.04) was an independent predictor of adverse in-hospital outcome. However, new-onset AF was not an independent predictor. In the population studied, sPESI is an independent predictor of adverse in-hospital outcomes, whereas new-onset AF following acute PE is not, but it may add predictive value to sPESI., Competing Interests: None., (Thieme. All rights reserved.)

Aims: Accessory pathways (APs) successfully ablated at the aortomitral continuity (AMC) were sporadically reported but relevant data are very limited. We aimed to describe the electrophysiological characteristics of AMC-AP and the related anatomy., Methods and Results: This study involved eight (male/female = 3/5, mean age 42.6 ± 10.5 years) patients with left-sided AP successfully ablated in the AMC region. The retrograde atrial activation sequence was analysed and compared via recordings at the His-bundle (HB), coronary sinus (CS), and roving catheter during tachycardia, and the peak of QRS from the same cardiac circle used as time reference. Of the eight patients, two received prior ablations. During tachycardia, the activation time at the proximal CS (CSp), lateral CS (CSl), and HB region averaged 120 ± 26 ms, 124 ± 29 ms, and 117 ± 21 ms following the reference, respectively (P = 0.86). The latest atrial activation was recorded in the posterior CS which averaged 135 ± 25 ms following the reference. Placing the ablation catheter to AMC via retrograde approach was attempted in all cases but stable positioning achieved in none. Via transseptal approach, the ablation catheter could be easily placed at the AMC and recorded the earliest retrograde atrial activations with 60 ± 27 ms earlier than the relatively 'earliest' CS/HB recordings, and ablation at this site successfully eliminated AP conduction. No patients had recovered AP conduction after at least 12-month follow-up., Conclusion: AMC-AP is featured by recording comparable retrograde atrial activation times at CSp, CSl, and HB with the latest recordings at the posterior CS. Stable placement and successful ablation in the AMC via retrograde aortic approach was difficult but can be achieved via transseptal approach., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: The moderator band (MB) is an endocavitary structure with only 2 exits to the bulk of the ventricular myocardium. Whether this may lead to specific electrophysiological characteristics remains unknown., Objective: The purpose of this study was to investigate electrocardiographic (ECG), activation, and pace mapping characteristics of MB-originated ventricular arrhythmias (VAs)., Methods: Mapping and ablation of MB-VAs were performed in 12 patients under the guidance of a 3-dimensional electroanatomic mapping system and intracardiac echocardiography and ECG, and mapping data were analyzed. Of these patients, 11 underwent pace mapping study of 6 sites around the MB and the QRS morphology was compared., Results: The earliest activation site was free wall (FW) insertion in 8 patients (66.7%) and MB body in 4 patients (33.3%), preceding the QRS onset by 17.8±4.7 ms, and Purkinje-like potential was observed in 6 (50.0%). VAs were eliminated at the earliest activation site in the procedure, but recurrence was documented in 2 cases (16.7%) during a follow-up of 13.4±7.8 months. Pacing QRS complex from the MB was characterized by short QRS duration (P<.001), short intrinsicoid deflection time (P<.001), later precordial transition (P=.025), and notch on the descending limb of the inferior leads (P<.001) as compared with pacing from the adjacent anterior-lateral FW, and that notch could also differentiate MB from the anterior papillary muscle (P=.027). However, pacing QRS is identical between the MB body and the FW insertion in 11 of 11 patients and between the septal insertion and the MB body in 7 of 11 patients., Conclusion: Bidirectional conduction via the 2 exits during MB-VAs contributed to distinct ECG and electrophysiological characteristics, while pace mapping is of limited value in defining the ablation target., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Interleukin-18 (IL18) gene polymorphisms are related to many inflammatory and autoimmune diseases. However, a correlation analysis between IL18 -607C/A and -137G/C gene polymorphisms and Takayasu arteritis (TA) is lacking., Methods: This study enrolled 200 patients with TA as the case group and 334 region-, age-, and sex-matched healthy subjects as the control group. We genotyped alleles and genotypes at positions -607 and -137 of the IL18 gene and analyzed the distribution frequencies. Mann-Whitney U test, t test, Chi-squared test and Hardy-Weinberg equilibrium were performed., Results: After adjusting for risk factors, the adjusted odds ratios and 95% confidence intervals at position -607C/A were 0.533, 0.391 to 0.880 (P = 0.010); 0.266, 0.586 to 1.002 (P = 0.051); and 0.122, 0.552 to 1.420 (P = 0.613) under the dominant, additive, and recessive models, respectively. For the -137G/C polymorphism, the adjusted odds ratios and 95% confidence intervals were 1.571, 1.068 to 2.311 (P = 0.022); 1.467, 1.086 to 1.980 (P = 0.012); and 1.815, 0.901 to 3.656 (P = 0.095) under the dominant, additive, and recessive models, respectively. Moreover, regardless of the model used, we found no statistical difference in distribution frequency between the active and quiescent states of TA for the -607C/A (P = 0.355, 0.631, and 0.705, respectively) and -137G/C polymorphisms (P = 0.205, 0.385, and 0.208, respectively)., Conclusions: The IL18 -607C/A gene polymorphism may decrease the risk of TA, and thus is a protective factor, whereas -137G/C may increase the risk of TA, and thus is a risk factor. However, neither polymorphism was related to activity (active vs. quiescent) of TA.

Aims: This study aimed to describe baseline characteristics of patients with atrial fibrillation (AF) at risk of stroke with and without history of heart failure (HF) and report 2-year outcomes in the dabigatran-treated subset of a prospective, global, observational study (GLORIA-AF)., Methods and Results: Newly diagnosed patients with AF and CHA 2 DS 2 -VASc score ≥ 1 were consecutively enrolled. Baseline characteristics were assessed by the presence or absence of HF diagnosis at enrolment. Incidence rates for outcomes in dabigatran-treated patients were estimated with and without standardization by stroke (excluding HF component) and bleeding risk scores. A total of 15 308 eligible patients were enrolled, including 15 154 with known HF status; of these, 3679 (24.0%) had been diagnosed with HF, 11 475 (75.0%) had not. Among 4873 dabigatran-treated patients, 1169 (24.0%) had HF, and 3658 (75.1%) did not; the risk of stroke was high (CHA 2 DS 2 -VASc score ≥ 2) for 94.3% of patients with HF and 85.8% without, while 6.0% and 7.0%, respectively, had a high bleeding risk (HAS-BLED ≥ 3). Incidence rates of all-cause death in dabigatran-treated patients with and without HF, standardized for CHA 2 DS 2 -VASc and HAS-BLED scores, were 4.76 vs. 1.80 per 100 patient years (py), with roughly comparable rates of stroke (0.82 vs. 0.60 per 100 py) and major bleeding (1.20 vs. 0.92 per 100 py)., Conclusions: Patients with AF and history of HF may have greater disease burden at AF diagnosis and increased mortality rates vs. patients without HF. Stroke and major bleeding rates were roughly comparable between groups confirming the long-term safety and effectiveness of dabigatran in patients with HF., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: There are distinct results for the relationship between new-onset atrial fibrillation (NOAF) and subsequent incident cancer. To date, no systematic analysis has been conducted on this issue. This study aims to explore the relationship between NOAF and the risk of developing cancer through a meta-analysis with a large sample size., Methods: Electronic databases, such as PubMed and EMBASE, were searched for published relevant studies on NOAF patients diagnosed with cancer after and during follow-ups, including reported records of baseline information and the statistical result of morbidity. Two investigators independently reviewed the articles and extracted the data using uniform standards and definitions. The meta-analysis was conducted using the Cochrane Program Review Manager., Results: This meta-analysis consisted of five cohort studies and one case-control study, which comprised 533,514 participants. The pooled relative risk (RR) for incident cancer was 1.24 (95% CI: 1.10-1.39, P =0.0003). The temporal trend analysis demonstrated that an increased risk of cancer was observed during the initial 90 days (RR: 3.44, 95% CI: 2.29-5.57, P < 0.00001), but not after that. Lung cancer (RR: 1.51, 95% CI: 1.47-1.55, P < 0.00001) was associated with NOAF, but not colorectal cancer and breast cancer., Conclusion: This meta-analysis provides evidence that NOAF is associated with increased risk of cancer. The risk of incident cancer particularly increases within 90 days after NOAF diagnosis, but not after that., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Mengxia Zhang et al.)

Objective: This study explored the thromboembolism risk of low-risk atrial fibrillation (AF) patients (CHA 2 DS 2 -VASc score of 0 or 1 for male and 1 or 2 for female) with different clinical characteristics to provide the basis for anticoagulation decision-making in these patients. Methods: We prospectively enrolled consecutive 2 862 nonvalvular low-risk AF patients between August 2011 to December 2018 in China-AF (China Atrial Fibrillation Registry) Study, their CHA 2 DS 2 -VASc score was 0 or 1 for male and 1 or 2 for female. According to their age, sex, presence or absence of hypertension, diabetes mellitus, congestive heart failure, and vascular disease at the time of enrolling, patients were divided into CHA 2 DS 2 -VASc score 0 score group, 1 score group, and 2 score group. Patients were followed up every 6 months by outpatient clinic visit or telephone interview. The outcome was a thromboembolic event, including ischemic stroke and systemic embolism. Univariate Cox regression analysis was used to compare the thromboembolism risk between the patients with different risk factors and CHA 2 DS 2 -VASc score 0 group. Results: A total of 2 862 low-risk atrial fibrillation patients were enrolled in this study. 915 patients (32.0%) were female, and age was (55.0±10.7) years old. There were 933 patients (32.6%) in CHA 2 DS 2 -VASc score 0 group, 1 401 patients (49.0%) in score 1 group and 528 patients (18.5%) in score 2 group. During follow-up (median 1.5 years, 5 811.82 person-years), 33 cases of thromboembolic events were recorded, the annual rate of thromboembolism was 0.57% (95% CI 0.40%~0.80%). The number of thromboembolic events in patients with CHA 2 DS 2 -VASc score 0, 1 and 2 were 8, 11 and 14, respectively, and the annual thromboembolism event rates were 0.40% (95% CI 0.20%-0.81%), 0.39% (95% CI 0.22%-0.71%) and 1.34% (95% CI 0.80%-2.27%), respectively. The risk of thromboembolism of CHA 2 DS 2 -VASc score 2 group ( HR =3.53, 95% CI 1.48-8.44; P =0.005), especially female patients aged 65-74 years in CHA 2 DS 2 -VASc score 2 group ( HR =2.67, 95% CI 1.63-4.38; P <0.000) was significantly higher than that in patients of CHA 2 DS 2 -VASc score 0 group. Conclusion: Low-Risk Atrial Fibrillation patients with CHA 2 DS 2 -VASc score 2, especially female patients aged 65-74 years old with CHA 2 DS 2 -VASc score 2 are at higher risk of thromboembolism in low-risk AF patients. For such patients, intensified oral anticoagulant therapy might be helpful to reduce the risk of thrombolism.

Objective: To explore the practice patterns and the related factors of oral antiarrhythmic drug (AAD) treatment in Chinese patients with atrial fibrillation (AF), and to evaluate the compliance of AAD application to atrial fibrillation management guidelines. Methods: From August 2011 to August 2016, medical records from 18 014 patients with AF were analyzed based on data from the Chinese Atrial Fibrillation Registry trial. Patients were divided into AAD group (7 788 cases, 43.23%) and non-AAD group (10 226 cases, 56.77%) according to whether AAD was used at baseline or at the time of first use during follow-up. Amiodarone (4 129 cases, 53.02%) and propafenone (3 211 cases, 41.23%) were the mostly prescribed AAD and subgroup analysis was performed accordingly. Medical records were analyzed by random forest regression to evaluate the use of AAD and related factors in patients with AF, and the rationality of AAD was analyzed according to the guidelines for the management of atrial fibrillation. Result: A total of 18 014 patients were included in this study, of which 60.48% (10 895/18 014) were male patients, 22.65% (4 081/18 014) were elderly patients(≥75 years old), there were 7 788 patients (43.23%) in AAD group, and 10 226 patients(56.77%) in non-AAD group. Compared with the non-AAD group, the elderly patients (≥75 years old, 13.74%(1 070/7 788) vs. 29.44%(3 011/10 226)), persistent AF (28.95% (2 250/7 788) 45.80% (4 683/10 226)), heart failure(8.29% (646/7 788) vs. 21.95% (2 245/10 226)), stroke and (or) TIA(12.15% (946/7 788) vs. 19.95% (2 040/10 226)), renal dysfunction(16.36%(1 274/7 788) vs. 29.37% (3 003/10 226)), and high thromboembolism risk(60.17% (4 748/7 788) vs. 76.40% (7 813/10 226)) were less prevalent in the AAD subgroup ( P <0.001). Multivariate analysis showed that patients in tertiary hospitals ( OR =3.72, 95% CI 3.17-4.37) were more likely to use AAD, elderly patients (≥75 years old, OR =0.47, 95% CI 0.39-0.55), persistent atrial fibrillation ( OR =0.66, 95% CI 0.60-0.72), and patients with heart failure ( OR =0.54, 95% CI 0.47-0.63), stroke and (or) TIA ( OR =0.77, 95% CI 0.68-0.87), renal dysfunction ( OR =0.75, 95% CI 0.59-0.95) and high thromboembolism risk( OR =0.7, 95% CI 0.58-0.84) were more likely not to use AAD( P <0.05). In the AAD group, amiodarone and propafenone were the most commonly used AAD, accounting for 53.02% (4 129/7 788) and 41.23% (3 211/7 788), respectively. Multivariate analysis showed that patients with persistent atrial fibrillation ( OR =4.57, 95% CI 3.94-5.29) and coronary heart disease ( OR =4.14, 95% CI 3.03-5.64), heart failure ( OR =2.07, 95% CI 1.48-2.89), non-ischemic cardiomyopathy ( OR =4.84, 95% CI 2.41-9.73) were more likely to use amiodarone, and those with normal left ventricular ejection fraction ( OR =0.31, 95% CI 0.15-0.65) and low thromboembolism risk ( OR =0.78, 95% CI 0.63-0.97) were more likely to use propafenone ( P <0.001). The overall incidence of AAD treatment, which was not indicated by the guidelines was 6.5% (480/7 340); 5.1% (212/4 129) in the amiodarone group and 8.3% (268/3 211) in the propafenone group, respectively. Compared with the rational AAD use group, the proportion of irrational drug use was higher in the elderly (≥75 years old) (20.4% (98/480) vs. 12.9% (887/6 860)), patients of high thromboembolism risk (77.1% (379/480) vs. 59.0% (4 047/6 860)), and in non-tertiary hospitals (7.1% (34/480) vs. 3.3% (299/6 860)), but lower in men(50.8% (244/480) vs. 64.5% (4 427/6 860)), P <0.001. Conclusions: The patients with paroxysmal atrial fibrillation, who were treated with AAD, were mostly patients with fewer complications, and the patients who were treated with amiodarone were mostly patients with persistent atrial fibrillation, patients were more likely to complicate with organic heart disease. The incidence of AAD that do not comply with the guidelines was low, and it was more common in non-tertiary hospitals and the elder patients with high thromboembolism risk.

Objective: To investigate the impact of history of hypertension and blood pressure levels on the thromboembolism risk in the setting of nonvalvular atrial fibrillation (NVAF). Methods: China Atrial Fibrillation Registry Study prospectively enrolled 25 512 atrial fibrillation (AF) patients between August 2011 and December 2018. After exclusion of patients with valvular AF, hypertrophic cardiomyopathy, receiving anticoagulation or ablation therapy at the enrollment, 7 757 patients were included in analysis. The primary endpoint was the time to the first occurrence of ischemic stroke or systemic embolism. Cox proportional hazards models were performed to evaluate whether a history of hypertension or blood pressure levels were independently associated with thromboembolism. Results: During a mean follow up of (35±25) months, 455 （5.9%）thromboembolic events occurred. The crude incidence rate of thromboembolism in patients with a history of hypertension was higher than that in patients without hypertension (2.38 vs. 1.35 per 100 patient-years, χ²=16.8，Log-rank P <0.001). Patients were further divided into 4 groups according to systolic blood pressure (SBP) levels at baseline, the crude incidence rate of thromboembolism significantly increased in proportion to the elevation of SBP levels (χ²=17.9，Log-rank P <0.001). However, there was no significant difference in thromboembolism risk among 4 groups stratified by diastolic blood pressure (DBP) levels (χ²=0.6，Log-rank P =0.907). Multivariable regression analysis showed that history of hypertension was independently associated with a 27% higher risk of thromboembolism ( HR =1.27, 95% CI 1.01-1.61, P =0.045). Patients with SBP≥140 mmHg (1 mmHg=0.133 kPa) was associated with 36% higher risk of thromboembolism than patients with SBP<120 mmHg ( HR =1.36, 95% CI 1.02-1.82, P =0.036). However, patients with SBP 120-129 mmHg or 130-139 mmHg were not at a higher risk of thromboembolism as compared to the patients with SBP<120 mmHg (SBP 120-129 mmHg: HR =1.23, 95% CI 0.90-1.67, P =0.193; SBP 130-139 mmHg: HR =1.30, 95% CI 0.95-1.77, P =0.098). In addition, DBP levels were not independently associated with the increased thromboembolism risk. Conclusion: A history of hypertension and SBP≥140 mmHg are independent predictors of thromboembolism risk in patients with NVAF. These results indicate that intensive efforts to lower SBP below 140 mmHg might be an important strategy to reduce the risk of stroke in patients with NVAF.

Objective: We aimed to explore the impact of digoxin use on outcomes in Chinese patients with atrial fibrillation (AF). Methods: We used the dataset from the Chinese Atrial Fibrillation Registry, a prospective, multicenter, hospital-based registry study. According to the inclusion and exclusion criteria, 10 472 eligible patients enrolled from August 2011 to December 2016 were included in this ancillary study. The patients were classified into three groups according to the status of digoxin use at study enrollment, patients already receiving digoxin before registry were represented as continuous group, patients initiated on digoxin for the first time were represented as newly group, and patients without digoxin prescription at enrollment were represented as control group. Patients were followed by telephone or outpatient service every 6 months. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to investigate the association of digoxin use with adverse outcomes (all-cause death, cardiovascular death and cardiovascular hospitalization). Results: In the overall study population, men accounted for 42.8%, and the average age was (66.9±11.8) years. There were 777（7.42%）patients in continuous group, 375 (3.58%) patients in newly group, and 9 320 (89.00%) patients in control group. Compared with the control group, the patients in the newly group and the continuous group were older, had faster heart rate, lower estimated glomerular filtration rate, higher proportion of persistent atrial fibrillation, heart failure, renal insufficiency, diabetes mellitus, ischemic stroke, coronary heart disease, vascular disease and bleeding history. At the same time, the patients in the newly group and the continuous group were treated more often with anticoagulants, antiplatelet drugs, ACE inhibitors or angiotensin receptor blockers, beta-receptor blockers while the proportion of antiarrhythmic drugs was lower as compared to control group ( P <0.05). During a median follow-up of 36 months (interquartile range: 18-48 month), risk of all-cause mortality was significantly higher in newly group compared to control group (7.3% vs. 4.7%, P <0.05), the rates of all-cause mortality, cardiovascular death and cardiovascular hospitalization were all higher in continuous group than in control group (8.0% vs. 4.7%; 4.7% vs. 3.0%; 16.7% vs . 11.8%; P all<0.05). After adjustment for age, male, body mass index, blood pressure, heart rate, renal function, AF type, history of stroke, heart failure, diabetes, coronary artery disease and other drugs treatment, the association between newly group and adverse outcomes was not significant, however, digoxin use was associated with increased all-cause mortality ( HR 1.26; 95% CI 1.04-1.56; P =0.019), cardiovascular death ( HR 1.38; 95% CI 1.08-1.77, P =0.01), and cardiovascular hospitalization ( HR 1.10; 95% CI 1.06-1.52, P =0.02) in continuous group. Conclusion: Continuous digoxin use is associated with a significant increase in adverse outcomes among Chinese patients with atrial fibrillation.

Left ventricular diastolic dysfunction (LVDD) remains challenging to be assessed by echocardiography. We sought to explore the relationship between left atrial strain and left ventricular (LV) diastolic function in patients with normal left ventricular ejection fraction (LVEF) by invasive left-heart catheterization. 55 consecutive individuals with LVEF > 50% underwent LV catheterization. Standard transthoracic echocardiography was performed during 12 h before or after the procedure. Left atrial (LA) strain were obtained by speckle tracking echocardiography. When LVEF ≥ 50%, the group with elevated left ventricular end-diastolic pressure (LVEDP) (n = 35) showed decreased left atrial reservoir strain (LASr) (35.2 ± 7.7% vs 21.3 ± 7.2%, p < 0.001), left atrial conduit strain (LASct) (17.6 ± 6.3% vs 11.9 ± 4.1%, p < 0.001), left atrial contraction strain (LAScd) (16.6 ± 7.2% vs 9.5 ± 5.0%, p < 0.001) and increased E/e' ration(8.9 ± 2.6 vs 10.1 ± 3.5, p = 0.17). LVEDP negatively correlated with LASr (R = 0.662, p < 0.001), LASct (R = 0.575, p < 0.001) and LAScd (R = 0.456, p < 0.001), but not with E/e'. LASr, LASct and LAScd were all independent predictors of elevated LVEDP (p < 0.05), with a higher C-statistic for the model including LASr (0.95, 0.86 and 0.93 respectively). The area under the curve (AUC) for LASr is 0.914 (cutoff value is 26.7%, sensitivity is 90%, specificity is 82.9%). In patients with normal LV ejection fraction, left atrial strain presented good correlation with LVEDP, and LASr was superior to LASct and LAScd to predict LVEDP. LA strain demonstrated better agreement with the invasive reference than E/e'.

Background: The unique malformation of congenitally corrected transposition of the great arteries (cc-TGA) makes the pulmonary outflow tract (POT) a possible origin of atrial tachycardia (AT)., Objective: The purpose of this study was to investigate the mapping characteristics of ATs successfully ablated at the POT in patients with cc-TGA., Methods: Patients with cc-TGA with AT eliminated at the POT were analyzed. Activation mapping of the atria and POT was performed under the guidance of a 3-dimensional electroanatomic mapping system. The activation pattern of these chambers was investigated, with the local activation time (LAT; using coronary sinus ostium as a reference) of the earliest activation site (EAS) being compared., Results: AT eliminated at the POT was documented in 5 of 6 patients with cc-TGA. The EAS was at the right anteroseptal region with a LAT of 33 (21-120) ms in the right atrium and at the septal wall with a comparable LAT (26, 47, and 26 ms; P = .604) in the left atrium. The EAS of the POT was in the vicinity of the left-facing pulmonary sinus cusp in 3 cases and the nonfacing pulmonary sinus cusp in 2 cases, with a LAT of 106 (28-134) ms preceding both atria. Ablation at this site successfully eliminated AT in all 5 cases., Conclusion: AT arising adjacent to the POT is not an uncommon tachycardia in patients with situs solitus-type cc-TGA and can be safely eliminated by ablation targeting the EAS in the POT., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8 + T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

Objective: Atrial fibrillation (AF) is the most frequent form of cardiac arrhythmia and major cause of cardiac ischemia. Defective calcium homeostasis due to anomalous expression of ryanodine receptor type 2 (RyR2) or its hyperactivation by phosphorylation by serine threonine kinases has been implicated as a central mechanism of AF pathogenesis. Given the role of protein kinase C (PKC) isoforms in cardiac function we investigated role of PKC in AF using a rat model., Results: PMA induced global increase in protein synthesis in cardiac fibroblasts isolated from AF rats, but not healthy controls, and the increase was inhibited by PKC inhibition. PMA mediated activation of both PKC and ERK and either inhibition of PKC by Go6983 or ERK by the MEK inhibitor Trametinib attenuated both P-ERK and P-PKC in both cardiac fibroblasts isolated from AF rats or from healthy rats but transduced with PKC-delta. The PKC and ERK mediated induction of global protein synthesis was found to be mediated by increased phosphorylation of the ribosomal protein S6., Conclusion: Our findings provide a foundation for future testing of PKC and MEK inhibitors to treat AF in pre-clinical models. It also needs to be determined if PKC and MAPK pathway activation is functioning via RyR2 or some yet undefined substrates.

Background: The impact of different glycemic control conditions on in-hospital and long-term outcomes among patients with acute coronary syndrome (ACS) is less well defined., Hypothesis: Diabetes mellitus (DM) with different admission hemoglobin A1c (HbA1c) levels (different glycemic control) could affect outcomes among Chinese patients hospitalized as ACS., Methods: We categorized 8961 Chinese ACS patients into one of the following three groups: "no DM" (group 1, n = 3773; no DM history and admission HbA1c < 6.5%), "DM with optimal control"(group 2, n = 2241; DM with admission HbA1c < 7.0%), "DM with suboptimal control"(group 3, n = 2947; DM with admission HbA1c ≥ 7.0%). The primary outcome was in-hospital major adverse cardiovascular events (MACEs). 6098 patients were followed for a median of 3.85 years. Adjusted associations of these three groups with in-hospital MACEs and long-term mortality were determined., Results: DM with suboptimal control (group 3) was associated with greater in-hospital MACEs (OR 1.46, 95% CI 1.17-1.81, P = .001) than "no DM" (group 1). DM patients (group 2 and group 3) also had higher in-hospital MACEs (OR 1.42, 95% CI 1.16-1.73, P = .001) than "no DM" patients (group 1). It showed no significantly different in-hospital MACEs between optimal (group 2) and suboptimal (group 3) control group (OR 1.06, 95% CI 0.84-1.34, P = .63). Both optimal control (group 2) and suboptimal control (group 3) had a higher long-term mortality (HR 1.26, 95% CI 1.02-1.56, P = .03; HR 1.42, 95% CI 1.16-1.73, P = .001)., Conclusions: ACS patients with DM were associated with higher in-hospital MACEs and long-term mortality. Moreover, lower HbA1c level seems to have limited impact on cardiovascular events and long-term mortality in this high-risk population., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: We aimed to assess the extent to which drug persistence is better with non-vitamin K antagonist oral anticoagulants (NOACs) than vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients and to estimate the difference in therapy persistence depending on NOAC dosing regimen (once daily (QD) vs. twice daily (BID))., Methods: Consecutive patients were followed for 1 year in phase III of the GLORIA-AF registry. Drug persistence was defined as the use of OAC without any discontinuation in >30 days or switching to alternative therapy., Results: Among 21,109 eligible patients in phase III, 17,266 patients who were prescribed OAC at baseline and those who took ≥1 OAC dose were included. The 1-year proportion of patients receiving NOAC and VKA who persisted on treatment was 80% and 75%, respectively. The 1-year persistence with NOACs BID and NOACs QD was 81% and 80%, respectively. Female gender, hypertension, older age, alcohol use, permanent, asymptomatic, and minimally symptomatic AF were associated with better OAC persistence. Region, medication usage predisposing to bleeding, being a current smoker, treatment reimbursement, and proton pump inhibitors were associated with lower OAC persistence., Conclusions: Drug persistence was higher with NOACs (1-year persistence was 80%) than with VKAs (75%). There was little difference in 1-year persistence between NOAC dosing regimens.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways., Competing Interests: Disclosures: Dr. Chen reported grants from Bristol-Myers Squibb during the conduct of the study. Dr. Rosenfeld reported personal fees from Baylor Genetics Laboratories outside the submitted work. Dr. Milner reported a patent to use STAT3 inhibition to prevent anaphylaxis pending. Dr. Couderc reported non-financial support from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Novartis, and grants from LVL outside the submitted work. Dr. Catherinot reported financial support for travel and registration expenses related to international medical meetings (LVL Medical, CSL Behring). Dr. Uhlig reported grants from Celgene during the conduct of the study and grants from UCB and Eli Lilly outside the submitted work. Dr. Haerynck reported, "Centre for Primary Immune deficiency is recognized as a Jeffrey Modell Foundation diagnostic and research center and supported by the Jeffrey Modell Foundation; the University Hospital Ghent Spearhead Initiative for Immunology Research (until 7/2019); the Grand Challenges Program of VIB (this VIB Program received support from the Flemish Government under the Management Agreement 2017-2021; VR 2016 2312 Doc.1521/4); Simon Tavernier is a postdoctoral fellow at PID research lab with the Fund for Scientific Research Flanders (FWO, 12W9119N); I am funded by a university research grant (BOF-University Ghent)." No other disclosures were reported., (© 2020 Béziat et al.)

Background: Revascularization for the treatment of coronary artery disease (CAD) is advancing rapidly and is used increasingly in old patients. This study aimed to compare the efficacy and safety of revascularization with drug therapy in CAD patients aged over 80 years at a real-world clinical setting., Methods: A total of 501 CAD patients aged over 80 years were consecutively enrolled from January 2011 to January 2016 in Anzhen Hospital (Beijing, China), Capital Medical University. The patients were treated with percutaneous coronary intervention (PCI) (n=283), coronary artery bypass grafting (CABG) (n=106), or drug therapy (n=112). All-cause mortality, cardiovascular-related mortality, readmission rate, and Seattle Angina Questionnaire (SAQ) score were compared between the three treatment methods., Results: A total of 411 patients (82.04%) were followed with a median duration of 25 months. All-cause mortality and cardiovascular-related mortality in the drug therapy group were significantly higher than the PCI and CABG groups (both P<0.05). Readmission rate for cardiovascular events in the CABG group was significantly lower than the PCI and drug therapy groups (both P<0.05). Scores of physical limitation, angina frequency, treatment satisfaction, and disease perception of the SAQ in the PCI and CABG groups were significantly higher than the drug therapy group (both P<0.05). Scores of angina stability did not differ significant between the three groups (P=0.127)., Conclusions: Revascularization is superior to drug therapy in efficacy and safety in the treatment of oldest-old patients with CAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/cdt-20-185). The authors have no conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

This study was to assess the feasibility of using non-standardized single-lead electrocardiogram (ECG) monitoring to automatically detect atrial fibrillation (AF) with special emphasis on the combination of deep learning based algorithm and modified patch-based ECG lead. Fifty-five consecutive patients were monitored for AF in around 24 hours by patch-based ECG devices along with a standard 12-lead Holter. Catering to potential positional variability of patch lead, four typical positions on the upper-left chest were proposed. For each patch lead, the performance of automated algorithms with four different convolutional neural networks (CNN) was evaluated for AF detection against blinded annotations of two clinicians. A total of 349,388 10-second segments of AF and 161,084 segments of sinus rhythm were detected successfully. Good agreement between patch-based single-lead and standard 12-lead recordings was obtained at the position MP1 that corresponds to modified lead II, and a promising performance of the automated algorithm with an R-R intervals based CNN model was achieved on this lead in terms of accuracy (93.1%), sensitivity (93.1%), and specificity (93.4%). The present results suggest that the optimized patch-based ECG lead along by deep learning based algorithms may offer the possibility of providing an accurate, easy, and inexpensive clinical tool for mass screening of AF.

Objective: To compare left ventricular myocardial mechanics detected by cardiac magnetic resonance tissue tracking(CMR-TT) between patients with constrictive pericarditis(CP) and restrictive cardiomyopathy(RCM),and see if those can be used to differentiate CP from RCM patients. Methods: A total of 23 patients with CP, 20 patients with RCM, who hospitalized in Beijing Anzhen Hospital from January 2014 to April 2019 were included in this study and 25 healthy subjects served as control group, all subjects underwent cardiac magnetic resonance examination. Myocardial mechanics were evaluated by 2-dimensional(2D) and 3-dimensional(3D) CMR-TT in terms of global longitudinal strain(GLS), circumferential strain(GCS), radial strain(GRS) and the lateral wall strain to septal wall strain ratio(lateral/septal ratio) of basal, mid-cavity and apical. The diagnostic area under the receiver operating characteristic curve (ROC) was evaluated for differentiating CP from RCM. Results: Age, sex and heart rate were similar between CP and RCM patients(all P> 0.05). 2D-GLS, 3D-GLS, GCS and GRS in CP and RCM groups were significantly lower than those in normal control group(all P< 0.05).3D-GLS value was significantly lower in RCM patients than in CP patients( P< 0.05), the area under the curve ( AUC )=0.787(sensitivity 80%, specificity 78%). 3D-GCS was significantly lower in CP group than in RCM group( P< 0.05), the AUC =0.737(sensitivity 80%, specificity 65%). However, there was no significant difference between CP and RCM in 3D-GRS( P> 0.05). Compared with RCM, the circumferential and radial lateral/septal ratios of the basal were significantly lower in CP group than in RCM group(both P< 0.05), AUC =0.737(sensitivity 70%, specificity 83%) and 0.737 (sensitivity 60%, specificity 87%), respectively. The left ventricular myocardial mechanics strain curve of the CP,RCM and normal control were different. The CP patients presented as " rapidly down-a platform" form, the RCM presented as "slowly down" form, and normal control presented as "rapidly down" form. Conclusion: Evaluating the differences in the diastolic process of left ventricular myocardium and left ventricular myocardial mechanics strain curve is helpful to differentiate CP from RCM patients.

Objective: To determine the predictors of recurrent hospitalizations among atrial fibrillation (AF) patients. Methods: We analyzed data from the Chinese Atrial Fibrillation Registry (CAFR), a prospective cohort study involving non-valvular atrial fibrillation (NVAF) patients from Augest 2011 to December 2017. A total of 5 349 NVAF patients with a minimum of 48 months follow-up were included for analysis. Data including patient demographics, complications, medical and ablation history were collected. The maximum number of all-cause hospitalizations within one-year for each patient served as the primary endpoint. Patients hospitalized less than twice within one-year were defined as non-recurrent hospitalizations group, those hospitalized at least twice within one-year were definned as recurrent hospitalizations group. Logistic regression model was used to identify associated risk factors for recurrent hospitalizations. Results: Of 5 349 NVAF patients, those hospitalized for 0, 1, 2, 3, 4 and at least 5 times within one-year was 2 703 (50.5%), 1 776 (33.2%), 642 (12.0%), 161(3.0), 52 (1.0%), 15 (0.3%), respectively. Eight hundred and seventy (16.3%) patients were included in recurrent hospitalizations group, 4 479 (83.7%) patients were included in non-recurrent hospitalizations group. Compare with non-recurrent hospitalizations group, patients in recurrent hospitalizations group was more likely to be older and female, more frequently had a history of hypertension, heart failure, coronary heart disesase, ischaemic stroke/transient ischaemic attack, diabetes mellitus, peptic ulcer, a AF duration for more than 1 year, medication including drugs for ventricular rate control, statin, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocker (ARB) and higher CHA(2)DS(2)-VASc scores ( P< 0.05), but less frequently had higher education, a history of drinking, smoking and ablation ( P< 0.05). Multivariable analysis showed that age 50-64 ( OR= 1.47, 95 %CI 1.20-1.80), age≥65 ( OR= 1.89, 95 %CI 1.50-2.38), female ( OR= 1.21, 95 %CI 1.01-1.46), hypertension history ( OR= 1.42, 95 %CI 1.16-1.74), heart failure history ( OR= 1.73, 95 %CI 1.37-2.18), coronary heart disease history ( OR= 1.63, 95 %CI 1.31-2.03), peptic ulcer history ( OR= 2.00, 95 %CI 1.18-3.39) were independent risk factors for recurrent hospitalizations, while higher education (college or above) ( OR= 0.82, 95 %CI 0.69-0.99) was the protective factor for recurrent hospitalizations. Conclusions: Nearly 1 in 6 of AF patients were admitted to hospital more than once within one year in this NVAF cohort. Age≥50, female, hypertension history, heart failure history, coronary heart disease history, peptic ulcer history are associated with an increased risk of recurrent hospitalizations.

Objective: To investigate the relationship between high sensitivity C-reactive protein (hs-CRP) level and incidence of left atrial spontaneous echocardiographic contrast (LASEC) in the patients with nonvalvular atrial fibrillation (AF). Methods: Four hundred and ninety consecutive patients with nonvalvular atrial fibrillation who underwent radiofrequency ablation for the first time from January 1, 2018 to June 30, 2018 in the Department of Cardiology, Beijing Anzhen Hospital were enrolled. According to the results of transesophageal echocardiography before radiofrequency ablation, patients were divided into the group without LASEC ( n= 338) and the group with LASEC ( n= 152). hs-CRP was determined by latex enhanced immunoturbidimetry. The relationship between hs-CRP and LASEC in patients with nonvalvular atrial fibrillation was investigated by univariate and multivariate logistic analysis. Results: LASEC was detected in 152 (31%) of 490 patients. Significant differences in age, type of atrial fibrillation, previous embolic events, fibrinogen, D-dimer, the left atrial anteroposterior diameter and CHA(2)DS(2)-VASc scores were found between patients with and without LASEC (all P< 0.05). Compared with the group without LASEC, the serum hs-CRP level was significantly higher in the group with LASEC (3.16 (1.30, 5.23) mg/L vs. 0.67 (0.37, 1.48) mg/L, P< 0.001). Multivariate logistic regression analysis showed that hs-CRP ( OR= 1.136, 95 %CI 1.060 - 1.217, P< 0.001) and D-dimer ( OR= 1.040, 95 %CI 1.011 - 1.070, P= 0.007) were independent determinants for LASEC in this patient cohort. Conclusions: hs-CRP is an independent determinant for LASEC in patients with nonvalvular atrial fibrillation. Inflammation may thus be involved in the formation of prethrombotic state in patients with nonvalvular atrial fibrillation.

Background: To investigate the distribution of metastatic cancer cells in the mesentery (referred to as metastasis V) and enrich the understanding of the metastasis of colorectal cancer., Methods: A total of two hundred ninety-nine patients who received colorectal operations at the Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between April 2018 and December 2018 were included. Samples were acquired from the dissected mesentery after the operation, and hematoxylin-eosin staining or immunohistochemistry was used to detect metastatic cancer cells. Pathological factors, including tumor position, tumor size, invasion depth, tumor differentiation, lymph node involvement, local vessel invasion, and perineural invasion, were recorded., Results: Metastatic cancer cells in the colorectal mesentery (metastasis V) were detected in 62 of 299 patients. Metastasis V was closely correlated with tumor invasion depth, lymph node metastasis, tumor differentiation, and perineural and vessel invasion by cancer cells. Metastasis V occurred more frequently in patients with T3 stage (26.27%) and T4 stage (40.00%) than in patients with T1 and T2 stages (0% and 2%, respectively). Metastasis V was frequently detected in patients with N2a and N2b stage tumors (51.72% and 61.54%, respectively). Metastasis V was more frequently detected in patients with perineural metastasis and local vessel invasion. In addition, metastasis V incidences in colon and rectal cancer were similar., Conclusion: The incidence rate of metastasis V is correlated with tumor staging factors and occurs more frequently in advanced-stage patients.

Background: Increasingly, patients with breast cancer undergo bilateral mastectomy (BLM). To the authors' knowledge, the magnitude of benefit is unknown., Methods: The authors used data from the Surveillance, Epidemiology, and End Results (SEER) program regarding all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 through 2015 and treated with BLM versus breast-conserving therapy including surgery and radiotherapy (BCT) or unilateral mastectomy (ULM). The authors measured relative risks of second contralateral breast cancer (CBC) and breast cancer death using Fine and Gray multivariable regression modeling adjusted for the competing risk of death and death from another cause, respectively, and potential confounding factors. Absolute excess risk of CBC was measured as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk., Results: Among 245,418 patients with a median follow-up of 6.7 years, 7784 patients (3.2%) developed CBC. Relative risks were lower after BLM (hazard ratio [HR], 0.10; 95% CI, 0.07-0.14) and higher after ULM (HR, 1.07; 95% CI, 1.02-1.13) versus BCT. Absolute excess risks were higher after BCT and ULM (5.0 and 13.6 more cases, respectively) compared with BLM (28.6 fewer cases). BLM reduced risk more among older women (38.0 fewer cases for women aged ≥50 years vs 17.9 fewer cases among women aged <50 years) but provided similar risk reduction across categories of tumor grade and tumor hormone receptor status. Compared with BCT, the risk of breast cancer death was equivalent after BLM (HR, 1.03; 95% CI, 0.96-1.11) and higher after ULM (HR, 1.21; 95% CI, 1.17-1.25)., Conclusions: BLM may reduce second breast cancer risk by 34 to 43 cases per 10,000 person-years compared with other surgical procedures, but is not associated with a lower risk of death. Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM., (© 2019 American Cancer Society.)

Background: Three-dimensional electroanatomic mapping systems have demonstrated a significant reduction in radiation exposure during radiofrequency catheter ablation procedures. We aimed to investigate the safety, feasibility and efficacy of a completely zero-fluoroscopy approach for catheter ablation of supraventricular tachycardia using the Ensite NavX navigation system compared with a conventional fluoroscopy approach., Methods: A multicenter prospective non-randomized registry study was performed in seven centers from January 2013 to February 2018. Consecutive patients referred for catheter ablation of supraventricular tachycardia were assigned either to a completely zero-fluoroscopic approach (ZF) or conventional fluoroscopy approach (CF) according to the operator's preference. Patients with atrial tachycardia were excluded., Results: Totally, 1020 patients were enrolled in ZF group; 2040 patients ablated by CF approach were selected for controls. There was no significant difference between the zero-fluoroscopy group and conventional fluoroscopy group as to procedure time (60.3 ± 20.3 vs. 59.7 ± 22.6 min, P = 0.90), immediate success rate of procedure (98.8% vs. 99.2%, P = 0.22), arrhythmia recurrence (0.4% vs. 0.5%, P = 0.85), total success rate of procedure (98.4% vs. 98.8%, P = 0.39) or complications (1.1% vs. 1.5%, P = 0.41). Compared with the conventional fluoroscopy approach, the zero-fluoroscopy approach provided similar outcomes without compromising the safety or efficacy of the procedure., Conclusion: The completely zero-fluoroscopy approach demonstrated safety and efficacy comparable to a conventional fluoroscopy approach for catheter ablation of supraventricular tachycardia, and mitigated radiation exposure to both patients and operators., Trial Registration: clinicaltrials.gov Identifier: NCT03042078; first registered February 3, 2017; retrospectively registered.