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Prospective studies evaluating persistence to nonvitamin K antagonist oral anticoagulants in patients with atrial fibrillation are needed to improve our understanding of drug discontinuation. The study objective was to evaluate if and when patients with newly diagnosed atrial fibrillation stop dabigatran treatment and to report outcomes following discontinuation. Patients prescribed dabigatran in diverse clinical practice settings were consecutively enrolled and followed for 2 years. Dabigatran persistence over time, reasons for discontinuation, and outcomes post discontinuation were assessed. Of 4,859 patients, aged 70.2 ± 10.4 years, 55.7% were male. Overall 2-year dabigatran persistence was 70.9% (95% confidence interval [CI] 69.6 to 72.2). Persistence probability was lower in the first 6-month period (83.7% [82.7 to 84.8]) than in subsequent periods for patients on dabigatran at the start of each period (6 to 12 months, 92.5% [91.6 to 93.3]; 12 to 18 months, 95.1% [94.3 to 95.8]; 18 to 24 months, 96.3% [95.6 to 96.9]). Of 1,305 patients (26.9%) who discontinued dabigatran, adverse events were reported as the reason for discontinuation in 457 (35.0%). Standardized stroke incidence rate post discontinuation (per 100 patient-years) in patients discontinuing without switching to another oral anticoagulant was 1.76 (95% CI 0.89 to 2.76) and 1.02 (95% CI 0.43 to 1.76) in those who switched, consistent with the expected benefit of remaining on treatment. Patients persistent with treatment at 1 year had >90% probability of remaining persistent at 2 years suggesting clinical interventions to improve persistence should be focused on the early period following treatment initiation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Both the prevalence of atrial fibrillation (AF) and frailty are increasing with age, and they often occur simultaneously, leading them to become the central concerns in this aging society. The incidence of frailty in patients with AF is highly variable, ranging from 4.4% to 75.4%, depending on different evaluating instruments used. Moreover, the incidence of frailty among patients with AF is on the rise, which indicated that patients with AF are more prone to frailty compared to patients without AF. The relationship between AF and frailty is complicated. Frailty elevates the risk of stroke and mortality in AF patients and is also associated with longer hospitalizations. On the other hand, it may reduce the appropriate anticoagulation in AF patients. However, the evidence of the effects of frailty on anti-arrhythmic and interventional therapy in patients with AF is scarce. Frailty affects both the management and the prognosis of AF in the geriatric population. Vice versa, AF could worsen the frail state and may represent a marker of frailty. However, there are still questions need to be resolved, for example, the impact of frailty on the interventional therapy of patients with AF. Therefore, the geriatric assessment of frailty should be considered when planning individualized management of AF in older patients., (Institute of Geriatric Cardiology.)

Climate warming has increased the frequency of extreme heat events. Alien species usually invade new areas with a low-density population and often have limited mating opportunities due to the unsynchronized emergence of adults. Early-emerging virgin adults often have to wait to mate with later-emerging partners at the cost of aging, which reduces thermal tolerance. To understand the adaptive strategies of virgin males/females versus those of mated males/females in response to heat stress during aging, we conducted a fully factorial experiment to test the basal and plastic heat tolerance (CTmax, critical thermal maximum) of males and females with different mating statuses (virgin and mated) at different ages (5, 10, and 15 days after eclosion) after different acclimation regimes (null, rapid and developmental heat acclimation) in a well-known invasive species, Drosophila suzukii. We found that mating could change the heat tolerance of adults during aging. Mated females had higher basal heat tolerance than virgin females, while mated males had lower tolerance than virgin males. Mating could generally decrease the acclimation capacity (i.e., plasticity of heat tolerance) during aging. Aged virgin adults had a much higher acclimation capacity than aged mated adults. Our findings suggest that phenotypic plasticity of heat tolerance may be a main strategy used by virgin adults to cope with heat events. The phenotypic plasticity of thermal tolerance could increase the invasion success of alien species in new areas by allowing them to rapid respond to local temperature changes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Right free-wall (RFW) accessory pathway (AP) with branched atrial insertions is a rare, underrecognized AP that may be associated with initial ablation failure., Objective: The purpose of this study was to investigate the clinical and electrophysiological characteristics of this AP., Methods: From January 2011 to March 2018, 10 patients identified with branched RFW-AP were enrolled in this study, and 30 consecutive patients with conventional RFW-APs served as control group. Right atrium (RA) was activation-mapped and 3-dimensionally reconstructed during AP-mediated orthodromic tachycardia or right ventricular pacing. Atrial insertions were defined as the earliest breakout sites, and their relationship with the tricuspid annulus (TA) were described and analyzed., Results: An average of 3 separate atrial insertions on the atrial side were documented among these 10 cases (5 female and 5 male; mean age 38.0 ± 13.9 years). All atrial insertions were away from the TA. The nearest atrial insertions averaged 15.9 ± 3.4 mm away from the TA, and the farthest atrial insertions were 22.6 ± 5.7 mm away from the TA. Anterograde and retrograde AP conduction remained unaffected after ablation of the first earliest breakout site but were eliminated by ablating all insertions after an average of 2.5 (range 2-2.5) remaps, 3 sites of ablation (range 2.5-4.5), 21 (range 15.5-37.8) radiofrequency applications, and 659.5 (range 464.3-1144.3) seconds of radiofrequency ablation duration. After 12-month follow-up, no patients reported AP conduction recovery or recurrent tachycardia., Conclusion: RFW-AP with branched atrial insertions is an atypical AP variant and featured by >1 distinct atrial insertions on atrial side. Stepwise ablation rather than single focal ablation is required to eliminate all retrograde conduction., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Variants in MAGT1 have been identified as the cause of an immune deficiency termed X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease. Here, we describe 2 cases of XMEN disease due to novel mutations in MAGT1, one of whom presented with classical features of XMEN disease and another who presented with a novel phenotype including probable CNS vasculitis, HHV-8 negative multicentric Castelman disease and severe molluscum contagiosum, thus highlighting the clinical diversity that may be seen in this condition. Peripheral blood immunophenotyping of these 2 patients, together with an additional 4 XMEN patients, revealed reduced NKG2D expression, impaired CD28 expression on CD8 + T cells, CD4 + T cell lymphopenia, an inverted CD4:CD8 ratio and decreased memory B cells. In addition, we showed for the first time alterations to the CD8 + T cell memory compartment, reduced CD56 hi NK cells, MAIT and iNKT cells, as well as compromised differentiation of naïve CD4 + T cells into IL-21-producing Tfh-type cells in vitro. Both patients were treated with supplemental magnesium with limited benefit. However, one patient has undergone allogeneic haematopoietic stem cell transplant, with full donor chimerism and immune reconstitution. These results expand our understanding of the clinical and immunological phenotype in XMEN disease, adding to the current literature, which we further discuss here.

Cytokines play critical roles in regulating the development, survival, differentiation, and function of immune cells. Cytokines exert their function by binding specific receptor complexes on the surface of immune cells and activating intracellular signaling pathways, thereby resulting in induction of specific transcription factors and regulated expression of target genes. While the function of cytokines is often fundamental for the generation of robust and effective immunity following infection or vaccination, aberrant production or function of cytokines can underpin immunopathology. IL-21 is a pleiotropic cytokine produced predominantly by CD4+ T cells. Gene-targeting studies in mice, in vitro analyses of human and murine lymphocytes, and the recent discoveries and analyses of humans with germline loss-of-function mutations in IL21 or IL21R have revealed diverse roles of IL-21 in immune regulation and effector function. This review will focus on recent advances in IL-21 biology that have highlighted its critical role in T cell-dependent B cell activation, germinal center reactions, and humoral immunity and how impaired responses to, or production of, IL-21 can lead to immune dysregulation., (© 2019 Tangye and Ma.)

Aims: We aimed to investigate the safety of discontinuing oral anticoagulation (OAC) therapy after apparently successful atrial fibrillation (AF) ablation, using data from the Chinese Atrial Fibrillation Registry study., Methods and Results: We identified 4512 consecutive patients who underwent successful AF ablation between August 2011 and December 2017. Of them, 3149 discontinued OAC 3 months post-ablation (Off-OAC group) and 1363 continued OAC beyond this period (On-OAC group). Regular follow-up examinations were undertaken to detect AF recurrence, monitor OAC therapy, and measure clinical outcomes. Primary outcomes included thromboembolic and major bleeding (MB) events experienced beyond 3 months after ablation. Low thromboembolic and MB event rates were noted in the on-treatment analysis. The incidence rates for thromboembolism were 0.54 [95% confidence interval (CI) 0.39-0.76] and 0.86 (95% CI 0.56-1.30) per 100 patient-years, and that for MB events were 0.19 (95% CI 0.11-0.34) and 0.35 (95% CI 0.18-0.67) per 100 patient-years, for the Off-OAC and On-OAC groups over mean follow-up periods of 24.2 ± 14.7 and 23.0 ± 13.6 months, respectively. Similar results were observed in the intention-to-treat analysis. Previous history of ischaemic stroke (IS)/transient ischaemic attack (TIA)/systemic embolism (SE) [hazard ratio (HR) 3.40, 95% CI 1.92-6.02; P < 0.01] and diabetes mellitus (HR 2.06, 95% CI 1.20-3.55, P = 0.01) were independently associated with thromboembolic events, while OAC discontinuation (HR 0.71, 95% CI 0.41-1.23, P = 0.21) remained insignificant in multivariable analysis., Conclusions: This study suggests that it may be safe to discontinue OAC in post-ablation patients under diligent monitoring, in the absence of AF recurrence, history of IS/TIA/SE, and diabetes mellitus. However, further large-scale randomized trials are required to confirm this., Trial Registration: Chinese Clinical Trial Registry ChiCTR-OCH-13003729. URL: http://www.chictr.org.cn/showproj.aspx?proj=5831., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the feasibility and safety of wire-guided pericardial access without contrast., Methods: From January 2014 to February 2019, patients who received epicardial mapping and ablation of ventricular tachycardia in the Beijing Anzhen Hospital were entered into the current study. They were divided into contrast-guided access group or wire-guided access group according to the pericardial puncture technique used. The baseline variables, procedure parameters, complications were collected and compared., Results: During the study period, a consecutive of 73 patients received epicardial access. The initial 32 patients received contrast-guided puncture with success achieved in 30 patients, the remaining 41 patients underwent wire-guided puncture with success achieved in 40 patients (30/32 and 40/41, P = .581). Fluoroscopy time (4.45 ± 0.52 and 4.38 ± 0.46 minutes, P = .891) and access time (5.14 ± 0.58 and 5.34 ± 0.50 minutes, P = .657) were comparable between the two groups. Inadvertent right ventricular puncture occurred more commonly in the contrast-guided group (5/32 and 1/41, P = .038). Though more pericardial effusions (2/32 and 1/41, P = .575), tamponade (2/32 and 1/41, P = .575), and surgical repair (1/32 and 0/41, P = .432) occurred in the contrast-guided group, they reached no statistical difference., Conclusion: Wire-guided pericardial puncture exhibits better safety and similar success rates to contrast-guided technique with a trend towards less complications., (© 2019 Wiley Periodicals, Inc.)

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated β-amyloid (Aβ). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol β-Sitosterol has a potential role in inhibiting the production of platelet Aβ, suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of β-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with β-Sitosterol for four weeks, from the age of seven months. Brain Aβ metabolism was evaluated using ELISA and Western blotting. We found that β-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. β-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of β-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that β-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases Aβ deposition., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflicts of interest., (Copyright © 2020 The Korean Physiological Society and The Korean Society of Pharmacology.)

Aims: To assess antithrombotic therapy choices in relation to patient age in a large, global registry on atrial fibrillation (AF)., Methods and Results: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international programme involving patients with newly diagnosed AF and ≥1 risk factors for stroke. We used Phase II data (from November 2011 through December 2014), which commenced immediately following first non-vitamin K antagonist oral anticoagulants (NOACs) approval in participating countries. Of 15 092 patients (mean age 70.5 ± 11.0 years), enrolled at 982 centres, 26.9% were aged <65 years, 33.9% 65-74, 30.5% 75-84, and 8.6% ≥85 years old. Oral anticoagulant (OAC) use was 73.5%, 81.4%, 83.3%, and 82.3% (overall NOACs use was 44.4%, 49.7%, 48.7%, and 45.6%) for those aged <65, 65-74, 75-84 and ≥85 years, respectively. Corresponding proportions for antiplatelet monotherapy and no treatment were: 16.2% and 10.2%; 11.2% and 7.3%; 10.0% and 6.5%; 10.5% and 7.0%, respectively. Of those aged 65-74, 75-84, and ≥85 years, respectively, 83.7, 86.8 and 85.4% received OAC unless bleeding risk was high (HAS-BLED ≥3), whereby 64.1%, 63.5%, and 64.5% were anticoagulated, and 31.1%, 30.3%, and 31.3% received antiplatelets only. Of patients ≥85 years, OAC use was 88.1% in Europe (NOAC 45.1%), 79.5% in North America (NOAC 44.8%), and 54.1% in Asia (NOAC 40.2%)., Conclusion: Despite geographic differences in OAC use, neither OAC nor NOAC uptake was lower for patients ≥85 years old compared with younger patients. Although the majority of patients was prescribed OAC at all ages, nearly one-third received antiplatelet monotherapy when bleeding risk was increased., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT01468701., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: To investigate the incidence and clinical characteristics of left atrial appendage (LAA) thrombus in patients with hypertrophic cardiomyopathy (HCM) and non-valvular atrial fibrillation (AF) . Methods: Data from 10 440 patients with AF who had undergone transesophageal echocardiography (TEE) before cardioversion or catheter ablation at Beijing Anzhen Hospital from April 2006 to December 2018 were retrospectively screened. Two hundred and five HCM patients were included, 820 AF patients with the same CHA(2)DS(2)-VASc score over the same period were selected as the control group. HCM patients were divided into two subgroups based on presence or absence of LAA thrombus/sludge. The baseline of clinical information, transthoracic echocardiographic and TEE measures were compared among all the groups. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of left atrial diameter (LAD) for LAA thrombus/sludge. Multivariate logistic regression analysis was applied to analyze the correlative factors of LAA thrombus/sludge in HCM patients. Results: The incidences of LAA thrombus or sludge were higher in HCM group than in control group (10.7% (22/205) vs. 0.7% (6/820); 8.8% (18/205) vs.7.0% (57/820), P< 0.001) . In HCM patients, LAD was significantly larger in LAA thrombus/sludge subjects than in those without thrombus/sludge ((48.9±5.1)mm vs. (45.2±6.1) mm, P< 0.001). CHA(2)DS(2)-VASc score was similar between the two subgroups ((2.0±1.4) vs. (1.8±1.4), P> 0.05). There was no difference in the rate of patients with a CHA(2)DS(2)-VASc scores ≥2 between the subgroups(62.5% (25/40) vs. 57.0% (94/165), P= 0.525). The incidences of LAA thrombus in HCM and AF patients with CHA(2)DS(2)-VASc scores of 0, 1 and 2 were 8.8% (3/34) , 9.6% (5/52) , 11.8% (11/119) , respectively; and the rate of LAA sludge were 8.8% (3/52) , 7.7% (4/52) , 9.2% (11/119) , respectively. The cut off value of LAD for the diagnosis of LAA thrombus/sludge was 44.5 mm. Multivariate logistic regression analysis showed that LAD≥44.5 mm ( OR= 5.134, 95 %CI 1.862-14.156, P= 0.002) , non-paroxysmal AF ( OR =2.782, 95 %CI 1.238-6.252, P= 0.013) , previous thromboembolism or stroke ( OR =1.820, 95 %CI 0.774-4.227, P= 0.017) were independent determinants of LAA thrombus/sludge. Conclusions: The incidence of LAA thrombus/sludge is higher in patients with HCM and AF than in AF patients without HCM. The CHA(2)DS(2)-VASc score is similar between HCM and AF patients with LAA thrombus/sludge and those without thrombus/sludge. Patients with CHA(2)DS(2)-VASc score 0-1 are also likely to suffer LAA thrombus/sludge. Left atrial enlargement is associated with LAA thrombus/sludge.

BACKGROUND Whether ablation therapy reduces the risk of death and embolic events in elderly patients with atrial fibrillation (AF) remains unclear. MATERIAL AND METHODS AF patients ≥65 years old receiving either catheter ablation or non-ablation therapy at 2 tertiary and 2 non-tertiary hospitals in Beijing from November 2009 to December 2012 were enrolled. Patients were followed up every 6 months for information on treatment and clinical event occurrence. A propensity score matching algorithm produced comparable 2 groups of patients treated with ablation or non-ablation. Rates of a composite of all-cause death, non-fatal stroke, and peripheral embolism were the primary outcomes. Each composite component and major bleeding were the secondary outcomes. RESULTS There were 596 ablated patients and 1144 patients with non-ablation therapy enrolled. Propensity score algorithm matched 347 comparable pairs of patients. Patient characteristics variables were well balanced. During 523.5 and 497.5 patient-years follow-up, respectively, ablation therapy was associated with a significant lower risk of experiencing the primary composite outcome (hazard ratio [HR]=0.40; 95% confidence interval [CI]: 0.19-0.85), all-cause death (HR=0.13 95% CI: 0.04-0.43), and major bleeding (HR=0.23; 95% CI: 0.12-0.67), without apparent heterogeneity by age, sex, and AF type, and for risk score subgroups. CONCLUSIONS In this propensity-matched elderly sample, ablation therapy was associated with lower risk of composite outcome consisting of all-cause death, non-fatal stroke, and peripheral embolism, and therefore might be an alternative to conservative therapy.

Background: Impact of body mass index (BMI) on all-cause mortality in atrial fibrillation (AF) patients remains controversial., Methods: A total of 10,942 AF patients were prospectively enrolled and categorized into four BMI groups: underweight (BMI < 18.5 kg/m 2 ), normal weight (BMI 18.5-24 kg/m 2 ), overweight (BMI 24-28 kg/m 2 ) and obesity (BMI ≥ 28 kg/m 2 ). The primary outcome was all-cause mortality. Different Cox proportional hazards models were performed to evaluate the association between BMI and all-cause mortality., Results: During a median follow-up of 30 months (IQR 18-48 months), 862 deaths events occurred. Compared to normal BMI, higher BMI was associated with a lower mortality risk (overweight: HR 0.70; 95% CI 0.61-0.81, P < 0.0001 and obesity: HR 0.54; 95% CI 0.44-0.67, P < 0.0001) and lower BMI was associated with a higher mortality risk (HR 2.23, 95% CI 1.67-2.97, P < 0.0001)., Conclusion: A reversed relationship between BMI and all-cause mortality in AF patients was found. Higher risk of mortality was observed in underweight patients compared to patients with a normal BMI, while overweight and obese patients had a lower risk of all-cause mortality., Clinical Trial Registration: URL: http://www.chictr.org.cn/showproj.aspx?proj=5831. Unique identifier: ChiCTR-OCH-13003729.

Background: Data on management of maternal arrhythmia among Chinese were limited. Radiofrequency catheter ablation (RFCA) proved to be a reliable treatment choice for sustained tachyarrhythmia but it has rarely been performed during pregnancy due to radiation exposure., Objective: To investigate the incidence of idiopathic sustained maternal arrhythmia and the feasibility of RFCA in the pregnant patients without fluoroscopy., Methods: From January of 2015 to December of 2018, the medical records on pregnancy-related admissions in Beijing Anzhen Hospital (Beijing, China) were retrospectively analyzed. Patients who had sustained tachyarrhythmia episodes without structural heart disease were identified. Catheter ablation was performed in those with drug resistant and severely frequent tachyarrhythmia under the guidance of electroanatomical mapping system and intracardiac echocardiography catheter (ICE), if appropriate., Results: During the study period, 12 584 consecutive pregnant women were admitted for pregnancy-related reasons, 156 (1.2%) of them were identified as sustained maternal tachyarrhythmia. Twenty-eight patients (age 21-37 years) received catheter ablation because the arrhythmias were drug resistant and severely frequent. The RFCA was successfully performed in all patients with zero fluoroscopy after 72.4 ± 24.7 min. Transseptal puncture was performed in 11 patients under the guidance of ICE. In a median of 37 (interquartile range [IQR]: 34-39) weeks' pregnancy, 28 healthy fetuses were delivered. No cardiac-related adverse event occurred during delivery. During later follow-up, all patients were free of arrhythmia, and all the infants were well developed., Conclusion: Sustained maternal tachyarrhythmia is not uncommon in the clinical practice. To those with drug resistant and severely frequent arrhythmia, RFCA with zero fluoroscopy could be safely performed with acceptable efficacy., (© 2019 Wiley Periodicals, Inc.)

Background: Lifestyle and risk factor management may improve outcomes in patients with atrial fibrillation (AF). We aim to evaluate the prevalence of modifiable risk factors and how these factors impact clinical outcomes in patients with AF., Methods and Results: Data on 17 898 AF cohort patients with AF enrolled between 2011 and 2016 was analyzed. A healthy lifestyle was defined as not smoking, not drinking, a healthy body mass index (BMI), untreated total cholesterol less than 200 mg/dL, untreated blood pressure (BP) less than 120/80 mm Hg, and untreated fasting plasma glucose (FPG) less than 100 mg/dL. The association between risk factors and risk of the composite endpoint of all-cause mortality and nonfatal ischemic stroke were assessed using Cox proportional hazards regression model. Only 4.0% of patients achieved a healthy lifestyle. In multivariate analysis, current smoking, a low BMI, not well-controlled FPG were independently and significantly associated with higher risk of all-cause mortality and nonfatal ischemic stroke, with corresponding hazard ratio (HR) estimates 1.22 (95% confidence interval [CI], 1.00-1.47), HR = 1.72 (95% CI, 1.34-2.20), and HR = 1.25 (95% CI, 1.06-1.46), respectively. High BP was also associated with higher risk with the outcomes (HR = 1.15, 95% CI, 1.00-1.34). Compared with patients with no risk factor, those who failed to maintained or achieved optimal risk factor control had a progressively higher risk of death and nonfatal ischemic stroke (HR for 1 risk factor = 1.44; 95% CI, 1.07-1.92; and more than 2 risk factors =  1.75; 95% CI, 0.99-3.09)., Conclusions: Maintenance of well-controlled risk factors may substantially lower the risk of death and ischemic stroke in patients with AF., (© 2019 Wiley Periodicals, Inc.)

GLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly diagnosed atrial fibrillation (AF) in clinical practice. This report provides the final analysis of 2-year clinical outcomes of the full cohort of 4873 patients prescribed dabigatran and followed for a mean of 18.0 +/- 9.4 months out of the 15,308 eligible patients enrolled in Phase II (2011-2014). The overall incidence rates per 100 person-years were: stroke 0.65 (95% CI 0.48-0.87), major bleeding 0.97 (0.76-1.23) and myocardial infarction (MI) 0.50 (0.35-0.69), with observed event rates broadly consistent in all study regions, which confirms the sustained safety and effectiveness of dabigatran over 2 years of observation in clinical practice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8 , the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' T H 17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3 , further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-β-dependent homeostasis of connective tissues., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Several studies have reported on atrial fibrillation (AF) outcomes, including thromboembolism in patients with paroxysmal and non-paroxysmal AF; however the findings still remain controversial on whether risks differ between these clinical subtypes and limited data are available in Asian cohorts., Methods: We compared the risk of thromboembolism between paroxysmal and persistent AF patients, in a large contemporary Chinese cohort study. A total of 8529 non-valvular atrial fibrillation (NVAF) patients from the Chinese Atrial Fibrillation Registry (CAFR) study were enrolled. The study subjects were divided into two groups: paroxysmal AF (PaAF, defined as AF lasting within 7 days, n = 4642) and persistent AF (PeAF, lasting over 7 days, n = 3887) groups., Results: In non-anticoagulated patients, PeAF group demonstrated a higher risk of stroke, all-cause death, cardiac/ non-cardiac death and composition of stroke/ transient ischemic attack (TIA)/peripheral thromboembolism (PT)/all-cause death, compared to the PaAF group. No significant difference was found in anticoagulated subjects. On multivariate analysis in non-anticoagulated patients, age ≥ 75 years (P = 0.046) and prior stroke/TIA/PT (P = 0.018) but not AF type (P = 0.63) were significantly associated with the risk of stroke/TIA/PT events., Conclusions: Stroke, all-cause death and cardiac/non-cardiac death in Chinese NVAF population was increased in non-anticoagulated PeAF patients compared with PaAF group, but same between anticoagulated PeAF and PaAF patients. After adjustment, AF type was not an independent predictor of thromboembolism in NVAF patients., Clinical Trial Registration: Chinese Clinical Trial Registry ChiCTR-OCH-13003729. Registered 22 October 2013.

Introduction: The outcomes of atrial fibrillation (AF) ablation remain suboptimal. It is important to identify which AF patients will most likely benefit from ablation and who are more likely to show treatment failure, especially in those with structural heart disease such as hypertrophic cardiomyopathy (HCM)., Methods and Results: We enrolled 120 HCM patients who underwent primary AF ablation (48 with persistent AF). Preprocedural QTc was measured and corrected using the Bazett's formula, and the distribution of fragmentation of the QRS complex (fQRS) was recorded. Arrhythmia recurrence was defined as any kind of documented atrial tachyarrhythmia of more than 30 seconds. Overall, arrhythmia recurrence occurred in 69 patients after 13.4 months' follow-up. fQRS was present in 71 (59.17%) patients and was most commonly (81.69%) observed in the inferior leads. QTc more than 448 ms could predict arrhythmia recurrence with a sensitivity of 68.1% and specificity of 68.6%. Patients with QTc more than 448 ms (hazard ratio [HR]: 1.982; 95% confidence interval [CI]: 1.155-3.402; P = .013) or those with fQRS+ (HR: 1.922; 95% CI: 1.151-3.210; P = .012) were at an increased risk of recurrence. A combination of fQRS+ and QTc more than 448 ms was superior to fQRS or QTc alone in predicting arrhythmia recurrence., Conclusion: In patients with HCM undergoing AF ablation, QTc prolongation, specifically >448 ms, and presence of fQRS are independent risk factors for arrhythmia recurrence at follow-up. The combination of these two parameters has greater predictive value and would help to identify patients who are at the highest risk of procedural failure., (© 2019 Wiley Periodicals, Inc.)

BACKGROUND There is a growing recognition of sex-related disparities in atrial fibrillation (AF). However, limited data is available in Chinese AF patients. MATERIAL AND METHODS We compared symptoms, quality of life (QoL), and treatment of AF according to sex from the China AF Registry study. RESULTS We studied 14 723 patients with non-valvular AF, of whom 5645 patients (38.3%) were female. Women were older than men (67.5±10.6 vs . 62.2±12.2). Compared to men, women had more comorbidities and a higher proportion of CHA₂DS₂-VASC score ≥2. Women with AF experienced more severe or disabling symptoms than men (33.7% vs . 22.9% in age <75 group; 40.3% vs . 28.7% in age ≥75 group; both P <0.0001). After multivariate analysis, women with AF still had lower QoL (OR 0.69; 95%CI, 0.63-0.76; P <0.0001). Women tended to have lower rates of ablation and rhythm-control drug use in those aged <75 years. Oral anticoagulant use was low and had no sex difference in AF patients with a CHA₂DS₂-VASC score ≥2. CONCLUSIONS In Chinese AF patients, women were older and more symptomatic, and had worse QoL. Despite all these differences, women tended to receive less rhythm-control treatment in those aged <75 years. Oral anticoagulant was substantially underused in high stroke risk patients, regardless of sex.

Whether or not the 3-dimensional surface morphologies of a crystal sample can be reconstructed at atomic-scale from a single 2-dimensional image becomes an interesting issue in high-resolution transmission electron microscopy, after the work by Jia et al. [1]. Here we propose an improved and self-validated algorithm to enhance such an electron tomography method and to make it applicable to more general crystal surfaces even with thin amorphous layers. Our study shows that a resolution in the beam (z) direction and a confidence level have to be defined and estimated after performing tomographic reconstruction in order to evaluate the quality and the reliability of its result. Applying the proposed procedure to the Si[110] image to recover the surface morphologies of a silicon crystal with amorphous contamination, the obtained results show that an atomic-resolution of 0.384 nm in the z-direction and a high confidence level of 95% are achieved for imaging the Si-surface structures, quantitatively described by tomographic parameters, i.e., the height (defocus) and the thickness (atom number) of Si-atomic columns., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The advent of flow cytometry has revolutionized the way we approach our research and answer specific scientific questions. The flow cytometer has also become a mainstream diagnostic tool in most hospital and pathology laboratories around the world. In particular the application of flow cytometry has been instrumental to the diagnosis of primary immunodeficiencies (PIDs) that result from monogenic mutations in key genes of the hematopoietic, and occasionally non-hematopoietic, systems. The far-reaching applicability of flow cytometry is in part due to the remarkable sensitivity, down to the single-cell level, of flow-based assays and the extremely user-friendly platforms that enable comprehensive analysis, data interpretation, and importantly, robust and rapid methods for diagnosing PIDs. A prime example is the absence of peripheral blood B cells in patients with agammaglobulinemia due to mutations in BTK or related genes in the BCR signaling pathway. Similarly, the development of intracellular staining protocols to detect expression of SAP, XIAP, or DOCK8 expedites the rapid diagnosis of the X-linked lymphoproliferative diseases or an autosomal recessive form of hyper-IgE syndrome (HIES), respectively. It has also become evident that distinct cohorts of PID patients exhibit unique "lymphocyte phenotypic signatures" that are often diagnostic even prior to identifying the genetic lesion. Flow cytometry-based sorting provides a technique for separating specific subsets of immune cells such that they can be studied in isolation. Thus, flow-based assays can be utilized to measure immune cell function in patients with PIDs, such as degranulation by cytotoxic cells, cytokine expression by many immune cells (i.e., CD4 + and CD8 + T cells, macrophages etc.), B-cell differentiation, and phagocyte respiratory burst in vitro . These assays can also be performed using unfractionated PBMCs, provided the caveat that the composition of lymphocytes between healthy donors and the PID patients under investigation is recognized. These functional deficits can assist not only in the clinical diagnosis of PIDs, but also reveal mechanisms of disease pathogenesis. As we move into the next generation of multiparameter flow cytometers, here we review some of our experiences in the use of flow cytometry in the study, diagnosis, and unraveling the pathophysiology of PIDs.

Background: Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear., Objective: The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms., Methods: In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca 2+ handling and action potentials in atrial myocytes were evaluated., Results: Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca 2+ handling disorders in atrial myocytes, such as reduced Ca 2+ transient amplitude, enhanced spontaneous Ca 2+ release, and reduced sarcoplasmic Ca 2+ capacity; (5) enhanced delayed afterdepolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17., Conclusion: The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca 2+ handling disorders in the atrium., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: This study explored the relationship between weight control and atrial fibrillation (AF) recurrence after catheter ablation in overweight and obese patients. Methods: We prospectively enrolled consecutive 333 overweight and obese patients aged 28 to 87 years old, who underwent catheter ablation for AF in Beijing Anzhen Hospital between October 2015 and February 2016. Data of patients' characteristics, laboratory examination and treatment were collected at baseline. Each patient was followed up at 3, 6 and 12 months after ablation to collect information on weight, AF recurrence, stroke, major bleeding, hospitalization for cardiovascular reasons and death, etc. Patients were divided into weight controlled group (ΔBMI<-1 kg/m(2)) and weight uncontrolled group (ΔBMI≥-1 kg/m(2)), according to the changes in the most recent exposure BMI before AF recurrence in patients with recurrence or the BMI at 12 months' follow-up in patients without recurrence and the BMI at baseline. Multivariate logistic regression was performed to adjust other known risk factors of AF recurrence and to explore the association between weight control and AF recurrence after catheter ablation. Results: There were 54 patients in weight controlled group and 279 patients in weight uncontrolled group. There were no significant differences in age, gender, education level, left atrial size and history of hypertension between the two groups (all P> 0.05). The proportion of patients using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was higher in the weight controlled group (50.0%(27/54) vs. 34.8%(97/279), P= 0.034). However, there was no significant difference in the proportion of patients with obesity (33.3% (18/54) vs. 29.7% (83/279)), paroxysmal AF (59.3% (32/54) vs. 56.6% (158/279)) and AF duration less than 5 years (76.9% (40/52) vs. 65.4% (178/272)) between the weight controlled group and the uncontrolled group. During 1-year follow-up after ablation, the recurrence rate of AF was significantly lower in the weight controlled group than that in the weight uncontrolled group (14.8% (8/54) vs. 32.6%(91/279), P= 0.009). Multivariable logistic regression analysis shows that weight control is independently associated with a lower postoperative AF recurrence rate ( OR= 0.40, 95 %CI 0.18-0.90, P= 0.026). Conclusion: Weight control is strongly associated with a lower AF recurrence rate after catheter ablation in overweight and obese patients.

Cluster analysis aims at separating patients into phenotypically heterogenous groups and defining therapeutically homogeneous patient subclasses. It is an important approach in data-driven disease classification and subtyping. Acute coronary syndrome (ACS) is a syndrome due to sudden decrease of coronary artery blood flow, where disease classification would help to inform therapeutic strategies and provide prognostic insights. Here we conducted an outcome-driven cluster analysis of ACS patients, which jointly considers treatment and patient outcome as indicators for patient state. Multi-task neural network with attention was used as a modeling framework, including learning of the patient state, cluster analysis, and feature importance profiling. Seven patient clusters were discovered. The clusters have different characteristics, as well as different risk profiles to the outcome of in-hospital major adverse cardiac events. The results demonstrate cluster analysis using outcome-driven multi-task neural network as promising for patient classification and subtyping.

Although thermal variability is known to influence the performance of ectotherms, there is limited information on the influence of variation in diurnal temperature range (DTR) during early developmental stages. Here we test variation in DTR ( ±0 °C, ±4 °C, ±6 °C, ±8 °C, ±10 °C and±12 °C) with a constant mean temperature (25 °C) on the larval stage of diamondback moth (DBM), Plutella xylostella (L.), and assess immediate effects on larval development and survival, and delayed effects on pupal development and survival and adult longevity and reproductive performance. Wide amplitudes ( ±10 °C and±12 °C) inhibited larval development and adult performance, but increased the proportion of eggs laid early, while moderate amplitudes ( ±4 °C, ±6 °C and±8 °C) resulted in only minor effects. Larval development rate under wide amplitudes ( ±10 °C and±12 °C) was faster than predicted by a degree-hour model. Overall, the intrinsic rate of increase of the population was lowered with increasing DTR, despite mean temperatures being the same. These findings highlight marked cross-stage effects of DTR when temperatures fluctuate substantially, likely linked to maximum temperature, and they emphasize the importance of considering DTR when assessing effects of climate warming., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Heatwaves are increasing in frequency and there is growing interest in their impact on pest organisms. Previous work indicates that effects depend on the timing of the stress event, whose impact needs to be characterized across the full set of developmental stages and exposure periods of an organism. Here, we undertake such a detailed assessment using heat stress (20-35 °C diurnal cycle) across the nymph and adult stages of the English grain aphid, Sitobion avenae (Fabricius)., Results: Stress-related mortality increased with stress duration at all stages; effects were less severe at the late nymphal stage. Effects on longevity adults after stress showed a complex pattern with nymphal heat stress, increasing with stress duration at the late nymphal stage, but decreasing with duration at the early nymphal stage. Longevity was also reduced by adult stress although to a lesser extent, and patterns were not connected to duration. Post-stress productivity decreased following adult and nymphal stress and the decrease tended to be correlated with stress duration. The rate of offspring production was more affected by adult stress than nymphal stress. Productivity and longevity effects, when combined, showed that the largest effect of heat stress occurred at the early nymphal stage., Conclusion: These findings highlight the complex ways in which heat stress at a particular life stage influences later fitness and they also emphasize the importance of considering multiple fitness components when assessing stress effects. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

Background: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8 + T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4 + T cells in disease pathogenesis., Objective: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4 + T-cell function., Methods: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4 + T cells and a novel murine disease model caused by overactive PI3K signaling., Results: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (T FH ) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human T FH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a T FH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4 + T cells also acquired an aberrant T FH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and T FH cells was largely CD4 + T-cell extrinsic, whereas changes in cytokine production and T FH cell function were cell intrinsic., Conclusion: Our studies reveal that CD4 + T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Objective: To determine the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and aortic diameter in predicting in-hospital mortality in acute aortic dissection (AD)., Methods: A single-center prospective study was designed in the setting of University hospital in China. 122 patients with acute AD were enrolled. Admission plasma NT-proBNP levels and aortic diameter were measured., Results: Plasma NT-proBNP concentrations (P < 0.001), aortic diameter (P = 0.002), and admission systolic blood pressure (SBP) (P = 0.011) were significantly increased in patients who died compared to those who survived during hospitalization. Furthermore, aortic diameter had positive correlations with NT-proBNP levels (r = 0.270, P = 0.003) and admission diastolic blood pressure (DBP) (r = 0.202, P = 0.025), respectively. Multiple logistic regression analysis demonstrated that NT-proBNP ≥569.75 pg/ml and aortic diameter ≥40 mm were strongly associated with in-hospital mortality. The odds ratio (OR) and 95% confidence interval (CI) were 3.246, 1.212-8.693 (P = 0.019); and 2.917, 1.102-7.722 (P = 0.031), respectively. Moreover, when NT-proBNP ≥1325.6 pg/ml, the sensitivity and specificity of NT-proBNP in predicting in-hospital mortality risk were 55.2% and 95.7% (95% CI, 0.707-0.891; P < 0.001), respectively. In addition, when aortic diameter ≥47 mm, the sensitivity and specificity were 58.6% and 88.2% (95% CI, 0.607-0.841; P < 0.001), respectively., Conclusions: NT-proBNP ≥569.75 pg/ml and aortic diameter ≥40 mm were important risk factors and independently associated with acute AD in-hospital mortality. NT-proBNP ≥1325.6 pg/ml or aortic diameter ≥47 mm showed higher specificity in predicting in-hospital mortality. Using NT-proBNP and aortic diameter together showed better performance in predicting in-hospital mortality with higher sensitivity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Ticagrelor is an oral, reversible, direct-acting P2Y 12 receptor inhibitor approved for the prevention of cardiovascular events in acute coronary syndrome (ACS). In China, drug intensive monitoring regulations for new drugs require additional safety data post-approval., Methods: YINGLONG, a single-arm, phase-IV, 1-year, non-interventional study, described the safety of ticagrelor 90 mg twice daily in Chinese patients (≥ 18 years) with ACS treated with ≥ 1 dose of ticagrelor. Primary outcomes were the incidence of adverse events (AEs), in particular, PLATelet inhibition and patient Outcomes (PLATO)-defined bleeding AEs, and other serious AEs during the 1-year follow-up. Key secondary outcomes were the incidence of major cardiovascular events., Results: Patients (n = 1041, median age 61.0 years) had started ticagrelor and had post-dose data. Median duration of ticagrelor treatment was 357 days; 577 patients (55.4%) completed 1-year ticagrelor treatment; 973 patients (93.5%) completed 1-year follow-up. Overall, 38.7% of patients reported an AE during treatment. The most common AEs were dyspnea (n = 37, 3.6%), petechiae (n = 30, 2.9%), and chest discomfort (n = 28, 2.7%). Serious AEs, excluding bleeding, were reported in 9.8% of patients during treatment. Incidence of PLATO-defined major bleeding events was 1.1% (n = 11). Of the 21 deaths that occurred during the study (8 post-treatment), 1 was a fatal bleed. Major cardiovascular events were reported in 37 patients (3.6%)., Conclusions: Ticagrelor was well tolerated with a low rate of PLATO-defined major bleeding events in Chinese ACS patients. Safety results were consistent with the known ticagrelor profile., Trial Registration: ClinicalTrials.gov identifier, NCT02430493., Funding: AstraZeneca Investment (China) Co., Ltd.

BACKGROUND Several factors determine the efficacy of warfarin anticoagulation in patients with non-valvular atrial fibrillation (NVAF). This study aimed to use data from the Chinese Atrial Fibrillation Registry study to assess the control of anticoagulation therapy in Chinese patients with NVAF treated with warfarin. MATERIAL AND METHODS From the Chinese Atrial Fibrillation Registry study the anticoagulant use and dosing, the time in therapeutic range (TTR) of the international normalized ratio (INR), and standard deviation of the observed INR values (SDINR), and their influencing factors were evaluated. RESULTS The median INR and SDINR were 2.04 (IQR 1.71-2.41) and 0.50 (IQR, 0.35-0.69), respectively. The median TTR was 51.7% (IQR, 30.6-70.1%) and only 25.1% had a TTR ≥70%. Age was ≥70 years (OR, 0.72; 95% CI, 0.55-0.94; P=0.015), bleeding history (OR 0.48; 95% CI, 0.23-0.89; P=0.029), the use of a single drug (OR, 0.62; 95% CI, 0.42-0.92; P=0.016), more than drug (OR, 0.60; 95% CI, 0.41-0.88; P=0.009), and lack of assessment of bleeding risk (OR, 0.72; 95% CI, 0.54-0.97; P=0.033) were associated with TTR <70% (INR 2.0-3.0). Coronary heart disease (CHD) and peripheral artery disease (PAD) (OR, 0.69; 95% CI, 0.52-0.90; P=0.007) and diabetes mellitus (OR, 0.79; 95% CI, 0.62-0.99; P=0.044) were associated with increased variability in INR (SDINR ≥0.5). CONCLUSIONS In Chinese patients with NVAF, warfarin anticoagulation was associated with lower TTR and less stable anticoagulation than in current guidelines, and risk factors for reduced safety and efficacy were identified.

Background: A few recent studies have demonstrated that hepatitis C virus (HCV) infection was associated with coronary artery diseases (CAD). However, there still existed studies did not confirm this correlation., Objective: The objective of this study was to evaluate the association between HCV infection and CAD using a meta-analysis., Methods: Pubmed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers and pooled odds ratio (OR) and relative risk (RR) with 95% confidence interval (CI) were calculated using the fixed and random effects models., Results: Eight cohort studies and six case-control and cross-sectional studies were enrolled in this meta-analysis. In the cohort studies, the overall RR and 95% CIs of HCV infection for CAD was 1.25, 1.12-1.40 in random effects model. For the case-control and cross-sectional studies, the overall OR and 95% CIs of HCV infection for CAD were 1.94, 1.58-2.38 in fixed effects model. No publication bias was found in this meta-analysis., Conclusions: This meta-analysis showed that HCV infection was a risk factor for CAD., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

BACKGROUND Oral anticoagulants (OACs) such as warfarin and non-VKA oral anticoagulants (NOACs) have been recommended for patients with atrial fibrillation (AF) who are at risk for stroke. Whether NOACs have a higher persistence than warfarin is still unclear. This is especially true in China. MATERIAL AND METHODS Data from a large hospital-based cohort in China (China-AF Registry) from 2011 to 2017 were used for this study. Non-valvular AF patients with newly initiated OACs were included. A time-to-event approach was used to analyze patient persistence. The survival distributions of persistence were compared using the log-rank test. A multivariable Cox regression model was used to explore predictors of warfarin and NOACs non-persistence. RESULTS Patients with newly initiated warfarin (n=4845) or NOACs (n=854) were included in this study. Persistence rates at 1, 2, and 3 years were 93.2%, 89.4%, and 87.2% in the warfarin group and 88.8%, 84.3%, and 81.3% in the NOAC group respectively. Non-persistence was significantly higher with NOACs than with warfarin. On multivariate analysis, age <75 years old, outpatient clinic visits, asymptomatic AF, paroxysmal AF, duration of AF <3 years, history of peptic ulcer, and no previous TIA, stroke or thromboembolism were strong predictors of warfarin non-persistence, while in the NOACs group, age <75 years old, outpatient clinic visits, lower education status and no history of congestive heart failure were predictors. CONCLUSIONS Treatment persistence of NOACs was lower than that of warfarin among Chinese patients with AF. Patients with characteristics of non-persistence predictors need special attention to maintain their therapy.

Background: Coronary heart disease is a leading cause of mortality among women. Systematic evaluation of the quality of care and outcomes in women hospitalized for acute coronary syndrome (ACS), an acute manifestation of coronary heart disease, remains lacking in China., Methods: The CCC-ACS project (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. Using data from the CCC-ACS project, we evaluated sex differences in acute management, medical therapies for secondary prevention, and in-hospital mortality in 82 196 patients admitted for ACS at 192 hospitals in China from 2014 to 2018., Results: Women with ACS were older than men (69.0 versus 61.1 years, P<0.001) and had more comorbidities. After multivariable adjustment, eligible women were less likely to receive evidence-based acute treatments for ACS than men, including early dual antiplatelet therapy, heparins during hospitalization, and reperfusion therapy for ST-segment-elevation myocardial infarction. With respect to strategies for secondary prevention, eligible women were less likely to receive dual antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins at discharge, and smoking cessation and cardiac rehabilitation counseling during hospitalization. In-hospital mortality rate was higher in women than in men (2.60% versus 1.50%, P<0.001). The sex difference in in-hospital mortality was no longer observed in patients with ST-segment-elevation myocardial infarction (adjusted odds ratio, 1.18; 95% CI, 1.00 to 1.41; P=0.057) and non-ST-segment elevation ACS (adjusted odds ratio, 0.84; 95% CI, 0.66 to 1.06; P=0.147) after adjustment for clinical characteristics and acute treatments., Conclusions: Women hospitalized for ACS in China received acute treatments and strategies for secondary prevention less frequently than men. The observed sex differences in in-hospital mortality were mainly attributable to worse clinical profiles and fewer evidence-based acute treatments provided to women with ACS. Specially targeted quality improvement programs may be warranted to narrow sex-related disparities in quality of care and outcomes in patients with ACS., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02306616.

Background: Arteriovenous grafting offers an alternative for patients whose vessels are unsuitable for arteriovenous fistula. However, as a result of subcutaneous tunnel dissection, postoperative pain and edema of the operated limb present early after surgery. As a traditional therapeutic approach, cryotherapy has the ability to suppress postoperative pain and edema., Aims: The purpose of the study was to investigate the feasibility of cryotherapy after arteriovenous graft surgery to decrease perioperative medication usage., Design: This study was a randomized controlled trial., Setting: A large integrated health care facility in South China., Participants/subjects: A total of 85 hemodialysis patients who received arteriovenous graft surgery from March 2011 to February 2017 were enrolled., Methods: The participants were divided into an intervention group and a control group according to the postoperative management. Ice packs were applied covering the operative forearm for 120 minutes after wound closure in the intervention group. General information, pain score, analgesic consumption, wound inflammation, forearm edema, and participant satisfaction were compared between the two groups., Results: Cryotherapy-treated patients required less analgesia (26.19% vs. 48.84%, p < .05), reported lower pain score from 30 minutes to 48 hours postoperative (p < .05), less wound inflammation (11.90% vs. 25.58%, p < .05), and higher participant satisfaction (8.92 ± 0.57 vs. 6.52 ± 0.63, p < .05), whereas the incidence of forearm edema was equivalent (p > .05). No adverse events were reported in either group., Conclusions: Cryotherapy is a preferable intervention for patients after arteriovenous graft implantation as a result of its favorable cost, convenience, and fewer side effects., (Copyright © 2019 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Interleukin-9 (IL-9) producing CD4 + Th9 cells are a unique subset of effector cells involved in both health and disease. Th9 cells have been associated with protective immunity during parasitic infections with helminths, protozoans and extracellular pathogens, but implicated in disease states such as allergic asthma, atopic dermatitis, food allergy and autoimmune conditions including multiple sclerosis and ulcerative colitis. Here, we review the cytokine signaling pathways and downstream transcription factors required for IL-9 expression and how human primary immunodeficiencies caused by monogenic mutations can help elucidate the complex requirements for human Th9 cell differentiation. Primary immunodeficiencies are a platform for investigating IL-9 expression in primary human lymphocytes and by inference whether Th9 cells are implicated in the clinical phenotype characteristic of these patients., (© 2018 Australasian Society for Immunology Inc.)

Background and Aims: Despite the advantage of arterial expansion for life-threatening vascular pathologies, the occurrence of neointima formation remains a prominent complication, with the underlying mechanisms largely unknown. A disintegrin and metalloprotease 22 (ADAM22) belongs to the family of ADAMs that possesses various biological capacities regulating vascular physiopathology. However, little is known about ADAM22 in vascular smooth muscle cell (VSMC)-mediated neointima formation. Here, we aimed to evaluate the potential functional regulation of ADAM22 in neointima formation and to further explore the underlying mechanisms., Methods: In our study, platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation was examined using a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and a cell counting kit-8 (CCK8) assay, while VSMC migration was detected using a modified Boyden chamber method and a scratch-wound assay. The functional role of ADAM22 in neointima formation was evaluated based on a left carotid artery wire injury model in mice at 14 and 28 days., Results: ADAM22 was significantly up-regulated in both PDGF-BB-challenged VSMCs and restenotic arteries of mice. When ADAM22 was overexpressed in VSMCs, cell proliferation, migration and phenotypic switching were simultaneously aggravated, whereas the opposite was observed when ADAM22 was knocked down in vitro. In ADAM22 heterozygote mice, wire-injury induced neointima formation was significantly ameliorated compared to wild-type control mice. Mechanistically, significantly up-regulated ERK phosphorylation is closely involved in the regulatory effects of ADAM22 in neointima formation. Interestingly, an ERK inhibitor largely reversed the aggravated VSMCs migration, proliferation and phenotypic switching induced by ADAM22 overexpression., Conclusions: Our results indicate that ADAM22 accelerates neointima formation by enhancing VSMC migration, proliferation and phenotypic switching via promoting ERK phosphorylation. Suppressing ADAM22 expression may be an effective strategy for ameliorating neointima formation., (Copyright © 2019. Published by Elsevier B.V.)

Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology., (© 2019 Australasian Society for Immunology Inc.)

Honeybee populations in Côte d'Ivoire have been previously identified as belonging to one subspecies, Apis mellifera scutellata , but other studies have since reported a mixed population consisting of A. m. adansonii and A. m. jemenitica. The population structure and the geographic distribution of honeybees in Côte d'Ivoire remain unclear. This study aimed to profile the population structure of honeybees and their biogeography in Côte d'Ivoire. A total of 33 honeybee colonies were sampled from 15 localities to investigate the maternal ancestry of indigenous honeybee populations using the DraI COI - COII mtDNA test. The results revealed that the honeybee population in Côte d'Ivoire is composed of African haplotypes, all belonging to the A I sublineage. Haplotypes A₁ and A₄ were recorded with five new sequence variants, including three types of haplotype A₁ and two types of haplotype A₄. The A 1e variant was the most frequent in the A. m. adansonii distributional area. The distribution of the haplotype variants was correlated with the climate pattern in Côte d'Ivoire. This is the first study in Côte d'Ivoire that gives insights into the biogeography and mitotype structure of the local honeybee populations.

Purpose: Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations., Patients and Methods: This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics-University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute-who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate)., Results: Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested., Conclusion: In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results., Competing Interests: Employees of Myriad Genetic Laboratories served as coinvestigators in this study and provided material support, including germline testing and interpretation, as described in the manuscript. The specific coinvestigators listed as authors participated in the review and final approval of the submitted manuscript., (© 2018 by American Society of Clinical Oncology.)

Organisms often experience adverse high temperatures during the daytime, but they may also recover or repair themselves during the night-time when temperatures are more moderate. Thermal effects of daily fluctuating temperatures may thus be divided into two opposite processes (i.e. negative effects of daytime heat stress and positive effects of night-time recovery). Despite recent progress on the consequences of increased daily temperature variability, the independent and combined effects of daytime and night-time temperatures on organism performance remain unclear. By independently manipulating daily maximum and minimum temperatures, we tested how changes in daytime heat stress and night-time recovery affect development, survival and heat tolerance of the lady beetle species Propylea japonica Thermal effects on development and survival differed between daytime and night-time. Daytime high temperatures had negative effects whereas night-time mild temperatures had positive effects. The extent of daytime heat stress and night-time recovery also affected development and critical thermal maximum, which indicates that there were both independent and combined effects of daytime and night-time temperatures on thermal performances. Our findings provide insight into the thermal effect of day-to-night temperature variability and have important implications for predicting the impacts of diel asymmetric warming under climate change., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn 2+ in modulating B cell receptor signal strength and positive selection.

Climate warming is characterized by increase in extreme heat events (EHEs). EHEs and mild temperature periods alternate with each other and form complex climate scenarios. Among these scenarios, low-frequency and short-duration extreme heat events during long mild periods (sporadic short EHEs) and low-frequency and short-duration mild periods during long extreme heat events (sporadic short mild periods) commonly occur in nature. The biological effects of these two types of temperature events have not been thoroughly elucidated to date. To clarify the biological effects of these temperature events on organisms, we selected the English grain aphid, a globally important cereal pest, as our model system. We exposed aphids to simulated 24-h diurnal fluctuating temperatures, inserted these events during the wheat growing season and then investigated development, adult longevity, fecundity, survival, and demographic parameters. We found that sporadic short mild periods during a long EHE could improve their life history traits. Increasing the duration of mild periods from 1 day to 2 days did not significantly change their demographic performance. Sporadic short EHEs during a long mild period did not significantly affect vital rates, while increasing the duration of EHEs from 1 day to 2 days worsened the aphids' performance. We found that short mild episodes in the hot season may benefit small insects to buffer long duration heatwaves. We discussed how sporadic short mild periods during a long EHE supplied aphids a chance to recover from heat stress. Thus, we suggest that sporadic temperature events should be considered in population prediction of small insects under climate change and should be integrated into pest management., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 + T cells, including, in particular, mycobacterium-specific T H 1* cells (CD45RA - CCR6 + ), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1 , IL12RB2 , and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)