Clonal landscape of autoantibody-secreting plasmablasts in COVID-19 patients.

Whereas severe COVID-19 is often associated with elevated autoantibody titers, the underlying mechanism behind their generation has remained unclear. Here we report clonal composition and diversity of autoantibodies in humoral response to SARS-CoV-2. Immunoglobulin repertoire analysis and characterization of plasmablast-derived monoclonal antibodies uncovered clonal expansion of plasmablasts producing cardiolipin (CL)-reactive autoantibodies. Half of the expanded CL-reactive clones exhibited strong binding to SARS-CoV-2 antigens. One such clone, CoV1804, was reactive to both CL and viral nucleocapsid (N), and further showed anti-nucleolar activity in human cells. Notably, antibodies sharing genetic features with CoV1804 were identified in COVID-19 patient-derived immunoglobulins, thereby constituting a novel public antibody. These public autoantibodies had numerous mutations that unambiguously enhanced anti-N reactivity, when causing fluctuations in anti-CL reactivity along with the acquisition of additional self-reactivities, such as anti-nucleolar activity, in the progeny. Thus, potentially CL-reactive precursors may have developed multiple self-reactivities through clonal selection, expansion, and somatic hypermutation driven by viral antigens. Our results revealed the nature of autoantibody production during COVID-19 and provided novel insights into the origin of virus-induced autoantibodies.

Extensive ablation for elderly patients with persistent atrial fibrillation: insights from the EARNEST-PVI prospective randomized trial.

BACKGROUND: In patients with persistent atrial fibrillation (AF), extensive ablation for substrate modification, such as linear ablation or complex fractionated atrial electrogram ablation in addition to pulmonary vein isolation (PVI) remains controversial. Previous studies investigating extensive ablation have demonstrated its varying efficacy, suggesting the possible heterogeneity of its efficacy. Aging is a major risk factor for AF and is associated with atrial remodeling. We aimed to compare the efficacy and safety of the extensive ablation strategy compared with PVI alone strategy between young and elderly patients. METHODS: This study is a post-hoc analysis of the multicenter, randomized controlled, noninferiority trial investigating the efficacy and safety of PVI-only (PVI-alone arm) compared with extensive ablation (PVI-plus arm) in patients with persistent AF (EARNEST-PVI trial). We divided the overall population into 2 groups based on age and assessed treatment effects. RESULTS: In the young group (age <65 years, N = 206), there was no significant difference in the recurrence rate between the PVI-alone group and PVI-plus group [hazard ratio (HR): 1.00, 95 % CI: 0.57-1.73, p = 0.987], whereas the recurrence rate was significantly lower in the PVI-plus group compared to the PVI-alone group in the elderly group (age ≥65 years, N = 291) (HR: 0.47, 95 % CI: 0.29-0.76, p = 0.0021) (p for interaction = 0.0446). There were no fatal procedural complications. CONCLUSION: In patients with persistent AF, the extensive ablation strategy was more effective than the PVI-alone strategy in elderly patients, while the effectiveness of both approaches was comparable in young patients. TRIAL REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT03514693. URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000022454 Unique ID issued by UMIN: UMIN000019449.

Quantitative selection of sample structures in small-angle scattering using Bayesian methods.

Small-angle scattering (SAS) is a key experimental technique for analyzing nanoscale structures in various materials. In SAS data analysis, selecting an appropriate mathematical model for the scattering intensity is critical, as it generates a hypothesis of the structure of the experimental sample. Traditional model selection methods either rely on qualitative approaches or are prone to overfitting. This paper introduces an analytical method that applies Bayesian model selection to SAS measurement data, enabling a quantitative evaluation of the validity of mathematical models. The performance of the method is assessed through numerical experiments using artificial data for multicomponent spherical materials, demonstrating that this proposed analysis approach yields highly accurate and interpretable results. The ability of the method to analyze a range of mixing ratios and particle size ratios for mixed components is also discussed, along with its precision in model evaluation by the degree of fitting. The proposed method effectively facilitates quantitative analysis of nanoscale sample structures in SAS, which has traditionally been challenging, and is expected to contribute significantly to advancements in a wide range of fields.

Ripple map delineation of the reentrant circuit in a tricuspid annular atrial tachycardia mimicking focal activity.

A 70-year-old man with hypertensive heart disease underwent catheter ablation of persistent atrial fibrillation. After completing the pulmonary vein isolation, atrial burst pacing induced an annular atrial tachycardia (AT). Overdrive pacing exhibited constant fusion, indicating a macroreentrant mechanism of the AT. However, the CARTO3 activation map created using the Octaray catheter (both Biosense Webster, Irvine, CA) exhibited a centrifugal spread with the earliest activation site at the 4 o'clock position of the tricuspid annulus. In contrast, the Ripple map revealed a clear reentrant circuit with its isthmus located at the 4-6 o'clock position of the tricuspid annulus. The local electrograms in these areas recorded systolic and diastolic potentials simultaneously, and the misannotation of the large far-field potentials caused this discrepant result. Handling low-amplitude complex fractionated electrograms remains a challenge in creating a precise activation mapping. The Ripple map, especially when combined with the Octaray catheter, was effective in dynamically visualizing all these electrograms and accurately delineating the reentrant circuit.

Extensive ablation for persistent atrial fibrillation patients with mitral regurgitation: Insights from the EARNEST-PVI prospective randomized trial.

BACKGROUND: Extensive ablation in addition to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) has not yielded consistent results, indicating diversity in their efficacy. Mitral regurgitation (MR) associated with AF may indicate a higher prevalence of arrhythmogenic substrate, suggesting potential benefits of extensive ablation for these patients. METHODS: This post-hoc analysis of the EARNEST-PVI trial compared PVI alone versus an extensive ablation strategy (PVI-plus) in persistent AF patients, stratified by MR presence. The primary endpoint of the study was the recurrence of AF. The secondary endpoints included death, cerebral infarction, and procedure-related complications. RESULTS: The trial included 495 eligible patients divided into MR and non-MR groups. The MR group consisted of 192 patients (89 in the PVI-alone arm and 103 in the PVI-plus arm), while the non-MR group had 303 patients (158 in the PVI-alone arm and 145 in the PVI-plus arm). In the non-MR group, recurrence rates were similar between PVI-alone and PVI-plus arms (Log-rank P = 0.47, Hazard ratio = 0.85 [95%CI: 0.54-1.33], P = 0.472). However, in the MR group, PVI-plus was significantly more effective in preventing AF recurrence (Log-rank P = 0.0014, Hazard ratio = 0.40 [95%CI: 0.22-0.72], P = 0.0021). No significant differences were observed in secondary endpoints between the two arms. CONCLUSIONS: For persistent AF patients with mild or greater MR, receiving PVI-plus was superior to PVI-alone in preventing AF recurrence. Conversely, for patients without MR, the effectiveness of extensive ablation was not demonstrated. These findings suggest tailoring ablation strategies based on MR presence can lead to better outcomes in AF management.

New Poisson denoising method for pulse-count STEM imaging.

With the recent progress in the development of detectors in electron microscopy, it has become possible to directly count the number of electrons per pixel, even with a scintillator-type detector, by incorporating a pulse-counting module. To optimize a denoising method for electron counting imaging, in this study, we propose a Poisson denoising method for atomic-resolution scanning transmission electron microscopy images. Our method is based on the Markov random field model and Bayesian inference, and we can reduce the electron dose by a factor of about 15 times or further below. Moreover, we showed that the method of reconstruction from multiple images without integrating them performs better than that from an integrated image.

Recurrent episodes of atrioventricular nodal reentrant tachycardia: Sites of ablation success, ablation endpoint, and primary culprits for recurrence.

Background: Atrioventricular nodal reentrant tachycardia (AVNRT) sometimes recurs even after anatomical slow pathway (SP) ablation targeting the rightward inferior extension (RIE). This multicenter study aimed to determine the reasons for AVNRT recurrence. Methods and Results: Forty-six patients were treated successfully for recurrent AVNRT. Initial treatment was for 38 slow-fast AVNRTs, 3 fast-slow AVNRTs, 2 slow-slow AVNRTs, 2 slow-fast and fast-slow AVNRTs, and 1 noninducible AVNRT. All initial treatments were of RF application to the RIE; SP elimination was achieved in 11, dual AVN physiology was seen in 29, and AVNRT remained inducible in 5. The recurrent AVNRTs included 34 slow-fast AVNRTs, 6 fast-slow AVNRTs, 3 slow-slow AVNRTs, 2 slow-fast and fast-slow AVNRTs, and 1 slow-fast and slow-slow AVNRTs. Successful ablation site was within the RIE in 39 and left inferior extension in 7. In 30 of 39, the successful RIE site was in the same area or higher than that of the initial procedure. Conclusion: For a high majority (around 85%) of patients in whom AVNRT recurs after initial ablation success, the site of a second successful procedure will be within the RIE even though the RIE was originally targeted. Furthermore, a high majority (around 86%) of sites of successful ablation will be higher than those originally targeted.

Appropriate Selection of Substrate Ablation for Persistent Atrial Fibrillation Using Intraprocedural Assessment.

BACKGROUND: It has not been fully elucidated which patients with persistent atrial fibrillation (PerAF) should undergo substrate ablation plus pulmonary vein isolation (PVI). This study aimed to identify PerAF patients who required substrate ablation using intraprocedural assessment of the baseline rhythm and the origin of atrial fibrillation (AF) triggers. METHODS AND RESULTS: This was a post hoc subanalysis using extended data of the EARNEST-PVI trial, a prospective multicenter randomized trial comparing PVI-alone and PVI-plus (i.e., PVI with added catheter ablation) arms. We divided 492 patients into 4 groups according to baseline rhythm and the location of AF triggers before PVI: Group A (n=22), sinus rhythm with pulmonary vein (PV)-specific AF triggers (defined as reproducible AF initiation from PVs only); Group B (n=211), AF with PV-specific AF triggers; Group C (n=94), sinus rhythm with no PV-specific AF trigger; Group D (n=165), AF with no PV-specific AF trigger. Among the 4 groups, only in Group D (AF at baseline and no PV-specific AF triggers) was arrhythmia-free survival significantly lower in the PVI-alone than PVI-plus arm (P=0.032; hazard ratio 1.68; 95% confidence interval 1.04-2.70). CONCLUSIONS: Patients with sinus rhythm or PV-specific AF triggers did not receive any benefit from substrate ablation, whereas patients with AF and no PV-specific AF trigger benefited from substrate ablation.

Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation.

Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation.

Impact of left atrial appendage flow velocity on thrombus resolution and clinical outcomes in patients with atrial fibrillation and silent left atrial thrombi: insights from the LAT study.

AIMS: Blood stasis is crucial in developing left atrial (LA) thrombi. LA appendage peak flow velocity (LAAFV) is a quantitative parameter for estimating thromboembolic risk. However, its impact on LA thrombus resolution and clinical outcomes remains unclear. METHODS AND RESULTS: The LAT study was a multicentre observational study investigating patients with atrial fibrillation (AF) and silent LA thrombi detected by transoesophageal echocardiography (TEE). Among 17 436 TEE procedures for patients with AF, 297 patients (1.7%) had silent LA thrombi. Excluding patients without follow-up examinations, we enrolled 169 whose baseline LAAFV was available. Oral anticoagulation use increased from 85.7% at baseline to 97.0% at the final follow-up (P < 0.001). During 1 year, LA thrombus resolution was confirmed in 130 (76.9%) patients within 76 (34-138) days. Conversely, 26 had residual LA thrombi, 8 had thromboembolisms, and 5 required surgical removal. These patients with failed thrombus resolution had lower baseline LAAFV than those with successful resolution (18.0 [15.8-22.0] vs. 22.2 [17.0-35.0], P = 0.003). Despite limited predictive power (area under the curve, 0.659; P = 0.001), LAAFV ≤ 20.0 cm/s (best cut-off) significantly predicted failed LA thrombus resolution, even after adjusting for potential confounders (odds ratio, 2.72; 95% confidence interval, 1.22-6.09; P = 0.015). The incidence of adverse outcomes including ischaemic stroke/systemic embolism, major bleeding, or all-cause death was significantly higher in patients with reduced LAAFV than in those with preserved LAAFV (28.4% vs. 11.6%, log-rank P = 0.005). CONCLUSION: Failed LA thrombus resolution was not rare in patients with AF and silent LA thrombi. Reduced LAAFV was associated with failed LA thrombus resolution and adverse clinical outcomes.

Effect of remission, clinical remission with active serology, and glucocorticoid dosage on the pregnancy outcome of pregnant patients with systemic lupus erythematosus.

BACKGROUND: Remission is a key treatment target in systemic lupus erythematosus (SLE) management. Given the direct correlation between lupus flares and elevated risks of adverse pregnancy outcomes (APOs), securing remission before conception becomes crucial. However, the association between clinical remission with active serology, and the risk of APOs is not thoroughly understood. Additionally, determining the optimal glucocorticoid dosage during pregnancy to mitigate APO risks remains under-researched. This study investigated the risk of APOs in relation to remission/serological activity status in patients in clinical remission/glucocorticoid dosage. METHODS: Pregnant patients with SLE, who were followed up at two Japanese tertiary referral centers, and had their remission status assessed at conception, were included in this study. We categorized the patients into two groups based on whether they achieved Zen/Doria remission at conception and analyzed the APO ratio. We also examined the influence of serological activity in pregnant patients with clinical remission and analyzed the optimal glucocorticoid dosage to minimize the APO ratio. RESULTS: Of the 96 pregnancies included, 59 achieved remission at conception. Pregnant patients who achieved remission showed a significant decrease in the APO ratio compared with those who did not. (overall APO: odds ratio (OR) 0.27, 95% confidence interval (CI) 0.11-0.65, p < 0.01, maternal APO: OR 0.34, 95%CI 0.13-0.85, p = 0.021, neonatal APO: OR 0.39, 95%CI 0.17-0.90, p = 0.028). Conversely, no statistical difference was observed in the APO ratio based on serological activity in pregnant patients with clinical remission. (overall APO: OR 0.62, 95%CI 0.21-1.79, p = 0.37, maternal APO: OR 1.25, 95%CI 0.32-4.85, p = 0.75, neonatal APO: OR 0.83, 95%CI 0.29-2.39, p = 0.73). A glucocorticoid dose of prednisolone equivalent ≥ 7.5 mg/day at conception correlated with increased APO. (overall APO: OR 3.01, 95%CI 1.23-7.39, p = 0.016, neonatal APO: OR 2.98, 95% CI:1.23-7.22, p = 0.016). CONCLUSIONS: Even with active serology, achieving clinical remission can be a clinical target for reducing APOs in patients who wish to conceive. In addition, if clinically feasible, reducing the glucocorticoid dosage to < 7.5 mg/day before conception could be another predictive factor.

Bayesian active learning with model selection for spectral experiments.

Active learning is a common approach to improve the efficiency of spectral experiments. Model selection from the candidates and parameter estimation are often required in the analysis of spectral experiments. Therefore, we proposed an active learning with model selection method using multiple parametric models as learning models. Important points for model selection and its parameter estimation were actively measured using Bayesian posterior distribution. The present study demonstrated the effectiveness of our proposed method for spectral deconvolution and Hamiltonian selection in X-ray photoelectron spectroscopy.

Uplift modeling to identify patients who require extensive catheter ablation procedures among patients with persistent atrial fibrillation.

Identifying patients who would benefit from extensive catheter ablation along with pulmonary vein isolation (PVI) among those with persistent atrial fibrillation (AF) has been a subject of controversy. The objective of this study was to apply uplift modeling, a machine learning method for analyzing individual causal effect, to identify such patients in the EARNEST-PVI trial, a randomized trial in patients with persistent AF. We developed 16 uplift models using different machine learning algorithms, and determined that the best performing model was adaptive boosting using Qini coefficients. The optimal uplift score threshold was 0.0124. Among patients with an uplift score ≥ 0.0124, those who underwent extensive catheter ablation (PVI-plus) showed a significantly lower recurrence rate of AF compared to those who received only PVI (PVI-alone) (HR 0.40; 95% CI 0.19-0.84; P-value = 0.015). In contrast, among patients with an uplift score < 0.0124, recurrence of AF did not significantly differ between PVI-plus and PVI-alone (HR 1.17; 95% CI 0.57-2.39; P-value = 0.661). By employing uplift modeling, we could effectively identify a subset of patients with persistent AF who would benefit from PVI-plus. This model could be valuable in stratifying patients with persistent AF who need extensive catheter ablation before the procedure.

Duration of atrial fibrillation persistence: Implications for recurrence risk after catheter ablation and efficacy of additional substrate ablation.

BACKGROUND: The optimal duration of atrial fibrillation (AF) persistence for predicting poor outcomes after catheter ablation of long-standing AF (LsAF) and the best ablation strategy for these patients remain unclear. OBJECTIVE: We aimed to assess the impact of the duration of AF persistence on outcomes after catheter ablation of AF. METHODS: We analyzed the Efficacy of Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation (EARNEST-PVI) trial data comparing pulmonary vein isolation (PVI) alone (PVI-alone) with additional linear ablation or defragmentation (PVI-plus) in persistent AF (PerAF). Patients who received catheter ablation by contact force-sensing catheter were enrolled in the study. In patients with LsAF, the optimal cutoff duration of AF persistence was evaluated. With use of the threshold, patients with LsAF were divided into 2 groups and compared with PerAF <1 year for arrhythmia-free survival after a 3-month blanking period. RESULTS: The optimal cutoff duration was 2.4 years. Of 458 patients, arrhythmia-free survival rates for LsAF 1-2.4 years were comparable to those of PerAF (hazard ratio [HR], 1.01; 95% CI, 0.67-1.52). However, LsAF >2.4 years had a higher recurrence risk than PerAF (HR, 2.22; 95% CI, 1.42-3.47). In LsAF >2.4 years, the PVI-plus strategy showed advantages over the PVI-alone strategy (HR, 0.36; 95% CI, 0.14-0.89). However, the interaction effect between LsAF 1-2.4 years and LsAF >2.4 years did not reach statistical significance (P = .116). CONCLUSION: Whereas LsAF 1-2.4 years has similar outcomes to those of PerAF, LsAF >2.4 years was linked to higher arrhythmia recurrence risks. For LsAF >2.4 years, the PVI-plus strategy showed a potential to be superior to the PVI-alone strategy.

Changes in alcohol intake and serum urate changes: longitudinal analyses of annual medical examination database.

INTRODUCTION: Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change. METHOD: We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates. RESULTS: We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day). CONCLUSIONS: This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU.

The WATCH-DM risk score estimates clinical outcomes in type 2 diabetic patients with heart failure with preserved ejection fraction.

The coexistence of heart failure is frequent and associated with higher mortality in patients with type 2 diabetes (T2DM), and its management is a critical issue. The WATCH-DM risk score is a tool to predict heart failure in patients with type 2 diabetes mellitus (T2DM). We investigated whether it could estimate outcomes in T2DM patients with heart failure with preserved ejection fraction (HFpEF). The WATCH-DM risk score was calculated in 418 patients with T2DM hospitalized for HFpEF (male 49.5%, age 80 ± 9 years, HbA1c 6.8 ± 1.0%), and they were divided into the "average or lower" (≤ 10 points), "high" (11-13 points) and "very high" (≥ 14 points) risk groups. We followed patients to observe all-cause death for 386 days (median). We compared the area under the curve (AUC) of the WATCH-DM score for predicting 1-year mortality with that of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score and of the Barcelona Bio-Heart Failure Risk (BCN Bio-HF). Among the study patients, 108 patients (25.8%) had average or lower risk scores, 147 patients (35.2%) had high risk scores, and 163 patients (39.0%) had very high risk scores. The Cox proportional hazard model selected the WATCH-DM score as an independent predictor of all-cause death (HR per unit 1.10, 95% CI 1.03 to 1.19), and the "average or lower" risk group had lower mortality than the other groups (p = 0.047 by log-rank test). The AUC of the WATCH-DM for 1-year mortality was 0.64 (95% CI 0.45 to 0.74), which was not different from that of the MAGGIC score (0.72, 95% CI 0.63 to 0.80, p = 0.08) or that of BCN Bio-HF (0.70, 0.61 to 0.80, p = 0.25). The WATCH-DM risk score can estimate prognosis in T2DM patients with HFpEF and can identify patients at higher risk of mortality.

A retrospective analysis of the safety of tacrolimus use and its optimal cut-off concentration during pregnancy in women with systemic lupus erythematosus: study from two Japanese tertiary referral centers.

BACKGROUND: Tacrolimus is one of the major treatment options for systemic lupus erythematosus (SLE) and is considered to be a pregnancy-compatible medication. Since little is known about tacrolimus safety during pregnancy complicated by SLE, this study was designed. METHODS: We included SLE pregnant patients who were followed up at two Japanese tertiary referral centers. We performed multivariate logistic regression analysis to assess each adverse pregnancy outcome (APO) risk. Moreover, we assessed the influence of tacrolimus on the APO ratio in pregnant patients with lupus nephritis, and the impact of combined tacrolimus-aspirin therapy on the APO ratio relative to patients exclusively administered tacrolimus. RESULTS: Of the 124 pregnancies, 29 were exposed to tacrolimus. Multivariate analysis showed no statistical difference in APO ratio. (overall APO: adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.23-2.03; p = 0.50; maternal APO: aOR, 1.17; 95% CI, 0.36-3.83; p = 0.80; neonatal APO: aOR, 1.10; 95% CI, 0.38-3.21; p = 0.86; PROMISSE APO: aOR, 0.50; 95% CI, 0.14-1.74; p = 0.27). Blood pressure and estimated glomerular filtration rate (eGFR) during pregnancy and after delivery did not differ between the two groups. Receiver operating characteristic (ROC) curve showed that tacrolimus concentration > 2.6 ng/ml was related to reduced preterm birth rate. (AUC = 0.85, 95% CI: 0.61-1.00, sensitivity: 93% and specificity: 75%). Regarding effect of tacrolimus on lupus nephritis during pregnancy, tacrolimus showed no increased risk of APO, blood pressure or eGFR during pregnancy and after delivery. (overall APO: OR, 1.00; 95% CI, 0.25-4.08; p = 0.98; maternal APO: OR 1.60, 95% CI, 0.39-6.64; p = 0.51; neonatal APO: OR, 0.71; 95% CI, 0.17-3.03; p = 0.65, PROMISSE APO: OR, 0.50; 95% CI, 0.08-3.22; p = 0.47). Tacrolimus-aspirin combination therapy showed a protective tendency against hypertensive disorders during pregnancy, preeclampsia and low birth weight. CONCLUSIONS: Tacrolimus use during pregnancy with SLE and lupus nephritis showed no significant influence on APO, blood pressure, or renal function; therefore tacrolimus may be suitable for controlling lupus activity during pregnancy. In addition, when using tacrolimus during pregnancy, we should aim its trough concentration ≥ 2.6 ng/ml while paying careful attention to possible maternal side effects of tacrolimus. TRIAL REGISTRATION: Retrospectively registered.