Atomic Bose-Einstein condensate in twisted-bilayer optical lattices.

Observation of strong correlations and superconductivity in twisted-bilayer graphene1-4 has stimulated tremendous interest in fundamental and applied physics5-8. In this system, the superposition of two twisted honeycomb lattices, generating a moiré pattern, is the key to the observed flat electronic bands, slow electron velocity and large density of states9-12. Extension of the twisted-bilayer system to new configurations is highly desired, which can provide exciting prospects to investigate twistronics beyond bilayer graphene. Here we demonstrate a quantum simulation of superfluid to Mott insulator transition in twisted-bilayer square lattices based on atomic Bose-Einstein condensates loaded into spin-dependent optical lattices. The lattices are made of two sets of laser beams that independently address atoms in different spin states, which form the synthetic dimension accommodating the two layers. The interlayer coupling is highly controllable by a microwave field, which enables the occurrence of a lowest flat band and new correlated phases in the strong coupling limit. We directly observe the spatial moiré pattern and the momentum diffraction, which confirm the presence of two forms of superfluid and a modified superfluid to insulator transition in twisted-bilayer lattices. Our scheme is generic and can be applied to different lattice geometries and for both boson and fermion systems. This opens up a new direction for exploring moiré physics in ultracold atoms with highly controllable optical lattices.

Outcome prediction of cardiac arrest with automatically computed gray-white matter ratio on computed tomography images.

BACKGROUND: This study aimed to develop an automated method to measure the gray-white matter ratio (GWR) from brain computed tomography (CT) scans of patients with out-of-hospital cardiac arrest (OHCA) and assess its significance in predicting early-stage neurological outcomes. METHODS: Patients with OHCA who underwent brain CT imaging within 12 h of return of spontaneous circulation were enrolled in this retrospective study. The primary outcome endpoint measure was a favorable neurological outcome, defined as cerebral performance category 1 or 2 at hospital discharge. We proposed an automated method comprising image registration, K-means segmentation, segmentation refinement, and GWR calculation to measure the GWR for each CT scan. The K-means segmentation and segmentation refinement was employed to refine the segmentations within regions of interest (ROIs), consequently enhancing GWR calculation accuracy through more precise segmentations. RESULTS: Overall, 443 patients were divided into derivation N=265, 60% and validation N=178, 40% sets, based on age and sex. The ROI Hounsfield unit values derived from the automated method showed a strong correlation with those obtained from the manual method. Regarding outcome prediction, the automated method significantly outperformed the manual method in GWR calculation (AUC 0.79 vs. 0.70) across the entire dataset. The automated method also demonstrated superior performance across sensitivity, specificity, and positive and negative predictive values using the cutoff value determined from the derivation set. Moreover, GWR was an independent predictor of outcomes in logistic regression analysis. Incorporating the GWR with other clinical and resuscitation variables significantly enhanced the performance of prediction models compared to those without the GWR. CONCLUSIONS: Automated measurement of the GWR from non-contrast brain CT images offers valuable insights for predicting neurological outcomes during the early post-cardiac arrest period.

The Influencing Factors of Implementation in Emergency Medical Service Systems - A Scoping Review.

OBJECTIVES: Emergency medical services (EMS) provide health care in situations with limited time and resources. Challenges arise when introducing novel medications, treatments, or technologies or modifying existing practices in these settings. Effective implementation strategies are pivotal for their success. This study aims to identify and categorize potential facilitators and barriers in the implementation of prehospital EMS through a review of relevant research articles.METHODS: We searched PubMed and EMbase to identify studies published before December 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our search strategy and scoping review. We included original articles written in English that report on the factors that influence the implementation in prehospital settings. We extracted and categorized the factors into different themes.RESULTS: Out of the 371 retrieved papers, we selected 19 (5%) for inclusion in this review. We extracted 46 influencing factors from the selected articles and categorized them into ten themes: (1) Outer system, (2) Inner system, (3) Practitioner characteristics, (4) Resources, (5) Communication and collaboration, (6) Patient factors, (7) Intervention characteristics, (8) De-implementation of prior practices, (9) Logistical issues, and (10) Quality improvement.CONCLUSIONS: This study examined the literature on EMS implementation factors and proposed a 10-theme EMS model framework. Key factors include training/education, equipment/tools, communication with hospitals, and practitioners' attitudes.

Clinical Validation of Explainable Deep Learning Model for Predicting the Mortality of In-Hospital Cardiac Arrest Using Diagnosis Codes of Electronic Health Records.

Background: Using deep learning for disease outcome prediction is an approach that has made large advances in recent years. Notwithstanding its excellent performance, clinicians are also interested in learning how input affects prediction. Clinical validation of explainable deep learning models is also as yet unexplored. This study aims to evaluate the performance of Deep SHapley Additive exPlanations (D-SHAP) model in accurately identifying the diagnosis code associated with the highest mortality risk. Methods: Incidences of at least one in-hospital cardiac arrest (IHCA) for 168,693 patients as well as 1,569,478 clinical records were extracted from Taiwan's National Health Insurance Research Database. We propose a D-SHAP model to provide insights into deep learning model predictions. We trained a deep learning model to predict the 30-day mortality likelihoods of IHCA patients and used D-SHAP to see how the diagnosis codes affected the model's predictions. Physicians were asked to annotate a cardiac arrest dataset and provide expert opinions, which we used to validate our proposed method. A 1-to-4-point annotation of each record (current decision) along with four previous records (historical decision) was used to validate the current and historical D-SHAP values. Results: A subset consisting of 402 patients with at least one cardiac arrest record was randomly selected from the IHCA cohort. The median age was 72 years, with mean and standard deviation of 69 ± 17 years. Results indicated that D-SHAP can identify the cause of mortality based on the diagnosis codes. The top five most important diagnosis codes, namely respiratory failure, sepsis, pneumonia, shock, and acute kidney injury were consistent with the physician's opinion. Some diagnoses, such as urinary tract infection, showed a discrepancy between D-SHAP and clinical judgment due to the lower frequency of the disease and its occurrence in combination with other comorbidities. Conclusions: The D-SHAP framework was found to be an effective tool to explain deep neural networks and identify most of the important diagnoses for predicting patients' 30-day mortality. However, physicians should always carefully consider the structure of the original database and underlying pathophysiology.

Genome-wide CRISPR-based gene knockout screens reveal cellular factors and pathways essential for nasopharyngeal carcinoma.

Early diagnosis of nasopharyngeal carcinoma (NPC) is difficult because of a lack of specific symptoms. Many patients have advanced disease at diagnosis, and these patients respond poorly to treatment. New treatments are therefore needed to improve the outcome of NPC. To better understand the molecular pathogenesis of NPC, here we used an NPC cell line in a genome-wide CRISPR-based knockout screen to identify the cellular factors and pathways essential for NPC (i.e. dependence factors). This screen identified the Moz, Ybf2/Sas3, Sas2, Tip60 histone acetyl transferase complex, NF-κB signaling, purine synthesis, and linear ubiquitination pathways; and MDM2 proto-oncogene as NPC dependence factors/pathways. Using gene knock out, complementary DNA rescue, and inhibitor assays, we found that perturbation of these pathways greatly reduces the growth of NPC cell lines but does not affect growth of SV40-immortalized normal nasopharyngeal epithelial cells. These results suggest that targeting these pathways/proteins may hold promise for achieving better treatment of patients with NPC.

Tezepelumab in Adults with Uncontrolled Asthma.

BACKGROUND: In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. This trial evaluated the efficacy and safety of tezepelumab (AMG 157/MEDI9929), a human monoclonal antibody specific for the epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP), in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids. METHODS: In this phase 2, randomized, double-blind, placebo-controlled trial, we compared subcutaneous tezepelumab at three dose levels with placebo over a 52-week treatment period. The primary end point was the annualized rate of asthma exacerbations (events per patient-year) at week 52. RESULTS: The use of tezepelumab at a dose of 70 mg every 4 weeks (low dose; 145 patients), 210 mg every 4 weeks (medium dose; 145 patients), or 280 mg every 2 weeks (high dose; 146 patients) resulted in annualized asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22, respectively, as compared with 0.67 in the placebo group (148 patients). Thus, exacerbation rates in the respective tezepelumab groups were lower by 61%, 71%, and 66% than the rate in the placebo group (P<0.001 for all comparisons). Similar results were observed in patients regardless of blood eosinophil counts at enrollment. The prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups than in the placebo group (difference, 0.12 liters with the low dose [P=0.01], 0.11 liters with the medium dose [P=0.02], and 0.15 liters with the high dose [P=0.002]). A total of 2 patients in the medium-dose group, 3 in the high-dose group, and 1 in the placebo group discontinued the trial regimen because of adverse events. CONCLUSIONS: Among patients treated with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts. (Funded by MedImmune [a member of the AstraZeneca Group] and Amgen; PATHWAY ClinicalTrials.gov number, NCT02054130 .).

Safety and tolerability of anifrolumab, a monoclonal antibody targeting type I interferon receptor, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Objectives: This study evaluated the safety and tolerability of anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, in Japanese patients with moderate-to-severe systemic lupus erythematosus (SLE).Methods: In this open-label, phase 2, dose-escalation study, patients received intravenous (IV) anifrolumab 100, 300, or 1000 mg every 4 weeks from days 29 to 337 (Stage 1). Patients who completed Stage 1 continued anifrolumab 300 mg every 4 weeks for 156 weeks (Stage 2). The primary objective was to evaluate the safety of anifrolumab for 48 weeks (Stage 1) and 156 weeks (Stage 2). The pharmacokinetics and pharmacodynamics of anifrolumab were also assessed.Results: Of 20 patients enrolled in Stage 1, 17 received IV anifrolumab 100 mg (n = 6), 300 mg (n = 5), or 1000 mg (n = 6). Adverse events (AE) and serious AE (SAE) incidences were similar between dose cohorts. SAEs occurred in 41% (Stage 1) and 33% (Stage 2) of patients; AEs leading to discontinuation occurred in 24% (Stage 1) and 22% (Stage 2) of patients. Anifrolumab had non-linear pharmacokinetics after the first and last dose and dose-dependently suppressed the IFN gene signature.Conclusion: Anifrolumab was well tolerated among Japanese patients with moderate-to-severe SLE.

Safety and tolerability of sifalimumab, an anti-interferon-α monoclonal antibody, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Objectives: To evaluate the safety of sifalimumab in Japanese patients with systemic lupus erythematosus (SLE).Methods: This phase 2, open-label study consisted of a 52-week initial stage (Stage I) and a long-term extension (Stage II). In Stage I, sequential cohorts of patients received ascending doses of sifalimumab (intravenous [IV] 1.0, 3.0, and 10.0 mg/kg or subcutaneous 100 mg every 2 weeks; IV 600 and 1200 mg every 6 weeks). In Stage II, patients enrolled before June 2012 received the same dose of sifalimumab as during Stage I for up to 157 weeks or sifalimumab 600 mg IV every 4 weeks if they enrolled later. The safety of sifalimumab was assessed by adverse events (AEs).Results: Thirty patients enrolled in Stage I and 21 patients entered Stage II. The majority of patients experienced AEs (96.7% in Stage I and 100% in Stage II); most were mild or moderate in severity. Serious AEs occurred in 30.0% and 57.1% of patients in Stage I and II, respectively; most were instances of SLE flares. The proportion of patients in Stage I and II who had AEs leading to discontinuation was 10.0% and 28.6%, respectively.Conclusion: Sifalimumab was well tolerated in Japanese patients with SLE.

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study.

OBJECTIVES: The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). METHODS: 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. RESULTS: Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. CONCLUSIONS: Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. TRIAL REGISTRATION NUMBER: NCT01283139; Results.

Application of strong transverse magneto-optical Kerr effect on high sensitive surface plasmon grating sensors.

A high sensitive sensor is demonstrated by exploiting strong transverse magneto-optical Kerr effect on a ferromagnetic surface plasmon grating. The surface plasmon grating, made of a hybridized Au/Fe/Au layer, exhibits a very dispersive Kerr parameter variation near the surface plasmon polariton (SPP) wavelength via coherent scattering of the SPP on the grating structure. Interrogating this Kerr parameter can be utilized for detecting chemical or biological objects in a fluid medium. The experiment results show the minimal detectable mass concentration of sodium chloride in a saline solution is 4.27 × 10(-3) %, corresponding to a refractive index change of 7.60 × 10(-6) RIU. For an avidin-biotin interaction experiment, the sensitivity of avidin detection in PBS solution is 1.97 nM, which is limited by the index fluctuation of flowing media during measurement.

Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.

OBJECTIVE: To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). METHODS: In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. RESULTS: Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n=4) versus 2.5% (n=1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. CONCLUSION: The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

A Robust Framework for One-Shot Key Information Extraction via Deep Partial Graph Matching.

Text field labelling plays a key role in Key Information Extraction (KIE) from structured document images. However, existing methods ignore the field drift and outlier problems, which limit their performance and make them less robust. This paper casts the text field labelling problem into a partial graph matching problem and proposes an end-to-end trainable framework called Deep Partial Graph Matching (dPGM) for the one-shot KIE task. It represents each document as a graph and estimates the correspondence between text fields from different documents by maximizing the graph similarity of different documents. Our framework obtains a strict one-to-one correspondence by adopting a combinatorial solver module with an extra one-to-(at most)-one mapping constraint to do the exact graph matching, which leads to the robustness of the field drift problem and the outlier problem. Finally, a large one-shot KIE dataset named DKIE is collected and annotated to promote research of the KIE task. This dataset will be released to the research and industry communities. Extensive experiments on both the public and our new DKIE datasets show that our method can achieve state-of-the-art performance and is more robust than existing methods.

Bevacizumab is associated with a higher gastrointestinal/genitourinary fistula or perforation risk in cervical cancer patients undergoing pelvic radiotherapy.

BACKGROUND: Bevacizumab serves as an effective treatment in cervical cancer patients with metastatic, recurrent, or advanced disease. However, gastrointestinal (GI)/genitourinary (GU) toxicities have been observed after bevacizumab treatment. Radiotherapy (RT) is the mainstay of treatment of cervical cancer. OBJECTIVES: To investigate the risk of GI/GU toxicities with bevacizumab plus RT compared with RT alone in cervical cancer patients. SEARCH STRATEGY: In this meta-analysis, PubMed, Embase, Web of Science, and Cochrane databases were searched from inception to September 25, 2022. SELECTION CRITERIA: Cohort studies evaluating the association between bevacizumab and GI/GU fistula or perforation in irradiated metastatic, recurrent, or advanced cervical cancer patients. DATA COLLECTION AND ANALYSIS: Results are expressed as odds ratios (OR) with 95% confidence intervals (CI). The inconsistency test (I2) was used to assess heterogeneity. Egger's regression test with a two-tailed P value was used to evaluate publication bias. MAIN RESULTS: Four cohort studies met the inclusion criteria with a total of 597 women included. There was a significant association between GI fistula/perforation and GU fistula/perforation in irradiated cervical cancer patients receiving bevacizumab (OR 4.03 [95% CI: 1.76-9.20] and OR 4.71 [95% CI: 1.51-14.70], respectively). CONCLUSIONS: The bevacizumab-containing regimen was associated with an increased risk of GI or GU toxicities in cervical cancer individuals undergoing pelvic RT. These results suggest the bevacizumab-associated benefits and risk should be better weighted to reach an optimal treatment strategy. Further investigation on optimal dosage and timing of bevacizumab and RT is vital to minimize the adverse events and maximize the benefits.

CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

Adipose-derived stem cell exosomes ameliorate traumatic brain injury through the NLRP3 signaling pathway.

The exosomes of mesenchymal stem cells have immunoregulatory properties and can effectively mitigate secondary neuroinflammation due to traumatic brain injury (TBI). In this study, we found that adipose-derived stem cell exosomes (ADSCs-Exo) could reduce the inflammatory response after traumatic brain injury by reducing NLRP3 inflammasome secretion by microglial. ADSCs-Exo were monitored by Western blot and electron microscopy. An in-vitro lipopolysaccharide (LPS)-caused primary microglia model and a TBI rat model were constructed. Functional recovery was examined using the modified neurological severity score and foot fault tests. Inflammasome inactivation in LPS-stimulated microglial, ADSCs-Exo can reduce the secretion of interleukin (IL)-1ß, IL-6 and tumor necrosis factor α. Compared with PBS-processed controls, the sensorimotor functional recovery was significantly improved by exosome treatment after injury at 14-35 days. Additionally, NLRP3 inflammasome was stimulated within 24 h after TBI. ADSCs-Exo application led to remarkable down-expression of NLRP3 and caspase-1. ADSCs-Exo can ameliorate LPS-induced inflammatory activation by reducing microglial pro-inflammatory cytokines. Moreover, the neuroprotective effect of ADSCs-Exo may be partially attributed to the inhibition thereof on the formation of NLRP3-mediated inflammasome. Such findings imply a potential function of ADSCs-Exo in treating TBI.

H ∞ state estimation of quaternion-valued inertial neural networks: non-reduced order method.

This paper concentrates on the problem of H ∞ state estimation for quaternion-valued inertial neural networks (QVINNs) with nonidentical time-varying delay. Without reducing the original second order system into two first order systems, a non-reduced order method is developed to investigate the addressed QVINNs, which is different from the majority of existing references. By constructing a new Lyapunov functional with tuning parameters, some easily checked algebraic criteria are established to ascertain the asymptotic stability of error-state system with the desired H ∞ performance. Moreover, an effective algorithm is provided to design the estimator parameters. Finally, a numerical example is given out to illustrate the feasibility of the designed state estimator.

The MIDORA trial: a phase II, randomised, double-blind, placebo-controlled, mechanistic insight and dosage optimisation study of the efficacy and safety of dazodalibep in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the safety, efficacy and response duration of four different dosing regimens of dazodalibep (DAZ), a non-antibody biological antagonist of CD40L, in patients with rheumatoid arthritis (RA). METHODS: This double-blind study included adult patients with moderate-to-severe active RA with a positive test for serum rheumatoid factor and/or anticitrullinated protein antibodies, an inadequate response to methotrexate, other conventional disease-modifying antirheumatic drugs or tumour necrosis factor-α inhibitors, and no prior treatment with B-cell depleting agents. Eligible participants were randomised equally to five groups receiving intravenous infusions of DAZ or placebo. The primary endpoint was the change from baseline in the Disease Activity Score-28 with C reactive protein (DAS28-CRP) at day 113. Participants were followed through day 309. RESULTS: The study randomised 78 eligible participants. The change from baseline in DAS28-CRP (least squares means±SE) at day 113 was significantly greater for all DAZ groups (-1.83±0.28 to -1.90±0.27; p<0.05) relative to PBO (-1.06±0.26); significant reductions in DAS28-CRP were also observed for all DAZ groups at day 309. The distribution of adverse events was generally balanced among DAZ and PBO groups (74% and 63%, respectively). There were four serious adverse events deemed by investigators to be unrelated to study medication. CONCLUSIONS: DAZ treatment for all dosage regimens significantly reduced DAS28-CRP at day 113 relative to PBO. The safety data suggest an acceptable safety and tolerability profile. Treatment effects at day 113 and the prolonged duration of responses after DAZ cessation support the use of longer dosing intervals. TRIAL REGISTRATION NUMBER: NCT04163991.

Neuroligin-1 plays an important role in methamphetamine-induced hippocampal synaptic plasticity.

The neurotoxic effects of methamphetamine (METH) include not only neuronal apoptosis and autophagy, but also lead to substance use disorder and have become increasingly prominent. Studies suggest that synaptic plasticity may be the structural basis of METH-induced neurological impairment. Neuroligins are postsynaptic adhesion molecules involved in the regulation of synaptic organization and function. Animal studies have shown that neuroligin (NLG)- 1 is involved in memory formation; however, its role in METH-induced neurotoxicity is not clear. In the present study, we used 1 mM METH in vitro; mice in the acute and subacute exposure groups received intraperitoneal injections of 30 mg/kg METH (1 injection) or 15 mg/kg METH (8 separate injections at 12-h intervals). We found that the expression of NLG-1, Synapsin-1, and postsynaptic density-95 were increased after METH exposure. We further observed that METH-induced inhibition of long-term potentiation and spatial memory loss could be alleviated when mice were pretreated with NLG-1 small interfering RNA. Therefore, our study provides evidence that NLG-1 is involved in METH-induced hippocampal synaptic plasticity and may be a potential target for the treatment of METH-induced neurotoxicity.

H∞ synchronization of delayed neural networks via event-triggered dynamic output control.

This paper investigates H∞ exponential synchronization (ES) of neural networks (NNs) with delay by designing an event-triggered dynamic output feedback controller (ETDOFC). The ETDOFC is flexible in practice since it is applicable to both full order and reduced order dynamic output techniques. Moreover, the event generator reduces the computational burden for the zero-order-hold (ZOH) operator and does not induce sampling delay as many existing event generators do. To obtain less conservative results, the delay-partitioning method is utilized in the Lyapunov-Krasovskii functional (LKF). Synchronization criteria formulated by linear matrix inequalities (LMIs) are established. A simple algorithm is provided to design the control gains of the ETDOFC, which overcomes the difficulty induced by different dimensions of the system parameters. One numerical example is provided to demonstrate the merits of the theoretical analysis.

Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.

OBJECTIVE: Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. METHODS: Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. RESULTS: Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). CONCLUSION: These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.