Age-related differences in takeover performance: A comparative analysis of older and younger drivers in prolonged partially automated driving.

OBJECTIVE: Vehicle automation technologies have the potential to address the mobility needs of older adults. However, age-related cognitive declines may pose new challenges for older drivers when they are required to take back or "takeover" control of their automated vehicle. This study aims to explore the impact of age on takeover performance under partially automated driving conditions and the interaction effect between age and voluntary non-driving-related tasks (NDRTs) on takeover performance. METHOD: A total of 42 older drivers (M = 65.5 years, SD = 4.4) and 40 younger drivers (M = 37.2 years, SD = 4.5) participated in this mixed-design driving simulation experiment (between subjects: age [older drivers vs. younger drivers] and NDRT engagement [road monitoring vs. voluntary NDRTs]; within subjects: hazardous event occurrence time [7.5th min vs. 38.5th min]). RESULTS: Older drivers exhibited poorer visual exploration performance (i.e., longer fixation point duration and smaller saccade amplitude), lower use of advanced driving assistance systems (ADAS; e.g., lower percentage of time adaptive cruise control activated [ACCA]) and poorer takeover performance (e.g., longer takeover time, larger maximum resulting acceleration, and larger standard deviation of lane position) compared to younger drivers. Furthermore, older drivers were less likely to experience driving drowsiness (e.g., lower percentage of time the eyes are fully closed and Karolinska Sleepiness Scale levels); however, this advantage did not compensate for the differences in takeover performance with younger drivers. Older drivers had lower NDRT engagement (i.e., lower percentage of fixation time on NDRTs), and NDRTs did not significantly affect their drowsiness but impaired takeover performance (e.g., higher collision rate, longer takeover time, and larger maximum resulting acceleration). CONCLUSIONS: These findings indicate the necessity of addressing the impaired takeover performance due to cognitive decline in older drivers and discourage them from engaging in inappropriate NDRTs, thereby reducing their crash risk during automated driving.

Rapid detection of tebuconazole based on hydrogel SERS chips.

Tebuconazole is one of the most commonly used fungicides in agricultural production, that has the merits of highly effectiveness, broad spectrum and systemic function. Excessive tebuconazole may pose a great threat to human and animal health. Traditional detection techniques for tebuconazole usually have limitations such as expensive equipment, poor antibody stability, and time-consuming procedures. Herein, a sensitive sensor is developed for the rapid detection of tebuconazole based on hydrogel surface-enhanced Raman scattering (SERS) chips. Aggregated Ag nanoparticles (a-AgNPs) with tunable localized surface plasmon resonance (LSPR) wavelength are in-situ synthesized in polyvinyl alcohol (PVA) solution for preparing hydrogel SERS chips. Three hydrogel SERS chips are obtained to match the three commonly used laser wavelengths. On the basis, a match laser wavelength is selected according to the energy levels of tebuconazole and the Fermi level of a-AgNPs to gain a strong chemical enhancement. At the same time, the chip with a corresponding LSPR wavelength to the laser is applied to obtain a strong electromagnetic enhancement. Thus, highly sensitive SERS signal of tebuconazole is obtained. Furthermore, the obtained hydrogel SERS chips have good repeatability, outstanding reproducibility and strong anti-interference ability, and show outstanding reliability in practical applications. As a result, the SERS chips offer a reliable and convenient platform for the quick detection of tebuconazole in foods. The detection limit is as low as 1 ppb, and the recoveries is distributed in the range of 94.66-106.70 %. This work would promote greatly the application of SERS in small molecule detection.

Flexible filament winding strategy to prepare COF@polyionic liquid-coated fibers for non-selective exclusion of macromolecules in electro-enhanced solid-phase microextraction.

BACKGROUND: Accurate quantitative analysis of small molecule metabolites in biological samples is of great significance. Hydroxypolycyclic aromatic hydrocarbons (OH-PAHs) are metabolic derivatives of emerging pollutants, reflecting exposure to polycyclic aromatic hydrocarbons (PAHs). Macromolecules such as proteins and enzymes in biological samples will interfere with the accurate quantification of OH-PAHs, making direct analysis impossible, requiring a series of complex treatments such as enzymatic hydrolysis. Therefore, the development of matrix-compatible fiber coatings that can exclude macromolecules is of great significance to improve the ability of solid-phase microextraction (SPME) technology to selectively quantify small molecules in complex matrices and achieve rapid and direct analysis. RESULTS: We have developed an innovative coating with a stable macromolecular barrier using electrospinning and flexible filament winding (FW) technologies. This coating, referred to as the hollow fibrous covalent organic framework@polyionic liquid (F-COF@polyILs), demonstrates outstanding conductivity and stability. It accelerates the adsorption equilibrium time (25 min) for polar OH-PAHs through electrically enhanced solid-phase microextraction (EE-SPME) technology. Compared to the powder form, F-COF@polyILs coating displays effective non-selective large-size molecular sieving. Combining gas chromatography-tandem triple quadrupole mass spectrometry (GC-MS/MS), we have established a simple, efficient quantitative analysis method for OH-PAHs with a low detection limit (0.008-0.05 ng L-1), wide linear range (0.02-1000 ng L-1), and good repeatability (1.0%-7.3 %). Experimental results show that the coated fiber exhibits good resistance to matrix interference (2.5%-16.7 %) in complex biological matrices, and has been successfully used for OH-PAHs analysis in human urine and plasma. SIGNIFICANCE: FW technology realizes the transformation of the traditional powder form of COF in SPME coating to a uniform non-powder coating, giving its ability to exclude large molecules in complex biological matrices. A method for quantitatively detecting OH-PAHs in real biological samples was also developed. Therefore, the filament winding preparation method for F-COF@polyILs coated fibers, along with fibrous COFs' morphology control, has substantial implications for efficiently extracting target compounds from complex matrices.

MMP2hi Fibroblasts Regulate CD8+ T Cell Residency and Inflammation via CD100 in Psoriasis.

BACKGROUND: Psoriasis, a T cell-mediated chronic inflammatory skin condition, is characterized by the interaction of T cells with various cell types, forming an inflammatory microenvironment that sustains psoriatic inflammation. The homeostasis of these tissue-resident T cells are supported by fibroblasts, the primary structural cells in the dermis. In psoriasis, there is an increased expression of matrix metalloproteinase 2 (MMP2), mediating the structural alterations of skin tissues and the modulation of inflammation. Additionally, the CD100-PLXNB2 axis is known to enhance psoriasis inflammation via keratinocytes, and CD103 levels are associated with the severity of psoriasis upon relapse. OBJECTIVE: To elucidate the role of fibroblasts and the MMP2/CD100 axis in modulating psoriasis inflammation. METHODS: CD100 expression and function in psoriasis were assessed using immunofluorescence, ELISA, single-cell transcriptome sequencing, cellular interaction analyses, and qRT-PCR. CD8+ T cells from psoriasis patients were isolated using magnetic beads to investigate the regulatory effect of MMP2 on CD100 expression on their membranes. Single-cell transcriptome sequencing, spatial transcriptome sequencing, mimetic timing analysis, immunofluorescence, and flow cytometry were utilized to determine the origin of MMP2 and its impact on CD103+CD8+ T cells. The hypotheses were further validated in vivo using MMP2 and CD100 inhibitors. RESULTS: Soluble CD100 (sCD100) was significantly upregulated in both psoriatic lesions and peripheral blood, amplifying psoriasis inflammation by promoting the production of inflammatory cytokines by keratinocytes, fibroblasts, and endothelial cells through the sCD100-PLXNB2 axis. Fibroblasts with high MMP2 expression (MMP2hi) exacerbate psoriasis symptoms by facilitating CD100 shedding from CD8+ T cell membranes. Additionally, it was demonstrated that fibroblasts enhance the upregulation of the CD8+ T cell residency factor CD103 in co-cultures with CD8+ T cells. Inhibitors targeting MMP2 and CD100 proved effective in reducing inflammation in a model of imiquimod-induced psoriasis. CONCLUSION: Our findings underscore the pivotal role of MMP2hi fibroblasts in the amplification and recurrence of inflammatory responses in psoriasis. These fibroblasts augment psoriasis inflammation through the CD100-PLXNB2 axis by facilitating CD100 shedding on CD8+ T cell membranes and by upregulating CD103, thereby enhancing CD8+ T cell residency.

Gallic acid attenuates LPS-induced inflammation in Caco-2 cells by suppressing the activation of the NF-κB/MAPK signaling pathway.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by intestinal barrier dysfunction, inflammatory synergistic effects and excessive tissue injury. Gallic acid (GA) is renowned for its remarkable biological activity, encompassing anti-inflammatory and antioxidant properties. However, the underlying mechanisms by which GA protects against intestinal inflammation have not been fully elucidated. The aim of this study is to investigate the effect of GA on the inflammation of a lipopolysaccharide (LPS)-stimulated human colon carcinoma cell line (Caco-2) and on the intestinal barrier dysfunction, and explore the underlying molecular mechanism involved. Our findings demonstrate that 5 µg/mL GA restores the downregulation of the mRNA and protein levels of Claudin-1, Occludin, and ZO-1 and decreases the expressions of inflammatory factors such as IL-6, IL-1ß and TNF-α induced by LPS. In addition, GA exhibits a protective effect by reducing the LPS-enhanced early and late apoptotic ratios, downregulating the mRNA levels of pro-apoptotic factors ( Bax, Bad, Caspase-3, Caspase-8, and Caspase-9), and upregulating the mRNA levels of anti-apoptotic factor Bcl-2 in Caco-2 cells. GA also reduces the levels of reactive oxygen species increased by LPS and restores the activity of antioxidant enzymes, namely, superoxide dismutase and catalase, as well as the level of glutathione. More importantly, GA exerts its anti-inflammatory effects by inhibiting the LPS-induced phosphorylation of key signaling molecules in the NF-κB/MAPK pathway, including p65, IκB-α, p38, JNK, and ERK, in Caco-2 cells. Overall, our findings show that GA increases the expressions of tight junction proteins, reduces cell apoptosis, relieves oxidative stress and suppresses the activation of the NF-κB/MAPK pathway to reduce LPS-induced intestinal inflammation in Caco-2 cells, indicating that GA has potential as a therapeutic agent for intestinal inflammation.

The copper (II) complex of salicylate phenanthroline induces immunogenic cell death of colorectal cancer cells through inducing endoplasmic reticulum stress.

BACKGROUND: In our previous study, Cu(sal)phen was found to have anti-tumor effects, yet its precise mechanism remains unknown. Research has shown that dying tumor cells release damage-associated molecular patterns (DAMPs) to promote anti-tumor immune response. Therefore, we have further explored the effects and potential molecular mechanisms of Cu(sal)phen-induced immunogenic cell death (ICD) in colorectal cancer (CRC). METHODS: ELISA and flow cytometry were used to detect the effects of Cu(sal)phen treatment on ICD markers. The molecular mechanisms of Cu(sal)phen-induced ICD were investigated through the detection of endoplasmic reticulum stress (ERS) and reactive oxygen species (ROS) in vitro using Western blot and flow cytometry. Additionally, a mouse model was constructed to study the effects of Cu(sal)phen on immune cells and anti-tumor-related cytokines in vivo. RESULTS: Cu(sal)phen induced the release of calreticulin (CRT), adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1), the main molecular markers of ICD, by promoting the accumulation of ROS and inducing ERS. Furthermore, Cu(sal)phen promoted the maturation of dendritic cells (DCs) and activation of CD8+T cells, as well as the secretion of interleukin-12 (IL-12) and interferon-γ (IFN-γ), while downregulating transforming growth factor-ß (TGF-ß) levels, thereby activating the anti-tumor immune response. CONCLUSION: Cu(sal)phen has the potential to induce ICD in tumors and activate the adaptive immune response to achieve anti-tumor effects. This makes Cu(sal)phen a promising candidate for the treatment of CRC.

Comprehensive analysis of lactate-related gene profiles and immune characteristics in lupus nephritis.

Objectives: The most frequent cause of kidney damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN), which is also a significant risk factor for morbidity and mortality. Lactate metabolism and protein lactylation might be related to the development of LN. However, there is still a lack of relative research to prove the hypothesis. Hence, this study was conducted to screen the lactate-related biomarkers for LN and analyze the underlying mechanism. Methods: To identify differentially expressed genes (DEGs) in the training set (GSE32591, GSE127797), we conducted a differential expression analysis (LN samples versus normal samples). Then, module genes were mined using WGCNA concerning LN. The overlapping of DEGs, critical module genes, and lactate-related genes (LRGs) was used to create the lactate-related differentially expressed genes (LR-DEGs). By using a machine-learning algorithm, ROC, and expression levels, biomarkers were discovered. We also carried out an immune infiltration study based on biomarkers and GSEA. Results: A sum of 1259 DEGs was obtained between LN and normal groups. Then, 3800 module genes in reference to LN were procured. 19 LR-DEGs were screened out by the intersection of DEGs, key module genes, and LRGs. Moreover, 8 pivotal genes were acquired via two machine-learning algorithms. Subsequently, 3 biomarkers related to lactate metabolism were obtained, including COQ2, COQ4, and NDUFV1. And these three biomarkers were enriched in pathways 'antigen processing and presentation' and 'NOD-like receptor signaling pathway'. We found that Macrophages M0 and T cells regulatory (Tregs) were associated with these three biomarkers as well. Conclusion: Overall, the results indicated that lactate-related biomarkers COQ2, COQ4, and NDUFV1 were associated with LN, which laid a theoretical foundation for the diagnosis and treatment of LN.

The Treatment of Refractory Vitiligo With Autologous Cultured Epithelium Grafting: A Real-World Retrospective Cohort Study.

BACKGROUND: Surgical intervention is the main therapy for refractory vitiligo. We developed a modified autologous cultured epithelial grafting (ACEG) technique for vitiligo treatment. Between January 2015 and June 2019, a total of 726 patients with vitiligo underwent ACEG in China, with patient characteristics and clinical factors being meticulously documented. Using a generalized linear mixed model, we were able to assess the association between these characteristics and the repigmentation rate. RESULTS: ACEG demonstrated a total efficacy rate of 82.81% (1754/2118) in treating 726 patients, with a higher repigmentation rate of 64.87% compared to conventional surgery at 52.69%. Notably, ACEG showed a better response in treating segmental vitiligo, lesions on lower limbs, age ≤ 18, and stable period > 3 years. A keratinocyte:melanocyte ratio below 25 was found to be advantageous too. Single-cell RNA sequencing analysis revealed an increase in melanocyte count and 2 subclusters of keratinocytes after ACEG, which remained higher in repigmented sites even after 1 year. CONCLUSIONS: ACEG is a promising therapy for refractory vitiligo. Patient age, clinical type, lesion site, and stability before surgery influence repigmentation in ACEG. The mechanism of repigmentation after ACEG treatment is likely not confined to the restoration of melanocyte populations. It may also involve an increase in the number of keratinocytes that support melanocyte function within the affected area. These keratinocytes may aid the post-transplant survival and function of melanocytes by secreting cytokines and extracellular matrix components. TRIAL REGISTRATION: registered with Chictr.org.cn (ChiCTR2100051405).

Chin Augmentation and Treatment of Chin Retrusion with a Flexible Hyaluronic Acid Filler in Asian Subjects: A Randomized, Controlled, Evaluator-Blinded Study.

BACKGROUND: Aesthetic improvement of the chin is increasingly requested by patients, including those of Chinese origin. METHODS: A randomized, evaluator-blinded, no-treatment controlled study evaluated the effectiveness and safety of a flexible hyaluronic acid (HA) filler, Restylane® DefyneTM (HADEF), in the correction of chin retrusion in a Chinese adult population over 12 months after treatment. On Day 1, subjects were randomized 3:1 into two groups, HADEF or delayed-treatment controls, and those in the HADEF group were administered treatment. An optional touch-up treatment was administered 1 month after treatment to obtain optimal chin augmentation. The initially untreated control group was offered delayed-treatment after 6 months (including 1-month touch-up). RESULTS: HADEF was superior to no-treatment in improving chin retrusion according to the blinded evaluator at 6 months [Galderma Chin Retrusion Scale (GCRS) responder rate (≥ 1-point improvement from baseline) of 81% vs. 5% for untreated controls; p < 0.001, meeting the primary effectiveness objective. A majority of subjects maintained improvement at 12 months (61% in the HADEF group). All subjects reported satisfaction with results at 6 months after treatment with HADEF and aesthetic improvement rates per the global aesthetic improvement scale (GAIS) were high for 12 months following treatment, with an acceptable safety profile. CONCLUSIONS: These results demonstrated HADEF to be effective and safe for the correction of mild-to-moderate chin retrusion in Chinese subjects, confirming findings previously observed in a western population. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Tildrakizumab for moderate-to-severe plaque psoriasis in Chinese patients: A 12-week randomized placebo-controlled phase III trial with long-term extension.

BACKGROUND: There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. METHODS: In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. RESULTS: At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician's Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs . 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs . 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. CONCLUSION: Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05108766.

Enhanced quality of hESC-derived melanocytes through modified concentration of endothelin-1.

The study investigated the effectiveness of EDN1 and EDN3 cytokines in the differentiation of melanocytes from hESCs. The findings showed that 100 nM EDN1 was more effective in promoting hESC to CD117+/TYR+ melanoblasts compared to 100 nM EDN3. Additionally, maintaining melanoblasts is beneficial for preserving the ability to proliferate. The study found that 10 nM EDN1 helped maintain the proliferation of melanoblasts without over maturing them into melanocytes in the late stage of differentiation. Thus, using 100 nM EDN1 in the initial stage and 10 nM EDN1 in the late stage proved to be an efficient and cost-effective method for obtaining hESC-derived melanocytes. The preliminary results suggest that EDN1 promotes melanoblast formation during the initial differentiation stage through its binding to both the EDNRB receptor and EDNRA receptor. This study provides a valuable tool for studying the development of human melanocytes and modelling the biology of disease.

Single-cell sequencing reveals increased LAMB3-positive basal keratinocytes and ZNF90-positive fibroblasts in autologous cultured epithelium.

Autologous cultured epithelium grafting (ACEG) presents a promising treatment for refractory vitiligo, yet concerns regarding infections and immunological reactions hinder its surgical use due to serum and feeder dependencies. Addressing this, we culture autologous epithelium under serum- and feeder-free (SFF) conditions, comparing its safety and efficacy with serum- and feeder-dependent (SFD) conditions in stable vitiligo patients, and we discover no significant differences in repigmentation between the SFF and SFD grafts. Single-cell RNA transcriptomics on SFF- and SFD-cultured epithelium alongside healthy skin reveal increased populations of LAMB3+ basal keratinocytes and ZNF90+ fibroblasts in the SFF sheets. Functional analyses showcase active cellular metabolism in LAMB3+ basal keratinocytes, vital in extracellular matrix homeostasis, while ZNF90+ fibroblasts demonstrate increased differentiation, essential in collagen formation for cell adhesion. Importantly, these cell populations in SFF sheets exhibit enhanced interactions with melanocytes compared to SFD sheets. Further, knockdown experiments of LAMB3 in keratinocytes and ZNF90 in fibroblasts lead to a downregulation in melanocyte ligand-receptor-related genes. Overall, SFF sheets demonstrate comparable efficacy to SFD sheets, offering superior safety. LAMB3+ basal keratinocytes and ZNF90+ fibroblasts act as potential drivers behind repigmentation in ACEG under SFF conditions. This study provides translational insights into ACEG repigmentation and potential therapeutic targets for vitiligo.

Controllable synthesis of flower-like hierarchical porous TiO2 at room temperature and its affinity application.

Flower-like particles have attracted much attention due to their efficient surface accessible sites and unique hierarchical porous structure. However, their synthesis is usually challenging and requires complex procedures. Herein, we present a simple method for rapid preparation of flower-like hierarchical porous TiO2 (FHP-TiO2) at room temperature for the first time. This method can accurately control the size of FHP-TiO2 from 150 nm to 400 nm by combining co-assembly and Stober reaction. The formation mechanism and influencing factors of FHP-TiO2 were systematically investigated, and its excellent metal oxide affinity was confirmed by theoretical calculations. Due to its hierarchical porous structure, large surface area and high specificity performance, FHP-TiO2 served as an appealing restricted-access adsorbent for specific and efficient enrichment of molecules with phosphate groups in a complex sample matrix, thereby realizing the quantitative analysis of these important biomolecules by coupling with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Moreover, compared with other morphologies (rough surface, and hollow dendritic and mesoporous structure) of TiO2 and flower-like SiO2, FHP-TiO2 showed the best affinity binding ability. This research not only presents a novel approach for tunable room-temperature synthesis of FHP-TiO2 with different sizes, but also expands the application of FHP-TiO2 as an appealing sample-enricher for food safety monitoring and early disease diagnosis.

Mechanochemical synthesis ionic covalent organic frameworks/cotton composites for pipette tip solid-phase extraction of domoic acid in seafood.

Pipette tip solid-phase extraction (PT-SPE) as a miniaturized solid-phase extraction technique have a wide range of applications in the field of sample pretreatment. In this study, ionic covalent organic frameworks@cotton (iCOF@cotton) were facilely synthesized by mechanochemical grinding method only in half an hour, and used as the adsorbents of PT-SPE. The synthesized iCOF@cotton not only had high specific surface area, suitable pore structure and cationic charge groups of iCOF that can extract polar targets quickly, but also reduced the problem of high back pressure of PT-SPE by the addition of cotton, thus accelerating extraction time. Combined with high performance liquid chromatographic tandem mass spectrometry (HPLC-MS/MS), an efficient and sensitive method was established for detection of domoic acid (DA, a toxin produced by algae). Under the optimal conditions, the proposed analysis method displayed excellent analytical performance, including broad range of linearity (10-1000 pg mL-1), low limit of detection (LOD, 5 pg mL-1), high correlation coefficient (0.9993), satisfactory precision (RSDs ≤6.4 %). In addition, the developed method was applied to the detection of DA in marine samples, and detected trace DA (18.6 pg mL-1) with satisfactory recovery (85.7%-107.2 %). The above results indicated that the prepared iCOF@cotton have great potential as the adsorbents for PT-SPE.

Efficacy and safety of rademikibart (CBP-201), a next-generation mAb targeting IL-4Rα, in adults with moderate to severe atopic dermatitis: A phase 2 randomized trial (CBP-201-WW001).

BACKGROUND: Rademikibart (CBP-201) is a next-generation IL-4 receptor alpha-targeting antibody. OBJECTIVE: We sought to evaluate rademikibart in adults with moderate to severe atopic dermatitis. METHODS: A total of 226 patients were randomized, double-blind, to subcutaneous rademikibart (300 mg every 2 weeks [Q2W], 150 mg Q2W, 300 mg every 4 weeks [Q4W]; plus 600-mg loading dose) or placebo. Randomization began in July 2020. The trial was completed in October 2021. RESULTS: The WW001 phase 2 trial achieved its primary end point: significant percent reduction from baseline in least-squares mean Eczema Area Severity Index (EASI) to week 16 with rademikibart 300 mg Q2W (-63.0%; P = .0007), 150 mg Q2W (-57.6%; P = .0067), 300 mg Q4W (-63.5%; P = .0004) versus placebo (-39.7%). EASI scores decreased significantly with 300 mg Q2W and Q4W at the earliest assessment (week 2), with no evidence of plateauing by week 16. Significant improvements were also observed in secondary end points, including pruritus. Across the primary and secondary end points, efficacy tended to be comparable with 300 mg Q2W and Q4W dosing. Rademikibart and placebo had similar, low incidence of treatment-emergent adverse events (TEAEs) (48% vs 54%), serious TEAEs (1.8% vs 3.6%), TEAEs leading to treatment discontinuation (1.2% vs 1.8%), conjunctivitis of unspecified cause (2.9% vs 0%), herpes (0.6% vs 1.8%), and injection-site reactions (1.8% vs 1.8%). Although no discontinuations were attributed to coronavirus disease 2019, pandemic-related restrictions likely had an impact on trial conduct. CONCLUSIONS: Rademikibart was efficacious and well tolerated at Q2W and Q4W intervals. Q4W dosing is a more convenient frequency than approved for current therapies.

A solid phase extraction column based on SiO2@ZIF-8 for efficient analysis of domoic acid toxins in the seawater environment: experiments and DFT calculations on adsorption behaviour.

Algal toxins are important metabolites of toxic harmful algal blooms (HABs), and their qualitative and qualitative detection can serve as early warning indicators for toxic HABs, complementing traditional HAB monitoring and improving the accuracy of early warning. Therefore, this work took the detection of domoic acid (DA) as an example and prepared zeolitic imidazolate framework-8 (ZIF-8) with high enrichment performance and high water stability and its core-shell composite material SiO2@ZIF-8 as an adsorbent filler. Density functional theory (DFT) calculations and interference experiments verified that Zn2+ on SiO2@ZIF-8 played a crucial role in enriching DA on SiO2@ZIF-8. By using it as a solid-phase extraction (SPE) filler, it showed excellent performance compared with other SPE columns (C18/HLB/SAX/ZIF-8). Therefore, the SiO2@ZIF-8 column was coupled to high-performance liquid chromatography-mass spectrometry (SPE-HPLC-MS/MS) to establish a highly sensitive detection method for algal toxins in seawater, which had a wide linear range (12.0-5000.0 ng L-1), good reproducibility (RSD) and low limit of detection (4.0 ng L-1), and realized the monitoring of trace DA in the Pingtan sea area of Fujian Province from 2021 to 2022. By comparing other HAB early warning indicators such as salinity and pH and combining them with the information released by the Fujian Provincial Ocean and Fisheries Bureau, the content of DA in seawater measured by the established SPE-HPLC-MS/MS method can provide reference information for HAB monitoring and early warning.

Efficacy and Safety of Spesolimab in Patients with Generalized Pustular Psoriasis: A Subgroup Analysis of Chinese Patients in the Effisayil 1 Trial.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease. The global Effisayil 1 study investigated the efficacy and safety of spesolimab, a humanized monoclonal antibody targeting the IL-36 receptor, in patients experiencing GPP flare. This analysis aimed to explore the efficacy and safety of spesolimab in the Chinese subgroup of Effisayil 1. METHODS: Effisayil 1 was a multicenter, randomized, double-blind, placebo-controlled phase II study. Eligible patients with a GPP flare were randomly assigned (2:1) to receive a single intravenous dose of spesolimab (900 mg) or placebo on day 1. On day 8, patients who had persistent symptoms that met a predefined criterion could receive open-label spesolimab. After day 8, patients with recurrent flares following clinical response could receive rescue treatment with open-label spesolimab. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 at week 1. The key secondary end point was a GPPGA total score of 0 or 1 at week 1. RESULTS: Eleven Chinese patients were randomized, with five patients receiving spesolimab and six receiving placebo. At week 1, 60.0% (3/5) of patients in the spesolimab group and 16.7% (1/6) of patients in the placebo group achieved a GPPGA pustulation sub-score of 0 (risk difference 43.3%; 95% CI -22.6, 86.2); 60.0% and 16.7% of patients in the spesolimab and placebo group, respectively, achieved a GPPGA total score 0 or 1 (risk difference 43.3%; 95% CI -22.6, 86.2). Overall, four patients in each group of the spesolimab and the placebo groups reported at least one adverse event (AE) by week 1, with two and three reporting drug-related AEs, respectively. One patient reported a serious AE that was not considered to be drug related. No death occurred during the study period. CONCLUSION: In the Chinese subgroup of the Effisayil 1 study, more patients receiving spesolimab experienced lesion clearance than those on placebo at week 1, with an acceptable safety profile that was consistent with the global study population. TRIAL REGISTRATION: NCT03782792.

The role of B-cell ferroptosis in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the dysregulation of B cell subpopulation and function. Recent studies have suggested a potential role of ferroptosis, an iron-dependent form of regulated cell death, in the pathogenesis of SLE. Here, we demonstrate that B-cell ferroptosis occurs both in lupus patients and MRL/lpr mice. Treatment with liproxstatin-1, a potent ferroptosis inhibitor, could reduce autoantibody production, improve renal damage, and alleviate lupus symptoms in vivo. Furthermore, our results suggest that ferroptosis may regulate B cell differentiation and plasma cell formation, indicating a potential mechanism for its involvement in SLE. Taken together, targeting ferroptosis in B cells may be a promising therapeutic strategy for SLE.

Single-shot 3D photoacoustic computed tomography with a densely packed array for transcranial functional imaging.

Photoacoustic computed tomography (PACT) is emerging as a new technique for functional brain imaging, primarily due to its capabilities in label-free hemodynamic imaging. Despite its potential, the transcranial application of PACT has encountered hurdles, such as acoustic attenuations and distortions by the skull and limited light penetration through the skull. To overcome these challenges, we have engineered a PACT system that features a densely packed hemispherical ultrasonic transducer array with 3072 channels, operating at a central frequency of 1 MHz. This system allows for single-shot 3D imaging at a rate equal to the laser repetition rate, such as 20 Hz. We have achieved a single-shot light penetration depth of approximately 9 cm in chicken breast tissue utilizing a 750 nm laser (withstanding 3295-fold light attenuation and still retaining an SNR of 74) and successfully performed transcranial imaging through an ex vivo human skull using a 1064 nm laser. Moreover, we have proven the capacity of our system to perform single-shot 3D PACT imaging in both tissue phantoms and human subjects. These results suggest that our PACT system is poised to unlock potential for real-time, in vivo transcranial functional imaging in humans.