Converting kitchen waste into value-added fertilizer using thermophilic semi-continuous composting-biofiltration two-stage process with minimized NH3 emission.

Thermophilic semi-continuous composting (TSC) is effective for kitchen waste (KW) treatment, but large amounts of NH3-rich odorous gas are generated. This study proposes a TSC-biofiltration (BF) two-stage process. Compost from the front-end TSC was used as the packing material in the BF to remove NH3 from the exhaust gas. The BF process was effective in removing up to 83.7 % of NH3, and the NH3 content was reduced to < 8 ppm. Seven days of BF improved the quality of the product from TSC by enhancing the germination index to 134.6 %, 36.5 % higher than that in the aerated-only group. Microbial community analysis revealed rapid proliferation and eventual dominance in the BF of members related to compost maturation and the nitrogen cycle from Actinobacteria, Proteobacteria, Chloroflexi, and Bacteroidetes. The results suggest that the TSC-BF two-stage process is effective in reducing NH3 emissions from TSC and improving compost quality.

Wearable surface deformation myography (sDMG) system for recognition of locomotion modes.

This study designs a wearable sensing system for locomotion mode recognition using lower-limb skin surface curvature deformation caused by the morphological changes of musculotendinous complexes and soft tissues. Flexible bending sensors are embedded into stretch pants, enabling curvature deformations of specific skin segments above lower-limb muscle groups to be captured in a noncontact manner. To evaluate the performance of this system, we conducted experiments on eight able-bodied subjects completing seven common locomotive activities, including walking, running, ramp ascending/descending, stair ascending/descending, and standing. The system measured seven channels of deformation signals from two cross-sections on the shank and the thigh. The collected signals were distinguishable across different locomotion modes and exhibited consistency when monitoring steps. Using selected time-domain features and a linear discriminant analysis (LDA) classifier enabled the proposed system to continuously recognize locomotion modes with an average accuracy of 96.5%. Furthermore, the system maintains recognition performance with 95.7% accuracy even after removing and reapplying the sensors. Finally, we conducted comparison experiments to analyze how window length, feature selection, and the number of channels affect recognition performance, providing insights for optimization. We believe that this novel signal platform holds great potential as a valuable supplementary tool in wearable human motion detection, enriching the information diversity for motion analysis, and enabling new possibilities for further advancements and applications in fields including biomedical engineering, textiles, and computer graphics.

Remote Sensing Retrieval of Cloud Top Height Using Neural Networks and Data from Cloud-Aerosol Lidar with Orthogonal Polarization.

In order to enhance the retrieval accuracy of cloud top height (CTH) from MODIS data, neural network models were employed based on Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) data. Three types of methods were established using MODIS inputs: cloud parameters, calibrated radiance, and a combination of both. From a statistical standpoint, models with combination inputs demonstrated the best performance, followed by models with calibrated radiance inputs, while models relying solely on calibrated radiance had poorer applicability. This work found that cloud top pressure (CTP) and cloud top temperature played a crucial role in CTH retrieval from MODIS data. However, within the same type of models, there were slight differences in the retrieved results, and these differences were not dependent on the quantity of input parameters. Therefore, the model with fewer inputs using cloud parameters and calibrated radiance was recommended and employed for individual case studies. This model produced results closest to the actual cloud top structure of the typhoon and exhibited similar cloud distribution patterns when compared with the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) CTHs from a climatic statistical perspective. This suggests that the recommended model has good applicability and credibility in CTH retrieval from MODIS images. This work provides a method to improve accurate CTHs from MODIS data for better utilization.

Effect of the inoculation of Phanerochaete chrysosporium on nitrogen migration and organic matter conversion during electrolytic manganese residue composting.

Composting has made it practicable to dispose electrolytic manganese residues (EMR) in a less toxic way, nevertheless, the decomposition and the loss of nitrogen is a critical issue. This study aimed to investigate the role of Phanerochaete chrysosporium (PC) inoculation on nitrogen migration and promotion of decomposing organic matter (OM), as well as the effect on bacterial community structure during EMR composting. The results exhibited that nitrogen loss tallied with the first-order kinetic model. PC inoculation increased the relative microbial abundance of Firmicutes, which improved the efficiency of nitrogen nitrification and OM degradation, and increased the germination index and total nitrogen content by 13.8% and 2.95 g/kg, respectively. Moreover, aromatic benzenes replaced heteropolysaccharides, alcohols and ethers as the main components of OM in fertilizer, leading up to a more stable humus structure. This study provides a rationale and a novel perspective on the resource and nutrient conservation of EMR-contaminated soils.

Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H2O2) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo. Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.

Voice disorder classification using convolutional neural network based on deep transfer learning.

Voice disorders are very common in the global population. Many researchers have conducted research on the identification and classification of voice disorders based on machine learning. As a data-driven algorithm, machine learning requires a large number of samples for training. However, due to the sensitivity and particularity of medical data, it is difficult to obtain sufficient samples for model learning. To address this challenge, this paper proposes a pretrained OpenL3-SVM transfer learning framework for the automatic recognition of multi-class voice disorders. The framework combines a pre-trained convolutional neural network, OpenL3, and a support vector machine (SVM) classifier. The Mel spectrum of the given voice signal is first extracted and then input into the OpenL3 network to obtain high-level feature embedding. Considering the effects of redundant and negative high-dimensional features, model overfitting easily occurs. Therefore, linear local tangent space alignment (LLTSA) is used for feature dimension reduction. Finally, the obtained dimensionality reduction features are used to train the SVM for voice disorder classification. Fivefold cross-validation is used to verify the classification performance of the OpenL3-SVM. The experimental results show that OpenL3-SVM can effectively classify voice disorders automatically, and its performance exceeds that of the existing methods. With continuous improvements in research, it is expected to be considered as auxiliary diagnostic tool for physicians in the future.

Pathological voice classification based on multi-domain features and deep hierarchical extreme learning machine.

The intelligent data-driven screening of pathological voice signals is a non-invasive and real-time tool for computer-aided diagnosis that has attracted increasing attention from researchers and clinicians. In this paper, the authors propose multi-domain features and the hierarchical extreme learning machine (H-ELM) for the automatic identification of voice disorders. A sufficient number of sensitive features are first extracted from the original voice signal through multi-domain feature extraction (i.e., features of the time domain and the sample entropy based on ensemble empirical mode decomposition and gammatone frequency cepstral coefficients). To eliminate redundancy in high-dimensional features, neighborhood component analysis is then applied to filter out sensitive features from the high-dimensional feature vectors to improve the efficiency of network training and reduce overfitting. The sensitive features thus obtained are then used to train the H-ELM for pathological voice classification. The results of the experiments showed that the sensitivity, specificity, F1 score, and accuracy of the H-ELM were 99.37%, 98.61%, 99.37%, and 98.99%, respectively. Therefore, the proposed method is feasible for the initial classification of pathological voice signals.

Valorizing kitchen waste to produce value-added fertilizer by thermophilic semi-continuous composting followed by static stacking: Performance and bacterial community succession analysis.

To explore an effective decentralized kitchen waste (KW) treatment system, the performance and bacterial community succession of thermophilic semi-continuous composting (TSC) of KW followed by static stacking (SS) was studied. A daily feeding ratio of 10% ensured stable performance of TSC using an integrated automatic reactor; the efficiencies of organic matter degradation and seed germination index (GI) reached 80.88% and 78.51%, respectively. SS for seven days further promoted the quality of the compost by improving the GI to 91.58%. Alpha- and beta-diversity analyses revealed significant differences between the bacterial communities of TSC and SS. Firmicutes, Actinobacteria, Chloroflexi, Gemmatimonadetes, and Myxococcota were dominant during the TSC of KW, whereas the members of Proteobacteria and Bacteroidetes responsible for product maturity rapidly proliferated during the subsequent SS and ultimately dominated the compost with Firmicutes and Actinobacteria. These results provide new perspectives for decentralized KW treatment using TSC for practical applications.

MHADTI: predicting drug-target interactions via multiview heterogeneous information network embedding with hierarchical attention mechanisms.

MOTIVATION: Discovering the drug-target interactions (DTIs) is a crucial step in drug development such as the identification of drug side effects and drug repositioning. Since identifying DTIs by web-biological experiments is time-consuming and costly, many computational-based approaches have been proposed and have become an efficient manner to infer the potential interactions. Although extensive effort is invested to solve this task, the prediction accuracy still needs to be improved. More especially, heterogeneous network-based approaches do not fully consider the complex structure and rich semantic information in these heterogeneous networks. Therefore, it is still a challenge to predict DTIs efficiently. RESULTS: In this study, we develop a novel method via Multiview heterogeneous information network embedding with Hierarchical Attention mechanisms to discover potential Drug-Target Interactions (MHADTI). Firstly, MHADTI constructs different similarity networks for drugs and targets by utilizing their multisource information. Combined with the known DTI network, three drug-target heterogeneous information networks (HINs) with different views are established. Secondly, MHADTI learns embeddings of drugs and targets from multiview HINs with hierarchical attention mechanisms, which include the node-level, semantic-level and graph-level attentions. Lastly, MHADTI employs the multilayer perceptron to predict DTIs with the learned deep feature representations. The hierarchical attention mechanisms could fully consider the importance of nodes, meta-paths and graphs in learning the feature representations of drugs and targets, which makes their embeddings more comprehensively. Extensive experimental results demonstrate that MHADTI performs better than other SOTA prediction models. Moreover, analysis of prediction results for some interested drugs and targets further indicates that MHADTI has advantages in discovering DTIs. AVAILABILITY AND IMPLEMENTATION: https://github.com/pxystudy/MHADTI.

Thermophilic semi-continuous composting of kitchen waste: Performance evaluation and microbial community characteristics.

This study evaluated the feasibility, system stability, and microbial community succession of thermophilic semi-continuous composting of kitchen waste (KW). The results revealed that treatment performance was stable at a 10 % feeding ratio, with an organic matter (OM) degradation efficiency of 81.5 % and seed germination index (GI) of 50.0 %. Moreover, the OM degradation efficiency and GI were improved to 83.4 % and 70.0 %, respectively, by maintaining an optimal compost moisture content (50-60 %). However, feeding ratios of ≥ 20 % caused deterioration of the composter system owing to OM overloading. Microbial community analysis revealed that Firmicutes, Actinobacteria, Chloroflexi, Proteobacteria, and Gemmatimonadetes were dominant. Additionally, moisture regulation significantly increased the Proteobacteria abundance by 57.1 % and reduced the Actinobacteria abundance by 57.8 %. Moreover, network analysis indicated that the bacterial community stability and positive interactions between genera were enhanced by moisture regulation. This information provides a useful reference for practical KW composting treatment in the semi-continuous mode.

Actuation Timing Perception of a Powered Ankle Exoskeleton and Its Associated Ankle Angle Changes During Walking.

Robotic ankle exoskeletons have the potential to extend human ability, and actuation timing serves as one of the critical parameters in its controller design. While many experiments have investigated the optimal actuation timing values to achieve different objective functions (e.g. minimizing metabolic cost), studies on users' perception of control parameters are gaining interest as it gives information on people's comfort, coordination, and trust in using devices, as well as providing foundations on how the sensorimotor system detects the exoskeleton behavior changes. The purpose of this study was to evaluate people's sensitivity to changes in exoskeleton actuation timing and its associated exoskeleton ankle angle changes during walking. Participants (n =15) with little or no prior experience with ankle exoskeletons were recruited and performed a psychophysical experiment to characterize their just-noticeable difference (JND) thresholds for actuation timing. Participants wore a bilateral active ankle exoskeleton and compared pairs of torque profiles with different actuation timings and low peak torque (0.225 Nm/kg) while walking on the treadmill. The mean timing JND across participants was 2.8±0.6% stride period. Individuals exhibited different sensitivity towards actuation timing, and their associated exoskeleton ankle angle changes also varied. The variance in ankle angle changes might be explained by their differences in ankle stiffness and different ankle torques provided during walking. The results provide insights into how people perceive the changes in exoskeleton control parameters and show individual differences in exoskeleton usage. The actuation timing JND found in this study can also help determine the necessary controller precision.

The effectiveness of Tai Chi for postpartum depression: A protocol for systematic review and meta-analysis.

BACKGROUND: As a specific type of depression, postpartum depression (PPD) causes an adverse hazard to the mother's physical and mental health. Considering the safety requirements for lactation and the expectation of the rapid response to treatment, the search for safe and effective alternative therapies has attracted wide attention. Tai Chi, a traditional Chinese exercise therapy, has been widely used to relieve the symptoms and complications of patients with PPD, which the clinical efficacy is questioned. We conduct a comprehensive systematic review and meta-analysis to find clinical medical evidence of Tai Chi in the treatment of PPD. METHODS: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Science, and Technology Journal Database and Chinese Biomedical Literature Database will be searched from their inception of databases to September 30, 2021. Two reviewers will select articles, extract data, and assess the risk of bias independently. Any disagreement will be resolved by discussion with the third reviewer. Review Manager 5.3 software will be used for data synthesis. The Cochrane risk of bias assessment tool will be used to assess the risk of bias. RESULTS: This study will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the effectiveness of Tai Chi for PPD. CONCLUSIONS: The findings of our study will provide updated evidence to determine whether Tai Chi is an effective intervention for patients with PPD, which will help clinicians make a better alternative treatment schedule of PPD patients and provide a reliable basis for health-related policymakers. STUDY REGISTRATION NUMBER: CRD42021276676.

Perception of Powered Ankle Exoskeleton Actuation Timing During Walking: A Pilot Study.

Actuation timing is an important parameter in powered ankle exoskeleton control that can significantly influence user experience and human-system performance. Previous studies have investigated the actuation timing through optimization under different objective functions, such as minimizing metabolic cost. However, little is known about people's psychological sense of actuation timing. This pilot study measured two subjects' sensitivity to small changes in actuation timing during walking. The just-noticeable difference (JND) threshold was determined via a fitted psychometric function, which quantified subjects' performance in discriminating between a pair of actuation timings. Subjects could detect changes of 3.6% and 6.8% stride period in actuation timing respectively, showing the difference in perception between individuals. The results from this pilot study provide a preliminary understanding of human perception towards exoskeleton control parameters, which offers insight on individual differences in exoskeleton usage and informs exoskeleton precision requirements to minimize undesired human-system interaction.

Clinical efficacy and safety of traditional Chinese medicine Xiao Yao San in insomnia combined with anxiety.

BACKGROUND: Patients with long-term insomnia generally experience anxiety and depression. Traditional sleeping pills and anti-anxiety drugs have certain limitations. Xiao Yao San (XYS), a complementary and alternative therapy, has been widely used to treat insomnia combined with anxiety. This study aims to evaluate the efficacy and safety of XYS in the treatment of insomnia combined with anxiety. METHODS: Related literature was retrieved from 8 electronic databases from the establishment time to March 2021. The subjects were diagnosed with insomnia combined with anxiety. We assessed the methodological quality of randomized controlled trials (RCTs) according to the Cochrane Handbook. Data analysis was conducted using RevMan 5.3 software. RESULTS: The analysis includes 9 RCTs involving 681 patients. Meta-analysis supported that as an auxiliary drug for Western medicine (WM), XYS could enhance the clinical efficacy of insomnia calculated according to the traditional Chinese medicine (TCM) syndrome score scale (risk ratio [RR]: 1.26; 95% confidence interval [CI]: 1.13-1.43; P = .0002) and reduced the scores of Hamilton Anxiety Scale (mean difference [MD]: -5.19; 95% CI: -7.78 to -2.60; P < .001), Pittsburgh Sleep Quality Index (MD: -3.35; 95% CI: -4.86 to -1.84; P < .001), Self-rating Anxiety Scale (MD: -9.38; 95% CI: -10.20 to -8.75; P < .001), TCM syndrome score scale for insomnia (MD: -4.45; 95% CI: -6.65 to -2.24; P < .001), and TCM syndrome score scale for anxiety (MD: -5.54; 95% CI: -9.48 to -1.6; P = .006). The summary analysis also shows that the separate use of XYS was advantageous in reducing the scores of the Hamilton Anxiety Scale (MD: -3.70; 95% CI: -6.31 to -1.09; P = .005), Pittsburgh Sleep Quality Index (MD: -1.82; 95% CI: -2.39 to -1.24; P < .001), and Self-rating Anxiety Scale (MD: -10.79; 95% CI: -14.09 to -7.49; P < .001). The incidence of adverse events with XYS as an ancillary drug or used separately was lower than that in the WM. CONCLUSION: Our systematic evaluation and meta-analysis showed that XYS combined with WM or XYS alone was beneficial for improving sleep quality and relieving anxiety. Due to the low methodological quality, small sample size, and significant heterogeneity of RCTs, more rigorous and scientific clinical trials are required to further evaluate the efficacy and safety of XYS. PROSPERO REGISTRATION NUMBER: CRD42020190613.

Use of Tape Strips to Detect Immune and Barrier Abnormalities in the Skin of Children With Early-Onset Atopic Dermatitis.

Importance: Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking. Objective: To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies. Design, Setting, and Participants: This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children's hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018. Main Outcomes and Measures: Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry. Results: A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 [71.4%] and white (15 [71.4%]). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 [66.7%]) and white (22 [73.3%]). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc ε RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 [IL-8] and IL-6), helper T cell 2 (TH2; IL-4, IL-13, and chemokines CCL17 and CCL26), and TH17/TH22 (IL-19, IL-36G, and S100A proteins) genes were significantly increased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was -15.2 (0.91) and normal was -19.5 (0.48); P < .001. Parallel decreases occurred in epidermal barrier gene products (FLG, CLDN23, and FA2H) and negative immune regulators (IL-34 and IL-37). For example, the decrease for FLG lesional was mean (SE) -2.9 (0.42) and for normal was 2.2 (0.45); P < .001. Associations were found between disease severity or transepidermal water loss and TH2 (IL-33 and IL-4R) and TH17/TH22 (IL-36G and S100As) products in lesional and nonlesional AD skin (evaluated using the SCORing Atopic Dermatitis, Eczema Area and Severity Index, and Pruritus Atopic Dermatitis Quickscore tools). Conclusions and Relevance: In this study, tape strips provide a minimally invasive alternative for serially evaluating AD-associated cutaneous biomarkers and may prove useful for tracking pediatric AD therapeutic response and predicting future course and comorbidities.

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (TH2/TH22/TH17/TH1) and epidermal differentiation. OBJECTIVE: We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. METHODS: Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. RESULTS: ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2 (IL4 receptor [IL4R], IL13, CCL13/monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), TH17/TH22 (lipocalins, PI3/elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and TH1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. CONCLUSION: The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.

GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis.

BACKGROUND: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD). OBJECTIVE: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD. METHODS: Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71. RESULTS: GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001). CONCLUSIONS: Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.

Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. OBJECTIVE: We sought to characterize age-related changes in the AD profile. METHODS: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). RESULTS: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b+ and FcεRI+, P < .05) decreased with age. TH2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with TH2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). TH22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of TH1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and TH17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with TH2 downregulation (CCL26; r = -0.32, P < .1) and TH1 upregulation (IFN-γ; r = 0.48, P < .01) with age. CONCLUSION: The adult AD profile varies with age. Although TH1/TH17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in TH2/TH22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.