Biological mitigation of soil nitrous oxide emissions by plant metabolites.

Plant metabolites significantly affect soil nitrogen (N) cycling, but their influence on nitrous oxide (N2O) emissions has not been quantitatively analyzed on a global scale. We conduct a comprehensive meta-analysis of 173 observations from 42 articles to evaluate global patterns of and principal factors controlling N2O emissions in the presence of root exudates and extracts. Overall, plant metabolites promoted soil N2O emissions by about 10%. However, the effects of plant metabolites on N2O emissions from soils varied with experimental conditions and properties of both metabolites and soils. Primary metabolites, such as sugars, amino acids, and organic acids, strongly stimulated soil N2O emissions, by an average of 79%, while secondary metabolites, such as phenolics, terpenoids, and flavonoids, often characterized as both biological nitrification inhibitors (BNIs) and biological denitrification inhibitors (BDIs), reduced soil N2O emissions by an average of 41%. The emission mitigation effects of BNIs/BDIs were closely associated with soil texture and pH, increasing with increasing soil clay content and soil pH on acidic and neutral soils, and with decreasing soil pH on alkaline soils. We furthermore present soil incubation experiments that show that three secondary metabolite types act as BNIs to reduce N2O emissions by 32%-45%, while three primary metabolite classes possess a stimulatory effect of 56%-63%, confirming the results of the meta-analysis. Our results highlight the potential role and application range of specific secondary metabolites in biomitigation of global N2O emissions and provide new biological parameters for N2O emission models that should help improve the accuracy of model predictions.

Nitrogen-loss and carbon-footprint reduction by plant-rhizosphere exudates.

Low-carbon approaches to agriculture constitute a pivotal measure to address the challenge of global climate change. In agroecosystems, rhizosphere exudates are significantly involved in regulating the nitrogen (N) cycle and facilitating belowground chemical communication between plants and soil microbes to reduce direct and indirect emissions of greenhouse gases (GHGs) and control N runoff from cultivated sites into natural water bodies. Here, we discuss specific rhizosphere exudates from plants and microorganisms and the mechanisms by which they reduce N loss and subsequent N pollution in terrestrial and aquatic environments, including biological nitrification inhibitors (BNIs), biological denitrification inhibitors (BDIs), and biological denitrification promoters (BDPs). We also highlight promising application scenarios and challenges in relation to rhizosphere exudates in terrestrial and aquatic environments.

ß-Catenin and SOX2 Interaction Regulate Visual Experience-Dependent Cell Homeostasis in the Developing Xenopus Thalamus.

In the vertebrate brain, sensory experience plays a crucial role in shaping thalamocortical connections for visual processing. However, it is still not clear how visual experience influences tissue homeostasis and neurogenesis in the developing thalamus. Here, we reported that the majority of SOX2-positive cells in the thalamus are differentiated neurons that receive visual inputs as early as stage 47 Xenopus. Visual deprivation (VD) for 2 days shifts the neurogenic balance toward proliferation at the expense of differentiation, which is accompanied by a reduction in nuclear-accumulated ß-catenin in SOX2-positive neurons. The knockdown of ß-catenin decreases the expression of SOX2 and increases the number of progenitor cells. Coimmunoprecipitation studies reveal the evolutionary conservation of strong interactions between ß-catenin and SOX2. These findings indicate that ß-catenin interacts with SOX2 to maintain homeostatic neurogenesis during thalamus development.

Efficacy and Safety of Dupilumab in Patients With Erythrodermic Atopic Dermatitis: A Post Hoc Analysis of 6 Randomized Clinical Trials.

Importance: Erythrodermic atopic dermatitis (AD) is a severe AD subtype defined by extensive skin involvement, leading to complications and sometimes hospitalization. Objective: To assess dupilumab's efficacy and safety in patients with erythrodermic AD in clinical trials. Design, Setting, and Participants: This post hoc analysis included patients enrolled in 6 multicenter, multinational, randomized, double-blind, placebo-controlled trials. Patients included in this analysis met erythrodermic AD criteria of 90% or greater body surface area (BSA) affected by AD and Global Individual Sign Score for erythema of 1 or higher. Data analyses for this post hoc analysis were conducted between March 5, 2019, and October 24, 2020. Interventions: Dupilumab once weekly or every 2 weeks, or placebo, either as monotherapy or with concomitant topical corticosteroids (TCS). Main Outcomes and Measures: Efficacy (BSA, Eczema Area and Severity Index [EASI] score, Peak Pruritus Numerical Rating Scale [PP-NRS] score), changes in serum biomarkers (thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase), and safety (incidence of adverse events) at week 16. Data were pooled within each regimen; monotherapy and concomitant TCS results are shown separately. Results: Of 3075 randomized patients, 209 met criteria for erythrodermic AD at baseline, with the median age being 31 and 39 years in the monotherapy and concomitant TCS trials, respectively, similar to the overall populations (34 and 36 years, respectively); 71.3% (n = 97) and 74.0% (n = 54) of patients, respectively, were male (compared with 58.7% and 60.6% in the overall populations). In patients with erythrodermic AD, dupilumab once weekly and every 2 weeks vs placebo significantly improved percentage of BSA affected by AD (least squares mean percent change [SE]) with monotherapy (-42.0% [7.7%] and -39.9% [6.5%] vs -17.2% [11.0%]; P = .03) and concomitant TCS (-63.2% [6.7%] and -56.1% [9.1%] vs -14.5% [7.3%]; P < .001); EASI score with monotherapy (-58.5% [9.0%] and -58.3% [7.9%] vs -22.3% [12.4%]; P = .004 and P = .003, respectively) and concomitant TCS (-78.9% [7.8%] and -70.6% [10.1%] vs 19.3% [8.2%]; P < .001); and PP-NRS score in monotherapy (-45.9% [7.8%] and -33.9% [6.6%] vs -0.6% [9.4%]; P < .001) and concomitant therapy (-53.0% [8.1%] and -55.7% [10.8%] vs -26.0% [8.8%]; P = .006 and P = .01, respectively). Nominally statistically significant improvement was seen as early as week 1 (EASI and PP-NRS scores with monotherapy). Biomarker levels were significantly reduced vs placebo. The most frequent adverse events in dupilumab-treated patients were injection-site reaction, conjunctivitis, and nasopharyngitis. Conclusions and Relevance: In this post hoc analysis of 6 randomized clinical trials, treatment with dupilumab resulted in rapid, sustained improvements in AD signs and symptoms with acceptable safety in patients with erythrodermic AD, similar to those in the trials' overall patient population. Trial Registration: ClinicalTrials.gov Identifiers: NCT01859988, NCT02277743, NCT02277769, NCT03054428, NCT02260986, NCT02755649.

The nitrification inhibitor 1,9-decanediol from rice roots promotes root growth in Arabidopsis through involvement of ABA and PIN2-mediated auxin signaling.

1,9-decanediol (1,9-D) is a biological nitrification inhibitor secreted in roots, which effectively inhibits soil nitrifier activity and reduces nitrogen loss from agricultural fields. However, the effects of 1,9-D on plant root growth and the involvement of signaling pathways in the plant response to 1,9-D have not been investigated. Here, we report that 1,9-D, in the 100-400 µM concentration range, promotes primary root length in Arabidopsis seedlings at 3d and 5d, by 10.1%-33.3% and 6.9%-32.6%, and, in a range of 50-200 µM, leads to an increase in the number of lateral roots. 150 µM 1,9-D was found optimum for the positive regulation of root growth. qRT-PCR analysis reveals that 1,9-D can significantly increase AtABA3 gene expression and that a mutation in ABA3 results in insensitivity of root growth to 1,9-D. Moreover, through pharmacological experiments, we show that exogenous addition of ABA (abscisic acid) with 1,9-D enhances primary root length by 23.5%-63.3%, and an exogenous supply of 1,9-D with the ABA inhibitor Flu reduces primary root length by 1.0%-14.3%. Primary root length of the pin2/eir1-1 is shown to be insensitive to both exogenous addition of 1,9-D and ABA, indicating that the auxin carrier PIN2/EIR1 is involved in promotion of root growth by 1,9-D. These results suggest a novel for 1,9-D in regulating plant root growth through ABA and auxin signaling.

Epigenetic regulation of GABAergic differentiation in the developing brain.

In the vertebrate brain, GABAergic cell development and neurotransmission are important for the establishment of neural circuits. Various intrinsic and extrinsic factors have been identified to affect GABAergic neurogenesis. However, little is known about the epigenetic control of GABAergic differentiation in the developing brain. Here, we report that the number of GABAergic neurons dynamically changes during the early tectal development in the Xenopus brain. The percentage of GABAergic neurons is relatively unchanged during the early stages from stage 40 to 46 but significantly decreased from stage 46 to 48 tadpoles. Interestingly, the histone acetylation of H3K9 is developmentally decreased from stage 42 to 48 (about 3.5 days). Chronic application of valproate acid (VPA), a broad-spectrum histone deacetylase (HDAC) inhibitor, at stage 46 for 48 h increases the acetylation of H3K9 and the number of GABAergic cells in the optic tectum. VPA treatment also reduces apoptotic cells. Electrophysiological recordings show that a VPA induces an increase in the frequency of mIPSCs and no changes in the amplitude. Behavioral studies reveal that VPA decreases swimming activity and visually guided avoidance behavior. These findings extend our understanding of histone modification in the GABAergic differentiation and neurotransmission during early brain development.

Bisdemethoxycurcumin Alleviates Dextran Sodium Sulfate-Induced Colitis via Inhibiting NLRP3 Inflammasome Activation and Modulating the Gut Microbiota in Mice.

Our previous study showed that bisdemethoxycurcumin (BUR) exerts anti-inflammatory properties in lipopolysaccharide-induced intestinal injury, and studies have revealed that NOD-like receptor superfamily, pyrin domain containing 3 (NLRP3) inflammasome activation plays a vital role in the pathogenesis of colitis. However, it is not clear whether BUR could attenuate colitis-mediated intestinal inflammation via NLRP3 inflammasome inactivation and modulate the gut microbiota dysbiosis. The results demonstrated that BUR attenuated DSS-induced body weight decrease, histopathological changes, and epithelial apoptosis. BUR significantly improved the intestinal barrier defects and abrogated DSS-induced inflammatory response. Consistently, BUR reduced the expression of NLRP3 family members, confirming its inhibitory effects on NLRP3 inflammasome activation and pyroptosis. BUR regulated microbiota dysbiosis and altered the gut microbial community. BUR supplementation enriched the relative abundance of beneficial bacteria (such as Lactobacillus and Bifidobacterium), which showed significant negative correlations with the pro-inflammatory biomarkers. Collectively, these findings illustrated that BUR could ameliorate DSS-induced colitis by improving intestinal barrier function, reducing apoptosis, inhibiting NLRP3 inflammasome activation, and regulating the gut microbiota.

MicroRNAs Are Involved in Regulating Plant Development and Stress Response through Fine-Tuning of TIR1/AFB-Dependent Auxin Signaling.

Auxin, primarily indole-3-acetic acid (IAA), is a versatile signal molecule that regulates many aspects of plant growth, development, and stress response. Recently, microRNAs (miRNAs), a type of short non-coding RNA, have emerged as master regulators of the auxin response pathways by affecting auxin homeostasis and perception in plants. The combination of these miRNAs and the autoregulation of the auxin signaling pathways, as well as the interaction with other hormones, creates a regulatory network that controls the level of auxin perception and signal transduction to maintain signaling homeostasis. In this review, we will detail the miRNAs involved in auxin signaling to illustrate its in planta complex regulation.

Syringic acid from rice roots inhibits soil nitrification and N2O emission under red and paddy soils but not a calcareous soil.

Syringic acid (SA) is a novel biological nitrification inhibitor (BNIs) discovered in rice root exudates with significant inhibition of Nitrosomonas strains. However, the inhibitory effect of SA on nitrification and nitrous oxide (N2O) emissions in different soils and the environmental factors controlling the degree of inhibition have not been studied. Using 14-day microcosm incubation, we investigated the effects of different concentrations of SA on nitrification activity, abundance of ammonia-oxidizing microorganisms, and N2O emissions in three typical agricultural soils. The nitrification inhibitory efficacy of SA was strongest in acidic red soil, followed by weakly acidic paddy soil, with no significant effect in an alkaline calcareous soil. Potential nitrification activity (PNA) were also greatly reduced by SA additions in paddy and red soil. Pearson correlation analysis showed that the inhibitory efficacy of SA might be negatively correlated with soil pH and positively correlated with clay percentage. SA treatments significantly reduced N2O emissions by 69.1-79.3% from paddy soil and by 40.8%-46.4% from red soil, respectively, but no effect was recorded in the calcareous soil. SA addition possessed dual inhibition of both ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) abundance in paddy and red soil. Structural equation modelling revealed that soil ammonium (NH4 +) and dissolved organic carbon content (DOC) were the key variables explaining AOA and AOB abundance and subsequent N2O emissions. Our results support the potential for the use of the BNI SA in mitigating N2O emissions and enhancing N utilization in red and paddy soils.

Dupilumab treatment induced similar improvements in signs, symptoms, and quality of life in adults with moderate-to-severe atopic dermatitis with baseline Eczema Area and Severity Index Score <24 or ≥24.

BACKGROUND: In multiple phase 3 trials, dupilumab improved signs, symptoms (including pruritus), and quality-of-life (QoL) in adults with moderate-to-severe atopic dermatitis (AD). In Italy, dupilumab received innovation status but is currently only reimbursed by the National Health Service for adults with Eczema Area Severity Index (EASI) scores ≥24. This analysis assesses disease burden and dupilumab efficacy in adults with EASI scores above and below this threshold. METHODS: This post-hoc analysis included 299 adults pooled from two, randomized, placebo-controlled, phase 3 trials, LIBERTY AD CAFÉ (NCT02755649) and LIBERTY AD CHRONOS (NCT02260986), who received the approved dupilumab regimen (300 mg every 2 weeks) or placebo, with concomitant topical corticosteroids. EASI, Peak Pruritus Numerical Rating Scale (PP-NRS), and Dermatology Life Quality Index (DLQI) were assessed in patients with EASI scores ≥20 to <24 and ≥24 at week 16. RESULTS: At baseline, EASI was weakly correlated with PP-NRS and DLQI (Spearman's correlation coefficient: 0.22 and 0.29, respectively). At week 16, in both the EASI<24 and EASI≥24 populations, respectively, significantly more patients vs. control achieved: ≥50% improvement in EASI (95.5% vs. 55.6%; 80.6% vs. 33.1%); ≥3-point improvement in PP-NRS (68.4% vs. 35.3%; 55.3% vs. 17.7%); and ≥4-point improvement in DLQI (83.3% vs. 43.8%; 84.2% vs. 41.9%); from baseline. Dupilumab was generally well tolerated with an acceptable safety profile. CONCLUSIONS: Dupilumab treatment improves signs, symptoms, and QoL in moderate-to-severe AD adults with EASI<24, who can present with high disease burden. Opportunity may exist to use additional parameters to define disease severity and access to new therapies.

Combination of Compound Kushen Injection and cisplatin shows synergistic antitumor activity in p53-R273H/P309S mutant colorectal cancer cells through inducing apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Colorectal cancer (CRC) is one type of worldwide popular and refractory tumors. Compound Kushen Injection (CKI) is a frequently applied traditional Chinese medicine formula as an adjuvant drug for the chemotherapy of CRC. P53 is the most commonly mutated gene in CRC, accounting for the development, malignant and prognosis progression of CRC. However, effect of CKI on the therapeutic efficacy of p53-mutant CRC remains understood. Besides, the combined efficacy of different chemotherapeutics drugs in combination with CKI for CRC treatment is rarely concerned. AIM OF STUDY: To investigate the combined efficacy of the CKI-derived combination strategies in the p53-mutant CRC. MATERIALS AND METHODS: Two CRC cell lines HCT116 and SW480 cells, which respectively harbor wild-type p53 and p53-R273H/P309S mutant, were applied. Cisplatin (Cis) and 5-fluorouracil (5FU) were combined chemotherapeutics drugs of CKI-derived combination strategies in this article. In vitro antitumor activity was detected by sulforhodamine B (SRB) assay and colony formation assay. Combenefit soft was applied to evaluate the synergetic/antagonistic effect of drug combination. Lentivirus-mediated overexpression method was used to generate a set of p53-mutant and wild-type CRC cell lines harboring identical genomes. Transcriptomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were applied to predicate the underlying mechanism of synergetic interaction between drug combination. Western blot was performed to verify predicated pathways contributing to the synergy of drug combination. RESULTS: CKI preferentially combined with Cis but not 5FU, to produce a synergistical antitumor efficiency for p53-R273H/P309S mutant, rather than wild-type p53 harboring CRC cells. The combination of CKI and Cis strongly reprogrammed the transcriptional profiles of SW480 cells. Cytokine-cytokine receptor interaction pathway was a key pathway involved in cooperativity between CKI and Cis in SW480 cells. Mechanistically, compared to that Cis individually triggered necroptosis, the co-treatment of CKI and Cis reinforced the cell death of SW480 cells in a possible synergistic manner by inducing extrinsic apoptosis pathway. CONCLUSION: This article provides a novel perspective into the precision clinical application of CKI-derived combination therapy programs of CRC based on genetic variation and the classes of chemotherapeutics drugs.

OsGF14b is involved in regulating coarse root and fine root biomass partitioning in response to elevated [CO2] in rice.

Elevated [CO2] can increase rice biomass and yield, but the degree of this increase varies substantially among cultivars. Little is known about the gene loci involved in the acclimation and adaptation to elevated [CO2] in rice. Here, we report on a T-DNA insertion mutant in japonica rice exhibiting a significantly enhanced response to elevated [CO2] compared with the wild type (WT). The root biomass response of the mutant was higher than that of the WT, and this manifested in the number of adventitious roots, the average diameter of roots, and total root length. Furthermore, coarse roots (>0.6 mm) and thin lateral roots (<0.2 mm) were more responsive to elevated [CO2] in the mutant. When exposed to lower light intensity, however, the response of the mutant to elevated [CO2] was not superior to that of the WT, indicating that the high response of the mutant under elevated [CO2] was dependent on light intensity. The T-DNA insertion site was located in the promoter region of the OsGF14b gene, and insertion resulted in a significant decrease in OsGF14b expression. Our results indicate that knockout of OsGF14b may improve the response to elevated [CO2] in rice by enhancing carbon allocation to coarse roots and to fine lateral roots.

Association Between a Type 2 Inflammatory Disease Burden Score and Outcomes Among Patients with Asthma.

BACKGROUND: Although prevalence of co-existing type 2 inflammatory diseases (cT2) in asthma patients has been reported, limited data exist regarding their impact on asthma outcomes. OBJECTIVE: To assess the impact of cT2 burden on asthma outcomes and to evaluate patterns of clustering of cT2 in a real-world setting. METHODS: From medical records of 4.5 million enrollees in 650 primary care practices in the UK (January 2010-December 2017), patients with ≥1 diagnosis code for asthma at any time pre-index date (date of most recent asthma-related medical encounter) and ≥2 asthma-related prescriptions during the year before index date were categorized into the Global Initiative of Asthma (GINA) guideline severity steps. A cT2 burden score (range 0-9) was assigned based on the total number of co-existing conditions (allergic conjunctivitis, allergic rhinitis, anaphylaxis, eczema/atopic dermatitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, nasal polyps, or urticaria) for which patients received a medical diagnosis. Multivariate regression models evaluated associations between cT2 burden score and asthma exacerbations and asthma control. Factor analysis was performed to assess which cT2 comorbidities were correlated and exhibited patterns of clustering. RESULTS: Overall, 245,893 patients with asthma were included (mean [SD] age 44.8 [22.1] years; 43.8% male). Between 55% (GINA step 1) and 60% (GINA step 5) of asthma patients had a medical diagnosis for ≥1 other type2dx. Patients with increased cT2 burden were significantly more likely to experience asthma exacerbations and less likely to achieve asthma control. CONCLUSION: Asthma patients with a higher cumulative cT2 burden score were more likely to experience worse asthma outcomes than those without any cT2 (burden score of 0).

Female chronic posterior urethritis is underestimated in patients with lower urinary tract symptoms.

BACKGROUND: As one of the causes of urethral symptoms, female chronic posterior urethritis is a common and distressing disease; however, it is often neglected and misdiagnosed as overactive bladder (OAB) or interstitial cystitis/bladder pain syndrome (IC/BPS). Currently, little is known about the urothelium and lamina propria of the bladder neck and proximal urethra. Thus, identifying urethral lesions is necessary for the diagnosis and treatment of female chronic posterior urethritis. Transurethral electroresection is an effective and safe approach for treating female chronic posterior urethritis. This study sought to determine if urethral lesions are necessary for the diagnosis and treatment of female chronic posterior urethritis, and evaluate the efficacy and safety of the transurethral electroresection of mucosa and submucosa in treating female chronic posterior urethritis. METHODS: A single-center, retrospective, observational study was conducted at a teaching and referral hospital. A total of 147 female patients who had been diagnosed with chronic papillary urethritis underwent transurethral electroresection between 2015 and 2018. Each patient underwent a follow-up examination. A chart review was also performed. RESULTS: Patients had a mean age of 54 years (range, 23-82 years), and the average follow-up period was 54.8 months (range, 6-600 months). Urinary frequency and urgency (51.7%) were the most common clinical manifestations of chronic posterior urethritis. Forty-two-point two percent of patients had positive urine culture results, most commonly with Mycoplasma genitalium. The cystoscopic findings revealed that chronic posterior urethritis has tuft-like, pseudopodia-like, finger-like, and follicular-like polyps and villi, and a pebble-like appearance with mucosal hyperemia. The success rate of the transurethral electroresection was 88.6%, and patients showed no apparent or serious complications. CONCLUSIONS: This study showed that female chronic posterior urethritis is a cause that contributes to LUT symptoms. Its characteristic cystoscopic appearance and biopsy play a vital role in its diagnosis. The transurethral electroresection of urethral lesions is simple, effective, and minimally invasive without any apparent complications.

Stigmasterol root exudation arising from Pseudomonas inoculation of the duckweed rhizosphere enhances nitrogen removal from polluted waters.

Rhizospheric microorganisms such as denitrifying bacteria are able to affect 'rhizobioaugmention' in aquatic plants and can help boost wastewater purification by benefiting plant growth, but little is known about their effects on the production of plant root exudates, and how such exudates may affect microorganismal nitrogen removal. Here, we assess the effects of the rhizospheric Pseudomonas inoculant strain RWX31 on the root exudate profile of the duckweed Spirodela polyrrhiza, using gas chromatography/mass spectrometry. Compared to untreated plants, inoculation with RWX31 specifically induced the exudation of two sterols, stigmasterol and ß-sitosterol. An authentic standard assay revealed that stigmasterol significantly promoted nitrogen removal and biofilm formation by the denitrifying bacterial strain RWX31, whereas ß-sitosterol had no effect. Assays for denitrifying enzyme activity were conducted to show that stigmasterol stimulated nitrogen removal by targeting nitrite reductase in bacteria. Enhanced N removal from water by stigmasterol, and a synergistic stimulatory effect with RWX31, was observed in open duckweed cultivation systems. We suggest that this is linked to a modulation of community composition of nirS- and nirK-type denitrifying bacteria in the rhizosphere, with a higher abundance of Bosea, Rhizobium, and Brucella, and a lower abundance of Rubrivivax. Our findings provide important new insights into the interaction of duckweed with the rhizospheric bacterial strain RWX31 and their involvement in the aquatic N cycle and offer a new path toward more effective bio-formulations for the purification of N-polluted waters.

Factors Influencing Viral Clearance in Mild COVID-19 and Clinical Characteristics of Asymptomatic Patients.

BACKGROUND: The outbreak of coronavirus disease (COVID-19) has become a global public health emergency. OBJECTIVE: To evaluate the characteristics and outcomes of patients with COVID-19 in Anhui and to identify predictors of viral clearance. METHODS: We retrospectively analyzed the data collected from discharged patients with laboratory-confirmed SARS-CoV-2 infections. We compared clinical features between viral clearance and viral persistence, and evaluated factors associated with SARS-CoV-2 shedding using multiple linear regression. RESULTS: Among the 83 patients involved in the study, the median age was 43 years, while 60.2% were male, 35.4% had comorbidities, and the mortality was zero. The median time from illness onset to admission was 5 days (interquartile range (IQR), 2-7 days), and the median time from the illness onset to SARS-CoV-2 RNA detection was 16 days (IQR, 13-18 days). The factors influencing viral clearance were as follows: (1) delayed admission (beta 1.057, 95% CI 0.810-1.304; p ≤ 0.001) and (2) underlying comorbidities (beta 1.907, 95% CI 0.198-3.616; p = 0.029). No significant differences were observed in the length of stay (p = 0.246) and pneumonia between asymptomatic and symptomatic patients based on computed tomography (CT) (p = 0.124). CONCLUSIONS: Delayed admission and underlying comorbidities may effectively predict SARS-CoV-2 RNA clearance. For those infected with SARS-CoV-2, even asymptomatic patients without any clinical symptoms should be traced and isolated. This practice may reduce the spread of SARS-CoV-2 and slow the COVID-19 pandemic caused by the virus. Clinical Trial Registration Number: This trial is registered with 2020-051.

Dupilumab Improves Asthma and Sinonasal Outcomes in Adults with Moderate to Severe Atopic Dermatitis.

BACKGROUND: Dupilumab has demonstrated efficacy with acceptable safety in clinical trials in patients with moderate to severe atopic dermatitis (AD). OBJECTIVE: To assess dupilumab's impact on asthma and sinonasal conditions in adult patients with moderate to severe AD in four randomized, double-blinded, placebo-controlled trials. METHODS: In LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02755649), CHRONOS (NCT02260986), and CAFÉ (NCT02755649), patients received placebo, dupilumab 300 mg every 2 weeks (q2w), or dupilumab 300 mg weekly (qw). In CHRONOS and CAFÉ, patients received concomitant topical corticosteroids. This post hoc analysis assessed Asthma Control Questionnaire-5 (ACQ-5) scores in patients with asthma, Sino-Nasal Outcome Test-22 (SNOT-22) scores in patients with sinonasal conditions, and AD signs and symptoms in all patients. RESULTS: Of the 2444 patients, 463 had asthma with baseline ACQ-5 ≥ 0.5 (19%); 1171 had sinonasal conditions (48%); and 311 had both (13%). At week 16, ACQ-5 scores (least squares mean change from baseline [standard error]) improved by 0.27 (0.07), 0.59 (0.08), and 0.56 (0.07) in placebo-, q2w-, and qw-treated patients with asthma, respectively, whereas SNOT-22 scores improved by 5.1 (0.8), 9.9 (0.9), and 10.8 (0.8) in patients with sinonasal conditions (P < .01 for all dupilumab vs placebo). Improvements in ACQ-5 and SNOT-22 were also seen in patients with both conditions. Dupilumab also significantly improved AD signs and symptoms among all subgroups. CONCLUSIONS: In this first analysis of patients with comorbid moderate to severe AD, asthma, and/or chronic sinonasal conditions, dupilumab improved all three diseases in a clinically meaningful and statistically significant manner (vs placebo), based on validated outcome measures.

Efficacy of dupilumab on clinical outcomes in patients with asthma and perennial allergic rhinitis.

BACKGROUND: Comorbid perennial allergic rhinitis (PAR) or year-round aeroallergen sensitivity substantially contributes to disease burden in patients with asthma. Dupilumab blocks the shared receptor for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation that play important roles in asthma and PAR. In the LIBERTY ASTHMA QUEST trial (NCT02414854), dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline (blood eosinophils and fractional exhaled nitric oxide). OBJECTIVE: To assess dupilumab efficacy in LIBERTY ASTHMA QUEST patients with comorbid PAR. METHODS: Severe asthma exacerbation rates, FEV1, asthma control (5-item Asthma Control Questionnaire), rhinoconjunctivitis-specific health-related quality of life (Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores), and type 2 inflammatory biomarkers during the 52-week treatment period were assessed. RESULTS: A total of 814 of the 1902 patients (42.8%) had comorbid PAR (defined as an allergic rhinitis history and ≥1 perennial aeroallergen specific immunoglobulin E (IgE) level ≥0.35 kU/L at baseline). Dupilumab, 200 and 300 mg every 2 weeks, vs placebo reduced severe exacerbations rates by 32.2% and 34.6% (P < .05 for both) and improved FEV1 at week 12 by 0.14 L and 0.18 L (P < .01 for both); greater efficacy was observed in patients with elevated baseline blood eosinophil counts (≥300 cells/µL) and fractional exhaled nitric oxide. Dupilumab treatment also numerically improved the 5-item Asthma Control Questionnaire and Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores and suppressed type 2 inflammatory biomarkers. CONCLUSION: Dupilumab improved key asthma-related outcomes, asthma control, and rhinoconjunctivitis-specific health-related quality of life while suppressing type 2 inflammatory biomarkers and perennial allergen-specific IgE in patients with moderate-to-severe asthma and comorbid PAR, highlighting its dual inhibitory effects on IL-4 and IL-13 and its role in managing asthma and PAR.

Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma.

BACKGROUND: Dupilumab blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation, including IgE-mediated allergic inflammation in asthma. In the LIBERTY ASTHMA QUEST (NCT02414854) study, dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers (blood eosinophils and fractional exhaled nitric oxide) at baseline. OBJECTIVE: We assessed dupilumab's effect on key asthma outcomes in QUEST patients with/without evidence of allergic asthma (total serum IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline). METHODS: Severe exacerbation rates and change from baseline in FEV1, asthma control, and markers of type 2 inflammation during the 52-week treatment period were assessed. RESULTS: In the allergic asthma subgroup (n = 1083), dupilumab 200/300 mg every 2 weeks versus placebo reduced severe asthma exacerbation rates (-36.9%/-45.5%; both P < .01), improved FEV1 at week 12 (0.13 L/0.16 L; both P < .001; improvements were evident by the first evaluation at week 2) with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline, and improved asthma control. Dupilumab treatment also resulted in rapid and sustained reductions in type 2 inflammatory biomarkers. Comparable results were observed in patients without evidence of allergic asthma (n = 819). CONCLUSION: Dupilumab reduced severe exacerbation rates, improved FEV1 and asthma control, and suppressed type 2 inflammatory biomarkers in patients with uncontrolled, moderate-to-severe asthma with or without evidence of allergic asthma, highlighting the key role of IL-4 and IL-13 in airway inflammation.