Blood eosinophil (B‐Eos) count is an emerging biomarker in the management of respiratory disease but determinants of B‐Eos count besides respiratory disease are poorly described. Therefore, we aimed to evaluate the influence of non‐respiratory diseases on B‐Eos count, in comparison to the effect on two other biomarkers: fraction of exhaled nitric oxide (FeNO) and C‐reactive protein (CRP), and to identify individual characteristics associated with B‐Eos count in healthy controls.n = 3333 and n = 7,894, respectively) or not having respiratory disease . After excluding any respiratory disease, the association between B‐Eos count, FeNO or CRP, and non‐respiratory diseases was analyzed in multivariate models and multicollinearity was tested. After excluding also non‐respiratory diseases independently associated with B‐Eos count , the independent association between individual characteristics and B‐Eos count was analyzed.Children/adolescents (<18 years) and adults with complete B‐Eos data from the US National Health and Nutritional Examination Surveys 2005–2016 were included, and they were divided into having respiratory diseases . A significant influence of race/ethnicity was also noted, and current smokers had 17% higher B‐Eos count than never smokers (p < 0.001).In adults, metabolic syndrome, heart disease or stroke was independently associated with higher B‐Eos count , whereas no associations were found with FeNO or CRP. In healthy controls, male sex or being obese was associated with higher B‐Eos counts, both in children/adolescents  and adults  (Non‐respiratory diseases influence B‐Eos count but not FeNO or CRP. Male sex, obesity, certain races/ethnicities, and current smoking are individual characteristics or exposures that are associated with higher B‐Eos counts. All these factors should be considered when using B‐Eos count in the management of respiratory disease. Moreover, in addition to the type of inflammation, its location is also important for the disease assessment. To this end, it may be necessary to have a comparison with other systemic markers and local type‐2 markers, such as C‐reactive protein (CRP) and FeNO, respectively.The aim of this investigation was to (a) evaluate the influence of non‐respiratory disease on B‐Eos count, FeNO, and CRP, and (b) to identify individual characteristics that are associated with B‐Eos count in healthy individuals.22.1We analyzed the data publicly available from six 2‐year surveys (2005–2016) of the National Health and Nutritional Examination Surveys (NHANES), representing a total of 60,936 individuals from 0 to 85 years old. NHANES is a continuous nationally representative cross‐sectional survey of civilian noninstitutionalized persons in the United States of America. Detailed information can be found elsewhere.2.2B‐Eos count was analyzed using a quantitative hematologic analyzer and leukocyte differential cell counter, Beckman Coulter HMX (Beckman Coulter). Complete details on blood collection procedures, quality assurance, and control procedures are described elsewhere.n = 6178%; 28%). Please see Additional file 1 for detailed exclusion criteria.FeNO was measured following the ATS/ERS recommendationsSerum CRP was quantified by latex‐enhanced nephelometry using a Dade Behring Nephelometer II Analyzer System (Dade Behring Diagnostics Inc.). Further details can be found elsewhere.n = 19,800), serum CRP is available only in survey years 2005–2010 , whereas B‐Eos counts were measured during all included surveys . Thus, all three markers were available in the 2007–2010 survey years .FeNO measurements are currently available only for NHANES survey years 2007–2012 (2.3children/adolescents (if < 18 years) and adults (≥18 years).Demographic characteristics, such as age, sex, race/ethnicity, body mass index (BMI), and smoking status were analyzed. Two age groups were defined: Race/Ethnicity was categorized as non‐Hispanic white, non‐Hispanic black, Mexican/Hispanic, and other . BMI was categorized according to international recommendations, both for children/adolescentsSmoking status was defined as: never smokers, current smokers, and former smokers. Children/adolescents were considered as nonsmokers (see Data Respiratory diseases were considered when having a self‐reported diagnosis of asthma and/or hay fever (in children/adolescents), or self‐reported diagnosis of asthma and/or hay fever, and/or other respiratory diseases (in adults). Asthma was defined as an affirmative response to the question “Has a doctor ever told you that you had asthma?” Hay fever was defined if the subject answered positively to either: “Has a doctor ever told you that you had hay fever?” or “During the past 12 months, have you had an episode of hay fever?” Other respiratory diseases were defined if the subject answered positively to “Has a doctor or other health professional told you that you had emphysema and/or chronic bronchitis?”Healthy control groups were obtained by excluding children/adolescents with any of the respiratory diseases described above. In adults, healthy controls were obtained by excluding subjects having: any respiratory disease and at least one of the non‐respiratory diseases  that were significantly associated with B‐Eos after adjustment for individual characteristics (see below). Details on the definition of the non‐respiratory diseases are described in the Data respiratory disease groups were defined as: (a) children/adolescents with respiratory disease; and (b) adults with respiratory disease and without any significant non‐respiratory disease associated with elevated B‐Eos counts , and a statistical significance level was set at p < 0.20 were considered for inclusion in the final model. Adjustments were made for co‐variables: sex, age, race, smoking status, height, and BMI, and weight instead of BMI, in all models. Diagnostic for multicollinearity was performed using the variance inflation factor (VIF) test. A VIF above 5 was considered to indicate a high degree of correlations among the predictor variables.svygof function. Sensitivity analysis was performed by multiple imputation of missing values . Also, we categorized both B‐Eos count and FeNO measurements by using the most commonly used cut‐offs.s Figure  using thTo analyze the prevalence of the non‐respiratory disease factors, we divided age into tertiles . Spearman correlation coefficients were calculated between B‐Eos count and other markers (FeNO and CRP), in both healthy control and respiratory disease groups .33.1NHANES included a total of 60,936 participants from 2005 to 2016, and 82% had complete data on B‐Eos count across all ages  and adults (n = 5667), respectively , we obtained healthy control groups with children/adolescents , being obese and being of non‐Hispanic black or other race/ethnicity, were all independently associated with higher B‐Eos counts in children/adolescents . When introducing heart diseases, stroke, and metabolic syndrome as independent factors in this model, the age effect was no longer significant (p = 0.290).Of note, in adults where only respiratory diseases had been excluded .B‐Eos count correlated weakly with CRP in adults, both in the healthy control group and the respiratory disease group, whereas no correlation was found in children/adolescents  from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd  and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. João A. Fonseca reports grants and personal fees from AstraZeneca, personal fees from Novartis, grants and personal fees from Mundipharma, outside the submitted work. All other authors report no conflicts of interest pertaining to the submitted work.Supplementary MaterialClick here for additional data file.


To determine the long‐term safety of switching to brexpiprazole from aripiprazole or non‐aripiprazole dopamine antagonists.Post‐hoc analysis of 56‐week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4‐week switching period with further titration (1–4 mg/day) allowed during the 52‐week, open‐label period. Major assessment items: total/low‐density lipoprotein (LDL)‐/high‐density lipoprotein (HDL)‐cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc).84/186 (45.2%) patients  discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL‐/HDL‐cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight . Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non‐aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients . Few changes occurred in extrapyramidal symptom scales or QTc interval.Switching to brexpiprazole is associated with a low long‐term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms. However, medication adherence is often poor among patients with schizophrenia because of attitudes to antipsychotics caused by present and past adverse events of antipsychotic drugs  and non‐aripiprazole (dopamine antagonist) antipsychotics. This grouping and classification of agents was performed based on the known actions of these agents on the dopamine D22.1This study was a post‐hoc analysis of an open‐label, long‐term study of brexpiprazole administration in Japanese outpatients with schizophrenia  or a dopamine antagonist (non‐aripiprazole), including olanzapine, quetiapine, risperidone, paliperidone, blonanserin, and perospirone. In patients who had received more than one antipsychotic concomitantly, the main antipsychotic was defined as that with the highest chlorpromazine equivalent dose of antipsychotics 30 days before consent was obtained.During the 4‐week switching period, patients were switched from their prior antipsychotic therapy to brexpiprazole 2 mg/day using an add‐on and taper‐off method. Specifically, brexpiprazole 1 mg/day was added to the previous antipsychotic regimen and the dose was increased to 2 mg/day after 2 to 3 weeks. The previous antipsychotic(s) were reduced from 2 weeks and discontinued after 4 weeks. During the subsequent 52‐week, open‐label period, patients were started at a dose of brexpiprazole 2 mg/day, and the dose was titrated, if necessary, within the range of 1 to 4 mg/day depending on Clinical Global Impression‐Improvement (CGI‐I) or tolerability issues.2.3Major assessment items included in this analysis were related to safety and consisted of metabolic parameters, including cholesterol levels ‐cholesterol, high‐density lipoprotein (HDL)‐cholesterol, triglycerides), and blood glucose levels; body weight; and serum prolactin levels. In addition, the following assessments were included for secondary evaluation: efficacy, as assessed by the Positive and Negative Syndrome Scale (PANSS) and the CGI‐Severity (CGI‐S); treatment emergent adverse events (TEAEs); extrapyramidal symptom rating scales, including the Abnormal Involuntary Movement Scale (AIMS), Barns Akathisia Rating Scale (BARS), and Drug‐induced Extrapyramidal Symptoms Scale (DIEPSS); and the corrected QT interval (QTc).2.42 receptor. In addition, results for patients treated with non‐aripiprazole antipsychotics were further divided into those who had previously received risperidone or paliperidone  and those who had previously received olanzapine or quetiapine  was shown at baseline, Week 4, Week 8, Week 28, and Week 56. Overall, the change in the mean value of each item was calculated using observed cases. It should be noted that no formal statistical tests were carried out and only descriptive statistics were performed.Descriptive statistics related to mean change in quantity and frequency of values or patient numbers, respectively, were tabulated for patients who received brexpiprazole for 56 weeks (switching and open‐label periods) and results were divided into those who had previously received aripiprazole or non‐aripiprazole antipsychotics. This main classification was based on the action of aripiprazole and non‐aripiprazole antipsychotics on the dopamine D33.1n = 14), protocol deviation (n = 6), and antipsychotics not taken 30 days before the date of consent (n = 2), thus leaving a total analysis population of 186 patients for this post‐hoc analysis.Of a total of 250 de novo patients screened for eligibility for the open‐label study, 42 patients failed screening such that 208 patients were initially enrolled at the start of the 4‐week switching period and received brexpiprazole. Of these 208 treated patients, 22 patients were excluded due to pretreatment antipsychotics being a typical antipsychotic  patients discontinued treatment, including 27 of 82 (32.9%) patients in the aripiprazole group and 57 of 104 (54.8%) patients in the nonaripiprazole group. The most common reasons for discontinuation were withdrawal of consent  and adverse events . Exacerbation of schizophrenia was the most common adverse event that led to discontinuation . Overall, the mean daily dose of brexpiprazole at 56 weeks was 3.12 mg .Demographic and baseline clinical characteristics of enrolled patients treated with brexpiprazole during the switching phase are shown in Table 3.2In terms of metabolic parameters, mean changes in total cholesterol, triglycerides, LDL‐cholesterol, HDL‐cholesterol and glucose levels from baseline to Week 56 were small in both aripiprazole and nonaripiprazole groups Table  and variWith regard to body weight, both groups showed slight increases in mean (SD) body weight over 56 weeks of 0.4 (4.6) kg in the nonaripiprazole group and 1.1 (4.4) kg in the aripiprazole group Table . Mean we2  than in those with BMI ≥30 kg/m2 .The mean changes in body weight from baseline to Week 56 by BMI at baseline is shown in Figure At baseline, prolactin levels were higher in the nonaripiprazole group than in the aripiprazole group. The mean change in prolactin levels was slightly increased in the aripiprazole group but decreased in the nonaripiprazole group in female and males Table . Table S3.3n = 30), schizophrenia , headache , akathisia , somnolence  and diarrhea , whereas the most common TEAEs in the nonaripiprazole group were schizophrenia , nasopharyngitis,  and insomnia . Serious TEAE occurred in 9.8% (n = 8) and 14.4% (n = 15) in the aripiprazole and nonaripiprazole groups, respectively, with almost all serious events being the emergence of schizophrenia symptoms . There were no deaths recorded during the study.TEAEs occurred in 161 of 186 (86.6%) patients overall, 69 of 82 (84.1%) patients in the aripiprazole group, and 92 of 104 (88.5%) patients in the nonaripiprazole group. The most common TEAEs (≥10% of patients) in the aripiprazole group were nasopharyngitis  and −12.1 (13.9) in the nonaripiprazole group (n = 47) with similar relative decreases from baseline levels in both groups. Changes in the PANSS positive, negative, and general psychopathology subscale scores showed comparable trends . Similarly, the mean (SD) change in CGI‐S score was −0.3 (0.7) in the aripiprazole group (n = 55) and −0.4 (0.7) in the nonaripiprazole group (n = 47).In terms of changes in psychiatric symptoms, mean changes in PANSS total and CGI‐S scores showed similar small decreases from baseline to Week 56 in both the aripiprazole and nonaripiprazole groups. Specifically, the mean (SD) change in PANSS total score was −8.4 (12.6) in the aripiprazole group  than in the group that received a nonaripiprazole antipsychotic (54.8%). Adverse events have been reported to be associated with discontinuation of treatment  were low, which also reduces the confidence and generalizability surrounding these results. Despite these limitations, a key strength of this analysis is that it was drawn from a high‐quality data set.In conclusion, the present demonstrated that switching to brexpiprazole was associated with a low risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and changes in QTc interval in the long‐term treatment. In addition, brexpiprazole was associated with minimal change in psychiatric symptoms. Brexpiprazole may be considered as a treatment option if there are safety or tolerability issues, especially those related to metabolic abnormalities or hyperprolactinemia, with current antipsychotic therapy.Jun Ishigooka has received research support or speakers' honoraria from, or has served as a consultant to Novartis, Otsuka Pharmaceutical Co., Ltd, Sumitomo Dainippon Pharma, Eli Lilly Japan, and Takeda Pharmaceutical Co., Ltd. Ken Inada has received speaker's honoraria from Eisai, Eli Lilly Japan, Janssen, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida, MSD, Novartis, Otsuka Pharmaceutical Co., Ltd., Shionogi, Sumitomo Dainippon Pharma, and Yoshitomiyakuhin Corporation, and research grants from the Japan Agency for Medical Research and Development (AMED), Ministry of Health, Labor and Welfare, Mitsubishi Tanabe Pharma, MSD, and National Center of Neurology and Psychiatry (NCNP). Kazunari Niidome, Kazuo Aoki, Yoshitsugu Kojima, Shuichi Iwashita and Sakiko Yamada are employees of Otsuka Pharmaceutical Co., Ltd.Jun Ishigooka advised on the study design and interpretation of the data. Ken Inada contributed to the conception and interpretation of the study. Shuichi Iwashita designed the study, wrote the protocol, supervised the data acquisition and monitoring activity, and contributed to interpretation of the data. Kazunari Niidome wrote the outline of the manuscript. Kazuo Aoki, Yoshitsugu Kojima, and Sakiko Yamada contributed to the study design and interpretation. All authors contributed to and approved the final manuscript.Supplementary MaterialClick here for additional data file.


Humulus pollen is an important cause of allergic asthma in East Asia. There have been some murine models for Humulus pollen allergy established by intraperitoneal (IP) sensitization and nasal drip stimulation, but they were not comprehensive enough. Here, we used atomized inhalation for challenge and compared the subcutaneous (SC) and IP sensitization routes to determine the optimal method to establish a model of asthma induced by Humulus pollen. Subsequently, we tried to develop a rapid subcutaneous immunotherapy (SCIT) model for Humulus allergy.Humulus pollen extract to induce asthma. To compare the two sensitization methods, airway hyperresponsiveness (AHR), inflammatory cell infiltration, allergen‐specific serum immunoglobulin (Ig)E (sIgE) levels, cytokine levels, and lung histopathology were assessed. The effects of SCIT (once every other day for 16 days) on airway inflammation, AHR, sIgE, and allergen‐specific serum IgG2a (sIgG2a) levels were evaluated by using the model established in this study.BALB/c Mice were sensitized through the SC or IP route, with respective reference to previously established sensitization methods and allergen dosing, and challenged with nebulized Although mice sensitized by the SC or IP routes both showed AHR and airway inflammation, the SC route elicited significantly higher levels of sIgE, eosinophil inflammation, and T helper type 2 cytokines, compared with the IP route. SCIT in the treatment group significantly reduced the titers of sIgE, enhanced the titers of sIgG2a, and effectively alleviated pulmonary inflammation and AHR, compared with the vehicle group.Humulus pollen allergy that recapitulates the characteristics of clinical allergic asthma. Short‐term SCIT can significantly improve symptoms and pathophysiology in asthmatic mice.The SC route can be used to establish a murine model of  Humulus pollen allergy that recapitulates the characteristics of clinical allergic asthma. Short‐term subcutaneous immunotherapy can significantly improve symptoms and pathophysiology in asthmatic mice.The SC route can be used to establish a murine model of  AHRairway hyperresponsivenessH. scandensHumulus scandensHSEH. scandens pollen extractIgimmunoglobulinIPintraperitonealMchmethacholinePenhenhanced pauseSCsubcutaneousSCITsubcutaneous immunotherapySHSsplenocyte homogenate supernatantssIgEspecific serum immunoglobulin EsIgG2aspecific serum IgG2a1Humulus scandens  is a widespread weed in East Asia.Humulus pollen constitutes approximately 18% of total pollen during the pollination period.Humulus pollen is an important allergen in summer and autumn, second only to Artemisia pollen.H. scandens‐specific serum IgE.H. scandens pollen are reportedly more serious than those induced by Artemisia pollen, although the mechanism underlying this effect has not been elucidated.Asthma is a chronic airway disease characterized by bronchial inflammation, airway hyperreactivity, and reversible airflow limitation; it is often triggered by inhalation of allergens.H. scandens pollen extract (HSE) has been used in China for many years; this type of therapy can effectively reduce the symptom scores and medication scores of patients with rhinitis and asthma.H. scandens pollen are treated with inhaled and oral corticosteroids, despite the considerable side effects associated with long‐term use of corticosteroids.Subcutaneous immunotherapy (SCIT) with crude Humulus pollen were previously established by Ya‐li et al.H. scandens is a kind of Chinese herbal medicine with antipyretic and detoxifying effectsMurine models of allergic asthma induced by Humulus immunotherapy.In the present study, we compared the IP and SC sensitization routes, with respective reference to previously established sensitization methods and allergen dosing,22.1Female, 6–8‐week‐old BALB/c mice  were purchased from the Academy of Military Medical Sciences of China and maintained under a 12‐h light–dark cycle with free access to water and standard laboratory chow. All experimental animal procedures conformed to international standards of animal welfare and were approved by the Animal Experimentation Ethics Committee of Peking Union Medical College Hospital.2.2H. scandens pollen was purchased from Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases . HSE was prepared using the extraction method previously described for Artemisia vulgaris pollen.H. scandens pollen was defatted with acetone, extracted with 0.125 M ammonium bicarbonate (weight/volume = 1:20), dialyzed against distilled water, then aliquoted into vials  and freeze‐dried. Subsequently, freeze‐dried HSE was diluted in phosphate‐buffered saline (PBS) before use. The presence of endotoxin in the pollen and HSE was assessed using the limulus amebocyte lysate test, and the test results were qualified. The total protein concentration was determined by the Bradford method. The concentration of HSE dissolved in 200 μl PBS was 5.6 μg/μl .2.32.3.1n = 10) were sensitized via SC injection on the back of the neck with 25 μg of HSE adsorbed to alum adjuvant  in a volume of 200 μl. Mice in the SC control group  received SC injections of PBS adsorbed to alum adjuvant (200 μl). Mice in the IP sensitization group  were sensitized via IP injection—at approximately 1 cm from the intersection point of a line running between the thighs and the midline—with 300 μg of HSE adsorbed to alum adjuvant in a volume of 200 μl. Mice in the IP control group  received IP injections of PBS adsorbed to alum adjuvant (200 μl). Sensitization injections were administered at weekly intervals for 3 weeks. To induce asthma, beginning on day 21, sensitized and control mice were placed in a plastic box and challenged for 30 min daily via the airways with aerosolized 1% HSE or an equal volume of saline (control group) using a jet nebulizer , for 7 consecutive days. Airway hyperresponsiveness (AHR) to methacholine  was measured 24 h after the last challenge in all animals. On day 29, mice were anesthetized with 2% sodium pentobarbital; sera were then obtained for measurement of specific IgE levels and of IgE profiles binding to HSE. Additionally, bronchoalveolar lavage fluid (BALF) was prepared from the right lung for inflammatory cell enumeration and cytokine quantitation. Paraffin sections from the left lung were used for histological assessment. The spleen was homogenized for cytokine measurements.Forty mice were randomly divided into four groups. Two different routes and doses were used for sensitization, based on studies by Ya‐li et al.2.3.2Humulus pollen allergy was developed on the basis of the asthma model established as shown in Figure The SCIT model for 2.4AHR was assessed using a whole‐body plethysmography system (Enterprise EMKA Technologies), as described elsewhere.2.5g for 10 min at 4°C; the supernatant was then stored at −80°C until cytokines were measured. Cell pellets from BALF were resuspended in PBS; leukocytes were classified and enumerated using an automatic blood analyzer . Results were expressed as the number of each cell type per 1 ml of BALF.After mice had been anesthetized, the trachea was surgically exposed and cannulated. The left lung was processed for paraffin section analysis. The right lung was lavaged three times with a single volume of warm PBS. The BALF was centrifuged at 4002.6g for 20 min at 4°C; supernatants were stored at −80°C until cytokines were measured.Spleens were removed and promptly homogenized in 5 ml of ice‐cold radioimmunoprecipitation assay buffer with a mortar. Homogenates were centrifuged at 12,0002.7The concentrations of interleukin (IL)‐4, IL‐13, interferon (IFN)‐γ, and IL‐10 in BALF and SHS were measured by sandwich enzyme‐linked immunosorbent assay (ELISA), in accordance with the manufacturer's instructions (eBioscience Co.). Values were interpolated from standard curves using recombinant cytokines and expressed in pg/ml.2.8Allergen‐specific serum IgE levels were measured by ELISA. Briefly, wells of microtiter plates  were coated with 100 μl/well of HSE (500 μg/ml) and reference wells were coated with purified anti‐mouse IgE capture antibody (BD Biosciences Pharmingen). The next day, the plates were blocked and washed, and then 50 μl of each serum sample (diluted 1:5 in blocking buffer) was applied to sample wells. A series of eight two‐fold dilutions of purified mouse IgE (BD Biosciences Pharmingen) were used in conjunction with reference wells as standards; plates were then incubated overnight. Subsequently, they were treated with 100 μl of biotinylated monoclonal anti‐mouse IgE antibody  and horseradish peroxidase‐streptavidin  for 1 h each at 37°C. Finally, 100 μl/well of TM Blue (Cwbiotech) was applied as a substrate, and the reactions were allowed to develop at room temperature for 20 min. The plates were read at 450 nm using an ELISA plate reader . A standard curve of murine IgE was used as a reference.2.9Allergen‐specific serum IgG2a levels were measured by ELISA. Briefly, plates were coated with 100 μl of HSE (5 μg/ml) overnight at 4°C and reference wells were coated with antimouse IgG2a . After the wells had been blocked and washed, serum (diluted 1:1000) was added to HSE‐coated wells and purified IgG2a (BD Biosciences Pharmingen) was added to reference wells; the plates were incubated overnight at 4°C. Plates were subsequently washed and incubated with alkaline phosphatase‐labelled goat anti‐mouse IgG2a  for 2 h at room temperature. After plates had been washed, a solution of 4‐nitrophenyl phosphate (Roche) was added to each well. Absorbance at 450 nm was measured 1 h after the addition of substrate. A standard curve of murine IgG2a was used as a reference.2.10Mouse lungs were fixed with 10% formalin, and paraffin sections were prepared by the Histology Core at Peking Union Medical College Hospital. Hematoxylin and eosin staining was performed to examine inflammatory infiltrates; Alcian blue‐periodic acid‐Schiff staining (Sigma‐Aldrich) was performed to evaluate mucus production. To determine the severity of inflammatory cell infiltration, peribronchial and perivascular inflammatory cell infiltration was blindly evaluated using a five‐point scoring system, as previously described2.11IgE antibody binding to HSE in mouse sera was analyzed by sodium dodecyl sulfate poly‐acrylamide gel electrophoresis (SDS‐PAGE) and Western blot analysis. Briefly, 20 μg of HSE was separated by SDS‐PAGE with a NuPAGE® Novex 4%–12% Bis‐Tris precast gel (Invitrogen) under reducing conditions. After electrophoresis, proteins were transferred to a polyvinylidene difluoride membrane. The membrane was blocked with PBS containing 5% skim milk and 0.05% Tween‐20 for 2 h at room temperature, then separated into strips and incubated with the sera of sensitized or control mice (diluted 1:6) overnight at 4°C. Subsequently, polyvinylidene difluoride strips were washed with PBS containing 0.05% Tween‐20 and incubated for 2 h at room temperature with rat–anti‐mouse IgE . IgE‐binding proteins were detected using BM Chemiluminescence Blotting Substrate (Roche), in accordance with the manufacturer's instructions.2.12SE of the mean (SEM). All statistical analyses were performed using SPSS Statistics, version 19.0 (IBM Corp). Analysis of variance and Student's t‐test were used to assess differences between groups. Differences with p < .05 were regarded as statistically significant. All experiments were performed independently three times with similar results. Representative results from one of the three experiments are shown.Data are presented as mean ± 2.13All experimental animal procedures conformed to international standards of animal welfare and were approved by the Animal Experimentation Ethics Committee of Peking Union Medical College Hospital.33.1p < .01 or p < .05). These changes were accompanied by recruitment of total white blood cells and inflammatory cell subpopulations  to the airways ; elevated levels of IL‐13  and IL‐10  in the BALF; inflammatory infiltrates around bronchi; and elevated mucus production . In contrast, IL‐13  levels and IL‐10  levels in SHS, and IFN‐γ  levels in both BALF and SHS, did not show any clear changes in HSE‐sensitized mice, compared with the respective control groups.Compared with the respective control groups, mice sensitized with HSE by either the IP or SC routes both developed severe AHR to Mch, characterized by significantly greater Penh values at 6.25, 12.5, 25 and 50 mg/ml of Mch inhalation ; higher numbers  and percentages  of BALF eosinophils; and higher production of IL‐4 in BALF  and SHS . However, these characteristics were not observed in the IP.HSE group, compared with the IP.PBS group ; numbers  and percentages  of BALF eosinophils; and production of IL‐4 in BALF  and SHS  were all significantly higher in the SC.HSE group than in the IP.HSE group.Notably, HSE‐specific serum IgE levels Figure , p < .01Futhermore, the protein profile of HSE (determined by SDS‐PAGE) is shown in Figure 3.2p < .05 or p < .01). It also reduced the infiltration of white blood cells , eosinophils , and lymphocytes , as well as the percentage of eosinophils  in BALF; inhibited HSE‐specific IgE production  and enhanced HSE‐specific IgG2a production ; reduced IL‐4 levels in BALF  and SHS ; enhanced IFN‐γ levels in BALF  and SHS , and reduced inflammatory infiltrates around the bronchi and diminished mucus production. Moreover, SCIT significantly reduced IL‐13 levels in BALF  and IL‐10 levels in SHS . Notably, SCIT did not significantly reduce allergen‐induced neutrophil accumulation in BALF .Compared with the vehicle group, SCIT with HSE in the treatment group led to significant reduction of Penh values at 12.5, 25, and 50 mg/ml of Mch inhalation . The recruitment of total white blood cells and inflammatory cell subpopulations to the airways ; percentages of BALF eosinophils ; inflammatory infiltrates around bronchi, and mucus production  were all significantly higher in the treatment group than in the control group. Besides, compared with the control group, SCIT with HSE in the treatment group enhanced HSE‐specific IgE production  and HSE‐specific IgG2a production ; enhanced IL‐4 levels  and IL‐13 levels  in BALF and IL‐10 levels in SHS , but did not affect IFN‐γ levels in BALF and SHS .Compared with the control group, the mice in the treatment group had larger Penh values. However, they only showed significantly greater Penh values at 25 mg/ml of Mch inhalation Figure , p < .05n Figure , p < .014Humulus pollen is an important allergen that causes asthma in East Asia. In this study, we showed that, compared with IP sensitization, SC sensitization provides a murine model that better recapitulates the typical clinical characteristics of allergic asthma. Using this model, we successfully developed a rapid SCIT model for HSE‐induced asthma. This SCIT model elucidated the mechanism of desensitization treatment, and provided a rationale for the use of HSE in clinical SCIT.Compared with animals in the IP.HSE group, animals in the SC.HSE group showed significantly higher levels of allergen‐specific IgE and significantly higher quantity and proportion of eosinophils in BALF. These findings are consistent with the typical characteristics of allergic asthma patients.Allergic asthma is characterized by elevated expression of Th2 cytokines  and reduced expression of Th1 cytokines .The SC and IP sensitization routes may produce different immune responses because of the presence of different local antigen‐presenting cell populations at the site of antigen contact. In the skin, dendritic cells, which vary in quantity and phenotype, are reportedly found in atopic individuals in a manner that favors type 2 immune responses.H. scandens pollen among Chinese individuals; we also identified the complete amino acid sequence of this protein (GenBank: ADB97919.1). Except for this 10 kDa component, Park et al.Humulus pollen extract were bound to IgE, among sera from more than 50% of the patients. Sun et al.Humulus pollen. The immunoblotting experiments in the present study showed that the IgE antibodies of sensitized mice were mainly bound to relatively large fragments (48–100 kDa), and rarely bound to the 10‐kDa band. This finding is consistent with the study work of U.S. Eitzer et al.Our group previously found that the approximately 10 kDa component is a major allergen in Clinically, SCIT typically requires SC injection twice per week for 3–5 years. Considering differences in the life cycles of mice and humans, we used a rapid desensitization treatment method (eight treatments every other day) and effectively alleviated pulmonary inflammation and AHR in asthmatic mice. Our results were similar to those of a study in which mice received weekly treatments for a continuous 8‐week period.Despite the short treatment duration, allergen‐specific IgE was significantly lower in the treatment group than in the vehicle group; anti‐IgE therapy has been effective for some allergic diseases.SCIT corrected the imbalance of Th1/Th2 immune responses in asthmatic mice and converted the immune response to a Th1 type. This may be the underlying mechanism of desensitization treatment. IL‐10 is a pleiotropic cytokine that has both pro‐ and anti‐inflammatory effects during immune responses.Notably, pulmonary inflammation and AHR to 25 mg/ml of Mch inhalation in mice of the treatment group were more serious than that of the control group, which suggests that although SCIT significantly improved the symptoms of asthmatic mice, it did not completely restore their condition to the level of healthy mice.There were some limitations in this study. Changes in the systemic immune response were examined by analysis of SHS because of limited laboratory conditions; the sensitivity of this method is relatively low, we will try to coculture spleen cells with specific allergens in vitro to observe changes in the systemic immune response in the further studies.Humulus pollen allergy through SC sensitization and atomization challenge. Using this model, short‐term and rapid SCIT improved symptoms and pathophysiology in asthmatic mice. The murine models of asthma and SCIT for Humulus pollen allergy developed in this study may be valuable tools for studying the mechanisms of asthma and SCIT for airborne allergens, as well as for designing more efficacious therapies for allergic asthma.In conclusion, we successfully developed a better murine asthma model for Guang P. Xi and Jia Yin designed the study. Guang P. Xi and Qian Zhang performed the experiments. Guang Peng Xi and Jia Yin wrote the paper. All authors edited the paper and provided substantial feedback.


Racial and ethnic disparities are well‐documented in cancer outcomes such as disease progression and survival, but less is known regarding potential disparities in symptom burden.The goal of this retrospective study was to examine differences in symptom burden by race and ethnicity in a large sample of cancer patients. We hypothesized that racial and ethnic minority patients would report greater symptom burden than non‐Hispanic and White patients.p = .016) and were more likely to report severe symptoms (p < .001) than self‐identified White patients. Patients with “other” race were also more likely to report severe symptoms than White patients (p = .032), but reported similar total symptom burden (p = .315). Asian and Hispanic patients did not differ from White or non‐Hispanic patients on symptom burden (ps > .05).A total of 5798 cancer patients completed the Edmonton Symptom Assessment Scale—revised (ESAS‐r‐CSS) at least once as part of clinical care. Two indicators of symptom burden were evaluated: (1) total ESAS‐r‐CSS score  and (2) number of severe symptoms . For patients completing the ESAS‐r‐CSS on multiple occasions, the highest score for each indicator was used. Zero‐inflated negative binomial regression analyses were conducted, adjusting for other sociodemographic and clinical characteristics. Symptomology varied across race. Patients who self‐identified as Black reported higher symptom burden (This study describes racial disparities in patient‐reported symptom burden during routine oncology care, primarily observed in Black patients. Clinic‐based electronic symptom monitoring may be useful to detect high symptom burden, particularly in patients who self‐identify their race as Black or other. Future research is needed to reduce symptom burden in racially diverse cancer populations. For example, Black or Hispanic women with breast cancer are more likely to report pain, skin irritations, and limitations in physical function when compared to those who are non‐Hispanic and White.Patient‐reported outcomes (PROs) offer distinct information from provider‐assessed adverse event reporting. For example, in a 2010 study of 1833 patient‐health care provider dyads, providers significantly underestimated the presence of severe pain, fatigue, generalized weakness, anorexia, depression, constipation, poor sleep, dyspnea, nausea, vomiting, and diarrhea.The goal of the current, retrospective study was to examine potential racial and ethnic disparities in patient‐reported symptom burden in adult oncology patients, controlling for other sociodemographic and clinical characteristics. It was hypothesized that patients self‐identifying as a member of a racial or ethnic minority group  would report higher total symptom burden and more severe symptoms compared to non‐Hispanic and White patients.22.1Patients presenting to the Moffitt Radiation Oncology or Supportive Care Medicine clinics completed the Edmonton Symptom Assessment Scale—revised (ESAS‐r‐CSS)2.2Demographic and clinical data: Demographic and clinical characteristics were extracted from Moffitt internal databases. Variables included date of birth, sex, self‐identified race, self‐identified ethnicity, marital status, primary cancer site, and cancer status (active disease vs. no active disease). Race was categorized as White, Black, Asian, and other. The “other” category comprised a combination of racial groups with small sample sizes . Ethnicity was categorized as Hispanic and non‐Hispanic.Symptom burden: A modified version of the ESAS‐r‐CSS2.3Because the combined effect of several mild or moderate symptoms may be as burdensome as a severe symptom, symptom burden was assessed by two derived variables: (1) ratings of all symptoms were summed to provide a total symptom burden score and (2) the number of symptoms rated as severe was summed to separately to capture severe symptomatology. For patients with data from multiple clinic visits, the highest score for each variable  was used. Scores for total symptom burden and number of severe symptoms could have been reported on the same clinic visit or different clinic visits. For example, a patient could have their highest total symptom burden recorded at a different time than their highest count of severe symptoms.Patients' demographic and clinical characteristics were summarized using descriptive statistics, and the distributions of the outcome variables were inspected visually via histograms (not shown). Zero‐inflated negative binomial (ZINB) models were conducted separately for both outcome variables, controlling for sociodemographic and clinical characteristics. ZINB models are appropriate for modeling count variables with high numbers of zeros and over‐dispersion. In this case, ZINB analyses account for the relatively high numbers of patients reporting no symptom burden and the fact that the average and variance differed for each symptom burden measure. ZINB analyses consist of two components, a zero‐inflation component to predict patients that have zero burden, and a negative binomial model to measure the burden score for patients not already predicted to have zero burden. First, multivariable logistic regression models were fit to identify relevant variables for inclusion in the ZINB models as predictors of zero symptom burden. Variable selection for the logistic regression models was evaluated by comparing the results of backward selection  and best subset selection.33.1Sociodemographic and clinical characteristics of the 5798 patients are shown in Table Patients completed a total of 19 670 individual surveys. Fewer than 3% of patients were missing any ESAS information. The median and range of surveys contributed by each patient was 2 (1–29). The highest overall symptom burden and highest severe symptom burden were retained for each of the 5798 patients. Patients' average worst overall symptom burden score was 31.2 (SD = 24.5) out of a possible score of 120. Responses ranged from 0 to 116, with a median of 24. An overall worst symptom burden of zero was reported by 356 patients (6.2%). Participants' average highest number of severe symptoms was 2.0 (SD = 2.5) out of a possible score of 12. Responses ranged from no severe symptoms to all 12 symptoms rated as severe, with a median of 1. No severe symptoms were reported by 2361 patients (42.0%).3.2The first step of the ZINB models was to identify predictors of zero symptom burden using multivariable logistic regression models. Results of the backward selection logistic regression analysis indicated that being male, not having active disease, and location of the primary cancer site were variables associated with higher odds of having a symptom burden of zero Table . This chp‐values, variables selected into the final negative binomial model were age, gender, primary cancer site, and cancer disease status. Results of this model are shown in Tables p < .0001). In the zero‐inflation component (Table p = .017) for patients predicted to have nonzero total burden. Specifically, the expected score for Black patients predicted to have nonzero burden is 11% higher than the expected score for Whites with all other variables held equal. The expected total score for Asian patients with nonzero burden is 15% lower than the corresponding expected score for Whites. Patients with “other” race reported total symptom burden scores reasonably similar to White patients . There were no meaningful differences in overall symptom burden between Hispanic and non‐Hispanic patients (p = .92). Younger age, having active disease, primary cancer site, and female gender were associated with higher reported symptom burden.The second step was to fit the complete ZINB models, holding the zero‐inflation predictors (gender and active cancer disease status) fixed based on the modeling described in the previous paragraph. In addition to race and ethnicity, which were included in the negative binomial component of the model regardless of their effect sizes and nt Table , consistnt Table  for pati3.3p = .0364), male sex (p = . 0311), absence of active disease (p < .0001), and primary cancer site (p < .0001) were associated with the probability of no severe symptoms .ZINB models were then created to examine associations among severe symptoms, race, ethnicity, and other important patient factors chosen by backward selection. Results of this model are shown in Tables p = .0002). Specifically, the expected number of severe symptoms for patients predicted to have at least one severe symptom was 24% higher for Blacks, 21% lower for Asian patients, and 20% higher for those of “other” race compared to White patients. No statistically detectable differences in severe symptoms were observed between Hispanic and non‐Hispanic patients (p = .43). Females predicted to have nonzero severe burden reported 20% higher expected counts of severe symptoms than males (p < .0001). Patients without active disease reported 20% lower expected counts of severe symptoms than did patients with active disease (p < .0001).The negative binomial component of the ZINB model facilitates an analysis of the expected number of severe symptoms for patients predicted to have at least one severe symptom. In addition to race and ethnicity, the final negative binomial model included age, sex, primary cancer site, and cancer disease status. Results of the ZINB regression model indicated that race was associated with the count of severe symptoms  would report higher total symptom burden and more severe symptoms compared to non‐Hispanic and White patients. Our hypotheses were partially supported, as analyses revealed disparities in higher overall symptom burden and more severe symptoms reported by Black patients as compared to their White counterparts. These results suggest that there is an unmet need for symptom management in patients who self‐identify as Black, and that supportive care interventions should be explored in order to reduce the high level of severe symptoms and impact of symptom burden in this patient group.We anticipated that Hispanic patients would report worse symptom burden and more severe symptoms than non‐Hispanic patients, in part due to previous findings that Hispanic cancer patients are at risk of higher symptom burden,The multilevel contextual modelRegardless of etiology, one intervention that may address racial disparities in symptom burden is implementation of PROs for all patients as part of routine clinical care. Implementation of electronic clinic‐based PROs results in more patient–clinician communication, better clinician awareness of patient symptoms, better treatment decision making, improved healthcare utilization, increased patient satisfaction, improved quality of life, and better clinical outcomes.Strengths of this study include a large, heterogeneous sample of cancer patients; multiple measures of symptomatology ; routine collection of data as part of clinical care that includes all patients; and an integrated electronic medical record system that allowed ESAS‐r‐CSS assessments to be linked with sociodemographic and clinical characteristics. Moreover, there were relatively large numbers of Black and Hispanic participants (400+ each) included in the analysis. Limitations include heterogeneous times of assessment relative to disease and treatment events and lack of data on cancer treatments received. Analyses presented in this paper use the presence of active disease as a control variable. Given the heterogeneity of the cancer types included, differing staging systems , and variability in staging documentation , we were unable to include a standardized staging variable in our analyses. Future studies focused on specific disease types should explore the role of disease stage in patient‐reported symptom burden and potential racial disparities. Additionally, a number of potential sociodemographic variables were unavailable in the current dataset, such as data about the patient's neighborhood, community/family support , and other social determinants of health. Future research should build on this study to examine the impact of other sociodemographic factors that may influence disparities in symptom burden. Nevertheless, the goal of the current study was to explore the presence of racial and ethnic differences in symptoms among oncology patients in clinical practice, which provides a basis for continued research promoting a comprehensive understanding of racial disparities in patient‐reported symptoms. Additionally, symptom data were not collected from patients presenting to clinics other than Radiation Oncology or Supportive Care Medicine.Despite limitations, this study contributes to the growing body of literature describing racial disparities in cancer outcomes, including patient‐reported symptom burden during routine oncology care. Results offer support for the use of clinic‐based electronic symptom monitoring to identify high symptom burden in oncology populations and provide a foundation for continued work evaluating clinical and social contributors to racial disparities in patient‐reported symptomatology. Future research is needed to determine whether use of electronic, clinic‐based PROs improves patient/physician communication, cues providers to address potentially unmet supportive care needs, and results in reduced disparities in symptom burden.This study was supported by the U.S. National Cancer Institute grants R25 CA090314 (PI: Brandon), K01 CA211789 , R01 CA214647 (PI: Jim), R01 CA219389 (PI: Jim), P30 CA076292 (PI: Cleveland) and the Taichung Veterans General Hospital and Veterans Affairs Council, Taiwan, R.O.C. (No. 2018Y‐77). Additional support was provided by the following shared resources at the H. Lee Moffitt Cancer Center: Biostatistics and Bioinformatics; Collaborative Data Services; and Participant Research, Interventions, and Measurement (PRISM).B.D.G.: Personal fees from SureMed Compliance and Elly Health, Inc. H.S.L.J.: Consultant with Red‐Hill Biopharma, Merck, and Janssen Scientific Affairs.The study was approved by the Advarra Institutional Review Board. Data were collected as part of routine clinical care.Conceptualization, H.B., P.H.C., A.H., B.G., H.J.; Methodology, H.B., N.B., J.M.Z., B.G.; Formal analysis, H.B., N.B., J.M.Z.; Resources, P.J., H.J.; Writing‐original draft, H.B.; Writing‐review & editing, H.B., P.H.C., N.B., J.M.Z., A.H., B.G., P.J., H.J.; Visualization, H.B., N.B., J.M.Z.; Supervision, P.J., H.J.; Funding acquisition, H.J.; Data curation, H.B., P.H.C., N.B., J.M.Z., A.H.; Validation, N.B., J.M.Z.; Project administration, P.J.TABLE S1 Multivariable logistic regression of Sum‐MaxClick here for additional data file.TABLE S2 Multivariable logistic regression of Severe‐MaxClick here for additional data file.


Spin‐orbit torque (SOT) opens an efficient and versatile avenue for the electrical manipulation of magnetization in spintronic devices. The enhancement of SOT efficiency and reduction of power consumption are key points for the implementation of high‐performance SOT devices, which strongly rely on the spin‐orbit coupling (SOC) strength and magnetic properties of ferromagnetic/non‐magnetic heterostructures. Recently, van der Waals‐layered materials have shown appealing properties for use in efficient SOT applications. On the one hand, transition‐metal dichalcogenides, topological insulators, and graphene‐based heterostructures possess appreciable SOC strength. This feature can efficiently converse the charge current into spin current and result in large SOT. On the other hand, the newly discovered layered magnetic materials provide ultra‐thin and gate‐tunable ferromagnetic candidates for high‐performance SOT devices. In this review, the latest advancements of SOT research in various layered materials are summarized. First, a brief introduction of SOT is given. Second, SOT studies of various layered materials and heterostructures are summarized. Subsequently, progresses on SOT‐induced magnetization switching are presented. Finally, current challenges and prospects for future development are suggested. Van der Waals‐layered materials and heterostructures show appealing advantages in improving spin‐orbit torque (SOT) efficiency. The recent SOT researches in various 2D materials are outlined. The current challenges and the future directions are also discussed. Van der Waals‐layered materials and heterostructures are expected to provide unprecedented opportunities in the fields of spintronics. The power dissipation and operation speed of these spin‐based devices hinge on effective methods of controlling their magnetic states. However, traditional methods of manipulating magnetic states by a magnetic field is unpractical for the realization of high‐performance devices. To address this challenge, electrical current‐induced torques have been exploited to manipulate magnetization over the last decades. A remarkable progress is the application of the spin‐transfer torque (STT) effect, which is a phenomenon in which electric current is spin‐polarized by a ferromagnetic layer and the spin‐polarized electrons affect the magnetization of another ferromagnetic layer. The utilization of STT conveniently facilitates the control of magnetization by electric current, and it has been used to fabricate commercial STT‐MRAMs. However, despite the promising merits of STT, the coupling of the read and write paths has a detrimental impact on device stability and performance.The discoveries of giant magnetoresistance and tunnel magnetoresistance (TMR) have significantly improved the storage density of hard disk drives in the past decades. A typical SOT structure comprises a ferromagnetic (FM) layer and a normal metal (NM) layer. As charge current flows in the NM/FM heterostructure, the shunted part of the NM layer is conversed to spin‐polarized current owing to the bulk or interfacial spin‐orbit interaction. The spin current is then accumulated at the NM/FM interface and diffused into the adjacent FM layer. As a result, the spin‐polarized electrons exert a torque on the local magnetic moment by transferring their angular momentum. The fundamental origin of SOT is the strong spin‐orbit coupling (SOC) of the NM layer. SOT has been employed for the electrical manipulation of magnetization, such as, fast magnetization switching, high‐speed domain wall motion, and spin‐wave excitation. Compared with STT devices, SOT devices have a number of advantages, including higher stability, faster response, and lower energy consumption.Meanwhile, another spin‐torque mechanism, current‐induced spin‐orbit torque (SOT), has recently emerged as a promising technique for efficient magnetization manipulation. However, their SOT efficiencies, characterized by the spin Hall angle and the Rashba parameter, are usually limited (less than 1). Thus, the SOT efficiency is enhanced by engineering the heterostructure or using novel materials with strong SOC. As an alternative, 2D van der Waals (vdW)‐layered materials have recently been proposed as building blocks for SOT devices. Among the diverse vdW materials, transition metal dichalcogenides (TMDs) are promising candidates owing to their non‐trivial energy band structure, tunable conductivity, and strong SOC. TMDs exhibit several advantages in SOT applications. For instance, the SOT can be tuned via designing a crystalline symmetry and via the electric field. Moreover, the SOT efficiencies of TMDs are larger than those of HMs, and such high SOT efficiencies can be scaled to the atomic layer limit. Additionally, semimetals such as WTe2 and PtTe2 have topological phases and strong SOCs with high electrical conductivities.For the efficient generation of spin current and magnetization switching, it is essential to enhance the SOC strength of the NM layer. A large number of FM and NM materials have been explored to construct FM/NM heterostructures. 5d heavy metals (HM), such as Pt, Ta, and W, were commonly used as spin sources in past studies because of their strong SOC. This large SOT efficiency allows for low‐power magnetization manipulation. In addition to TMDs and TIs, graphene‐based hybrid heterostructures have recently been proposed as suitable spin sources for SOT applications. Pristine graphene has been extensively studied as a spin transport channel owing to its long spin diffuse length and high electron mobility. Despite its considerably weak SOC, several studies have revealed that the enhancement of SOC in graphene is feasible via the extrinsic effect. Moreover, the combination of graphene with other materials having strong SOC can give rise to graphene‐based heterostructures with strong SOC. Such enhanced SOC result in appreciable charge‐spin interconversions, and they can be further tuned by an electric field. Most importantly, in graphene‐based heterostructures, high electron mobility can be maintained while enhancing the SOC.Another promising candidate is the family of topological insulators (TIs). Owing to their topologically non‐trivial surface states, TIs possess extremely large SOT efficiencies, which are several orders of magnitude larger than those of conventional HMs. providing a perfect paradigm for the investigation of magnetism in the 2D limit. These vdW magnetic crystals offer unprecedented opportunities for SOT devices. Particularly, ferromagnetic vdW materials such as Cr2Ge2Te6, CrI3, and Fe3GeTe2 possess intrinsic perpendicular magnetic anisotropy (PMA). Their robust PMA can be preserved down to the monolayer limit, which makes their magnetic properties very sensitive to external stimuli. These features make them appealing for ultra‐thin magnetic layers in SOT devices.Very recently, atomically thin vdW magnetic crystals have been used to further enrich the family of vdW materials, in which nonmagnetic vdW materials, such as, TMDs, TIs, and graphene, are mainly used as the spin current source or spin channel. In addition, magnetic vdW materials appear as promising candidates in SOT devices. Herein, we aim to provide an overview of state‐of‐the‐art progress of SOT in vdW materials and their heterostructures. First, we briefly discuss the generation of SOT. Second, we summarize SOT and charge–spin interconversion studies in non‐magnetic vdW materials and heterostructures. Third, we discuss magnetic vdW materials and their gate‐tunable magnetic properties, focusing on their SOT application. Afterward, we present SOT switching in various vdW heterostructures with low critical current density. Finally, we discuss current challenges and future perspectives for this emerging field.As research interests in SOT devices based on vdW materials have increased, several excellent reviews have summarized recent work of SOT in vdW materials,2 SHE is a bulk SOC effect, whereas REE is an interfacial SOC effect. As shown in Figure Js∝(ћ/2e)θSHJe × σ, where Js is the spin current density, Je is the charge current density, σ is the spin polarization direction, ћ is the reduced Planck's constant, e is the charge of an electron, and θSH is the spin Hall angle.Despite the controversy of the microscopic origin of SOT, it is generally agreed that SOT arises from spin accumulation at the NM/FM interface. Generally, spin accumulation comes from two different SOC phenomena, namely spin Hall effect (SHE) and Rashba–Edelstein effect (REE).E with a direction perpendicular to the film plane is generated at the interface/surface because of the spatial inversion symmetry breaking ‐induced effective magnetic field is called Rashba field HR. As a result, spin accumulation is induced in the direction perpendicular to both the directions of the charge current Je and out‐of‐plane electrical field E(E = Ezz). This spin current density is described as Js∝(αR/ћe)z × Je, where αR is the Rashba parameter and z is the out‐of‐plane unit vector.Compared to SHE, REE usually occurs at the interface or surface of a structure without spatial inversion symmetry. In this case, an internal electrical field g Figure . When any‐axis, the spin current is polarized along the x‐axis  is the longitudinal (Slonczewski‐like) torque , TFL = τFLm × ξ is the transverse torque , ξ is the polarization vector, τDL and τFL are the magnitudes of the damping‐like and field‐like torques, respectively. Both SHE and REE can contribute τDL and τFL. Distinguishing the contribution of SHE and REE to τDL and τFL is important to understand the underneath mechanism of SOT. The NM thickness dependence of SOT is a powerful tool to clarify the contribution from SHE and REE. Because in the simple model the interfacial Rashba effect is expected to be independent on the NM thickness, while the bulk SHE should scale with the NM thickness. At present, the exact mechanism of bulk and interfacial effects to τDL and τFL still requires a better understanding. However, it can be agreed that the τDL in most systems is strongly associated with SHE, while the important contribution of REE to the origin of the τFL is also well understood.Typically, in an NM/FM heterostructure, when the charge current flows along the in‐plane of the film, the spin accumulation is in‐plane‐polarized. In the case of current along the s Figure . As the σsh is used here. The relationship between the spin Hall angle and spin conductivity is θSH = (2e/ћ) σsh/σe, where σe is electrical conductivity.To obtain large spin current density and strong SOT, materials with large spin Hall angles and Rashba parameters, such as Pt and Ta, are preferred for FM/NM heterostructures. In addition to SHE and REE, topologically non‐trivial surface state has recently been found to significantly contribute to the spin current. Moreover, unconventional SOT has also been observed in some TMDs. For comparison, spin conductivity χSOT. It should be noted that the SOT efficiency is different from the spin Hall angle and the charge‐spin conversion efficiency. In SHE induced SOT picture, if the spin‐memory loss is negligible or the interface is transparent, the SOT efficiency is equal to the spin Hall angle. The relationship of the SOT efficiency and the spin Hall angle can be expressed as χSOT= TintθSH, where Tint is the interface spin transparency. In this review, for simplicity, we will use SOT efficiency to refer to the spin Hall angle and charge–spin conversion efficiency, unless otherwise specified.Spin Hall angle and Rashba parameter characterize the charge‐spin conversion efficiency, and they strongly depend on the SOC strengths in the NM layer and NM/FM interface. They are sometimes also referred to as charge–spin conversion efficiency or SOT efficiency 33.12 , are regarded as intrinsically strong SOC materials that can serve as highly efficient spin sources. Their high SOC strength has two important origins. First, the heavy metal element, such as Mo and W, can generate a strong SOC. Second, Rashba‐type or Zeeman‐type spin splitting can be induced at their surface owing to the inversion symmetry breaking, which gives rise to a strong SOC. These two contributions enable TMDs to have appreciable SOT efficiencies that induce high SOTs in TMDs/ferromagnetic structures.Monolayer TMDs, such as group‐VI dichalcogenides MX2 is as large as 12.7. Subsequently, current‐induced SOT was reported in a monolayer MoS2/permalloy (Py) heterostructure. Meanwhile, different SOT components can be identified and distinguished using spin‐torque‐ferromagnetic resonance (ST‐FMR) technique /CoFeB heterostructure and observed different results. They quantitatively measured the current‐induced SOT using second‐harmonic Hall (SHH) approach, and found that both the MoS2/CoFeB and WSe2/CoFeB samples exhibited a large τFL, whereas τDL was negligible, as shown in Figure τFL can be explained by REE, as τFL is much larger than τDL in this case. Furthermore, the extracted spin conductivities of MoS2 and WSe2 were 2.9 × 103 and 5.5 × 103 (ℏ/2e)(Ωm)−1, respectively, which suggest that monolayer MoS2 and WSe2 have appreciable SOT efficiencies. For the discrepancy between MoS2/CoFeB and MoS2/Py, the observed large symmetric peak possibly derives from the inverse REE induced by spin pumping rather than the SOT induced by the rf spin current. Another possible origin is that the ferromagnetic materials play a key role in the current‐induced SOT. More detailed experimental work is required to identify different contributions.Experimentally, a spin pumping measurement has shown that the spin‐charge conversion efficiency of MoS2 and WSe2, current‐induced SOT has also been investigated in a monolayer WS2/Py heterostructure using ST‐FMR, and the ST‐FMR spectra of the WS2/Py heterostructure exhibited a large symmetric peak , an additional angular dependence term sin (2φ) suggests the existence of τB apart from the contribution of the conventional SOT , this additional angular dependence vanishes and only conventional SOT is present (Ωm)−1, respectively. Moreover, the spin conductivity of the unconventional torque τB is also appreciable, with a value of 3.6 ± 0.8 × 103 (ℏ/2e)(Ωm)−1. For these three SOT components, their independency on thickness indicates the interface origin. It is worth noting that the bulk SHE also plays a key role in a much thicker WTe2. Shi et al. recently reported the dependence of SOT on thickness in a thick WTe2/Py heterostructure using ST‐FMR and magnetization switching. Both measurements showed that the SOT efficiency increased as the WTe2 thickness increased (Ωm)−1.Semimetal WTeT Figure . Once tht Figure . The fuls Figure . MacNeilp Figure , the ang2 Figure , which id Figure , suggestβ‐MoTe2 is another TMD with strong SOC and low symmetry. Similar to WTe2, in the surface symmetry of monolayer β‐MoTe2, only one mirror plane is perpendicular to the b‐axis −1, and semimetal WTe2 with σe ≈ 105 (Ωm)−1, resulting in a small effective charge current. Recently, several TMDs, such as, NbSe2, TaS2, and PtTe2, have been found to be ideal spin‐source materials owing to their high conductivity and strong SOC.Spin‐current source materials are expected to simultaneously possess high conductivity and strong SOC. Unfortunately, TMDs usually have small conductivities, such as semiconductor MoS2 is a fully metallic TMD with strong SOC and σe ≈ 6 × 105 (Ωm)−1. Using the ST‐FMR approach, conventional SOT was observed in a NbSe2/Py heterostructure (Ωm)−1. Interestingly, based on the symmetry requirements, unconventional SOT was prohibited in the heterostructure because of its highly symmetric structure. However, an unconventional in‐plane field‐like SOT with the form m × z was identified from the angular dependence −1. Furthermore, considerable SOT has been observed in TaS2/Py heterostructure using ST‐FMR and angle‐dependent planar Hall effect measurements, in which current‐induced τDL was found to dominate. This large τDL is attributed to the interplay between interfacial SOC and crystal symmetry. The spin conductivity of the TaS2/Py heterostructure was calculated as ≈14.9 × 105 (ℏ/2e)(Ωm)−1, which is comparable to that of Pd1−xPtx alloy. Meanwhile, this estimated SOT efficiency value is larger than that of β‐Ta.NbSee Figure . This un2 and TaS2, PtTe2 is a semimetal TMD that possesses room‐temperature high conductivity, σe ≈ 3.3 × 106 (Ωm)−1. Xu et al. recently studied the SOT in a PtTe2/Py heterostructure and observed that the ST‐FMR signal had a relatively large symmetric peak (Ωm)−1, which is comparable with those of Pt and Bi2Se3 at room temperature. Additionally, both the SOT efficiency and spin conductivity exhibited nonmonotonic thickness dependences, as shown in Figure τFL. Thus, bulk SHE and topological surface state (TSS) may contribute to the observed SOT. However, an understanding of the exact mechanism needs further investigation.Different from the metallic NbSek Figure .[86] T Similar to TIs, these topological semimetals possess TSSs, in which strong SOC and large SOT are expected. Indeed, SOT originating from TSSs was recently revealed in a Weyl semimetal WTe2/Py heterostructure, in which both τDL and τFL were observed. The spin conductivity of the τFL was significantly enhanced at low temperature when the applied current was along the b‐axis of WTe2. The enhanced spin conductivity is interpreted by the spin‐momentum locking in the topological Fermi arc surface state. Apart from WTe2, current‐induced SOT has also been studied in other Weyl and Dirac semimetal TMDs, such as MoTe2 and PtTe2. These Weyl and Dirac semimetals show potential and interesting applications in low‐power SOT devices.Some of the aforementioned TMDs are also categorized as Weyl or Dirac semimetals.3.20.9Sb0.1, was confirmed by angle‐resolved photoemission spectroscopy. Since then, more 3D TIs with larger bulk bandgaps have been discovered, including Bi2Se3, Bi2Te3, and Sb2Te3. In these 3D TIs, the TSS results in strong coupling of the electron spin and its momentum. Therefore, the conductive electrons are highly spin‐polarized and the spin direction is locked to its momentum, which is referred to as spin‐momentum locking (Ωm)−1) is comparable to that of bilayer HM/FM heterostructures, the magnitude of τDL per unit current is much larger than that of heavy metals. Additionally, the out‐of‐plane τFL was significantly large with a spin conductivity of ≈1.5 × 105 (ℏ/2e)(Ωm)−1 . Such a large τFL cannot be explained by τh. This SOT configuration agrees with the model of SOT derived from the TSS of TIs.Motivated by these unique advantages, experimental studies began to focus on current‐induced SOT in various TI/FM heterostructures.R Figure .[30] A The two latter states could make inevitable contributions to the spin current while reducing the role of TSS at room temperature. More importantly, TSS is sensitive to temperature, which may result in weak SOT at higher temperatures. As shown in Figure  The τDL at low temperature was ≈10 times larger than that at room temperature 2Te3 and Cr‐doped (Bi0.5Sb0.5)2Te3 served as the spin source and magnetic layer, respectively 2Te3, which is 30 times larger than the strength of τFL 2Te3. The largest SOT efficiency has been obtained in (Bi0.5Sb0.5)2Te3, which is in excess of 400 at low temperatures. However, the reported SOT efficiencies show large discrepancies. For example, very different SOT efficiencies have been reported in Bi2Se3/FM heterostructures, such as, Bi2Se3/NiFe with 3.5, Bi2Se3/CoFeB with 0.047, and Bi2Se3/CoFeB with 18.6. This discrepancy might result from different film qualities, magnon scattering mechanisms, etc., which need further investigation.Thus far, high SOT efficiencies have been observed in various TIs, including Bi3.3 The former two approaches have a disadvantage of reducing the electronic quality of graphene. The proximity effect strategy has been proven as an efficient remedy, especially for enhancing the SOC of graphene via interfacing it with strong SOC materials. It is expected that the combination of graphene with TMDs or TI materials can induce a significant SOC in graphene while simultaneously maintaining its high electron mobility. The utilization of these hybrid heterostructures facilitates the improvement of the SOT efficiency.Although TMDs and TIs are promising spin‐source materials, their relatively low electrical conductivities remain a critical issue for achieving high SOT efficiency. The most studied 2D material, graphene, has recently been proposed to overcome this issue via hybrid engineering. Graphene possesses a much higher electron mobility than other 2D materials. In terms of spintronic application, pristine graphene also exhibits compelling features as a spin transport tunnel material owing to its weak SOC, that is, the merits of long spin lifetime and spin diffusion distance. However, the weak SOC inevitably leads to inefficient spin current generation. Fortunately, previous studies have suggested that this weak SOC can be enhanced by chemical functionalization, adatom decoration, and proximity effect with other materials.2 is suggested to be a suitable substrate for graphene because of its comparable work function and strong SOC. Meanwhile, the presence of defects in WS2 could be helpful for the creation of electronic states that overlap in energy with the electronic states of graphene. Experimentally, when bringing graphene into proximity with WS2, the SOC strength has been demonstrated to be enhanced by three orders of magnitude 2Te3 heterostructure at room temperature. They studied the SOC by spin‐galvanic effect, which describes the conversion of spin current into charge current , and VSe2, and antiferromagnets (AFMs) such as, MPX3  and CrCl3, MnBi2Te4. Experimentally, ferromagnetic vdW crystals have been employed to construct conceptual spintronic devices. For instance, FGT and CrI3 have been successfully used to assemble FGT/hBN/FGT and graphene/CrI3/graphene magnetic tunnel junctions. Their reported TMR values are in excess of 10 000%. Most importantly, some ferromagnetic vdW crystals exhibit gate‐tunable magnetic properties in the 2D limit. Such unique magnetic properties could be very helpful for improving the performance of SOT devices. In the following section, we will summarize the recent progress of gate‐tunable magnetic properties and SOT research of vdW magnetsThe newly discovered vdW magnetic crystals provide exciting choices for SOT devices. VdW magnets are expected to inherit several merits of 2D materials, such as, flexibility and susceptibility to external stimuli. Most of them possess relatively low electrical conductivities; hence, they can increase the effective current in the NM layer. Furthermore, the flat surface and free‐of‐crystal mismatch are ideal for heterostructure construction. Till date, a number of vdW magnetic crystals have been experimentally confirmed, including ferromagnets such as, Cr4.12Ge2Te6, and CrI3 are ferromagnetic insulators that reduce the current shunt in SOT devices. Moreover, they both exhibit a PMA. Down to a few layers, their magnetic properties usually depend on the layer number. For few‐layer Cr2Ge2Te6, the coercivity and saturation field are electrically tunable via ionic liquid gating , the out‐of‐plane easy axis can be tuned to the in‐plane direction via electrostatic doping , CrI3 shows more robust PMA that is down to the monolayer limit. More interestingly, few‐layer CrI3 shows an intriguing magnetic phase associated with the number of layers. Monolayer and trilayer CrI3 were demonstrated to be ferromagnetically ordered by polar magneto‐optical Kerr effect microscopy. Meanwhile, bilayer CrI3 is an interlayer antiferromagnetic coupling with zero out‐of‐plane magnetization. However, the antiferromagnetic coupling is relatively weak and can be switched to the ferromagnetic order when the external field reaches a critical value. Magnetic properties in few‐layer CrI3 can also be electrically manipulated. Both electric field and electrostatic doping can effectively control its magnetic properties, such as, spin‐flipping magnetic field, coercive force, and transition temperature Tc. In bilayer CrI3, the magnetic state can be conversed from the antiferromagnetic state to the ferromagnetic ground state by electrostatic doping without employing an external magnetic field  and CrCl3, are much more abundant. Despite the well‐known difficulty of using AFMs because they do not have magnetization, AFMs have great potential in data storage and high‐frequency terahertz device applications. A typical application is to stabilize the magnetization of the “fixed layer” in magnetic tunnel junctions or spin valves. When assembling AFMs and ferromagnets in heterostructures, exchange bias is induced via exchange coupling. Such an exchange coupling can be tuned by the gate voltage in vdW AFM/FM heterostructures. This structure is useful in realizing efficient SOT devices, for instance, providing in‐plane exchange bias for SOT switching PMA magnets. Moreover, proximity‐coupling also plays an important role in these artificial structures. In a FGT/FePS3 heterostructure, the transition temperature and coercive field of FGT can be enhanced owing to the proximity of FePS3 (Ωm)−1 at room temperature. The temperature dependence of SOT suggests that the magnetization order may have an inevitable influence on the SOT. Meanwhile, the detailed mechanism is not fully understood.In contrast to ferromagnets, AFM, such as, MPXt Figure . As showFinally, vdW magnetic materials have shown their great potential for SOT applications. Further work needs to be extended to all‐vdW material heterostructures. Combined with a variety of vdW spin current source, such as, gate‐tunable, strong SOC, and non‐trivial vdW materials, vdW magnetic materials can promote the implementation of energy‐efficient SOT devices.57–108 A cm−2. However, such high current densities are impractical for SOT applications. The utilization of vdW‐layered materials for the construction of NM/FM heterostructures is expected to reduce the critical current of SOT switching.It is of great importance to reduce the critical current density of SOT‐induced magnetization switching  for application in SOT devices. In conventional HM/FM structures, the critical current density required for SOT switching is typically on the order of magnitude of 105.12/FM heterostructures, in which the magnetic layer was Py with in‐plane magnetization. The easy axis of Py was set along the a‐axis (or b‐axis), whereas the hard axis and current were set along the b‐axis (or a‐axis) to allow SOT switching without external magnetic field. When the current was along the a‐axis, the critical current density required for SOT switching was clearly lower than that in the b‐axis. These results indicate that τB increases the switching efficiency. Noticeably, current‐induced magnetization switching was completed via domain wall nucleation and propagation /Py (6 nm) sample. This critical current density can be decreased by a factor of three through shape engineering, which is due to the decrease of the domain nucleation energy by a reasonable shape design. High‐efficiency SOT switching was also demonstrated in PtTe2/CoTb heterostructure 1−x. Their magnetic properties can be modulated within a wide range of values via chemical composition engineering. Combining high transition‐temperature bulk PMA magnets with TI, efficient SOT switching has been achieved in Bi2Se3/CoTb heterostructures at room temperature. The critical current density for switching was approximately 2.8 × 106 Acm−2 with a 1000 Oe in‐plane bias field 1−x /CoFeB heterostructure  2Te3/Mo/CoFeB structure. Similarly, interfacial PMA magnetic layer and efficient SOT switching have been obtained in BixTe1−x /Pt/Co/Pt, Bi2Se3/Co/Pt.Recently, interfacial PMA magnetic layer was achieved by a thin insertion layer. Mahendra et al. successfully prepared a PMA CoFeB layer by sputtering and demonstrated SOT switching in Bi) Figure ,d. The r6 A cm−2 and Cr2Ge2Te6/Ta with 5 × 105 A cm−2, as shown in Figure  Although these SOT switchings are obtained at relatively low temperatures, they show great prospect in efficient SOT switching. Finally, we summarize the critical current density required for SOT switching in various vdW heterostructures in Table Compared to conventional ferromagnetic materials, vdW ferromagnets have atomically flat interfaces and ultra‐thin thicknesses, as well as gate‐tunable magnetic properties. These features are suggested to be helpful for high‐efficiency SOT switching. Few studies have revealed the low critical current density required for SOT switching in vdW ferromagnets/HM heterostructures, such as, FGT/Pt with 8.3 × 106Current‐induced SOT offers a powerful tool for efficiently controlling magnetization without external magnetic fields, and it allows the realization of high‐performance spintronic devices, such as SOT‐MRAM. To realize power‐efficient SOT devices, considerable efforts have been made to enhance the SOT efficiency and reduce the critical current density required for SOT switching. A number of vdW‐layered materials have been explored for this purpose, including TMDs, TIs, graphene‐based heterostructures, and vdW magnets. TMDs and TIs provide an attractive avenue for the realization of large SOT efficiency. First, they show very efficient charge‐to‐spin conversion. Second, the SOT in these materials can be tuned by designing the crystal symmetry and electrical field. Thus, unconventional SOT is allowed in TMDs with reduced crystal symmetry. This novel SOT makes the magnetization switching more efficient. Finally, TMDs or TIs can significantly enhance the SOC of graphene via the proximity effect. These hybrid heterostructures not only maintain the merit of high electron mobility and strong SOC but also show tunability by electrical field. Thus, they are promising spin current‐source materials.The newly discovered vdW magnets provide further opportunities for SOT devices. On the one hand, from metal to semiconductor, diverse ultra‐thin and gate‐tunable vdW ferromagnets have been demonstrated to reduce power consumption and improve the performance of SOT devices. On the other hand, vdW AFMs have been shown to be efficient spin sources owing to the interface effect. Finally, we discussed the SOT switching critical currents in various vdW heterostructures. TMDs and TIs exhibited much lower critical currents than the typical value of HM. Hence, these vdW materials have unprecedented potential implementation in efficient spintronic devices.Continuous endeavors need to be devoted to the field of SOT in vdW materials. First, as spin current‐source materials, TMDs and TIs exhibit considerable SOT efficiencies. However, their microscopic origin is not explicitly clear at the moment. Additionally, novel SOTs have been observed in some TMDs, such as out‐of‐plane antidamping‐like SOT and in‐plane field‐like SOT, which cannot be explained by the conventional SOC effect, such as, SHE and REE. The detailed mechanisms need further experimental and theoretical studies. Furthermore, most reported TMDs and TIs have small electrical conductivities, and it is challenging to find TMDs and TIs with high conductivities and strong SOCs.Although graphene‐TMD (or TI) hybrid structures showed enhanced SOC, the experimental investigation of current‐induced SOT in TMDs/graphene/FM or multiple‐layer TIs/graphene/FM heterostructures, is still lacking. Furthermore, the role of the interface in vdW NM/FM heterostructures remains unclear. For example, when inserting graphene between the TMD (TI) and FM layer, it is not clear whether the interface transparency will strongly affect the SOT efficiency.TC. Continuous efforts should be made to explore high TC vdW magnets. For example, the temperature can be increased by optimizing the exchange interaction and the magnetic anisotropy. Assembling the vdW heterostructure with other materials may also be helpful in enhancing the TC of vdW magnets. In addition, doping, such as, Ga implantion and Co doping were recently demonstrated to be effective to increase the TC.For the choice of magnetic layer, atomically thin vdW‐layered magnetic crystals are promising candidates. Unfortunately, at the current stage, most of them have relatively low Curie temperatures  long‐term technically fundamental challenges still need to be addressed, such as, wafer‐scale growth, efficient transfer, and high‐quality heterostructrue assembling.Finally, wafer‐scale scalability of vdW materials is still an important issue. At present, vdW materials are usually prepared by mechanical exfoliation in SOT devices, which is difficult to integrate with the modern semiconductor technology. Although the latest progress in the manufacture of large‐area vdW materials advances the spintronic development for industry applications,In conclusion, despite several challenges to be addressed, new opportunities in vdW material‐based SOT devices attract increasing interests in both fundamental research and technology applications. The progresses achieved in vdW materials, such as, large SOT efficiency, controllable SOC, and gate‐tunable magnetism, can promote the development of next‐generation efficient spintronic devices. We expect vdW materials to pave the way for more ambitious development of SOT devices.The authors declare no conflict of interest.


Growth (i.e. shoot length and shoot dry weight), leaf photosynthetic pigments (chlorophyll ‘a’ and chlorophyll ‘b’ content), air–canopy temperature (Tc–Ta), membrane stability index (MSI%), and relative water content, (RWC%) chlorophyll fluorescence (Fv/Fm) stomatal conductance (gs), total phenols, peroxidase (PO), polyphenol oxidase (PPO), nitrogen contents and water productivities  were positively affected and significantly (p < 0.05) differed in two seasons in response to the applied PGPR treatments. The highest yields (3.35 and 6.7 t ha−1 for grain and straw yields) as the average for both years were recorded under full irrigation and plants inoculated by PGPR. The results indicated that under water scarcity, application of (I80 + PGPR) treatment was found to be favorable to save 20% of the applied irrigation water, to produce not only the same yields, approximately, but also to save more water as compared to I100%.Inoculating rice plants by plant growth promoting rhizobacteria (PGPR) may be used as a practical and eco-friendly approach to sustain the growth and yield of drought stressed rice plants. The effect of rice inoculation using plant growth hormones was investigated under drip full irrigation , and deficit irrigation  on growth, physiological responses, yields and water productivities under saline soil (ECe = 6.87 dS m The climate is arid, characterized by low precipitation and rainfall occurs mainly during the period from December to April. The region is also characterized by more than 320 days a year of sunny days. The meteorological parameters , wind speed (m sin Table . Physio-2), each plot included 4 planting rows placed 20 cm apart with a distance of 10 cm between plants within rows. Two drip lines were placed 0.40 m apart in each elementary test plot. Healthy seeds of rice (Oryza sativa L.), variety Sakha 107 were sown on 20 May 2017 and 2018. The 4-week-old transplants were transported and replanted and then harvested on 6 October 2017 and 2018. Mineral fertilization, pest management, disease, and cultural practices were performed as the instructions of local commercial crop production. Irrigation water applied (IWA) was estimated as a percentage of the crop evapotranspiration (ETc) representing the following three treatments: FI = 100%, and DI = 80% of ETc. Daily ETo and ETc were estimated according to Allen et al. (3), A: irrigated plot area (m2), ETc: water consumptive use (mm day−1) and was computed as follow;−1) and Kc = crop coefficient. ETo was determined as follows:Two field experiments were conducted in a randomized complete block design (Split Plot). 2 irrigation treatments were applied  and two PGPR treatments . The 4 treatments were replicated three times, making a total of 12 plots. The area of the experimental plot was 16 m length × 0.8 m row width . Shoots of plants were weighed to record their fresh weights and then placed in an oven at 70 ± 2 °C till a constant weight to measure their dry weights.v/Fm) was measured by using a portable fluorometer  and calculated according to Maxwell and Johnson (ABS) was calculated as reported by Clark et al. . The SPAD was determined at 90 DAS for the three youngest completely expanded leaves per hill by .1: is the EC of the solution at 40 °C and C2: is the EC of the solution at100°C. Canopy temperature (Tc) was measured by a hand-held infrared thermometer  at an emissivity of 0.98 and a spectral response range of 8–14 µm.The RWC was determined according to Hayat et al.  equationa et al.  as folloTotal nitrogen was determined according to the well-known method described by Donald and Robert . Estimat−1 FW) according to the procedure given by Arnon , each strain was grown individually on sterilized nutrient broth medium in flasks with 1 L capacity on rotary shaker after shaking for 72 h incubation period at 30 °C. The growing organisms were concentrated by centrifuging the medium and cell sidements were aseptically collected and diluted, by the same medium, to 250 mL only (1/4 L). In the case of using a mixture of the two antagonizers, an equal volume of the three strains was mixed instantaneously before use. 20 mL of the resultant suspension was poured twice directly onto the rice seedlings in cones at the seedling and at 15 days after transplanting.Water productivities as mentioned byFernández et al.  level was used as mean separation test.Statistical analysis was performed through the procedure of GenStat (version 11) . The least significant difference (LSD) at 5% probability  than those under full irrigation. On the other hand, plants treated with PGPR had higher growth traits  than untreated plants. Growth traits were decreased significantly with increasing water stress, I80% resulted in decreases of plant height by 8%, tillers number by 11.8%, panicles number by 12.4%, and shoot dry weight by 25% as compared to fully irrigated plants. On the other hand, treated rice plants with PGPR increased significantly these parameters by 9.4%, 15.3%, 18.6%, and 29.6% for plant height, tillers number, panicles number, and shoot dry weight, respectively. The combined application of PGPR and irrigation at 100% of ETc recorded the best growth parameters, while the treatment I80 × −PGPR showed the lowest values of growth parameters. Otherwise, no significant differences were found between I100 × −PGPR and I80 × +PGPR treatments.Data in Table −PGPR plants (63.5 and 73.8). Interaction between PGPR and irrigation treatment significantly affected plant water status. According to the results in Table Results of rice water states  in responses to irrigation and PGPR treatments and their interaction are presented in Table The influences of plant growth promoting bacteria on stomatal conductance (gs) under full and deficit irrigation are presented in Fig. 100 × +PGPR treatment, while the minimum values for these parameters were observed under I80 × −PGPR treatment.Responses of chlorophyll fluorescence (Fv/Fm and PI), relative chlorophyll content , and photosynthetic pigments (chlorophyll a and chlorophyll b) of rice plants to irrigation and plant growth promoting bacteria treatments and their interactions are displayed in Table p < 0.05) affected by irrigation quantity and plant growth promoting bacteria and were not positively affected by season except for total phenol. Data in (Table p < 0.05) affected by the interaction between PGPR and irrigation treatments. The highest values of PO, PPO, total phenol, N content in leaves and grains were found when plants were irrigated at 100% of ETc and inoculated by PGPR treatment (I100 × +PGPR), while the lowest values for the aforementioned parameters were recoded when rice plants were exposed to water stress (I80) and untreated by PGPR (I80 × −PGPR).The effects of irrigation, PGPR treatments and their interaction on defense principles like , N% (leaves) and N% (grains) contents of rice plants were presented in Table in Table  reflecte−1, and 1000 grain weight (g) to cropping seasons, irrigation, PGPR, and their interaction are presented in Table −1 10.8%, and 1000 grain weight of rice plants by 17.8% as compared with unstressed plants. On the other hand, inoculated rice plants by PGPR increased yield component by 10.6, 28.0, 19.9, and 23.0% for panicle length, panicle weight, number of grains panicle−1, and 1000 grain weight as compared by untreated plants, respectively. Our results showed that rice yield components were strongly influenced by the interaction between PGPR and irrigation treatments. The highest values of panicle length, panicle weight, number of grains panicle−1 and 1000 grain weight  were recorded when plants received 100% of ETc and inoculated by PGPR (I100 × +PGPR), while the lowest values for aforementioned traits  were recorded when rice plants exposed to water stress (I80) and untreated by PGPR (I80 × −PGPR) treatment.Responses of rice yield components such as; panicle length, (cm), panicle weight (g), number of grains panicle−1) and water productivities . Plants grown under full irrigation had higher yields  than those grown under drought stress. Grains yield, straw yield, were decreased positively with increasing water stress, I80% resulted in decreases of grain yield by 19%, straw yield by 11.9%, in relation to fully irrigated plants. On the other hand, values of G-WP, and S-WP under I80% treatment were higher than those of I100% treatment by 1.3 and 10.4%, respectively, , straw yield (8.87 t ha−1), G-WP (kg m−3), and S-WP (kg m−3). Moreover, the lowest values for grains yield (3.65 t ha−1), straw yield (6.58 t ha−1), G-WP (kg m−3), and S-WP (kg m−3) were found when rice plants were irrigated at 80% of irrigation water requirements (I80) and untreated by PGPR.Table Bacillus subtilis subsp. and Bacillus megatherium] can produce plant growth promoting substances (PGPs) such as; Indoleacetic acid (IAA)  and it could use under normal conditions and overcome the negative effects of environmental stresses on some plants . Inoculating plants with PGPR showed greatly significant positive results for performance growth, water status, stomatal conductance (gs), and chlorophyll fluorescence efficiency, relative chlorophyll content and photosynthetic pigments, antioxidant enzymes and nitrogen contents, yield component, and yields and water productivities of rice plants grown under both DI and saline conditions. In our study, drought stress indirectly inhibited rice growth parameters may be attributed to the drought-induced reduction of cell division and enlargement, resulting in the reduction of shoot length, tillers number plant−1, the number of panicles plant−1 and shoot dry weight, simultaneously with the reduction of stomatal conductance, water status, chlorophyll fluorescence efficiency, relative chlorophyll content and photosynthetic pigments, as well as antioxidant enzymes and nitrogen contents  compared to full irrigation. Our results showed that inoculating rice plants with Bacillus subtilis subsp. and Bacillus megatherium as a plant growth promoting rhizobacteria (PGPR) stabilized membrane integrity and maintained cell turgor of rice leaves under drought stress. In this concern, increases of tissue RWC and MSI chlorophyll fluorescence (Fv/Fm and PI) SPAD value, chlorophyll ‘a’ and chlorophyll ‘b’ and decreases of canopy temperature (Tc–Ta) as metabolically available water, enabling to maintain tissue health and reflect on the metabolic processes in rice under drought stress. Our results are in line with those reported by Creus et al. (80%) positively decreased rice yield attributes  and yields (grain and straw) compared to fully irrigated plants (I100%). The reduction in yield components under water stress may be due to the decreases in growth, stomatal conductance, chlorophyll content, water status, N uptake, and photosynthesis efficiency of plants  is considered one of these strategies and it could play an important role in mitigating the detrimental effects of drought stress on plants. Bacteria strains used in our study [ sp Koch . The strs et al. , Arzaness et al. , Liu et s et al.  and Armas et al. , who reps et al. . In the s et al. , Abd El-s et al.  and Semis et al. . They res et al.  reporteds et al. . Our strs et al. , and morn et al. , Wu et an et al. , Kumar en et al.  and Yangn et al.  reporteda et al.  and Radya et al. , b. In ga et al. . Li et aa et al.  indicatea et al.  and Agama et al.  found tha et al.  for wheaa et al.  for soyba et al.  for maiza et al.  and Garca et al.  for rice100 × +PGPR) is the most suitable for obtaining the highest grain and straw yields. Under water deficit, the application of (I80 × +PGPR) treatment was found to be a favorable strategy to save 20% of the applied irrigation water, providing the same rice yield. Our results suggest that PGPR applications may find value as anti-abiotic stresses for improving rice growth and productivity under drought stress.Exposure of rice plants to drought stress positively reduced, physiological responses, RWC%, MSI%, antioxidant enzymes , polyphenol oxidase (PPO), total phenol), N% (in leaves and grains), growth attributes, grain, and straw yields and increased canopy temperature the of rice plants. However, inoculation rice plants with PGPR could mitigate the deleterious effects of water stress by enhancing leaf photosynthetic pigments, chlorophyll fluorescence, SPAD value, stomatal conductance, plant water status, antioxidant enzymes, plant growth, yields, and WP and reduce plant canopy temperature. Depending on the obtained results it could be summarized that the treatment (I