1.Status and influencing factors of the application of informatization tools for antimicrobial stewardship in Chinese county hospitals
Yuqi FU ; Xin LI ; Ying LI ; Hongwei WU ; Zhixin FAN ; Jinru LIU ; Xi CHEN ; Yuxiang XIA ; Qiang SUN ; Yingbo ZHAO
China Pharmacy 2026;37(16):2084-2089
OBJECTIVE To investigate the current status of informatization tools applied to antimicrobial stewardship in county hospitals in China, and to provide a reference for promoting the informatization development of antimicrobial stewardship in county hospitals.METHODS From August to September 2025, an online questionnaire survey was conducted among 1 007 county hospitals across 31 provinces(autonomous regions, and municipalities) in China. The survey focused on the application of four types of informatization tools:the real-time monitoring system for antimicrobial use, the pre-prescription review system, the irrational use warning system, and the electronic prescription evaluation system(hereinafter referred to as the “monitoring system”“review system”“warning system”“evaluation system”,respectively). Correlation analysis and binary Logistic regression analysis were employed to explore the influencing factors.RESULTS Of the county hospitals, 80.83% were equipped with at least one type of informatization tool for antimicrobial stewardship, while 19.17% had no relevant tool. Only 18.87% of the hospitals were equipped with all four types of tools. The monitoring system exhibited the highest equipped rate (70.80%), whereas the warning system was equipped in only 33.96% of the hospitals. Four types of tools are evenly and adequately deployed in the eastern region, the central and western regions have far lower deployment rates of intervention tools including review system and warning system, accompanied by prominent intra-provincial gaps. The total number of the health technicians, hospital grade, and prescription review rate of outpatient antibacterial drug were significantly and positively correlated with the deployment rates of the four informatization tools ( P <0.05). The results of the Logistic regression model fitting indicated that the model of the review system was rated “excellent” [area under the receiver operating characteristic curve (AUC)=0.81], and the model of the warning system was rated “further improvement” (AUC=0.67). The total number of health technicians was significantly positively correlated with the deployment rates of all four types of informatization tools (all P <0.05).CONCLUSIONS The informatization of antimicrobial stewardship in county hospitals in China remains in the initial stage of transitioning from “passive statistics” to “active prevention and control”, with challenges such as structural imbalance and regional disparities. In the future, differentiated support strategies should be implemented, the allocation of resources should be optimized, to enhance the level of refined antimicrobial stewardship.
2.Correlation between cognitive function and event-related potential P300 and its influencing factors in patients with depressive episodes of bipolar disorder with mixed features
Jian ZHANG ; Yuxiang HE ; Yanqing WU ; Fang LIU ; Yan ZHANG ; Yong ZHANG
Sichuan Mental Health 2026;39(4):318-323
BackgroundPatients with bipolar disorder exhibit persistent cognitive impairment across multiple domains, including executive function, memory, and attention. Furthermore, those with mixed features tend to have a poorer prognosis. Currently, research evidence regarding the characteristics of cognitive function and event-related potential P300, as well as their correlation, in patients with depressive episodes of bipolar disorder with mixed features remains limited. ObjectiveTo explore the correlation between cognitive function and event-related potential P300 in patients with depressive episodes of bipolar disorder with mixed features, analyze the influencing factors of cognitive function, so as to provide references for the improvement of cognitive function in this subtype of patients. MethodsA total of 73 patients who met the diagnostic criteria for depressive episodes of bipolar disorder in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) were enrolled from the outpatient and inpatient departments of Tianjin Anding Hospital from November 2021 to April 2024. The Hamilton Depression Scale-17 item(HAMD-17) was used to assess the severity of depressive symptoms, and the Clinically Useful Depression Outcome Scale Supplemented with Questions for the DSM-5 Mixed Features Specifier (CUDOS-M) was used to evaluate whether patients presented with mixed features. Based on the CUDOS-M total scores, patients were divided into two groups: the mixed features group (n=34) and the non-mixed features group (n=39). The MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive function, and auditory event-related potential P300 testing was performed. Spearman correlation analysis was used to examine the correlations between P300 indicators and MCCB scores. Multiple linear regression analysis was conducted to investigate the influencing factors of cognitive function. ResultsPatients with depressive episodes of bipolar disorder with mixed features had a longer total illness duration than those without mixed features, and the difference was statistically significant (t=2.030, P<0.05). Analysis of covariance showed that the MCCB scores for processing speed, attention/vigilance, and reasoning and problem solving were all lower in the mixed features group than those in the non-mixed features group (F=3.650, 3.520, 4.213, P<0.01). However, no significant difference was found between the two groups in P300 latency or amplitude (P>0.05). Correlation analysis revealed that the MCCB attention/vigilance score was negatively correlated with P300 latency in patients with depressive episodes of bipolar disorder with mixed features (rs=-0.576, P<0.01). Multiple linear regression analysis showed that, in the mixed features group, years of education positively predicted processing speed (β=0.378, P<0.05), while P300 latency (β=-0.699, P<0.01) and age (β=-0.424, P<0.01) negatively predicted attention/vigilance function. ConclusionPatients with depressive episodes of bipolar disorder with mixed features have a longer illness duration and more severe impairment in three cognitive domains: processing speed, attention/vigilance, and reasoning and problem solving. P300 latency may be an influencing factor of attention/vigilance function in patients with depressive episodes of bipolar disorder with mixed features [Funded by Tianjin Key Medical Discipline Construction Project (number, TJYXZDXK-3-015B); Hospital-level Scientific Research Project of Tianjin Anding Hospital (number, ADYKHT2021010)]
3.Probe into the Moxibustion Therapy Characteristics in ZHAO Xuemin's Chuanya Waibian
Han LIU ; Hongling CHEN ; Yuxiang HE
Journal of Zhejiang Chinese Medical University 2025;49(4):444-447
[Objective]To explore the characteristics of moxibustion application in Chuanya Waibian by ZHAO Xuemin,a doctor in Qing Dynasty,in order to provide ideas for the expansion of the application range of moxibustion and the design of new moxibustion tools.[Methods]By studying and analyzing the discussion about moxibustion in Chuanya Waibian,the author summarized the principle and experience of using moxibustion to treat diseases.[Results]Chuanya Waibian was written by ZHAO Xuemin on the basis of inheriting the essence of the theories of the ancients and combining with the medical practice experience of the folk doctors.The philosophy of moxibustion is"harmony between human and nature,treatment in line with the change of climate";in the treatment"selecting acupoints essentially,applying moxibustion moderately""using various materials of moxibustion,not confined to moxa",and characterized by"extensive clinical symptoms,good treatment of emergency"and"distinguishing Yin and Yang in the treatment of carbuncle and ulcer".[Conclusion]Chuanya Waibian reflects the characteristics of the clinical diagnosis and treatment of the folk doctors in the region of Jiangsu and Zhejiang in the Qing Dynasty,and to a certain extent embodies ZHAO Xuemin's academic thought of traditional Chinese medicine.Summarizing the rules of using moxibustion to treat diseases in this book can provide new ideas and methods for clinical diagnosis and treatment,as well as reference value for the innovation of moxa sticks and the design of new moxibustion equipment.
4.Identification and analysis of a novel RHCE allele underlying a RhD--phenotype
Li WANG ; Qiankun YANG ; Yuxiang LIN ; Hecai YANG ; Shuya WANG ; Ying XIE ; Xue LIU ; Yanli CHANG ; Yongkui KONG
Chinese Journal of Medical Genetics 2025;42(8):911-917
Objective:To explore the molecular mechanism of a case with RhD-phenotype.Methods:A proband with RhD-phenotype who attended the clinic of the First Affiliated Hospital of Zhengzhou University on January 29, 2024 was selected as the study subject. Peripheral blood samples were collected from the proband (8 mL) and her close relatives (father, mother and brother; 3 mL each) for Rh phenotyping and irregular antibodies testing with gel card and test tube methods. Direct agglutination reaction and absorption-elution test were used to detect the c antigen on the red blood cells of the proband. PCR-sequence specific primers (PCR-SSP) typing and gene sequencing were used to determine the RHCE gene of the proband and her relatives. The origin of the proband′s variant was traced by pedigree analysis. Three-dimensional structural models of the wild-type RhCE*cE protein and the RhD-phenotype protein were constructed to predict the alterations of the RhD-phenotype protein caused by the variant. The procedures of this study were approved by the Medical Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Ethics No.: 2023-KY-0870-003). Results:The red blood cells of the proband did not agglutinate with anti-C, anti-c, anti-E, and anti-e. The result of the serum irregular antibody test was negative. The results of direct agglutination reaction and absorption-elution test of the proband were both negative. Her Rh blood group was identified as RhD-. The results of the Rh blood grouping of her close relatives were normal. PCR-SSP detection showed that the RHCE genotypes of the proband and her close relatives were cE/cE and Ce/cE, respectively. Gene sequencing analysis showed that the RHCE genotypes of the proband and her close relatives were RHCE* cE (c.365C>A)/ RHCE* cE (c.365C>A) and RHCE* Ce/ RHCE* cE (c.365C>A), respectively. Pedigree analysis revealed that the variants in the proband were inherited from her father and mother, respectively. Homology modeling of RhCE*cE protein showed that the RhD-type peptide chain with a significantly shortened C-terminal was encoded by only 121 amino acid resides, which was 296 amino acid resides shorter compared to the wild-type RhCE*cE peptide chain encoded by 417 amino acid residues. Conclusion:Above results revealed the molecular biological mechanism of a RhD-phenotype. The c. 365C>A variant in the RHCE gene has rendered the RHCE* cE alleles invalid, which ultimately led to the RhD-phenotype.
5.2024 Update of Chinese Guidelines for the Management of Hyperuricemia and Gout Part Ⅱ: Recommendations for Patients with Common Comorbidities
Changgui LI ; Mingshu SUN ; Zhen LIU ; Detian LI ; Changqian WANG ; Zibin TIAN ; Yuxiang DAI ; Zhe FENG ; Chengfu XU ; Dongbao ZHAO ; Feng WEI ; Bo BAN ; Chao XIE ; Zhenmei AN ; Jia LIU ; Zhuo LI ; Yuwei HE ; Xinde LI ; Fei YAN ; Lin HAN ; Lidan MA ; Xiaoyu CHENG ; Tian LIU ; Xufei LUO ; Lingling CUI ; Ying GONG ; Can WANG ; Yaolong CHEN ; Zhaohui LYU ; Yip Ronald ML ; Jiajun ZHAO
Chinese Journal of Endocrinology and Metabolism 2025;41(11):918-929
The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.
6.Research trends and hotspots of bupivacaine liposomes: bibliometric analysis from 1994 to 2023
Yuxiang MENG ; Sumin YUAN ; Zijie LING ; Li ZHANG ; Zhibiao XU ; Yuyun LIU ; Chenyang SHI ; Hengrui ZHANG ; Yang NIU ; Su LIU ; Linlin ZHAO
Chinese Journal of Anesthesiology 2025;45(6):736-744
Objective:To analyze the research trends and hotspots of bupivacaine liposomes from 1994 to 2023 using bibliometrics.Methods:A comprehensive search was conducted for the literature related to bupivacaine liposomes in the Web of Science Core Collection from 1994 to 2023. The CiteSpace software was used to conduct an in-depth analysis of the included literature data, including publication year, country, institution, author, journal, cited references, keywords, etc.Results:A total of 875 papers related to bupivacaine liposomes were included. The research and development of bupivacaine liposomes were divided into 3 stages: slow development (1994-2011), a sharp rise (2011-2021), and stabilization (2021-2023). The United States was in a leading position in terms of the number of publications, centrality, and author cooperation, and Harvard University had the largest number of publications. de Paula E had the most publications, Bramlett K had the highest number of citations, and Boogaerts J had the highest centrality of publications. Journals such as Anesthesia and Analgesia made significant contributions to this field. The most cited references focused on the infiltration of wounds and the periprosthetic injection of bupivacaine liposomes. The keyword analysis showed that local anesthetics, postoperative pain, etc. were commonly used keywords, and enhanced recovery after surgery was an emerging hotspot. Conclusions:Bupivacaine liposomes show good application prospects in the field of peripheral nerve block due to their unique pharmacological properties and safety characteristics and are expected to prolong the duration of postoperative analgesia. However, there is a difference between the actual effect and the expectation, and more clinical trials are needed to evaluate the curative effect, providing a more solid and reliable theoretical basis and practical guidance for clinical practice.
7.Distribution characteristics of Traditional Chinese Medicine constitution and prognosis analysis in non-small cell lung cancer with different expression levels of PD-L1
Duo WAN ; Zhi WEN ; Sheng CHEN ; Zhengyi LIU ; Yuxiang HU ; Haozhu WANG ; Yinhui SUN ; Tonglin SUN ; Lihuai WANG
International Journal of Traditional Chinese Medicine 2025;47(4):449-455
Objective:To investigate the different expression levels of programmed cell death 1 ligand 1 (PD-L1) in non-small cell carcinoma (NSCLC) of distribution characteristics of TCM constitutions and prognosis.Methods:The clinical data of 355 NSCLC patients who had been treated with immune checkpoint inhibitors (ICIs) from January 2019 to June 2023 in the Cancer Medical Center of the First Affiliated Hospital of Hunan University of Chinese Medicine were retrospectively analyzed, and their TCM constitutions were determined. According to the expression level of PD-L1, they were divided into three groups: low expression group (TPS≤1%), medium expression group (1% < TPS < 49%) and high expression group (TPS≥50%). Overall survival (OS) of patients was followed up, and the median OS were compared. Kaplan-Meier method was used to draw survival curves, and Log-rank test was used to compare the difference of survival curves. The independent risk factors of OS were analyzed by COX regression.Results:The distribution of different TCM constitutions showed statistical significance across the three groups ( P<0.05). The median OS for the medium and high expression groups were 21.082 months and 25.714 months, respectively, both significantly higher than the 14.437 months for the low expression group ( P<0.05). The survival curve of TCM constitutions showed that the constitutions significantly correlated with the prognosis of ICIs treatment were qi deficiency, phlegm dampness, and blood stasis ( P<0.05 or P<0.01). The median OS from high to low was 44.971 months for phlegm-dampness constitution, 23.297 months for qi-deficiency constitution, and 11.763 months for blood-stasis constitution. COX regression analysis indicated that medium PD-L1 expression ( HR=0.622, 95% CI=0.459,0.844, P=0.002), high PD-L1 expression ( HR=0.509, 95% CI=0.361,0.718, P<0.001), phlegm-dampness constitution ( HR=0.556, 95% CI=0.335,0.924, P=0.024), and blood-stasis constitution ( HR=2.952, 95% CI=1.929,4.518, P<0.001) were independent prognostic factors. Conclusions:The higher the expression level of PD-L1 in NSCLC patients, the better the prognosis of ICIs treatment. The prognosis of ICIs treatment is better for people with phlegm-dampness constitution and poor for those with blood stasis constitution.
8.Analysis of the Distribution of Traditional Chinese Medicine Syndrome Types and Medication Rules for Novel Coronavirus Infection Complicated with Asthma
Jin CHEN ; Yueyang LI ; Linsheng ZENG ; Chuanjun GUO ; Yuxiang LIU ; Zhizhun MO ; Zhongyi ZENG
Journal of Guangzhou University of Traditional Chinese Medicine 2025;42(1):1-8
Objective To investigate the distribution of gender,age,and traditional Chinese medicine(TCM)syndrome elements and syndrome types in patients suffering from novel coronavirus infection complicated with asthma,and to explore the medication rules for the patients,thus to provide reference for the formulation of clinical diagnosis and treatment plans for novel coronavirus infection complicated with asthma.Methods From December 2022 to January 2023,the information of gender,age,syndrome elements,TCM syndrome types and medication frequency of the herbal medicine was collected among the patients suffering from novel coronavirus infection complicated with asthma who were treated in outpatient clinics of the respiratory department and emergency department of Shenzhen Traditional Chinese Medicine Hospital.The information data were statistically analyzed and then the network visualization of results was presented.Results A total of 63 cases were included,including 27 males and 36 females,with an average age of 51.8 years old.Thirteen TCM syndrome types were involved,of which the three with the leading occurrence frequency were wind-phlegm syndrome(17 cases),spleen deficiency with dampness accumulation syndrome(11 cases),and phlegm-heat stagnation in the lung syndrome(8 cases).There were four disease-location syndrome elements,and the top two were lung(36 cases)and spleen(12 cases).Eight disease-nature syndrome elements were involved,and the top three were wind(36 cases),phlegm(28 cases)and qi deficiency(24 cases).A total of 128 Chinese herbal medicines were used,and their properties and flavors were predomiated by being pungent,bitter,sweet and cold.Most of the Chinese herbal medicines had the meridian tropism of lung,spleen,liver and stomach meridians,and most of the Chinese herbal medicines had the therapeutic actions of resolving phlegm,easing cough and relieving asthma.The top four Chinese herbal medicines with higher medication frequency were Glycyrrhizae Radix et Rhizoma(51 times),Ephedrae Herba(47 times),blanching Armeniacae Semen Amarum(44 times),and Schisandrae Chinensis Fructus(40 times).The core two-drug groups were Ephedrae Herba-Glycyrrhizae Radix et Rhizoma,Ephedrae Herba-Schisandrae Chinensis Fructus,and blanching Armeniacae Semen Amarum-Pinelliae Rhizoma.The core three-drug groups were Pinelliae Rhizoma-blanching Armeniacae Semen Amarum-Ephedrae Herba,and Ephedrae Herba-Schisandrae Chinensis Fructus-Glycyrrhizae Radix et Rhizoma.Conclusion Pathogenic phlegm retention in lung is the core pathogenesis of novel coronavirus infection complicated with asthma,which is protracted through the disease.The pathogenic wind is the driving factor of the disease's development and progression,and in the middle and late stages of the disease,the complicated syndrome manifestations of pathogenic heat,qi deficiency,qi and yin deficiency,and blockage of upper orifice are commonly seen.Its therapeutic principles are to relieve exterior syndrome and clear heat,resolve phlegm,ease cough and relieve asthma,thus to restore the qi movement of the zang-fu organs,support the healthy qi,eliminate pathogens and strengthen body resistance.
9.Traditional Chinese Medicine Syndrome Patterns Distribution and Medication Characteristics in COVID-19 Patients Complicated with Chronic Bronchitis:A Retrospective Study
Man LI ; Linsheng ZENG ; Zhizhun MO ; Yuxiang LIU
Journal of Guangzhou University of Traditional Chinese Medicine 2025;42(7):1553-1560
Objective To investigate the distribution of traditional Chinese medicine(TCM)syndrome patterns and medication characteristics in corona virus disease 2019(COVID-19)patients complicated with chronic bronchitis at the initial phase of the termination of pandemic control policy in Shenzhen,and to provide evidence for TCM syndrome differentiation and treatment of these patients.Methods A retrospective analysis was performed on 76 COVID-19 patients complicated with chronic bronchitis who visited the Department of Respiratory and Critical Care Medicine or the Emergency Internal Medicine Clinic at Shenzhen Traditional Chinese Medicine Hospital between December 15,2022 and February 28,2023,an initial phase of the termination of pandemic control policy in Shenzhen.Data of demographics,TCM syndrome patterns,and herbal prescriptions were collected.TCM syndrome distribution and medication patterns of the COVID-19 patients complicated with chronic bronchitis were summarized to enhance understanding of post-COVID sequelae,post-COVID syndrome,long COVID,post-infectious cough,and chronic cough,and to provide references for TCM management of acute/chronic post-COVID cough,long COVID syndrome,and emerging respiratory infectious diseases.Results A total of 76 medical records with full information were included,covering 63 herbal formulas and 140 herbal medicinals were analyzed.The most common TCM syndrome pattern was phlegm-turbidity obstructing the lung syndrome,followed by phlegm-heat stagnating the lung syndrome and lung qi deficiency syndrome.The properties of the herbs used were predominantly warm,cold,or mild;their flavors were bitter,pungent,or sweet;and their meridian tropisms primarily involved the lung,spleen,stomach,and liver.Twenty-five medicinals used exceeding 15 times in the formulas were identified,including Glycyrrhizae Radix et Rhizoma(Gancao),Ephedrae Herba(Mahuang),Coicis Semen(Yiyiren),and Poira(Fuling).Association rule analysis revealed the frequent herbal pairs of Gancao-Mahuang,Belamcandae Rhizoma(Shegan)-Mahuang,Gancao-Fuling,Fuling-Yiyiren,etc.Cluster analysis categorized high-frequency herbs into four distinct groups.Conclusion The retrospective analysis highlights the complexity of clinical manifestations in COVID-19 patients complicated with chronic bronchitis at the initial phase of the termination of pandemic control policy in Shenzhen.The pathogenic factors of the patients predominantly involve phlegm-turbidity and phlegm-heat.Therapeutic principles for the patients focus on diffusing the lung to alleviate adverse flow of qi,resolving phlegm and removing dampness,and clearing and draining damp-heat.Commonly prescribed formulas include San'ao Decoction,Yuebi Plus Banxia Decoction,Xiaoqinglong Decoction,Shegan Mahuang Decoction,and Suhuang Zhike Decoction,and the formulas are used by modification according to the symptoms.
10.Injectable hydrogel loaded with bone marrow-mesenchymal stem cells promotes the repair of cartilage defect
Deguo LIU ; Hong CHEN ; Jiehong ZHANG ; Yuxiang ZHENG ; Zhengang LIU ; Xuanchen CHEN ; Zhenhai HOU
Basic & Clinical Medicine 2025;45(1):44-50
Objective To construct an injectable hydrogel(IH)entrapment system of bone marrow mesenchymal stem cells(BM-MSCs)and to explore its effect of promoting articular cartilage repair and underlying mechanism.Methods The primary BM-MSCs of mice were cultured by whole bone marrow adherent method.The differentiation potential was identified by alizarin red(ARS),oil red O(ORO)and Alcian blue(AB)staining,and the expres-sion of CD44,CD90,CD105,CD34 and CD45 on the surface was detected by flow cytometry.BM-MSCs loaded with IH(BM-MSC-IH)was prepared,and the rheological properties of BM-MSC-IH were tested by rheological test.The model of full-thickness injury of knee cartilage in mice was established,and the mice were randomly divided into normal saline group,BM-MSC group and BM-MSC-IH group with 8 in each.The mice were injected with BM-MSC-IH 0.2 mL,cell suspension 0.2 mL and 0.9%NaCl solidion,independently.After 6 and 12 weeks of in-jection,the repair of knee cartilage in mice was observed by safranin-fast green staining,and the expression of typeⅡ collagen in knee joint was examined by immunohistochemical staining microscopy.Results The primary cultured cells showed positive expression of CD44,CD90 and CD105,but negative expression of CD34 and CD45,and had the potential of osteogenic,adipogenic and chondrogenic differentiation.The constructed BM-MSC-IH sys-tem was solid colloid,and the rheological properties were consistent with the basic characteristics of hydrogel.BM-MSC-IH effectively promoted the regeneration of mouse knee cartilage and increase the local expression of typeⅡ collagen.Conclusions Bone marrow-mesenchymal stem cells embedded with injectable hydrogel effectively pro-mote the repair of injured cartilage and the underlying mechanism is potentially promoting the differentiation of chondrocytes and the expression of type Ⅱ collagen.Its effect is better than application of BM-MSCs alone.

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