Li metal batteries have been considered as the most promising batteries with high energy density for cutting-edge electronic devices such as electric vehicles, autonomous aircrafts, and smart grids. However, Li metal anode faces the issues of safety and capacity deterioration, which are closely related to Li dendrite growth. In this paper, we review the main strategies to improve the performance of Li metal anode. Due to Li dendrite's catastrophic influence, suppression of Li dendrite growth is prerequisite for each strategy. Apart from Li dendrite, interfacial resistance between electrolyte and electrode, ionic conductivity of electrolytes, mechanical strength, and volume fluctuation of Li metal anode are also discussed in these strategies. We outline these strategies based on the classifications of constructing solid electrolyte interphase, engineering of solid-state electrolyte and adopting matrix for Li metal anode. Each strategy is illustrated and discussed in detail by exemplification. For better understanding, some important theories related to Li metal anode have been also introduced. Finally, the outlooks for future research of Li metal anode are presented. Li-ion batteries (LIBs) have achieved great success since their commercial application in portable electronic devices in 1991  and lowest electrochemical potential (−3.04 V vs. the standard hydrogen electrode), and consequently it has been considered as an ideal anode for the rechargeable batteries such as Li-S and Li-O2 batteries  diffusion of Li+ ions, rather than one direction diffusion in flat surfaces, thereby accelerating Li precipitation on the tips , but the different dendrites have a similar mechanism on their formation and growth .SEI was firstly discovered by Peled , and it e of SEI . AccordiThe most severe problem of Li metal anode is Li dendrite growth on its surface, which not only causes catastrophic safety hazards, but also greatly deteriorates the performance of Li metal anode. Therefore, suppression of Li dendrite growth is prerequisite for each strategy. Nevertheless, some methods are effective to suppress Li dendrite formation, but they can also induce disadvantageous influence on the property of LMB at same time. Therefore, an optimal strategy should maximize the performance of Li metal anode while it can effectively suppress the formation of Li dendrites.4, LiBr, and LiAsF6  and organ polymers. Carbon is one of the commonly used inorganic materials for artificial SEI film. Zhang et al. have successfully coated a-CNx layer on the Li metal anode by magnetron sputtering technique  (PDMS) layer using spin-coating method, and then the layer was treated by HF acid, intentionally constructing nanopores as the pathways for transporting Li+ ions in the PDMS layer  can probably settle these safety issues .Synthesis method, including mechanical mixing and + ions. In the composite electrolyte, polymer can act as a binder to connect the inorganic electrolyte while maintaining high mechanical flexibility. The investigation conducted by Zhang et al. indicated that the utilization of nanosized solid inorganic electrolyte can greatly increase its contact area with PEO, and thus it significantly enhances the ionic conductivity of the composite electrolyte .Nanosized inorganic electrolytes. It is known that nanocrystallization can lead to high ionic conductivity because it can improve the diffusion routes for Li6.4La3Zr2Al0.2O12 (LLZO) nanofiber by electrospinning way, and then added the fillers into the PEO matrix, resulting in a 3D inorganic/polymer network. In the electrolyte, the randomly distributed nanofibers together with the interconnected nanofibers constitute the 3D networks, which are the framework for transporting continuous Li+ ion . Compared with 0D inorganic particles, 1D nanowire filler can induce larger contact area between the inorganic and polymer electrolytes, hence ameliorating the mechanical performance. In addition, 1D inorganic fiber fillers are very beneficial to form an ionic conduction networks in the composite electrolyte, significantly increasing the ionic conductivity of the electrolyte. Fu et al. synthesized a garnet-type LiApart from the ionic conductivity, the interfacial resistance between electrode and electrolyte is another important issue in the solid-state electrolyte.2O3 with an atomic layer deposition technique 3 with a rhombohedral structure react with Li metal anode at room temperature to form a Li+-conducting passivation layer 3 and also are wet by Li, thus resulting in a small Li+ charge transfer resistance at the interface. Recently, introduction of a third phase is commonly used to decrease the interfacial resistance. For example, addition of little liquid electrolyte can effectively wet the solid-state electrolyte, and ameliorate the contact between the Li metal anode and electrolyte, considerably decreasing the interfacial resistance , cells with GF layers exhibited enhanced coulombic efficiencies . Using graphene oxide (GO) as a porous matrix for Li metal, Lin et al. prepared Li-reduced oxide (rGO) by a facile “spark” technique  at 10 C using lithium cobalt oxide cathode.Liang et al. utilized lithiophilic oxidized polyacrylonitrile nanofiber (PAN) as a matrix to modify Li metal anode and the investigation indicated that the nanofibers can maintain the stable cycling performance of Li metal anode with a high coulombic efficiency (~97.4%) for 120 cycles at the current density of 3 mA cm+ ions to plate in it, instead of on the tip of the formed Li dendrites, consequently suppressing the Li dendrite growth. This assumption was verified by preparing Li7B6 with 3D structure (Cheng et al., 7B6 anode achieved a dendrite-retarded morphology at a high current density of 10 mA cm−2, while the normal Li plate anode rendered severe dendrite formation. Besides Li7B6, several structured Li metal anodes have been also developed, such as carbon nanotubes, graphene materials, carbon nanofibers, and Cu nanowires. The matrix plays a pivotal role for Li metal anode in that it can not only suppress Li dendrite growth, but also effectively relieve the large volume change during Li plating/stripping. However, the ratio of the matrix in the composite Li metal anode needs to optimize to ensure the high volume/mass energy density of the composite anode.A Li metal anode with a conductive matrix possesses excellent electrical conductivity and unique surface chemistry, which can obstruct and recycle the dead Li. Adoption of conductive matrix for Li anode has been demonstrated to be a successful approach to inhibit Li dendrite formation (Cheng et al., For better grasping the essential of the strategies in this review, we summary the main purpose and characteristic for each strategy/method, which are listed in To make Li metal anode to be a viable technology, many strategies have been proposed to overcome the dilemmas of Li metal anode, including the growth of Li dendrites, volume fluctuation, low mechanical strength, and high interfacial resistance between electrolyte and electrode. In this review, we outlined the main strategies to improve Li metal anode according to the classifications of constructing SEI, engineering of solid-state electrolyte and adopting matrix for Li metal anode. For better understanding, we illustrated the preparation, characteristic and mechanism of each strategy in detail by exemplification. Although great progress has been made in theoretical and experimental investigations, Li metal anode is in the early stage of LMBs development. We think that the following researches on Li metal anode should be further strengthened.+ ions transport through the interface of ceramic/polymer in the inorganic/polymer electrolyte while later investigations demonstrated that the ceramic phase is the transport channel for Li ion. This discovery rendered a revolution in designation of the composite electrolyte.More detailed and deeper theories on Li anode should be developed to guide the design of SEI, solid-state electrolyte and structured anode. For example, several models have been proposed to explain Li nucleation and growth, but they are limited to some specific parameters. A more general mechanism should be need to understand the whole process for Li dendrite growth. For another example, previous theories held that the LiA joint strategy is required to solve the problems of Li metal anode. Although each strategy has its unique advantage to deal with a dilemma of Li metal anode, it also has its own fatal weakness. For example, solid polymer electrolyte has enough mechanical strength to suppress the Li dendrite, but its ionic conductivity is very low. The joint strategy combining various methods can fully takes advantages of each method, and the synergetic effect among them could ultimately make Li metal anode a viable technology.With the development of science and technology, the advanced electronic devices are successively emerging and they urgently need high energy density batteries as their power sources. In addition, the rise of nanotechnology and advanced characterization technique render the golden age for LMBs researches. The problems hindering the application of Li metal anode will be perfectly solved, and the era of LMBs will come true in the near future.All authors wrote the manuscript. ZH and YZ supervised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors YZ.


The metal chloride perovskite protection strategy could open a promising avenue for advanced lithium metal batteries.Fabricating a robust interfacial layer on the lithium metal anode to isolate it from liquid electrolyte is vital to restrain the rapid degradation of a lithium metal battery. Here, we report that the solution-processed metal chloride perovskite thin film can be coated onto the lithium metal surface as a robust interfacial layer to shield the lithium metal from liquid electrolyte. Via phase analysis and density functional theory calculations, we demonstrate that the perovskite layer can allow fast lithium ion shuttle under a low energy barrier of 0.45 eV without the collapse of framework. Such perovskite modification can realize stable cycling of LiCoO Metal halide perovskite is well-known for the high absorption coefficient; however, its Li-ion transport property remains poorly explored. Here the authors coat an ion conducting metal chloride perovskite interfacial layer on the Li metal anode, enabling good battery performance. It stimulates extensive search of new materials to meet the increasing demands of high-energy densities of rechargeable batteries4. With 10 times the specific capacity of graphite (3860 versus 370 mAh g−1), metallic lithium (Li) is among the most promising candidates for future anode to support high-energy density batteries6. However, the practical application of Li metal batteries is hindered by a major issue associated with loose structure of deposited Li during cycling, which would result in accelerated electrolyte “dry-out” failure and probably short circuit of the battery7.Rapidly developing electronic devices provide us with better product experience, but simultaneously set a higher standard for energy storage systems9. In the early stage to reinforce the SEI layer, various electrolyte additives, including vinylene carbonate10, LiNO311, and fluorinated ethylene carbonate12, have been tried, but the obtained mechanical strength is not enough to suppress the growth of Li dendrites. Lately, the fabrication of artificial SEI protection layer via pre-treatment methodology has been proposed. A series of artificial SEI protection layers, including carbon spheres13, polymers15, alloy layer16, composite films18 have been applied on the surface of Li metal anodes. Despite these artificial SEI layers exhibited the capability to suppress the growth of Li dendrites19, the ultra-dense deposition of Li along with the suppressed detrimental side reactions with liquid electrolyte have not been achieved due to the permeation of liquid electrolyte throughout the protection layers.The solid electrolyte interphase (SEI) layer on the surface of Li metal anode plays a predominate role in controlling the deposition of Li metal20. To design a dense interfacial layer for Li+ ion conduction, the framework structure of material should own continuous channels for Li+ ion migration22. The perovskite structure with the general formula ABO3  provides a highly symmetric host to generate a classical Li+ ion conductor, lithium lanthanum titanate (LLTO)23, but the fabrication of this perovskite host needs high temperature sintering25, which hindered the application of LLTO thin film on the surface of Li metal anode. Similar to the LLTO perovskite solid electrolyte, other ceramic Li+ ion conductors with high shear modulus are also very challenging to be coated as thin films on the Li metal anodes due to their critical preparation conditions27.Directly fabricating a highly ionic conductive dense thin film on the surface of Li metal anode is a promising route to fully shield the Li metal from liquid electrolyte3  can be produced as the form of thin film via a facile solution-processable method30. The metal halide perovskites have shown high photoelectric conversion efficiency in planar solar cells and attracted intensive attention in the past decade31. Aside from their unique photo-electronic properties, the framework feature of metal halide perovskite can realize the Li+ ion intercalation33, indicating its potential as a fast Li+ ion transport material. In addition, to be an electronic insulating layer, metal halide perovskites can get its bandgaps enlarged by using chloride ions as the halide sources34. These features of metal chloride perovskite make it as an attractive interfacial material with high Li+ ion transport capability to isolate the Li metal anode from liquid electrolyte.As a new kind of perovskite, metal halide perovskite with a general formula ABX+ ion transport throughout its framework with a low energy barrier, endowing homogenous ion flux with excellent isolation from liquid electrolyte. Thus, the ultra-dense deposition of Li with high areal capacity (30 mAh cm−2) induced by a high current density of 5 mA cm−2 is demonstrated and the Li metal anode under the protection of metal chloride perovskite exhibits a stable Li stripping/plating voltage curve (<40 mV) at the current density of 1 mA cm−2 for over 800 h. Attractively, with lean electrolyte (20 μl mAh−1) and thin Li foil (50 μm), the LiCoO2-Li cell with an areal capacity of 2.8 mAh cm−2 can be cycled for more than 100 cycles.Herein, we develop a solid-state transfer process to apply solution processed metal chloride perovskite thin film as a new type of interfacial layer onto the Li metal anode. The metal chloride perovskite interfacial layer can allow fast Li+ ion transport gradient layer model to illustrate the shielding mechanism of perovskite thin film for the dense deposition of Li metal  calculation to simulate the migration of Li+ ions in the perovskite framework  and the potential energy surface along the migration pathway of Li+ ion is shown in Fig. + ion at its initial state, transition state and final state are displayed as the insets. To accommodate the migration of Li+ ions, the lattice undergoes mild yet measurable distortion, accompanied by the orientation adjustments of MA ion due to the nonuniform distribution of electric potential in the lattice 35, indicating the ease of Li+ ion conduction in the metal chloride perovskite framework.To unravel the conduction mechanism of Li3 or MAPbCl3 with high film quality on the substrates via solution spin-coating technique at first . Such highly oriented crystalline structure is consistent with our proposed framework structure in Fig. + ion transport throughout the perovskite layer.To demonstrate the gradient layer model of the perovskite, we fabricated the metal chloride perovskite thin films composed of MASnCl+ ions appearing at the potential peak higher than 1 V  in comparison to the flat current curve in the CV of bare substrate without the characteristic Li+ ion intercalation process. The other CV peaks with the potential around 0.4–0.7 V belong to the reduction process of interfacial perovskite to Li-Sn or Li-Pb alloy, and the final state of as-formed alloy is Li17Sn4 or Li17Pb438. As the potential approaches to −0.1 V, the current density of the substrate with MASnCl3 or MAPbCl3 is around 1.5 mA cm−2, much higher than the current density of bare substrate (~0.6 mA cm−2). Similarly, at the symmetric voltage position near +0.1 V, the perovskite-modified substrates also present much higher response currents, indicating the promotion of Li plating/stripping kinetics by the perovskite thin films. To further show the unique role played by the perovskite framework rather than as-formed Li–M alloy layer, we compared the CV curves of MAPbCl3 and PbCl2-coated substrates  of Li plating on these thin film-coated substrates and compared them to that of bare substrate. As shown in Fig. trate ~0. mA cm−2.3 and 15 % for MAPbCl3), corresponding to the absolute quantities  of perovskites, was reduced to form Li17Sn4 or Li17Pb4 layer. The limited perovskite consumption independent of the original thickness values of perovskite layer implies that the perovskite thin films are not completely reduced due to the formation of insulating LiCl layer, as well as the intrinsic property of wide band gap of metal chloride perovskite to isolate electrons coming from the current collector. Therefore, the finally formed gradient interfacial layer is consisted of perovskite framework on the top surface followed by the Li–M alloy/LiCl layer beneath, which is evidenced by the depth X-ray photoelectron spectroscopy (XPS) analysis  analyses  in vertical direction near the surface, implying a perovskite-alloy-lithium interfacial layer on the Li metal anode surface to resist the liquid electrolyte corrosion. Similarly, the ultra-dense Li deposition can be also realized on the MPC-Li anode with the retention of perovskite protection layer  was performed to deeply expose the cross-sectional morphologies of bare Li and MSC-Li after 2 h Li plating under a current density of 4 mA cm+ ion transfer kinetics caused by as formed nonuniform SEI layer. The symmetric cell of MPC-Li electrodes also shows attractive advantages with low overpotential of around 40 mV and a stable cycling life of over 600 h , which indicates the chemical stability of perovskite on the top surface of MSC-Li and high consistence with the XRD result. The XPS result is similar for MPC-Li electrode, showing that the lead on the top surface of MPC-Li electrode always retained the oxidation state before and after cycling /perovskite coated Li cells at a high rate of 5 C. As shown in Fig. −1 at 400th cycle. In contrast, the cells using MSC-Li and MPC-Li anode show stable cycling for more than 500 cycles with a low capacity decay rate of 0.07 % per cycle. The charge/discharge voltage profiles in Fig. To demonstrate the efficiency of perovskite protection for Li metal batteries, we tested the electrochemical performance of Li−2), limited Li source  and lean electrolyte (20 μl mAh−1) in the LiCoO2|Li cell at 0.5 C. As shown in Fig. We further explored the performance of perovskite protected Li metal battery by applying strict conditions including high-areal capacity cathode  and 0.948 g of stannous(II) chloride  were dissolved in 10 mL of N, N-dimethylformamide  to form MASnCl3 precursor solution with a concentration of 0.5 M. 0.676 g of methylamine hydrochloride . For MAPbCl3 perovskite thin films, 2.781 g of Lead chloride  were dissolved in 10 mL dimethyl sulfoxide  to form MAPbCl3 solution with a concentration of 1 M. Each type of as-prepared perovskite precursor solution was spun-coated onto UV–ozone treated stainless steel foil substrate (50 μl for every 1 cm−2 of substrate area) at 2000 r/min for 90 s. Then the perovskite coated stainless steel foils were annealed at 70 °C for 5 min. All the MASnCl3 and MAPbCl3 thin films were fabricated and stored in an argon-filled glove box with <1 ppm O2 and <1 ppm H2O.Stainless steel foil (50 or 100 μm) was washed with deionized water, acetone and ethanol in an ultrasonic cleaner  sequentially before drying in an oven at 70 °C for 30 min. For MASnCl−2 for 10 s. The perovskite thin film can be easily transferred from the stainless steel substrate onto the surface of Li metal after separating the Li foil from the stainless steel substrate. MSC-Li and MPC-Li electrodes are thus obtained. The transfer operations were performed at the room temperature of 25 °C in the glove box with <1 ppm O2 and <1  ppm H2O.Li metal foil  was polished to remove the oxidation layer to obtain a smooth and shinning surface. Then, the as-treated Li foil was pressed onto the perovskite-coated substrate with a pressure of 10 N cmλ = 0.15406 nm). The samples were tested in the Kapton tape-sealed devices for the XRD characterizations . All the Li electrodes unloaded from coin cells were washed with a mixed solvent of ethylene carbonate/dimethyl carbonate (EC:DMC = 1:1 vol%) and thoroughly dried before characterizations. All the characterizations were performed at the room temperature of 25 °C.XRD measurements were carried out on a X-PERTPRO powder X-ray diffractometer operating at 40 kV and 30 mA with a scanning step of 0.02 degree, using Cu K radiation (6 in ethylene carbonate/dimethyl carbonate (EC:DMC = 1:1 vol%). In deposition experiments tests using perovskite-coated stainless steel foils as electrodes, electrolyte containing 1 M LiPF6 in ethylene carbonate/dimethyl carbonate (EC:DMC = 1:1 vol%) with 2 vol% fluorinated ethylene carbonate (FEC) was applied. Supplementary Tables 6 in ethylene carbonate/dimethyl carbonate (EC:DMC = 1:1 vol%) with 1 vol% fluorinated ethylene carbonate (FEC) was applied. The Li4Ti5O12 (LTO) cathodes used for full cell tests were made by blade-coating the N-methyl-2-pyrrolidone (NMP) slurry composed of 80 wt% Li4Ti5O12 powder, 10 wt% super-P and 10 wt% poly(vinylidene difluoride) (PVDF) onto carbon-coated Al foil. The areal loading of active material is 3.2 mg cm−2. The LiCoO2 (LCO) cathodes were made by blade-coating the N-methyl-2-pyrrolidone (NMP) slurry composed of 80 wt% LiCoO2 powder, 10 wt% super-P and 10 wt% poly(vinylidene difluoride) (PVDF) onto carbon-coated Al foil. The areal loading of active material is 20 mg cm−2. Thin Li foil with thickness of 50 μm was purchased from Cellithium company. Electrochemical impedance spectroscopy (EIS) was tested on a VMP-3 (Biologic) electrochemical working station with a frequency range of 100 kHz to 100 mHz and an amplitude of 10 mV. Cyclic voltammetry tests were performed on a VMP-3 (Biologic) electrochemical working station with voltage ranges of 1 V to −0.1 V for perovskite-coated stainless steel foils at a scanning rate of 1 mV s−1. Other electrochemical data including cycling tests of Li/Li symmetric cells and Li/LTO full cells was collected by a multi-channel cell testing station . All the electrochemical measurements were conducted at a constant temperature of 25 °C.All the electrochemical tests were performed using CR2032 coin cells with a layer of commercial polypropylene (PP) separators . The electrolyte used for electrochemical deposition experiments on MSC-Li and MPC-Li electrodes, optically transparent cells, symmetric cells and full cells was 1 M LiPFSupplementary InformationPeer Review File


Background: Overuse of antibiotics significantly fuels the development of Antimicrobial resistance, which threating the global population health. Great variations existed in antibiotic prescribing practices among physicians, indicating improvement potential for rational use of antibiotics. This study aims to identify antibiotic prescribing patterns of primary care physicians and potential determinants.Methods: A cross-sectional survey was conducted on 551 physicians from 67 primary care facilities in Hubei selected through random cluster sampling, tapping into their knowledge, attitudes and prescribing practices toward antibiotics. Prescriptions  made by the participants from 1 January to March 31, 2018 were extracted from the medical records system. Seven indicators were calculated for each prescriber: average number of medicines per prescription, average number of antibiotics per prescription, percentage of prescriptions containing antibiotics, percentage of antibiotic prescriptions containing broad-spectrum antibiotics, percentage of antibiotic prescriptions containing parenteral administered antibiotics, percentage of antibiotic prescriptions containing restricted antibiotics, and percentage of antibiotic prescriptions containing antibiotics included in the WHO “Watch and Reserve” list. Two-level latent profile analyses were performed to identify the antibiotic prescribing patterns of physicians based on those indicators. Multi-nominal logistic regression models were established to identify determinants with the antibiotic prescribing patterns.Results: On average, each primary care physician issued 909  prescriptions over the study period. The mean percentage of prescriptions containing antibiotics issued by the physicians reached 52.19% (SD = 17.20%). Of those antibiotic prescriptions, an average of 82.29% (SD = 15.83%) contained broad-spectrum antibiotics; 71.92% (SD = 21.42%) contained parenteral administered antibiotics; 23.52% (SD = 19.12%) contained antibiotics restricted by the regional government; and 67.74% (SD = 20.98%) contained antibiotics listed in the WHO “Watch and Reserve” list. About 28.49% of the prescribers were identified as low antibiotic users, compared with 51.18% medium users and 20.33% high users. Higher use of antibiotics was associated with insufficient knowledge, indifference to changes, complacency with satisfied patients, low household income and rural location of the prescribers.Conclusion: Great variation in antibiotic prescribing patterns exists among primary care physicians in Hubei of China. High use of antibiotics is not only associated with knowledge shortfalls but also low socioeconomic status of prescribers. Antimicrobial resistance (AMR), one of the most alarming threats to global health, has resulted in significant human and economic loss worldwide. It was estimated that AMR led to 700,000 deaths in 2014 . WithoutOveruse of antibiotics is widely believed to be associated with the development of AMR . Given tPast studies revealed that great variations existed in antibiotic prescribing practices among physicians , which cInternationally, both restrictive and persuasive measures have been attempted to curtail irrational antibiotic prescribing behaviors . But verThis study aimed to identify individual antibiotic prescribing patterns in primary care physicians through latent profile analyses, a method that categorizes prescribing behaviors using multiple indicators. Our current understanding about antibiotic prescribing patterns is quite limited . Previou2 and more than 59 million populations. With a gross domestic product at $8,915 per capita in 2017, its economic status is ranked in the middle range of all provinces in China. According to the World Bank  having the authority to independently prescribe antibiotics; 2) having issued at least 100 prescriptions during the three-month study period, which contained at least one antibiotic prescription.In total, 645 physicians met the inclusion criteria and 551 (85.58%) agreed to participate in the study. Of those who agreed, 458 (71.01%) returned a valid questionnaire.Eight field investigators were recruited and trained to conduct data collection. A pair of the trained investigators visited each participating facility. The investigators had no servicing relationships with the facilities or their employees at the time. All eligible primary care physicians were approached and invited to participate in the study. Informed written consents were obtained prior to data collection.n = 458) during 23 April to June 6, 2018, tapping into their socioeconomic status and professional characteristics, and their knowledge and attitudes toward antibiotic prescribing. The respondents were asked to complete the questionnaire independently, which took roughly 15 min. A token gift ($1.65) was given to those who returned the questionnaire to the investigators. Missing items, if any, were re-filled by the investigators through an additional interview.Prescribing records issued by the 551 study participants over a three-month period (1 January–31 March 2018) were extracted from the medical records system of the participating facilities, including the name, formulation, dosage, administration route, and price of the prescribed medicines, and information about the prescribers and facilities. This was followed by a questionnaire survey of prescribers  “Watch and Reserve List.”Seven indicators were identified for measuring antibiotic prescribing patterns through a comprehensive literature review and expert consultations:The first three indicators were adapted from the prescribing indicators recommended by the WHO . They meWe added two additional indicators (indicator 4 and 5) in order to better assess irrational prescribing of antibiotics. Empirical evidence shows that broad-spectrum antibiotics is frequently used and is perhaps the most common form of antibiotic abuse in primary care . In addiOver the past two decades, China introduced some restrictive measures to reduce irrational antibiotic prescribing. These included a list of restricted antibiotics for primary care imposed by the regional governments . RestricAntibiotic prescribing behaviors can be influenced by the knowledge and attitudes of prescribers, their personal circumstances, availability of guidelines and influence of pharmaceutical companies, especially in LMICs. . PrescriThis study used a 37-item questionnaire to measure the knowledge, attitudes and personal circumstances of prescribers. The questionnaire was developed based on some existing instruments  with furThe questionnaire respondents were asked to indicate whether they agreed to prescribe antibiotics for 11 common conditions such as upper respiratory tract infections and diarrhea . A correThe attitudes of the questionnaire respondents toward antibiotic prescribing were assessed by 17 items, coded as a 5-point Likert scale . The scores were summed up to measure the tendency of complacency to satisfied patients (0–8 measured by four items), fearful of adverse events (0–12 measured by six items), ignorance of AMR (0–16 measured by eight items), indifference to changes (0–4 measured by two items), and responsibility avoidance by blaming others (0–28 measured by seven items), respectively . All iteThe personal circumstances measured in this study included the demographic characteristics (age and gender) of the respondents, and their socioeconomic status  and professional experiences . These factors have been proved to be significant determinants of antibiotic prescribing behaviors .Two datasets were prepared for data analyses. The first dataset contained 501,072 prescriptions made by 551 primary care physicians. For each physician, the seven prescription indicators were calculated. Antibiotics were defined according to the Anatomical Therapeutic Chemical (ATC) classification system and included only systemic use of antibiotics (ATC code J01) . They weTo determine the antibiotic prescribing patterns, latent profile analyses (LPA) were performed using the seven prescribing indicators at the physician level. LPA belong to finite mixture modeling which can identify and describe “hidden groups” within a population. Because the 551 physicians were clustered in 67 primary care facilities, a two-level LPA model was established. Differences at the facility level were treated as random effect. Maximum likelihood parameter estimates with standard errors (MLR) were applied. The model identification was checked using 1,000 initial stage starts and 1,000 final stage starts .p value (>0.05) represents a lack of statistical significance between the two compared models. cmP provides an overall assessment of all estimated models and a larger cmP value indicates a better model fit. Entropy assesses the accuracy of classification, with a higher value indicating better classification , Sample-size Adjusted BIC (SABIC), Vuong-Lo-Mendell-Rubin Adjusted Likelihood Ratio Test (VLMR-LRT), Correct Model Probability (cmP) and Entropy. A lower value of BIC and SABIC indicates better fitness of data into the estimated model. VLMR-LRT compares the model fit between two neighboring models . A non-significant fication . To avoiThe second dataset contained the 458 returned questionnaires, as well as the classification of the antibiotic prescribing patterns of the 458 respondents. A three-group model was identified in the LPA. Each questionnaire respondent was assigned into one of the antibiotic prescribing pattern groups with the highest probability.Differences in knowledge and attitudes scores and personal circumstances among the respondents in different antibiotic prescribing pattern groups were examined using Kruskal-Wallis rank tests, one-way analysis of variance (ANOVA), or chi-square tests. Post-hoc pairwise comparisons were performed using Dunn and Bonferroni tests. Multi-nominal logistic regression models were applied to determine significant factors predicting the three groups of antibiotic prescribing patterns after adjustments for variations in other factors. In the regression analyses, knowledge and attitudes scores were transformed into dichotomous variables with mean scores serving as a cut-off point. An enter approach was adopted in the modeling.p value < 0.05 was treated statistically significant.The statistical analyses were conducted using STATA (version 12.0) as well as Mplus (version 6.0). A On average, 909  prescriptions were issued by the 551 participating physicians over the three-month study period. Each physician prescribed an average of 2.87 (SD = 0.78) medicines and 0.65 (SD = 0.26) antibiotics per prescription, respectively. Of the prescribed antibiotics, cephalosporins (J01D) was the most commonly used (38.50%), followed by macrolides .The mean percentage of prescriptions involving antibiotics prescribed by the physicians was 52.19% (SD = 17.20%). Of those prescriptions containing antibiotics, an average of 82.29% (SD = 15.83%) involved broad-spectrum antibiotics; 71.92% (SD = 21.42%) involved parenteral administered antibiotics; 23.52% (SD = 19.12%) involved restricted antibiotics imposed by the provincial government; and 67.74% (SD = 20.98%) involved antibiotics listed in the WHO “Watch and Reserve” list .TABLE 1PThe latent profile analyses  identifiThe 20.33% high antibiotic prescribers contributed to 23.56% of prescribed medicines, 24.48% of prescribed antibiotics, 26.27% of broad-spectrum antibiotics, 27.84% of parenteral administered antibiotics, 23.65% of government-restricted antibiotics, and 27.36% of antibiotics in the WHO “Watch and Reserve” list.The 458 questionnaire respondents had an average age of 43.5 years (SD = 9.3) and 72% were male. Only 38.2% obtained a university degree. The vast majority worked in a rural setting (78.0%) and had an annual household income of less than 80,000 yuan (79.5%). About 48% of the respondents worked as a general practitioner. Slightly more than half (51.1%) had a junior professional title. The average knowledge score of the respondents sat in the middle range even though more than 75% reported attending continuing education on antibiotics .TABLE 2Cp = 0.003), had a lower educational qualification (p = 0.018), lived with a lower household income (p < 0.001), worked in rural facilities (p < 0.001), had a junior professional title (p = 0.017), and had a lower knowledge score (p = 0.002) were more likely to be in the high user group. There were also significant differences in the antibiotic prescribing patterns across sub-specialties (p = 0.025)  .The multinomial logistic regression analyses confirmed that knowledge, attitudes, clinical experiences, household income and workplace settings were significant predictors of the antibiotic prescribing patterns after adjustments for variations in other variables .TABLE 3Mp = 0.005) or high  antibiotic user groups as compared with the odds of low antibiotic user group. Similarly, those who reported lower indifference to changes were also less likely to be assigned into the medium  or high  antibiotic user groups. However, the respondents with lower complacency to satisfy patients were more likely to be assigned into the medium antibiotic user group only  as compared with the odds of low antibiotic user group.The respondents with a higher than average knowledge score were less likely to be assigned into the medium (Relative Risk Ratio (RRR) = 0.440, p < 0.001) or high  antibiotic user groups as compared with the odds of low antibiotic user group. The odds of being assigned into the medium  and high  antibiotic user groups decreased with household income. The respondents with an older age had a slightly lower odds of being assigned into the high antibiotic user group . But longer years of practice slightly increased the odds of being assigned into the high antibiotic user group .The respondents who worked in a rural facility were more likely than their urban counterparts to be assigned into the medium , much higher than the maximal level of 30% as recommended by the WHO . Of the About 20.33% of the prescribers in primary care were identified as high users of antibiotics in this study, compared with 51.18% medium users and 28.49% low users. This is a result of the combined effect of the seven prescribing indicators. The high user group contributed disproportionally across all the seven indicators. Previous studies usually classify high antibiotic prescribers using a single indicator .This study shows that great variation in primary care physicians’ antibiotic prescribing patterns in Hubei of China, which is shaped not only by the knowledge and attitudes of the prescribers, but also by their personal circumstances. High levels of antibiotic knowledge and attitudes in favor of practice changes are associated with low use of antibiotics. But lower household income and rural facilities are associated with high use of antibiotics.It seems that antibiotic prescribing in primary care in Hubei declined over time. The percentage of prescriptions containing antibiotics dropped from 68% in 2011  to the lDespite the decline, irrational antibiotic prescribing remains a serious issue of concern. The use of parenteral route for antibiotics is still very high at an average level of 71.92% as a proportion of antibiotic prescriptions, despite a slight decline in comparison with the level (84%) five years ago . The higThe domination of broad-spectrum antibiotics in antibiotic prescribing in Hubei of China is comparable to findings of other studies. A study monitoring antibiotic sales in primary cares in Hubei showed that broad-spectrum antibiotics were increasingly used in recent years, rising from 74.87% as a proportion of antibiotic sales in 2012 to 85.69% in 2017 . This isHowever, ignorance of the WHO AWaRe list in Hubei of China deserves increasing policy attention. There is serious under-use of the antibiotics in the WHO “Access” list in Hubei. The mean percentage of antibiotic prescriptions covered in the WHO “Access” list did not exceed 33% in the primary care participants in this study. This level is very low compared with the percentage of 60.17%–63.29% of “Access” antibiotics prescribed in primary care in the United Kingdom over the period from 2011 to 2017 . AlthougIn this study, three distinctive groups of prescribers were identified through the LPA. Great variations in the seven indicators across the three groups were revealed. The gap in the percentage of prescriptions containing antibiotics reached 2.02 times between the high and low user groups (74.43% vs. 36.76%). Despite a shortage of studies comparing individual prescribers, many existing studies point to the great variations in antibiotic prescribing across facilities and regions . The EurThis study found that knowledge and attitudes are significant predictors of antibiotic prescribing patterns in primary care, which is consistent with findings of previous studies . Good knPrescribing behaviors can also be shaped by work and policy environments , as wellHousehold income was found to be a significant predictor of high use of antibiotics in primary care. This is not surprising given that prescribing can bring financial gains to the prescribers in the Chinese health system. Although primary care workers are no longer able to make a profit margin on sales of medicines, a service fee and charge for disposable syringes can still be collected . PerversTo address AMR, many countries and institutions have established a surveillance system monitoring the use of antibiotics. The LPA adopted in this study can help identify high antibiotic prescribers. Such a strategy should only be used for targeted interventions for continuing quality improvement. It is inappropriate to punish those deemed “high users” because the major drivers of high use of antibiotics come from the system, not the individuals .To curb overuse of antibiotics in primary care in China, multiple strategies need to be taken. Both restrictive and persuasive measures should emphasize on the overall reduction of antibiotic prescriptions, as well as the limited use of broad-spectrum, parenteral administrated, and the WHO “Watch and Reserve” antibiotics. In addition, the regional list of restricted antibiotics imposed by the government should be better aligned with the WHO AWaRe list. Significant increase in governmental budget support to primary care is needed to break the perverse financial incentives .In addition, several potential initiatives could be considered to help change physicians irrational antibiotic prescribing patterns, which have been highlighted in existing evidence , includiExtensive studies have been undertaken to explore variations in antibiotic prescribing practices . But verThis study identified factors associated with antibiotic prescribing patterns based on an extended knowledge-attitude-practice theory, a framework commonly used for exploring behaviors of health practitioners . ValidatThere are several limitations to be mentioned. The study was conducted in Hubei province using a cross-sectional design. This does not allow us to draw causal conclusions. The results should not be generalized to other regions. Instead, replications of the study in other regions using the proposed approach are advised. Further studies also need to consider risk-adjustments, in particular in hospital settings where patient conditions vary considerably. This study was not able to adjust the results for variations in patient conditions, simply because such data and risk-adjustment tools were not available.In primary cares, over-use of antibiotics is prevalent in Hubei of China, particularly in the prescribing of broad-spectrum, parenteral administrated and restricted antibiotics. Great individual variation in antibiotic prescribing patterns exists. Those who are deemed high users contribute disproportionally to the inappropriate use of antibiotics. Prescribers worked in a rural setting and those with insufficient knowledge, low motivations for behavioral changes, and low household income are more likely to be high users. To curb physician irrational use of antibiotics in primary care, multiple strategies should to be taken, including developing a surveillance system comprehensively monitoring and analyzing physician antibiotic practices, training and education emphasizing on broad-spectrum and parenteral administrated antibiotic use and sufficient financial support for primary cares to break incentives.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by This study has been approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (No: IORG 0003571). The patients/participants provided their written informed consent to participate in this study.CXL designed the project and participated in the collection and interpretation of data. DW contributed to the acquisition, analysis and interpretation of data and drafted the manuscript. CJL participated in data analysis, interpretation of results, and writing of the manuscript. XZ participated in the cleaning and interpretation of data. All authors have read and approved the final version of the article.This study was funded by the National Natural Science Foundation of China (grant no. 71373092 & 71904053). The funding body played no part in the study design, collection, analysis and interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Inappropriate and over-prescriptions of antibiotics is commonly witnessed worldwide, contributing to antibiotic resistance and threatening global health and economic development. To address this issue, promoting physician’s rational prescribing of antibiotics is significant. However, our understanding about antibiotic prescribing patterns is quite limited, despite great variations existed in physician’s antibiotic prescribing practices which indicated huge potential for improvement. Therefore, this study adopted seven indicators to comprehensively assess physician’s antibiotic use behaviors and applied a two-level latent profile analysis to objectively classify physicians into different antibiotic use patterns. In addition, the identified physician’s prescribing patterns were further linked with their knowledge, five sub-kinds of attitudes and personal characteristics to diagnose why physicians showed different antibiotic use patterns. Based on the current study, physicians were classified as three different antibiotic use patterns and those who are deemed as high users contribute disproportionally to the inappropriate use of antibiotics. Higher antibiotic use pattern was linked with insufficient knowledge, indifference to changes, complacency with satisfied patients, limited household income and rural setting of the prescribers. The classification technique used in the current study can help identify high antibiotic prescribers and explore the underlying determinants of their behavioral patterns, informing more targeted interventions generated for improvement.


Background: Currently, there is no comprehensive evaluation of the quality of antibiotic prescribing in China’s primary care facilities based on longitudinal data.Methods: We randomly selected 11 community health centers in Shenzhen, China, and collected all outpatient prescriptions of these centers from 2010 to 2015. To evaluate the quality of antibiotic prescribing, we used six quality indicators for analysis, including number of antibiotics per 100 consultations, ratio between broad-spectrum and narrow-spectrum antibiotics (B/N ratio), percentage of first-line antibiotics recommended by guidelines, percentage of oral antibiotics with a duration exceeding the guideline recommendation, and new pediatric-specific indicators such as percentage of antibiotics with amoxicillin (A index) and ratio between amoxicillin and broad-spectrum antibiotics (A/B ratio).Results: During the study period, 571,362 outpatient consultations resulted in antibiotic prescriptions, which contained 706,411 antibiotics. The overall number of antibiotics per 100 consultations decreased significantly from 93.50 in 2010 to 19.98 in 2015 (p = 0.004), but the B/N ratio showed an upward trend over time (p = 0.009). In different populations and different common infections, the number of antibiotics used decreased to varying degrees, while the B/N ratio increased to varying degrees, with the most obvious change in children <5 years. The percentage of first-line antibiotics for common infections was not high, ranging from 3.45 to 44.25% during 2014–2015. The percentage of oral antibiotics with an exceeded duration ranged from 0.70 to 19.39%. Moreover, the A index and A/B ratio in children remained low for a long time, which was 0.76% and 0.01 in 2015.Conclusion: A review of antibiotic prescribing in Shenzhen, China, showed a substantial reduction in antibiotic use in primary care. However, problems such as widespread use of broad-spectrum antibiotics, insufficient use of first-line antibiotics and low use of amoxicillin were prevalent. Improving and optimizing the quality of antibiotic prescribing, particularly in children prescriptions, will be the focus of future antibiotic stewardship in China. Excessive and inappropriate use of antibiotics not only caused a huge economic burden to global health systems, but also rapidly increased the risk of antimicrobial resistance (AMR). Many countries, including China, are trying to tackle global AMR by reducing unnecessary or inappropriate prescribing . CrucialReliable quality indicators are needed to identify the quality of antibiotic prescribing. A common methodology for collecting and reporting national antimicrobial consumption data developed by the WHO program of surveillance provided information on the level of use and types of antimicrobials to prescribers . The quaGuidelines for Clinical Application of Antimicrobial Agents in China. In 2011, a long-term national antimicrobial stewardship campaign was launched nationwide. In 2012, China also implemented the strictest regulation yet for antibiotic stewardship, the Administrative Measures for Clinical Use of Antimicrobial Agents. Previous studies showed that overuse of antibiotics in China’s medical institutions at all levels have been significantly controlled .International Statistical Classification of Diseases, Tenth Revision (ICD-10) codes was used to classify and code disease diagnoses  classification, code J01 .We first adopted four quality indicators including number of antibiotics per 100 consultations, ratio between broad-spectrum and narrow-spectrum antibiotics (B/N ratio), percentage of first-line antibiotics recommended by guidelines and percentage of oral antibiotics with a duration exceeding the guideline recommendation to evaluate the quality of antibiotic prescribing in the overall populations . Then, tIn China, a patient is typically prescribed one prescription per outpatient consultation. A single prescription contains one or more drugs. The number of antibiotics (J01) per 100 consultations was used to reflect the amount of antibiotics consumed by outpatients. The B/N ratio was expressed as the ratio between the number of broad-spectrum antibiotics used and that of narrow-spectrum antibiotics. The smaller the B/N ratio, the most appropriate the prescribing. The percentage of first-line antibiotics recommended by guidelines was expressed as the percentage of the number of first-line antibiotics used over the total number of antibiotics. The percentage of oral antibiotics with a duration exceeding the guideline recommendation was expressed as the percentage of the number of oral antibiotics with an exceeded duration over the total number of oral antibiotics. So the higher the percentage of first-line antibiotics or the lower the percentage of oral antibiotics with an exceeded duration, the most appropriate the prescribing. Furthermore, the A index was defined as the percentage of the number of amoxicillin (J01CA04) used over the total number of antibiotics. The A/B ratio was defined as the ratio between the number of amoxicillin used and those of broad-spectrum antibiotics. Thus, the greater the A index or A/B ratio, the most appropriate the amoxicillin prescribing for children.In calculating percentage of first-line antibiotics and percentage of oral antibiotics with an exceeded duration, we included the 12 common infections in Chinese guidelines, including acute sinusitis, acute sore throat, acute cough and bronchitis, community-acquired pneumonia, acute otitis media, gastroenteritis, pericoronitis, acute periapical abscess, pelvic inflammatory disease, bacterial vaginosis, acute prostatitis, cellulitis . These ip values <0.05 were considered significant. All statistical analyses were performed using SAS version 9.4 .To explore the quality of antibiotic prescribing in different populations, particularly in children, we performed a stratified analysis by age group . To analyze trends in the quality of antibiotic prescribing, we combined all available annual data into three 2-year time periods  and reported the absolute changes in quality indicators during 2010–2011 vs. 2014–2015. Moreover, we also calculated the total number of excess antibiotic days for 12 common infections, defined as the cumulative number of days beyond the recommended duration in the guidelines. We used linear regression analysis to test linear trends of indicators over time. The confidence interval (CI) was calculated using a logit transformation based on the estimated standard error. All statistical tests were two sided, and Between 2010 and 2015, 1,482,223 outpatient consultations were conducted from 11 participating CHCs. Of these, 571,362 (38.55%) consultations led to antibiotic prescriptions, which contained 706,411 antibiotics. Among all antibiotic prescriptions, 79,496 (13.91%) antibiotic prescriptions were issued in young children <18 years. And the top three systematic diagnoses for antibiotic prescriptions were the diseases of respiratory, digestive, and genitourinary systems, accounting for 69.54, 9.84, and 8.49%, respectively. Among all antibiotics, the frequencies of oral antibiotics used were 337,208 (47.74%). A total of 90% of antibiotics were in turn covered by cephalosporins, macrolides, aminoglycosides, quinolones, imidazoles, and penicillins, involving 23 antibiotic classes. See p = 0.004). The number of antibiotics used in different age groups decreased to different degrees, and the decrease was most evident in children aged <5 years, from 85.47 in 2010 to 10.37 in 2015 (p = 0.009) (p = 0.009), and the increase was also most evident in children aged <5 years (p = 0.020) (p = 0.054) (p = 0.181)  . The ove= 0.020) . Referri= 0.054) . The per= 0.181) . Detailep = 0.198), the number of antibiotics used for other infections decreased to varying degrees. Acute otitis media decreased the most, with the number of absolute antibiotic changes per 100 consultations being −93.73 between 2010–2011 and 2014–2015 (p < 0.001) (p = 0.026), 19.39% (95% CI: 18.32–20.49%) was still found in this percentage of acute cough and bronchitis  . The B/N< 0.001) . Moreove< 0.001) . The totonchitis .p = 0.262 and p = 0.539)  . These tThis study comprehensively evaluated the quality of antibiotic prescribing in primary care facilities in Shenzhen, China. We found that, despite a significant decline in the number of antibiotic used, the B/N ratio increased over time, and the percentages of first-line antibiotics used for most infections and the use of amoxicillin in children were low. These inappropriate antibiotic prescribing might be an important aspect of future antibiotic stewardship in primary care facilities.In this study, both the overall antibiotic usage and the use of antibiotics for common infections showed a significant downward trend. This was consistent with those reported in previous studies in China , suggestAdministrative Measures for Clinical Use of Antimicrobial Agents in 2012, was to control the quantity of antibiotic use. For example, the stewardship campaign required that the percentage of outpatient prescriptions with antibiotics not exceed 20% by the end of 2013. However, there was no strict control requirement for the appropriate type of antibiotic use, such as broad-spectrum antibiotics. Second, although China formulated the Guidelines for Clinical Application of Antimicrobial Agents in China, insufficient attention had been paid to the implementation of this guidelines in prescribing behaviors. Because there was basically no research on evaluating the type conformity and time appropriateness of antibiotic prescribing based on Chinese guidelines. Therefore, improving the contents of the antibiotic policy and paying more attention to the practice guidelines, so as to guide the prescriber to prescribe antibiotics correctly, are also the work that cannot be ignored in the antibiotic stewardship.Our study suggested that the quality of antibiotic prescribing in Shenzhen’s primary care was not high. This might be due to the following reasons. First, the contents of China’s antibiotic policies were not perfect. The primary objective of these interventions, whether the national antimicrobial stewardship campaign in 2011 or the This study was the first to evaluate in detail the quality of antibiotic prescribing for common infections in primary care facilities in China. Our study selected rich quality indicators, involved many common infections, and carried out the specific evaluations of children. This comprehensive report provided clues to the future antibiotic stewardship from various aspects in China. Second, we used the published Chinese guidelines to evaluate the quality of antibiotic prescribing. This kind of guideline-based evaluation study was of great significance to identify the compliance of prescribers with the guidelines and the rationality of prescribing behaviors. Third, the data of our study were based on the entire prescriptions rather than sampling data, which avoided sampling bias and provided more realistic and reliable assessment. Furthermore, this electronic information system was regularly checked by data inspectors, which ensured the accuracy of the data in this study.However, our study had several limitations when interpreting the findings. First, this study only carried out the evaluation of prescription quality in primary care facilities in Shenzhen. Further studies with wider coverage and larger sample sizes are needed to evaluate the quality of antibiotic prescribing in China’s primary care. Nevertheless, this study serves as a practical case to provide policy makers and researchers with valuable information on prescription quality. Second, only one primary diagnosis, which was determined by the physician based on a patient’s chief complaint, was documented on our prescription records. It was not clear whether the prescriber decided to replace antibiotics or longer the duration of treatment because of the patient’s other diseases or conditions. Thus, the magnitude of irrational antibiotic use in this regard might be overestimated. Third, we did not get records for culture of infecting pathogens in patients. Therefore, we could not identify whether the antibiotic usage was based on empirical or definitive therapy. We also could not combine patients’ prescription records with laboratory results to determine the objective medication regimen developed by the prescribers. This is difficult because we have limited access to outpatient information. This implied the need to strengthen the standardization and integrity of prescription records in primary care facilities in order to provide more reliable data for prescription evaluation. Fourth, there is a time lag in this study. However, considering that inappropriate use of antibiotics in China’s medical institutions is a long-standing problem, the poor quality of these antibiotic prescriptions is unlikely to be improved significantly. Thus, our results should be still applicable. Furthermore, the comprehensive evaluation model of the quality of antibiotic prescribing in this study can optimize antibiotic stewardship and is worthy of reference in other regions.In summary, a practice study in Shenzhen, China, found a significant decrease in the use of antibiotics in primary care facilities. However, the prevalence of broad-spectrum antibiotics in most common infections, the low use of first-line antibiotics, and the poor quality of antibiotic prescribing in children were serious problems. China’s future antibiotic stewardship campaign should be devoted to improving the rationality of antibiotic types and treatment time, and standardizing the content of antibiotic use in children, so as to comprehensively improve the quality of antibiotic prescribing.


In China, more and more older people have encountered a situation called “empty nest.” Meanwhile, the health status of empty-nest older adults is an increasing public health concern. This research aims to examine the effectiveness of Self-Mutual-Group (SMG) model in improving quality of life of the empty-nest older adults to provide a scientific evidence for improving their health.A prospective intervention study was conducted among empty-nest older adults in Taiyuan, Shanxi. Multi-stage stratified random cluster sampling was employed to selected participants. A total of 396 empty nesters were enrolled as participants, of which 204 and 192 were in the intervention and control group, respectively. The intervention group received a seven-month SMG-based intervention. A participant’s quality of life was measured at the baseline and seven months after using the Short Form 36-Item Health Survey (SF-36).P > 0.05). After the intervention, participants’ scores on Mental Component Summary (MCS), Physical Component Summary (PCS), role emotional (RE), vitality (VT), social function (SF), mental health (MH) and general health (GH) increased significantly in the intervention group. Additionally, these scores differed significantly from those in the control group (P < 0.05).No significant difference was found between the intervention and control groups in terms of participant characteristics at baseline . Registration date: 26-04-2018. Retrospectively registered.Study on the ‘SMG’ Health Management Model Based on Community Organization Theory among empty-nest older adults (The online version contains supplementary material available at 10.1186/s12877-021-02155-4. With rapid economic development, the extension of average life expectancy, and the decrease in fertility rate, China has entered a period of accelerated population aging. Currently, on the mainland China, approximately one fifth of the total population is aged 60 years and older, accounting for more than 200 million people . At the Healthy aging is manifested in not only the extension of the life of the older people but also, more importantly, the improvement of their quality of life . HoweverPrevious studies have proposed various interventions to improve the quality of life of the older adults but showed limited effectiveness. Van Uffelen et al.  conducteBased on the above, we focused on improving individuals’ awareness of health management and ability in self-management, mutual-management, and group-management by increasing their self-efficacy, and then constructed a Self-Mutual-Group (SMG) model . ConsideFrom October 2016 to May 2017, a randomized controlled trial was conducted in Shanxi province, located in northern China. A multi-stage stratified random cluster sampling method was used to select participants. The study was approved by the institutional review boards of Shanxi Medical University, which was registered in a clinical trial registry (ChiCTR1800015884). A written informed consent was obtained from all participants.N1 = N2=d: Mean1-Mean2. , σ: the standard deviation of control group. According to the pretest survey, d = 6.77, σ = 15.69, α = 0.05, Zα = 1.96, β = 0.1, Zβ = 1.282. The sample size was determined to be 112. An additional 10% was added to this sample estimate in anticipation that the final sample would include individuals who would not consent to participate in the survey. Thus, the final sample size was estimated to be 150 at least. Factually, a total of 396 empty nesters were enrolled as participants, of which 204 and 192 were in the intervention and control group, respectively. Figure Taiyuan is the capital of the Shanxi Province and has six districts. In the first stage, according to the gross domestic product (GDP) based on the government’s website, the three districts Yingze (high economic level), Jiancaoping (medium economic level), and Jinyuan (low economic level) were randomly selected as the study sites. In the Second stage, each community in the three selected districts was numbered according to the order of communities in the government website, then two communities were selected randomly in each district using a random-number table. Finally, all the empty-nest older adults living in the selected communities were considered candidates for participation in the study. Inclusion criteria were aged greater than or equal to 60 years, who had no cognitive disorder or other mental illnesses, provided informed consent, were willing and able to complete the investigation, and were residing in the community for at least a year before the study. The exclusion criterion was having cognitive disorders or serious diseases, such as deafness, psychiatric disorders, or Alzheimer’s disease. The sample size was estimated according to the following formula The intervention group participated in a seven-month SMG-based intervention, which consisted of three stages: self-management 2 months), mutual-management (2 months), and group-management (3 months). The first stage (self-management) was aimed at the empty-nest older adults individuals to develop their self-health management awareness and ability, such as self-care awareness, active medical awareness, self-health assessment ability, and self-service medical equipment use ability. At mutual-management stage, the empty nesters in the same community were paired according to their age, sex, relationship status, home distance, and other factors to form mutual-management; if necessary, volunteers or study staff members were introduced to participate in the pairing. At this stage, empty nesters can share their experiences and knowledge with each other and provide necessary help through life or emotional support. The third stage involved the implementation of group health management based on the first two levels. Groups were categorized by disease type and residential area. For the former, because the empty-nest older adults often face common health problems, there is a common interest in implementing certain goals. For the latter, the principle of proximity was considered; participants were expected not to drop out of the intervention because of distance problems. Group interventions provided an arena within which participants can both provide and receive support. Details of the intervention are shown in Fig.  months, All participants were invited to complete a self-made standardized questionnaire , which was developed in the United States and designed to allow self-evaluation of quality of life , 20. ThiQuestionnaires were administered at baseline and post-intervention (seven months). The questionnaire was completed following a face-to-face interview between an interviewer and a participant and collected on the spot. To ensure quality, completed questionnaires were checked carefully by quality supervisors after the interview. The response rate was 100%.P value was statistically significant at (P < 0.05).EpiData was used for entering and checking the validity of data, and SPSS 22.0 software for statistical analysis. Data were expressed as mean ± SD (standard deviation). Difference between groups in terms of baseline characteristics was tested using chi-square test. The effect of the intervention versus control conditions was examined using ANCOVA analysis on post-intervention measurement values, controlling for pre-intervention scores. Cohen’s d was provided to evaluate the effect size with a guideline: trivial (< 0.20), small (0.20 to < 0.50), moderate (0.50 to < 0.80), and large (≥0.80) . P valueP > 0.05).Participants’ sociodemographic characteristics are shown in Table F = 105.146, P < 0.001, Cohen’s d = 0.62) and PCS  for intervention and control groups were significantly different. The scores of MCS and PCS increased significantly in the intervention group. Yet, for the eight subscales of QOL, the score changes of each dimension were different. For mental components, the scores on VT , SF , MH  and RE  for intervention and control groups were significantly different. For physical components, except for GH , no significant differences in the scores on PF, RP, and BP were observed between the intervention and control groups.The mean scores on the SF-36 for intervention and control groups at baseline and after the seven-month follow up are shown in Table The main finding of this study was that in comparison to the control group, empty nesters who participated in the seven-month SMG-based intervention had significant improvement in quality of life. The mean scores for MCS, PCS, RE, VT, SF, MH, and GH among empty-nest older adults increased significantly. Moreover, these scores differed significantly from the corresponding scores in the control group.In simplest terms, self-management describes what a person does to manage his/her disease . A crossSeveral studies have found that good social relationships  are the most commonly reported factor influencing quality of life in the older adults , 32. AftA cross-sectional study in Shaanxi province showed that education has a major influence on the quality of life among the older adults in China . For exaIn this study, no positive main effect on PF, RP, and BP was observed among empty-nest older adults. For physical function, this study assessed mainly the impact of participants’ health on daily life, such as strenuous exercise, housework, and going up and down the stairs. For physical role, this study assessed the impact of health status on the completion of work or social activities. For bodily pain, this study assessed the extent of physical pain. The result indicated that intervention had limited effects on improving physical health, which may be related to the limited duration of intervention In this survey, we found that some empty nesters have one or more chronic diseases. Therefore, the intervention has limited effect on improving the chronic disease status of empty nesters in the short term. Previous studies have showed that chronic disease is among the significant risk factors affecting quality of life in the older adults , 37. ChrAlthough there was no significant improvement in other dimensions of PCS, such as PF, RP, and BP, the current results indicated that the scores of GH and PCS also increased significantly after the intervention. The GH dimension is a self-assessment of overall health, whereas the PCS encompassed physical component scores. Findings indicate that participants felt their health improved after the intervention, which could be attributed to subjectivity of their self-assessment. Therefore, in future studies, multi-point measurement should be considered to evaluate better the intervention process and outcomes.There are some limitations in this study that must be acknowledged. First, the low literacy level and advanced age of the study population might have caused participants to misunderstand the questions or give inaccurate responses. Second, researchers were not blinded to group allocation and the final statistical analyses. Therefore, subjective biases might have occurred inevitably when researchers conducted face-to-face interviews with participants. This requires researchers to fully understand the purpose of the study and be familiar with the content of the study, so as to help the participants better understand and complete the survey. So, investigators need to be trained before investigation. Moreover, although the group allocation was not actively disclosed to participants during the research process, participants in the intervention group might have guessed what the researchers wanted, the intervention effects might have been exaggerated. In addition, studies have shown the potential value of using more than one measures in a trial . HoweverOur study demonstrated that the SMG-based health management has a positive effect on improving quality of life of empty-nest older adults. It provided a new perspective on bettering the quality of life of empty nesters, thereby establishing an important theoretical and practical foundation for the improvement and promotion of the model. These results should be tested further in larger samples and different settings.Additional file 1. A Study on Quality of Life of the Empty-nest Older adults.


Mycobacterium avium complex (MAC) is a major cause of non-tuberculous pulmonary and disseminated diseases worldwide, inducing bronchiectasis, and affects HIV and immunocompromised patients. In MAC, Mycobacterium avium subsp. hominissuis is a pathogen that infects humans and mammals, and that is why it is a focus of this study. It is crucial to find essential drug targets to eradicate the infections caused by these virulent microorganisms. The application of bioinformatics and proteomics has made a significant impact on discovering unique drug targets against the deadly pathogens. One successful bioinformatics methodology is the use of in silico subtractive genomics. In this study, the aim was to identify the unique, non-host and essential protein-based drug targets of Mycobacterium avium subsp. hominissuis via in silico a subtractive genomics approach. Therefore, an in silico subtractive genomics approach was applied in which complete proteome is subtracted systematically to shortlist potential drug targets. For this, the complete dataset of proteins of Mycobacterium avium subsp. hominissuis was retrieved. The applied subtractive genomics method, which involves the homology search between the host and the pathogen to subtract the non-druggable proteins, resulted in the identification of a few prioritized potential drug targets against the three strains of M. avium subsp. Hominissuis, i.e., MAH-TH135, OCU466 and A5. In conclusion, the current study resulted in the prioritization of vital drug targets, which opens future avenues to perform structural as well as biochemical studies on predicted drug targets against M. avium subsp. hominissuis. Mycobacterium species that do not cause tuberculosis are referred to as non-tuberculous mycobacteria (NTM) and are ubiquitous in nature. NTM cause pulmonary diseases in which organisms of Mycobacterium avium complex (MAC) are widely distributed [M. avium is found to be higher than that of the other Mycobacterium species. For example, a literature survey showed that the pulmonary infection rate in Japan is sevenfold greater by M. avium than any other Mycobacterium species [M. intracellulare and M. avium [M. avium is comprised of four subspecies: M. avium subsp. paratuberculosis (MAP), M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS) and M. avium subsp. hominissuis (MAH); and each one is host specific. The first two subspecies cause avian infection, while the third causes diseases in wild livestock and the last one is the most common pathogen in humans and other mammals, including pigs, and therefore has huge economic impact [tributed . The inc species . MAC conM. avium . Furtherc impact .Opportunistic MAH is responsible for causing disseminated and pulmonary infections that affect immunocompromised patients who are suffering from AIDS, leukemia, lung diseases or chemotherapy ,6. The bAcinetobacter baumannii [Helicobacter pylori [Mycobacterium species [Pseudomonas aeruginosa [MAC pulmonary diseases are controlled by treatment with antibiotics that include macrolide-based multidrug therapy, comprising macrolides (clarithromycin or azithromycin) in combination with rifampin, ethambutol, aminoglycosides (streptomycin or amikacin) and ciprofloxacin ,11. Howeaumannii , Helicobr pylori , Mycobac species , Pseudomruginosa  and otheruginosa ,26,27,28M. avium subsp. hominissuis (MAH), the subtractive genomics method was used, which is the most applicable approach to prioritize potential drug targets [With the aim to identify unique and potential druggable targets of  targets ,29,30,31M. avium subsp. hominissuis in the UniProt database. Their complete proteomes were downloaded in FASTA format in February 2019. On applying CD-HIT algorithm with 80% identity, 20 sequences were identified as paralogous out of 4614 proteins in MAH-TH135, 54 out of 5165 in MAH-OCU466 and 14 out of 4502 proteins of A5 strain. The CD-HIT clustered the paralogous sequences and, hence, reduced the total number of sequences of each strain. The sequence dataset was comprised of 4596, 5111 and 4488 protein sequences for the MAH-TH135, OCU466 and A5 strains, respectively.Three strains of MAH, i.e., MAH-TH135, OCU466 and A5, were selected from the available non-redundant strains of In this step, protein sequences that were only present in the pathogens were segregated. Thus, by applying a subtractive approach, sequences were excluded that showed similarity to the human host. The remaining orthologous sequences, retrieved from the previous step, were subjected to BLASTp against the complete human proteome, and the resultant file was parsed. The only sequences that were retained were those that showed “no hits found”, and a total of 3151, 3619 and 3072 non-homologous sequences were found in the MAH-TH135, OCU466 and A5 strains, respectively.http://www.essentialgene.org/). Homology with the sequences found in the DEG database is the basis of essentiality of non-homologous proteins. To do this, the parsed results of each strain from the last step were subjected to BLASTp against the DEG with a 10−5 threshold. The BLASTp results depict 1360, 1451 and 1352 essential protein sequences in MAH-TH135, OCU466 and A5, respectively. These identified sequences were considered viable for the pathogen’s life cycle. These sequences include functional, non-functional or uncharacterized proteins, and they were dealt with using different bioinformatics tools for further characterization.The Database of Essential Genes (DEG) provides information on essential genes of Gram-positive and Gram-negative bacteria determined from experimental methods  tool. Only the sequences whose functions were not known earlier were submitted to this tool. Hence, only uncharacterized sequences were retrieved from the non-homologous essential proteins’ sequences. About 193, 119 and 187 uncharacterized sequences of TH135, OCU466 and A5 strains, respectively, were predicted by the SVM-Prot method. The results of the SVM-Prot tool are depicted in The KEGG database provides a network of metabolic pathways with their complete annotation. It helps to predict which protein sequences are essential in playing a unique role in metabolism. This step predicts the potential drug target based on the pathogen’s unique metabolism. Metabolic pathways analysis was carried out for the essential protein sequences using the KEGG database. The DEG’s results were subjected to the KEGG database via the KEGG Automated Annotation Server (KAAS). Briefly, out of 675 protein sequences of the MAH-135 strain, 72, 70, 29, 16 and 103 proteins were found to take part in carbohydrate metabolism, energy metabolism, lipid metabolism, nucleotide metabolism and amino acid metabolism, respectively. For OCU-466, 76 were involved in carbohydrate metabolism, while 69, 30 and 15 took part in energy metabolism, lipid metabolism and nucleotide metabolism, respectively, whereas the A5 strain possessed 93 proteins that majorly contributed to amino acid metabolism. The distribution of proteins in different metabolisms is presented in Bacterial metabolism refers to the collection of the biochemical reactions required for bacterial survival and growth, which mainly includes respiration (aerobic and anaerobic) and fermentation. Bacteria, as a pathogen to humans, conduct all the same types of basic biochemical reactions a human cell performs. However, bacteria may have several types of energy generating metabolisms that do not exist in human or eukaryotic cells. This diversity of energy generation and metabolism allows bacteria to survive in a variety of habitats and flourish in otherwise not-suitable conditions. On the other hand, these differential metabolic pathways make bacteria susceptible by serving as an ideal target for antibiotics. Metabolic pathways that exist only in pathogens are called unique metabolic pathways (UMP). These UMPs are listed in Energy is a potential, needed to perform work and maintain life, usually acquired by breaking a chemical bond and stored by making another chemical bond, very often in the form of ATP. Methane metabolism is one of the UMPs by which bacteria can obtain energy by oxidizing one-carbon compounds . Methanotrophic bacteria are generally considered environmentally friendly organisms, as they contribute to oxidizing environmental methane, thereby mitigating the effects of global warming . MethaneSecondary metabolites are molecules not essentially required for the survival of an organism. A large portion of bacterial metabolism deals with the biosynthesis of secondary metabolites. However, these pathways have a minimal role in bacterial growth and viability and are not considered a suitable target for antibiotics. Even though secondary metabolites are not considered to be ideal as drug targets, many of these pathways are manipulated by researchers for valuable purposes such as penicillin and cephalosporin biosynthesis, carbapenem biosynthesis and streptomycin biosynthesis. D-alanine metabolism is a significant target; an antibiotic D-cycloserine targeting D-alanine metabolism is already in clinical use against Mycobacterium tuberculosis [Amino acid metabolism in bacteria is diverse in nature and performs a pivotal role in maintaining bacterial growth. Amino acid metabolism has emerged as a potential target for new antibiotics, and a number of new drug targets have been proposed in recent years ,35,36,37rculosis ,41. The Other types of metabolic activities in bacteria, such as terpenoids and polyketides, glycan biosynthesis and drug resistance, also perform supportive functions for bacterial growth and survival; however, these metabolic routes are not prioritized targets for anti-bacterial drugs. Rather, these metabolic routes are often manipulated for advantageous purposes . The potential drug targets were shortlisted based on obtained information from earlier successful literature reports. The druggability of non-host uncharacterized protein sequences was determined by performing BLASTp against the druggable protein sequences present in the DrugBank Database. For this purpose, the earlier shortlisted, non-host, uncharacterized proteins, which are essential in metabolic pathways, were analyzed for druggability by comparing their sequences with the DrugBank Database. In this search, only one protein was prioritized in TAH-135, whereas four and seven potential drug targets emerged with the OCU-466 and A5 strains, respectively . All theIt is noteworthy that all the proposed drug targets could be analyzed for 3D structural information to prioritize novel drug targets against pathogens. Therefore, BLASTp was performed for the target proteins against the Protein Data Bank (PDB) database, which revealed that 12 protein sequences had no 3D structure available yet in the PDB. Therefore, this study offers those 12 proteins’ sequences to not only consider as a potential druggable genome, but also for future studies of 3D structure determination either by homology modeling (template-based) or by ab initio (template-free) methods .An overview of the subtractive genomics approach is illustrated in Homo sapiens, and pathogen, i.e., Mycobacterium avium subsp. Hominissuis, were downloaded from the UniProt KB database [The whole proteome of the host, i.e., database  to retriThe CD-HIT tool  clustersH. sapiens database with an expectation value  of 10−3 [Standalone BLAST version 2.8.1 was downloaded from the NCBI FTP server . The ort of 10−3 . The outM. avium subsp. hominissuis). The non-homologous proteins were aligned with the DEG database using BLASTp, and the expectation value was set to 10−5. As a result, the non-homologous essential genes, which may have hypothetical or uncharacterized proteins, were obtained.The genes required to sustain the life cycle of bacteria are called essential genes. The Database of Essential Genes (DEG) contains lists of genes with their corresponding sequences, which are essential for the survival of bacterial life. . TherefoThe metabolic pathways of the identified non-homologous essential proteins were searched in the Kyoto Encyclopedia of Genes and Genomes (KEGG)  through Annotation of proteins includes information about the location of proteins in various regions of the cell and the family to which it belongs. PSORTb version 3.0  is well −3. The DrugBank Database provides detailed information on drugs and drug targets. A large database shows up to 8261 drugs, including FDA-approved drugs; experimental and nutraceutical drugs are available in the DrugBank Database.In order to detemine the novel drug targets, standalone BLASTp was run between hypothetical non-homologous essential proteins, and drug target sequences were taken from the DrugBank Database  with an Mycobacterium avium subsp. hominissuis. Protein sequences of M. avium subsp. hominissuis were parsed using multiple steps of the subtractive genomics approach, and a few of them were shortlisted as possible drug targets because they fulfilled the druggability criteria. The shortlisted sequences were non-homologous to the human host; thus, these can be proposed as ideal drug targets. All the identified drug targets of different strains of MAH have never been characterized before as drug targets, and we proposed them here as potential drug targets against which new drug compounds can be designed. Therefore, the study is significant to the scientific community, as it provides a prioritized list of possible drug targets sorted by the computational subtractive genomics method, and it has the potential to lead to the discovery of new and novel drug targets against M. avium subsp. hominissuis. Different bioinformatics tools were applied in this study to identify vital drug targets of