• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Global trends in diabetic eye disease research from 2012 to 2021

    2024-01-24 09:14:44YuanYuanShangliJiYaliSongZhaodiCheLuXiaoShiboTangJiaXiao

    Yuan Yuan ,Shangli Ji ,Yali Song ,Zhaodi Che ,Lu Xiao ,Shibo Tang,,Jia Xiao,,

    Abstract Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy,diabetic macular edema,diabetic cataracts,and diabetic glaucoma.However,the global epidemiology of these conditions has not been well characterized.In this study,we collected information on diabetic eye disease-related research grants from seven representative countries––the United States,China,Japan,the United Kingdom,Spain,Germany,and France––by searching for all global diabetic eye disease journal articles in the Web of Science and PubMed databases,all global registered clinical trials in the ClinicalTrials database,and new drugs approved by the United States,China,Japan,and EU agencies from 2012 to 2021.During this time period,diabetic retinopathy accounted for the vast majority (89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease,followed by diabetic macular edema (9.27%).The United States granted the most research funding for diabetic eye disease out of the seven countries assessed.The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country.Additionally,the United States was dominant in terms of research output,publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations.The United States and the United Kingdom led international collaborations in research into diabetic eye disease.Of the 415 clinical trials that we identified,diabetic macular edema was the major disease that was targeted for drug development (58.19%).Approximately half of the trials(49.13%) pertained to angiogenesis.However,few drugs were approved for ophthalmic (40 out of 1830;2.19%) and diabetic eye disease (3 out of 1830;0.02%) applications.Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active,and has yielded few new treatment methods and newly approved drugs.

    Key Words:clinical trials;diabetic cataracts;diabetic eye disease;diabetic glaucoma;diabetic macular edema;diabetic retinopathy;drug development;global research;publication;research grant

    Introduction

    According to estimates from the International Diabetes Federation in 2021,approximately 537 million adults between the ages of 20 and 79 years worldwide have been diagnosed with diabetes mellitus.This number is expected to increase to 643 million by 2030 and 783 million by 2045 (Sun et al.,2022).Diabetic eye disease (DED) refers a group of eye complications that affect patients with diabetes (Hanineva et al.,2022;So et al.,2022).These mainly include diabetic retinopathy(DR),diabetic macular edema (DME),diabetic cataracts(DC),and diabetic glaucoma (DG),as defined by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.In 2020,an estimated 103.12 million adults worldwide had DR,representing 22.27% of all adults with diabetes (Teo et al.,2021).Importantly,DR was the only major cause of blindness with a global increase in prevalence from 1990 to 2020 (an increase of 14.9% per 1000 persons),compared with other major eye diseases such as undercorrected refractive error,cataract,age-related macular degeneration,and glaucoma (GBD 2019 Blindness and Vision Impairment Collaborators,2021).The prevalence of DR varies across different regions of the world,with the highest rates in Africa (35.90%) and North America and the Caribbean(33.30%),while the rates are lower in South and Central America (13.37%) and Southeast Asia (16.99%) (Teo et al.,2021).DME can occur at any stage of DR and is characterized by an accumulation of excess fluid in the retinal macular area(Varma et al.,2014).It is the leading cause of vision loss in patients with type 2 diabetes (Romero-Aroca,2011).In the United States,DME affects more than 3.8% of adults aged 40 and above with diabetes,based on 2008 data (Varma et al.,2014;Lundeen et al.,2022).Persistently high blood glucose levels in diabetic patients can cause structural changes to the lens of the eye,accelerating the development of cataracts,also known as diabetic cataracts.Patients with diabetes are up to five times more likely to develop cataracts than individuals without diabetes,particularly at an earlier age (Saxena et al.,2004).Data on the prevalence of DC in the general and diabetic populations are limited.In the United Kingdom,the incidence of cataracts was 20.4 per 1000 person-years in patients with diabetes and 10.8 per 1000 person-years in the general population in 2015 (Becker et al.,2018).Diabetes can cause an obstruction in aqueous outflow and elevate intraocular pressure,which can eventually lead to primary open-angle glaucoma.When patients with diabetes also have blood circulation disorders,this can result in decreased blood flow to the eyes,causing optic nerve damage in glaucoma and normal tension glaucoma.Hyperglycemia can also cause swelling in the lens that can increase intraocular pressure and cause secondary angle-closure glaucoma.The most severe form of glaucoma caused by DR is neovascular glaucoma.Patients with diabetes are twice as likely to develop glaucoma,especially open-angle glaucoma,compared with non-diabetic individuals (Li et al.,2021).The prevalence of glaucoma in patients with diabetes ranges from 4.96% to 14.6%.However,the association between diabetes and DG is significantly influenced by geographic distribution and other factors such as race,age,and sex (Zheng et al.,2010;Zhao and Chen,2017).

    Overall,therapeutic options for DED are limited.Managing blood glucose levels and diabetic progression are crucial at all stages of DED (Stitt et al.,2016).Vascular endothelial growth factor (VEGF) inhibitors,including faricimab-svoa,ranibizumab,aflibercept,and bevacizumab,can help inhibit the growth of new blood vessels and decrease fluid buildup in the context of advanced DR and DME.Photocoagulation (or panretinal photocoagulation) can also be used in conjunction with VEGF inhibitors (Wong et al.,2018).Nevertheless,future retinal damage and vision loss are still possible despite drug or laser therapy slowing or halting the progress of DR/DME because diabetes is a chronic disease.Most types of cataracts,including DC,are preferentially treated with phacoemulsification.However,patients with diabetes have been reported to experience a higher rate of complications(e.g.,poorer vision outcomes) after phacoemulsification cataract surgery than non-diabetic (Pollreisz and Schmidt-Erfurth,2010).For patients with diabetes and primary openangle glaucoma,intraocular pressure (IOP)-lowering drugs(e.g.,prostaglandin analogs),laser,and surgery can be used,as for non-diabetic patients (Tang et al.,2023b).Owing to the rapidly increasing global prevalence of diabetes,a higher DED disease burden is expected in the coming decades.Effective,novel Food and Drug Administration (FDA)-approved drugs and therapies are urgently needed for the management of patients with DED.Developing new medications/treatments depends heavily on rigorous basic and clinical research designed to identify novel disease mechanisms and treatment targets,as well as to generate data on the efficacy and safety of new therapies.Thus,comprehensively analyzing global trends in basic and clinical research into DED is essential to devise evidence-based strategies for future research and therapy development.In this study,we analyzed trends(research grants,publications (from the Web of Science and PubMed databases),clinical trials,and newly approved drugs)in DED research from 2012 to 2021 at a global level.

    Methods

    Data collection

    We collected data on the number of funded projects and total funding amounts for DED-related projects from online information systems: The United States (National Institutes of Health,the USA-NIH): https://reporter.nih.gov/,China(National Natural Science Foundation of China,NSFC): https://kd.nsfc.gov.cn/fundingProjectInit,Japan (Grants-in-Aid for Scientific Research,KAKENHI): https://kaken.nii.ac.jp/,the United Kingdom (Research Councils UK,RCUK): https://gtr.ukri.org/,Spain (El Instituto de Salud Carlos III,ISCIII):https://portalfis.isciii.es/es/Paginas/inicio.aspx,Germany(German Research Foundation,DFG): https://gepris.dfg.de/gepris/OCTOPUS?language=en,and France (French National Research Agency,ANR): https://anr.fr/en/funded-projectsand-impact/funded-projects/.We searched project titles using the keywords “diabetic retinopathy,” “diabetic macular edema,” “diabetic cataracts,” and “diabetic glaucoma”(accessed December 13–15,2022).To assess DED-related journal publications,we searched the Web of Science Core Collection (https://apps.webofknowledge.com/) using the same keywords for the time period spanning 2012–2021(accessed December 15,2022).In addition,we downloaded papers related to DED from the PubMed-MeSH database(https://www.ncbi.nlm.nih.gov/mesh) using the same keywords (accessed December 17,2022).We eliminated duplicate papers and re-retrieved the remaining papers from the Web of Science database.For clinical trial information,we searched the ClinicalTrials website (https://clinicaltrials.gov/)using the keywords “diabetic retinopathy,” “diabetic macular edema,” “diabetic cataracts,” and “diabetic glaucoma” in the“condition or disease” tab (accessed December 17,2022).We collected newly approved drug information from the Food and Drug Administration (FDA) for the United States (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm),the National Medical Products Administration (NMPA) for China (https://www.cde.org.cn/hymlj/index), the Pharmaceuticals and Medical Devices Agency (PMDA) for Japan (https://www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0002.html), and the European Medicines Agency(EMA) for the European Union (https://www.ema.europa.eu/en/medicines/download-medicine-data#european-publicassessment-reports-(epar)-section) (accessed December 22,2022). We included only new medicinal products and orphan medicinal products, and excluded biosimilar and generic drug information. The authors YY and YS independently analyzed all information on grants, journal papers, clinical trials, and new drugs. Their analyses were later verified by the authors SJ and JX.

    Disease and research coding

    All research grants, journal papers, and clinical trials were manually assigned a disease code (DR, DME, DC, or DG). If a grant, paper, or trial described two diseases, we labeled it with two codes and counted it as 0.5 for each disease in the statistical analysis. We also manually assigned a research code to grants and journal papers to indicate whether they involved basic research (mechanistic study, therapeutic study, novel animal model study, and bioengineering study)or clinical research (epidemiological study, diagnostic study,observational study, or interventional study). If a grant or paper involved both types of research, we assigned it both codes and counted it as 0.5 for each type of study in the statistical analysis.

    Calculation of citations per article, relative citation impact,and closeness centrality of journal papers

    The frequency of citations per article is a relative index that can eliminate differences in country sizes and can better reflect the quality or impact of scientific research. The formula used to calculate this value is as follows: the cited frequency of papers in a country (or a research direction) = the cited frequency of papers in a country (or a research direction)/the number of papers in a country (or a research direction).

    Relative citation impact (RCI) refers to the ratio of the cited frequency of papers published by the country to the cited frequency of papers published by the world (country) (Grover et al., 2021), and it is used to measure the quality or impact of a country in a specified field. The formula used to calculate this value is as follows:

    where Cijrefers to the citation frequency of papers of country i in the discipline field j; Pijrefers to the number of papers of country i in the discipline field j; WCjrefers to the citation frequency of the world’s papers in the discipline field j; and WPjrepresents the number of papers in the world in the subject area j. If the RCI index value is greater than 1, this indicates that the quality or impact of papers in a given field from that country is higher than the average quality or impact of papers in that field from around the world. When the RCI is equal to 1, this means that the quality or impact of papers from that country in that field is equivalent to that of papers from around the world in that same field. Conversely,if the RCI value is less than 1, this indicates that the quality or impact of papers from that country in that field is lower than the average quality or impact of papers from around the world in that same field.

    Closeness centrality describes the control power and influence of nodes in a network (Diallo et al., 2016). The closeness centrality of a node measures its average farness (inverse distance) to all other nodes. Nodes with a high closeness score have a short distance to all other nodes. The “absolute overall centrality” of a point is the sum of the shortcut distances between the point and all other points in the graph, and is expressed as:

    where dijis the shortcut distance between point i and point j, and n is the total number of network nodes. To eliminate the impact of network size on the overall centrality value of points and enhance the comparability of the overall centrality value of network points of different sizes, we introduced the concept of “relative overall centrality.” Because the absolute overall centrality of the core points of the “star” network can reach the minimal valuen–1, the “absolute overall centrality”can be divided by the minimal overall centrality to obtain the“relative overall centrality” (standardization of the overall centrality), which is expressed as:

    wheredijis the shortcut distance between pointiand pointj, andnis the total number of network nodes. The overall centrality value in this study defaults to “relative overall centrality.”

    Statistical analysis

    Only descriptive analyses were conducted in this study.

    Results

    DR accounts for the vast majority of global DED research grants

    From 2012 to 2021, a total of 2288 research grants for DED were awarded by the governments of the seven representative countries (the United States, China, Japan, the United Kingdom, Spain, Germany, and France). DR accounted for the vast majority of global DED grants (2048.5 out of 2288;89.53%), followed by DME (212 out of 2288; 9.27%). DC- and DG-related grants accounted for only very small percentages of overall DED grants (0.9 out of 100 (0.90%) and 0.31 out of 100 (0.31%), respectively). The number and amount of global DED research funds remained relatively stable in this period,at 203 to 245 grants per year and 87.70 to 103.35 million USD per year. The USA-NIH approved 1748 DED grants with a total value of 901.86 million USD, which exceeded the sum of other countries: China approved 264 grants worth 16.07 million USD, Japan approved 161 grants worth 6.34 million USD, the United Kingdom approved 45 grants worth 31.19 million USD,Spain approved 34 grants worth 4.09 million USD, Germany

    approved 26 grants,and France approved eight grants worth 4.18 million USD.This indicated that the United States made the largest investment in this research field during this time period.Only the United States and China funded DC-related grants (12.5 and 8,respectively),and only the United States funded DG-related grants (seven) (Figure 1).

    Figure 1 |Proportions of research grants focusing on the four types of diabetic eye disease (DED)diseases,namely diabetic retinopathy (DR),diabetic macular edema (DME),diabetic cataracts (DC),and diabetic glaucoma (DG),funded by the governments of global representative countries,and trends in funding,from 2012 to 2021.

    The research objectives of DR and DME grants vary by country

    Next,we analyzed the research objectives of all DR-and DMErelated grants.DC-and DG-related grants were not included because there were too few.For DR-related grants,the United States,China,and Japan approved more basic studies than clinical studies,while in European countries (the United Kingdom,Germany,Spain,and France),the numbers of basic and clinical studies were similar (49vs.51;Figure 2A).In the United States,the NIH approved 786 mechanistic studies of DR from 2012 to 2021,followed by 325.5 studies of DR diagnosis and 179 DR clinical observational studies.In China,the NSFC encourages basic/mechanistic studies instead of clinical studies,and thus most of the approved DR grants were for studies that proposed to address molecular mechanisms(64.59%),followed by therapeutic studies conducted in animals (19.32%).Japan approved DR studies in a similar ratio,with mechanistic studies accounting for 57.42% of all DR-related grants,followed by clinical interventional studies(15.23%) and therapeutic studies in animals (10.94%).In European countries,mechanistic DR studies still accounted for the largest proportion of all DR-related grants (37.50%),followed by clinical diagnostic studies (28.50%) and clinical observational studies (12.50%).Of note,the ratio of clinical studies was higher for DME-related grants than that for DRrelated grants (77.5 basic studiesversus81 clinical studies for NIH-approved DME grants;32 basic studies versus 21.5 clinical studies for DME grants approved by the other six countries).Mechanistic studies and clinical interventional studies accounted for more than half of the total DME-related grants(Figure 2B).

    Figure 2 |Proportion of research grants for basic (mechanistic study,non-clinical therapeutic study,novel animal model study,and non-clinical bioengineering study) and clinical (epidemiological study,clinical diagnostic study,observational study,and interventional study) studies addressing (A) diabetic retinopathy (DR) and (B) diabetic macular edema (DME) funded by the governments of global representative countries,and trends in funding,from 2012 to 2021.

    DR and clinical observational studies account for the majority of journal papers addressing DED

    We analyzed 4697 DED journal papers published between 2012 and 2021 retrieved from the Web of Science and PubMed databases.The number of published papers addressing DED increased steadily from 2012 (241 papers)to 2021 (843 papers),reflecting a growing interest in DED research globally.DR was the most commonly studied disease,accounting for 3342 papers (71.15%),followed by DME(1058;22.52%),DC (169;3.60%),and DG (128;2.73%;Figure 3A).Of these 4697 DED journal papers,3746 were research articles (79.75%),and 951 were review articles (20.25%).DR accounted was the main topic of 2629.5 research articles(70.20% of all research articles),followed by 908.5 DME research articles (24.25%),159 DC research articles (4.24%),and 49 DG research articles (1.31%).The ratio of disease topics addressed in review articles was similar,while the ratio of reviews that addressed DG was higher than that of research articles that focused on DG (8.31%vs.1.31%).Analyzing DED research article type showed that the number of clinical research papers far exceeded the number of basic research papers (2693vs.783 papers).Although DR was the major topic of both basic and clinical research papers,DME was the focus of more clinical papers than basic papers (892vs.17.5;30.10%vs.2.23%;Figure 3B).The majority of DR,DME,and DG research articles were clinical observational studies,whereas therapeutic studies in animals accounted for nearly half of the DC research papers (Figure 3C).

    Figure 3 |Research trends of 4697 journal papers reporting on four types of diabetic eye disease (DED),namely diabetic retinopathy (DR),diabetic macular edema (DME),diabetic cataracts (DC),and diabetic glaucoma (DG),listed in the Web of Science and PubMed databases (2012–2021).

    The United States dominates research output related to DED

    From 2012 to 2021,China and the United States published 19.55% and 17.53% of global DED journal papers,respectively.Other countries (the United Kingdom,India,Japan,Korea,Italy,and Australia) published only 3.41% to 5.95%.DR remained the dominant paper topic for all countries except Italy (Figure 4A).From 2012 to 2021,published DED journal papers from the United States received 22.58% of the citations to all DED papers published globally,far exceeding China(11.55%),the United Kingdom (7.95%),Singapore (5.57%),Italy (5.47%),and Australia (5.23%).Other countries received less than 5% of citations (Figure 4B).Papers published from the Netherlands had the highest average citation frequency(110.76 per paper),followed by South Africa (102.88),Thailand (96.81),Singapore (70.60),Denmark (62.92),Norway (57.83),and Germany (57.18) (Figure 4C).The top 10 countries and the average citation frequency per paper for each DED are listed inTable 1.The Netherlands (135.09),Norway (277.00),Switzerland (44.00),and Mexico (865.00)had the highest average citation frequencies per paper for DR,DME,DC,and DG,respectively.Next,we calculated RCI values to determine the relative position of a country’s papers in a certain discipline worldwide.Nineteen countries had RCI values >1.DED papers from the Netherlands had the highest RCI value (3.61),followed by Ethiopia,South Africa,Thailand,Singapore,Grenada,and Denmark (Figure 4D).

    Table 1 |Top 10 countries of average citation frequency per paper of each diabetic eye disease [diabetic retinopathy (DR),diabetic macular edema (DME),diabeticcataract (DC),and diabetic glaucoma (DG)] papers from 2012–2021

    Figure 4 |Published journal papers addressing four types of diabetic eye diseases (DED),namely diabetic retinopathy (DR),diabetic macular edema (DME),diabetic cataracts (DC),and diabetic glaucoma (DG),listed in the Web of Science and PubMed databases.Research output of the top 20 countries,encompassing publication counts,proportion of papers addressing the different disease types,total citation counts,average citations per paper,and relative citation impact (RCI)(2012–2021).

    The United States and the United Kingdom lead international collaborations in DED research

    International collaboration plays an important role in development of science and technology.Thus,we quantitatively analyzed papers about DED generated by international cooperation in major countries based on bibliometric and cooperation network analyses.The United States and the United Kingdom were at the center of the international cooperation network constructed for all DED papers published from 2012 to 2021 and exhibited close collaborations with China,Germany,Australia,and India.Many other countries,including Singapore,Portugal,Canada,Brazil,France,South Africa,Spain,Italy,Saudi Arabia,Israel,and New Zealand,also closely participated in international DED research collaboration.The United States and the United Kingdom were also the leading countries in international collaboration in DR,DC,and DG research.For DME publications,the United States and Germany exhibited close collaborative relationships with Australia,India,France,Italy,and Spain (Figure 5).We also observed changes in the relative overall centrality ranking of each country overtime.As shown inTable 2andAdditional Table 1,compared with 2012,in 2021 the United Kingdom replaced the United States as the world’s top country in DED research.India and Australia maintained their rankings as third and fourth globally,respectively,while China rose from sixth to fifth place.Singapore’s ranking dropped significantly from fifth to ninth in the world during the same time period.

    Table 2 |Degree and centrality of Top 25 countries in the international cooperation network in the field of diabetes eye disease in 2012 and 2021

    Figure 5 |International collaboration networks in the field of diabetic eye disease (DED) and its four disease types,namely diabetic retinopathy (DR),diabetic macular edema (DME),diabetic cataracts (DC),and diabetic glaucoma (DG),from 2012 to 2021 (based on all published papers listed in the Web of Science and PubMed database).

    DME is the major topic of clinical trials investigating DED

    The ultimate goal of drug and therapy development is to bring a novel compound or method with proven therapeutic efficacy to market.To analyze new drug and treatment development trends for DED,we identified all DED-related clinical trials registered between 2012 and 2021.A total of 415 clinical trials were conducted during this period,comprising 165 trials for DR (39.76%),241.5 trials for DME (58.19%),5.5 trials for dry eye disease (1.33%),and three trials for dysthyroid eye (DG) (0.72%).The number of annual studies did not change significantly from 2012 to 2021,ranging from 34 to 56 trials per year (Figure 6A).The US registered 157 trials during this time period,followed by China (51),Egypt (21),Switzerland (19),and Canada (14).North American (178),Asian (108),and European (87) countries conducted most of the DED clinical trials (Figure 6B).Of note,a large majority of those trials were either in phase 2 (104 trials;25.06%)or phase 4 (91 trials;21.93%).We observed only a slightly increasing trend in the number of phase 3 trials during this period,in terms of annual trial number (Figure 6C).Next, we assessed the mechanisms of the new drugs tested in the identified clinical trials.Angiogenesis inhibitors accounted for the vast majority,including 85 trials in total,while 65 trials tested VEGF inhibitors.Other drug categories included antiinflammatory drugs (41 trials),metabolic regulators (16 trials),neuroprotective drugs (11 trials),IOP-lowering drugs (nine trials),antioxidant drugs (seven trials),and anti-infectious drugs (four trials).Unfortunately,many of the above drugs were not new drugs,having already been approved by the FDA,and only a small number of newly developed drugs were tested (62 out of 182;34.07%;Figure 6D).

    Figure 6 |Clinical trials of treatments for various types of diabetic eye disease (DED) diseases,including diabetic retinopathy (DR),diabetic macular edema (DME),diabetic cataracts (DC),and diabetic glaucoma (DG) (2012–2021).These data show the distribution and temporal trends of these diseases within clinical trials,ranked trials by country and continent,proportions of clinical trial phases,and drug statistics.

    Few ophthalmic and DED drugs were newly approved for use

    Increased DED diagnosis and disease burden have led to an increased need for novel ophthalmic disease treatments.From 2012 to 2021,the US FDA approved 353 new drugs,of which only five were for ophthalmic diseases (1.42% of all new drugs).During the same period (2012–2021),the National Medical Products Administration (NMPA,China),Pharmaceuticals and Medical Devices Agency (PMDA,Japan),and European Medicines Agency (EMA,European Union) approved 5,15,and 15 new drugs for eye diseases,accounting for 3.45%,2.49%,and 2.06% of each agency’s total drug approvals during the period,respectively (Figure 7A).Of the 40 new ophthalmic drugs approved by the above agencies during this time period,nearly half were for treating glaucoma/ocular hypertension (17 drugs;42.50%),followed by macular diseases (five drugs;12.50%).Of particular note,the EMA approved three new drugs (Eylea,Duloxetine Mylan,and Byooviz) for treating diabetic eye damage (Figure 7B).

    Figure 7 |Comparison of new drug approvals by the Food and Drug Administration (FDA),National Medical Products Administration (NMPA),Pharmaceuticals and Medical Devices Agency (PMDA),and European Medicines Agency (EMA).

    Discussion

    Our study provides a comprehensive and up-to-date evaluation of global DED research trends.It is the largest bibliometric analysis of DED research to date,encompassing the full course of the scientific research process from research funding to paper publication,clinical trial,and new drug approval.Our findings indicate that DR remained the primary area of interest for global scientists and clinicians in the preclinical stages,including research grants and journal publications,between 2012 and 2021 (Gardner and Chew,2016).The United States led the world in terms of research investment and publication output regarding DED during this time period,while China made significant progress in both grant funding and research output,becoming the secondlargest DED research funder globally,producing the highest number of published papers about DED,and garnering the second-largest number of paper citations in the world over the past decade.In addition,DME emerged as the main focus area of focus for DED clinical trials over the past decade.Although 53.01% of the 415 trials that were registered from 2012 to 2021 were successfully completed,only 7.50% (3 out of 40) of the new drugs that were tested were approved for the treatment of diabetic eye damage.

    Currently,DR is the most common complication of diabetes(Oshitari,2022;Tang et al.,2023a).Its molecular pathogenesis is still not fully understood,and its treatment is challenging.Although VEGF inhibitors and other angiogenesis inhibitors have been used for decades to treat patients with DR,and demonstrate remarkable clinical benefits for many patients,a large number of patients still do not achieve clinically significant visual improvement (Wang and Lo,2018).Therefore,a deeper understanding of the pathophysiological processes underlying DR progression is needed to identify novel drug targets.This explains why more than half of the DR research grants funded over the past decade have been for mechanistic studies.To inhibit or reverse the progression of DR,not only in ophthalmological diseases,a large number of the grants and journal articles identified in out study focused on adipose tissue regulation,lipid/glucose re-balance,and organ crosstalk.Moreover,16 clinical trials tested the application of metabolic regulators (e.g.metformin,empagliflozin,and pemafibrate),which target systemic lipid/glucose metabolism.Although the number and funding amount of research grants from the major representative countries remained largely unchanged in the past decade,the number of global research papers on DED has drastically increased,by approximately 3.5 times,from 241 in 2012 to 843 in 2021.DED has gradually become a key focus of ophthalmology research.There are several possible explanations for this trend: (1) researchers and clinicians receiving good funding (e.g.company or other government funding types) to support their studies (Suresh,2012;Woelbert et al.,2021);(2) more efficient use of research funds;and (3) lack of high-impact papers in this field.Although DR was still the major disease type addressed in DED research articles,in contrast to research grants,the article topics shifted from mechanistic studies to clinical observational and interventional studies,implying that researchers are focusing more on translational research and clinical applications for DED-related diseases.

    DME is mainly caused by destruction of the blood-retinal barrier (BRB) in the macular region,increased permeability of capillaries and microangiomas,and accumulation of extracellular fluid.DME can occur at any stage of DR,and is an important factor leading to visual impairment in patients with DR (Wong et al.,2016).The number of adults worldwide with clinically significant macular edema is predicted to rise to 28.61 million in 2045.Thus,early disease stages urgently need to be addressed,both in terms of public awareness and in the development of new treatments to supplement the currently available VEGF inhibitor therapy and laser photocoagulation(Teo et al.,2021).Unlike for research grants and published papers,DME was the major topic of clinical trials for DED from 2012 to 2021.This might be the result of a combination of factors.Compared with DR,DC,and DG,(1) the pathogenesis of DME is relatively clear (BRB damage);(2) DME symptoms are relatively distinctive (3) DME treatment efficacy is easy to observe (e.g.OCT and fundus photography);and (4) DME has a significant impact on patient vision (Das et al.,2015;Chakravarthy et al.,2018;Jampol et al.,2020).Of note,many drugs tested in these clinical trials were already on the market,with approval for indications other than DED (120 out of 182;65.93%).Therefore,increasing investment in basic and translational research is urgently needed in order to discover novel therapeutic targets and develop more new drugs for DED.

    The global market for ophthalmic disease therapeutics is projected to grow from 35.57 billion USD in 2023 to 54.87 billion USD by 2030,for an overall annual growth rate of 6.40% during the forecast period (Insights,2023).However,we found that only three out of 40 new drugs (7.50%)approved by the FDA/NMPA/PMDA/EMA from 2012 to 2021 were for DR or other diabetic eye complications.Because retinal diseases have dominated the market in the past years,and the DR/DME patient population is growing,companies are investing more resources in new drug development,particularly VEGF inhibitors.For example,Genetech Inc.received FDA and EMA approval for faricimab for DME treatment in January and September 2022,respectively(Shirley,2022).Several new drugs currently in clinical trials are promising for DED treatment.One such drug is a novel αvβ3 inhibitor called OTT-166.This drug has completed a phase 1/2 randomized controlled trial (RCT) for the treatment of DME (NCT02914613).Additionally,a phase 2 RCT is currently underway to assess the safety and efficacy of OTT-166 for treating DR (NCT05409235).Another potential treatment for DR is eye drops containing somatostatin,which is a corticotropin-releasing hormone/growth hormone-releasing hormone inhibitor.A phase 3 clinical trial of this drug for the treatment of DR has been completed (NCT01726075).In subjects with proliferative DR,the administration of oral emixustat hydrochloride (a retinoid isomerohydrolase inhibitor) significantly improved central subfield thickness and total macular volume compared with the control group in a phase 2 RCT study (NCT02753400).Overall,these new drugs offer hope for the future treatment of DED and DR,and ongoing clinical trials will provide further insight into their effectiveness and safety.Aldose reductase inhibitors and antioxidants have been reported to alleviate DC and DG phenotypes in animal models (Pollreisz and Schmidt-Erfurth,2010;Snow et al.,2015;Himori et al.,2021);however,further preclinical studies and clinical trials are needed to demonstrate their suitability for clinical application.In terms of DR diagnosis,the FDA has recently approved a revolutionary EyeArt artificial intelligence system.This system is equipped with multiple cameras and is capable of autonomously detecting DR.The approval of this system is a significant development because it provides primary care clinics with an additional screening option for diabetic populations.

    This study had some limitations.Given the retrospective nature of our study,we deliberately chose a specific time frame for analysis to focus our investigation.While this approach allowed us to examine a relevant and significant period,it inherently limited the breadth of our scope.Consequently,our findings may not provide a fully exhaustive representation of all DED research.The emphasis on highly cited papers could potentially lead to misunderstandings regarding influential research,overlooking emerging studies with promising insights that have yet to accumulate substantial citations.When discussing new drug development,our focus on traditional small-molecule drugs might not sufficiently encompass the contemporary pharmaceutical landscape,which is increasingly influenced by biologics and gene therapy approaches.Moreover,in the era of globalization,international collaboration has become pivotal for countries to foster scientific and technological advancements.While an increasing number of influential papers rely on successful international collaborations,it cannot be assumed that such collaborative papers are of higher research caliber than those originating from a single country.To thoroughly investigate this,it is imperative to conduct independent analyses observing the impact of papers resulting from collaborations between various nations.

    Future studies could use enhanced data collection and analysis methods to encompass a broader range of sources and regions,thereby ensuring a more comprehensive representation of the global research landscape.Recognizing the intricate interplay between data,collaboration,funding,and research methodologies is essential to advancing our understanding of this field.

    In conclusion,although the number of patients with diabetes and DED is rapidly increasing worldwide,the basic and translational research related to DED over the past decade has been somewhat lacking,with limited treatment methods explored and only a few new drugs approved.Because of the growing demand for DED research,the global scientific community needs to make a substantial commitment to basic and clinical research into DED,particularly DC and DG,through active academic investigation,global collaboration,and novel drug development.

    Author contributions:ST and JX designed the study.YY,SJ,and JX collected all required data.YY,SJ,YS,ZC,LX,analyzed the data.YY,ST,and JX wrote and revised the manuscript.All authors approved the final version.ST and JX are the guarantors of this work and,as such,had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Conflicts of interest:No potential conflicts of interest relevant to this study were reported.

    Data availability statement:All relevant data are within the paper and its Additional files.

    Open access statement:This is an open access journal,and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License,which allows others to remix,tweak,and build upon the work non-commercially,as long as appropriate credit is given and the new creations are licensed under the identical terms.

    Additional file:

    Additional Table 1:Papers from the top 5 countries with the highest average citation frequencies among the top 10 countries for each diabetic eye condition from 2012 to 2021.

    av专区在线播放| 19禁男女啪啪无遮挡网站| 99久久精品热视频| 亚洲内射少妇av| 女人十人毛片免费观看3o分钟| 别揉我奶头~嗯~啊~动态视频| 久久性视频一级片| 国产淫片久久久久久久久 | 淫妇啪啪啪对白视频| 啦啦啦韩国在线观看视频| 18+在线观看网站| 欧美不卡视频在线免费观看| 欧美最黄视频在线播放免费| 国产成人av激情在线播放| 麻豆成人午夜福利视频| 日韩有码中文字幕| 老司机午夜十八禁免费视频| 一卡2卡三卡四卡精品乱码亚洲| www.熟女人妻精品国产| 99久久精品一区二区三区| 真人做人爱边吃奶动态| 国产精品电影一区二区三区| 国产伦精品一区二区三区四那| 一本综合久久免费| 亚洲精品一卡2卡三卡4卡5卡| 日本黄大片高清| 亚洲精品在线观看二区| 久久亚洲精品不卡| 亚洲熟妇中文字幕五十中出| 国内毛片毛片毛片毛片毛片| 中亚洲国语对白在线视频| 午夜精品久久久久久毛片777| 狂野欧美激情性xxxx| 亚洲第一电影网av| 中文资源天堂在线| 欧美最新免费一区二区三区 | 18禁黄网站禁片免费观看直播| 神马国产精品三级电影在线观看| 美女大奶头视频| 搡女人真爽免费视频火全软件 | 精品国产美女av久久久久小说| 国产主播在线观看一区二区| 一区二区三区高清视频在线| 精品国产美女av久久久久小说| 亚洲国产欧美人成| 欧美午夜高清在线| 亚洲av电影不卡..在线观看| 欧美日韩福利视频一区二区| 精品无人区乱码1区二区| 日韩av在线大香蕉| 真人一进一出gif抽搐免费| 日本一二三区视频观看| 欧美成人a在线观看| 在线观看美女被高潮喷水网站 | 成年免费大片在线观看| 一级黄片播放器| 欧美成人免费av一区二区三区| 男女那种视频在线观看| 一级毛片高清免费大全| 国产午夜精品论理片| 免费无遮挡裸体视频| 岛国在线观看网站| 此物有八面人人有两片| 在线观看一区二区三区| 丰满乱子伦码专区| 色吧在线观看| 亚洲精品粉嫩美女一区| 日日干狠狠操夜夜爽| 午夜老司机福利剧场| 亚洲人与动物交配视频| 一卡2卡三卡四卡精品乱码亚洲| 99久久综合精品五月天人人| 国产精品 欧美亚洲| 日韩大尺度精品在线看网址| 欧美另类亚洲清纯唯美| 欧美大码av| 国产激情偷乱视频一区二区| 久久久久国产精品人妻aⅴ院| 日本黄色视频三级网站网址| 我的老师免费观看完整版| 97人妻精品一区二区三区麻豆| 国产私拍福利视频在线观看| 亚洲精品粉嫩美女一区| 国产精品精品国产色婷婷| 欧美性猛交黑人性爽| or卡值多少钱| 色精品久久人妻99蜜桃| 老司机午夜福利在线观看视频| 国产综合懂色| 国产探花在线观看一区二区| 熟妇人妻久久中文字幕3abv| 老汉色∧v一级毛片| 一区二区三区高清视频在线| 午夜影院日韩av| 男女床上黄色一级片免费看| 岛国在线免费视频观看| 黄片大片在线免费观看| 1024手机看黄色片| 久久久国产成人免费| 三级毛片av免费| 久久久国产成人精品二区| 色av中文字幕| 亚洲欧美精品综合久久99| 国产色婷婷99| 免费无遮挡裸体视频| 又粗又爽又猛毛片免费看| 一a级毛片在线观看| 搡女人真爽免费视频火全软件 | 成人高潮视频无遮挡免费网站| 国产乱人伦免费视频| 嫩草影视91久久| 欧美bdsm另类| 91麻豆精品激情在线观看国产| 极品教师在线免费播放| 国产高清有码在线观看视频| 日韩亚洲欧美综合| 最新在线观看一区二区三区| 国产伦精品一区二区三区四那| 日本黄色视频三级网站网址| 久久精品国产自在天天线| 国产精品免费一区二区三区在线| 成人午夜高清在线视频| 精品一区二区三区视频在线 | 91久久精品电影网| 国产高清激情床上av| 免费电影在线观看免费观看| 亚洲内射少妇av| 夜夜爽天天搞| 三级毛片av免费| 国产在线精品亚洲第一网站| 久久精品国产亚洲av涩爱 | 国产精品女同一区二区软件 | 一个人看视频在线观看www免费 | 久久久久久久精品吃奶| 俄罗斯特黄特色一大片| 男女床上黄色一级片免费看| 亚洲av熟女| 国产成人av教育| 欧美一级a爱片免费观看看| 国产精品一区二区三区四区免费观看 | 俄罗斯特黄特色一大片| 偷拍熟女少妇极品色| 欧美zozozo另类| 69av精品久久久久久| 在线观看免费午夜福利视频| 国产又黄又爽又无遮挡在线| 搞女人的毛片| 久久精品人妻少妇| 变态另类丝袜制服| 欧美乱妇无乱码| 国产av一区在线观看免费| 日本 欧美在线| 欧美色欧美亚洲另类二区| 国产成+人综合+亚洲专区| 国产爱豆传媒在线观看| 丰满乱子伦码专区| 最新在线观看一区二区三区| 搡老熟女国产l中国老女人| 精品久久久久久,| 午夜福利免费观看在线| 麻豆国产av国片精品| 看免费av毛片| 国内精品美女久久久久久| 久久精品影院6| 精品熟女少妇八av免费久了| 男女那种视频在线观看| 9191精品国产免费久久| 欧美日韩精品网址| 国产不卡一卡二| 十八禁人妻一区二区| 国内精品久久久久精免费| 91字幕亚洲| 欧美一区二区亚洲| www国产在线视频色| 可以在线观看毛片的网站| 三级国产精品欧美在线观看| 每晚都被弄得嗷嗷叫到高潮| av在线蜜桃| 日韩 欧美 亚洲 中文字幕| 久久精品综合一区二区三区| 男人的好看免费观看在线视频| 成年免费大片在线观看| 91在线观看av| 老汉色∧v一级毛片| 99热只有精品国产| 国产精品女同一区二区软件 | 久久伊人香网站| 精品久久久久久久久久免费视频| 成人国产一区最新在线观看| 黄片大片在线免费观看| 亚洲国产欧美网| 日本黄大片高清| 草草在线视频免费看| 欧美日韩中文字幕国产精品一区二区三区| 露出奶头的视频| 一本一本综合久久| 首页视频小说图片口味搜索| 国产精品久久电影中文字幕| 亚洲av中文字字幕乱码综合| 欧美日韩国产亚洲二区| 99久久九九国产精品国产免费| 国内精品美女久久久久久| 一进一出好大好爽视频| 亚洲av熟女| 亚洲国产色片| 丰满人妻熟妇乱又伦精品不卡| av专区在线播放| 变态另类成人亚洲欧美熟女| 黄色女人牲交| 免费人成视频x8x8入口观看| 成人亚洲精品av一区二区| 欧美绝顶高潮抽搐喷水| 免费看a级黄色片| 俄罗斯特黄特色一大片| 美女cb高潮喷水在线观看| 亚洲国产精品久久男人天堂| 欧美不卡视频在线免费观看| 搡老岳熟女国产| 欧美在线一区亚洲| 国产中年淑女户外野战色| 日韩欧美国产在线观看| 久久久久国产精品人妻aⅴ院| 不卡一级毛片| 国产av不卡久久| 午夜精品在线福利| 亚洲在线自拍视频| 悠悠久久av| a级毛片a级免费在线| 国产成人av教育| 99热这里只有是精品50| 老司机深夜福利视频在线观看| 在线观看av片永久免费下载| 中文字幕人妻丝袜一区二区| 亚洲五月婷婷丁香| 国内精品久久久久精免费| 99久久久亚洲精品蜜臀av| 久久久久久国产a免费观看| x7x7x7水蜜桃| 欧美+日韩+精品| 国产真人三级小视频在线观看| 国产高清视频在线观看网站| 国模一区二区三区四区视频| 欧美国产日韩亚洲一区| 欧美日韩精品网址| 国产精品久久久久久精品电影| 性色avwww在线观看| 国产成人a区在线观看| 老汉色∧v一级毛片| 午夜福利免费观看在线| 少妇的丰满在线观看| 一区二区三区高清视频在线| 国产亚洲av嫩草精品影院| 久久精品国产亚洲av涩爱 | 国内毛片毛片毛片毛片毛片| 色av中文字幕| 网址你懂的国产日韩在线| 欧美在线黄色| 日韩高清综合在线| 亚洲久久久久久中文字幕| 一级黄色大片毛片| 美女黄网站色视频| 亚洲欧美日韩卡通动漫| 欧美黄色淫秽网站| 色综合婷婷激情| 国产三级中文精品| 中文字幕人妻丝袜一区二区| 午夜福利在线观看吧| 色av中文字幕| 无限看片的www在线观看| 日韩欧美 国产精品| 他把我摸到了高潮在线观看| 搡老妇女老女人老熟妇| 99久久综合精品五月天人人| 国语自产精品视频在线第100页| 国产主播在线观看一区二区| 精品久久久久久久末码| 欧美极品一区二区三区四区| 手机成人av网站| 国产私拍福利视频在线观看| 欧美色视频一区免费| 99久久99久久久精品蜜桃| 在线观看一区二区三区| 欧美成人性av电影在线观看| 丰满人妻熟妇乱又伦精品不卡| 黄色日韩在线| 国产91精品成人一区二区三区| 欧美成人一区二区免费高清观看| 精品人妻一区二区三区麻豆 | 精品一区二区三区av网在线观看| 国产一区二区三区视频了| 噜噜噜噜噜久久久久久91| 精品久久久久久成人av| 成人三级黄色视频| 国产单亲对白刺激| 无遮挡黄片免费观看| 国产美女午夜福利| 成人av一区二区三区在线看| 国产欧美日韩一区二区精品| 日本黄大片高清| 中国美女看黄片| 欧美日韩瑟瑟在线播放| 一夜夜www| 在线播放国产精品三级| 国内少妇人妻偷人精品xxx网站| 亚洲av一区综合| 蜜桃久久精品国产亚洲av| 亚洲中文字幕一区二区三区有码在线看| 国产成人福利小说| 黄色片一级片一级黄色片| 国产成+人综合+亚洲专区| 男人舔女人下体高潮全视频| 69av精品久久久久久| 午夜福利成人在线免费观看| 欧美日韩综合久久久久久 | 首页视频小说图片口味搜索| 男女午夜视频在线观看| 欧美色欧美亚洲另类二区| 精品电影一区二区在线| 操出白浆在线播放| 国产高潮美女av| 久久九九热精品免费| 免费av不卡在线播放| 两个人视频免费观看高清| 99久久99久久久精品蜜桃| 国产一区二区激情短视频| 啦啦啦观看免费观看视频高清| 一进一出好大好爽视频| 国产综合懂色| 美女高潮喷水抽搐中文字幕| 亚洲在线观看片| 18禁国产床啪视频网站| 国产高清三级在线| 深夜精品福利| 免费观看精品视频网站| 国产欧美日韩精品亚洲av| 中文在线观看免费www的网站| 搡女人真爽免费视频火全软件 | 久久欧美精品欧美久久欧美| 三级毛片av免费| 老熟妇仑乱视频hdxx| 国产欧美日韩一区二区精品| 一进一出抽搐gif免费好疼| 一本久久中文字幕| 夜夜看夜夜爽夜夜摸| 91在线精品国自产拍蜜月 | 亚洲,欧美精品.| 十八禁人妻一区二区| 国产又黄又爽又无遮挡在线| 12—13女人毛片做爰片一| 露出奶头的视频| 久久伊人香网站| 大型黄色视频在线免费观看| 免费大片18禁| 亚洲男人的天堂狠狠| 一区二区三区高清视频在线| 日本a在线网址| 国产成人a区在线观看| 免费看a级黄色片| 午夜福利免费观看在线| 亚洲人成伊人成综合网2020| 黄色成人免费大全| 欧美黑人欧美精品刺激| 在线看三级毛片| h日本视频在线播放| 美女高潮喷水抽搐中文字幕| 毛片女人毛片| 午夜免费男女啪啪视频观看 | 淫秽高清视频在线观看| 日韩欧美在线乱码| 亚洲av一区综合| 国产精品99久久久久久久久| 狠狠狠狠99中文字幕| 少妇熟女aⅴ在线视频| 欧美性猛交黑人性爽| 欧美国产日韩亚洲一区| 好男人电影高清在线观看| 国产黄色小视频在线观看| 国产aⅴ精品一区二区三区波| 亚洲精品在线观看二区| 丝袜美腿在线中文| 中文字幕高清在线视频| 色综合亚洲欧美另类图片| 99久久精品国产亚洲精品| 国产乱人伦免费视频| 床上黄色一级片| 欧美中文综合在线视频| 嫩草影视91久久| 母亲3免费完整高清在线观看| 国内精品久久久久精免费| 久久精品国产清高在天天线| 精品久久久久久久久久久久久| 香蕉av资源在线| 九色国产91popny在线| eeuss影院久久| 日韩有码中文字幕| 日韩精品中文字幕看吧| 97超视频在线观看视频| 色视频www国产| 亚洲精品在线美女| 制服丝袜大香蕉在线| 脱女人内裤的视频| 国产一区二区在线观看日韩 | 国产精品 欧美亚洲| 久久久久亚洲av毛片大全| 久久久久久久精品吃奶| 国产欧美日韩精品一区二区| 亚洲18禁久久av| 99精品在免费线老司机午夜| 国产精品自产拍在线观看55亚洲| 在线十欧美十亚洲十日本专区| 久久6这里有精品| 白带黄色成豆腐渣| 美女cb高潮喷水在线观看| 老汉色∧v一级毛片| 女警被强在线播放| 亚洲精品在线观看二区| 色综合欧美亚洲国产小说| 亚洲片人在线观看| 男女那种视频在线观看| 五月玫瑰六月丁香| 欧美大码av| 3wmmmm亚洲av在线观看| 亚洲人与动物交配视频| 少妇高潮的动态图| 午夜免费观看网址| 欧美3d第一页| 悠悠久久av| 日本a在线网址| 韩国av一区二区三区四区| www.999成人在线观看| 国产成人啪精品午夜网站| 此物有八面人人有两片| 日本一二三区视频观看| 白带黄色成豆腐渣| 偷拍熟女少妇极品色| 久久久久精品国产欧美久久久| 欧美日本亚洲视频在线播放| 操出白浆在线播放| 91字幕亚洲| 最新在线观看一区二区三区| 热99在线观看视频| 国产在线精品亚洲第一网站| 欧美一区二区国产精品久久精品| 一个人看视频在线观看www免费 | 亚洲欧美日韩东京热| 最近视频中文字幕2019在线8| 高潮久久久久久久久久久不卡| 一级a爱片免费观看的视频| 狂野欧美白嫩少妇大欣赏| 夜夜看夜夜爽夜夜摸| 性色av乱码一区二区三区2| 久久国产精品人妻蜜桃| 五月伊人婷婷丁香| 无人区码免费观看不卡| 久久国产精品影院| 国产精品日韩av在线免费观看| 真实男女啪啪啪动态图| 啦啦啦免费观看视频1| bbb黄色大片| 在线天堂最新版资源| 免费观看人在逋| av专区在线播放| 色吧在线观看| 九九久久精品国产亚洲av麻豆| 禁无遮挡网站| 一区福利在线观看| 欧美成人免费av一区二区三区| 18禁黄网站禁片免费观看直播| 女人被狂操c到高潮| 亚洲欧美日韩无卡精品| 成人鲁丝片一二三区免费| 亚洲精品一卡2卡三卡4卡5卡| 免费搜索国产男女视频| 国产毛片a区久久久久| 日韩av在线大香蕉| 老司机在亚洲福利影院| 99国产精品一区二区蜜桃av| 国产精品99久久久久久久久| 久久久久久大精品| 99热精品在线国产| 国产精品一区二区三区四区久久| 成人18禁在线播放| 搡老岳熟女国产| 亚洲成a人片在线一区二区| 国产乱人视频| 亚洲国产色片| 动漫黄色视频在线观看| 国产精品 国内视频| 色老头精品视频在线观看| 51午夜福利影视在线观看| 韩国av一区二区三区四区| 亚洲无线在线观看| 99久久精品一区二区三区| 18禁国产床啪视频网站| 一卡2卡三卡四卡精品乱码亚洲| 97人妻精品一区二区三区麻豆| 国产成人欧美在线观看| 3wmmmm亚洲av在线观看| 精品一区二区三区av网在线观看| 国内毛片毛片毛片毛片毛片| av福利片在线观看| 一个人观看的视频www高清免费观看| 欧美精品啪啪一区二区三区| 性色av乱码一区二区三区2| 在线观看舔阴道视频| 琪琪午夜伦伦电影理论片6080| 九色国产91popny在线| 国产精品免费一区二区三区在线| 最近最新中文字幕大全电影3| 国产一区二区亚洲精品在线观看| 国产精品一区二区三区四区免费观看 | 真人一进一出gif抽搐免费| 日本与韩国留学比较| 国产av一区在线观看免费| 欧美一区二区国产精品久久精品| 国产乱人伦免费视频| 在线观看午夜福利视频| 亚洲 欧美 日韩 在线 免费| 亚洲最大成人手机在线| 在线天堂最新版资源| 中亚洲国语对白在线视频| 一个人看的www免费观看视频| 亚洲av熟女| 亚洲最大成人中文| 久久九九热精品免费| 免费看a级黄色片| 日韩欧美国产在线观看| 中文字幕熟女人妻在线| 99视频精品全部免费 在线| 亚洲欧美激情综合另类| 一进一出好大好爽视频| 国产亚洲精品av在线| 午夜老司机福利剧场| 日韩精品青青久久久久久| 日本在线视频免费播放| 淫秽高清视频在线观看| 精品不卡国产一区二区三区| 97超级碰碰碰精品色视频在线观看| 日韩欧美一区二区三区在线观看| 人人妻人人看人人澡| 久久天躁狠狠躁夜夜2o2o| 嫩草影视91久久| 在线播放国产精品三级| 乱人视频在线观看| 夜夜看夜夜爽夜夜摸| 成人鲁丝片一二三区免费| 美女高潮喷水抽搐中文字幕| 日本熟妇午夜| 好男人在线观看高清免费视频| 亚洲精品日韩av片在线观看 | 久久久久亚洲av毛片大全| 久久精品国产99精品国产亚洲性色| 18禁黄网站禁片免费观看直播| 国产单亲对白刺激| 日韩精品青青久久久久久| 免费在线观看亚洲国产| 日韩欧美精品v在线| 久久人妻av系列| 99国产综合亚洲精品| 亚洲人成网站在线播放欧美日韩| 夜夜夜夜夜久久久久| 美女高潮喷水抽搐中文字幕| 在线十欧美十亚洲十日本专区| 麻豆国产av国片精品| 午夜a级毛片| a级一级毛片免费在线观看| 亚洲精华国产精华精| 99国产极品粉嫩在线观看| 级片在线观看| 天堂√8在线中文| 丁香六月欧美| 一级a爱片免费观看的视频| 免费大片18禁| 国产免费男女视频| 欧美zozozo另类| 久久香蕉精品热| 最近在线观看免费完整版| 精品电影一区二区在线| 亚洲成a人片在线一区二区| 国产一区二区在线观看日韩 | 久久久久久久亚洲中文字幕 | 欧美性猛交╳xxx乱大交人| 性欧美人与动物交配| 国产毛片a区久久久久| 欧美黑人巨大hd| 亚洲国产高清在线一区二区三| 热99re8久久精品国产| 亚洲精品成人久久久久久| 黄色丝袜av网址大全| 亚洲,欧美精品.| 欧美高清成人免费视频www| 亚洲av熟女| 午夜福利在线观看免费完整高清在 | 制服人妻中文乱码| 九色成人免费人妻av| 91九色精品人成在线观看| 国产黄色小视频在线观看| 黄色成人免费大全| 毛片女人毛片| 老熟妇仑乱视频hdxx| 非洲黑人性xxxx精品又粗又长| 村上凉子中文字幕在线| 亚洲久久久久久中文字幕| 国产精品一区二区三区四区久久| 免费一级毛片在线播放高清视频| av在线天堂中文字幕| 一个人看的www免费观看视频| 一本一本综合久久| 国产精品久久久久久亚洲av鲁大| 欧美一级毛片孕妇| 亚洲激情在线av| 欧美最黄视频在线播放免费| 国产精品精品国产色婷婷| 老熟妇乱子伦视频在线观看| 一区二区三区免费毛片|