• <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 ?

    Minimum sample size estimates for trials in inflammatory bowel disease: A systematic review of a support resource

    2021-12-03 06:15:54MorrisGordonSvetlanaLakuninaVasilikiSinopoulouAnthonyAkobeng
    World Journal of Gastroenterology 2021年43期

    Morris Gordon, Svetlana a Lakunina, Vasiliki Sinopoulou, Anthony Akobeng

    Abstract

    Key Words: Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Gastroenterology; Statistics; Sample size

    INTRODUCTION

    Sample size estimation (SSE) is an extremely important calculation for designing a clinical trial. Failure to produce an appropriate calculation may lead to imprecise results[1]. If a sample size is too large, statistically significant outcomes may be theoretically detected that may not be clinically relevant (type 1 error). This, however,is rarely a concern as studies are rarely overpowered to balance the study power with the cost. On the other hand, if a sample size is too small then a clinically significant outcome may not be detected statistically (type 2 error)[2 ,3]. The reporting of SSE in randomised controlled trials (RCTs) is a standard requirement according to the consolidated standards of reporting trials (CONSORT) statement which was introduced as a guide to conducting RCTs in 1996 [4].

    In a previous systematic review[5], we showed that 25 % of RCTs on interventions for inflammatory bowel disease (IBD) have no power calculation (PC). A third of those who report PC do not achieve their target sample size. Based on those results, we decided to conduct a further systematic review.

    We set out to systematically review RCTs on interventions for the IBD management,extract the vital parameters needed for sample size calculations, and synthesise the data to demonstrate whether trials across the field are adequately powered. We also set out to use the actual clinical data across these comparisons to synthesise data for minimum sample sizes that would achieve appropriate power to support future researchers designing trials and performing SSEs.

    MATERIALS AND METHODS

    This review was performed in alignment with Cochrane guidelines[6] in April 2020 and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement[7].

    Eligibility criteria

    We followed the sampling methodology described within our systematic review protocol (uploaded within our institutional repository)[8] used for our previous review of the reporting of sample size calculations[5].

    In brief, we included RCTs investigating either induction or maintenance therapy with biologics, immunomodulators, and microbiome against control, placebo, or no intervention. We conducted a comprehensive search of the Cochrane IBD Specialized Trials Register, CENTRAL, Cochrane library of IBD reviews for primary RCTs. The search terms are presented in Supplementary material.

    We included RCTs published since 1996 (after the publication of the CONSORT statement). We excluded reports lacking clear information on the number of participants; cluster RCTs; pilot or feasibility studies; studies with mixed population of people with and without IBD; studies on secondary analyses of follow-up data collection after discontinuation of treatment. We excluded abstracts as these rarely allow space for such information to be presented. As we wanted to assess the established evidence for a PC of treatment for the IBD, we excluded RCTs describing all interventions where work may be at phase 3 (pharmacological:e.g.ustekinumab,golimumab, tofacitinib) or not under the three core headings (biologic, immunomodulators or anti-inflammatories).

    Complying to the above search strategy, two authors (SL and MG) identified RCTs titles that appeared to be applicable. These were independently screened and in cases of disagreement, a third review author (VS) was involved to reach consensus. Two review authors independently extracted and recorded data on a predefined checklist.When disagreements occurred, a third review author was involved, and the consensus was reached.

    We created an excel document to extract data regarding the trials. Firstly, we separated the studies into 8 categories [Crohn’s disease (CD)-clinical relapse, clinical remission, endoscopic relapse, endoscopic remission; ulcerative colitis (UC)-clinical relapse, clinical remission, endoscopic relapse, endoscopic remission]. Secondly, we grouped the studies according to the intervention used. One author extracted the data,and in case of any problems, the data was checked by the second author.

    The extracted data although is not available publicly can be obtainedviadirect contact with authors. The references of the included stuidies can be found in Supplementary material.

    Extracted data included

    (1 ) Number of events and participants originally assigned to each group; (2 ) Characteristics of participants; (3 ) The proportion that we calculated according to the number of events and participants (x = n/N), in which n is a number of events and N is a number of participants); (4 ) The difference achieved that we calculated according to the proportions of two groups (proportion 1 -proportion 2 ); (5 ) Intervention and control details; (6 ) Presence of SSE and calculation details [minimal clinically important difference (MCID) used for PC, power, significance level, target sample size]; and (7 )Outcomes (the number of patients recruited and completing study; the number of treatment success/failures; and the difference achieved).

    We used the studies in which intervention was compared to the control or placebo.We grouped those studies according to the interventions, type of treatment (induction,maintenance), and outcomes (relapse, remission) and calculated mean difference and mean MCID where it was possible.

    After resolving all the inconsistencies with data extraction regarding the use of sample size calculations for the studies with achieved difference of less than 10 %, we produced two tables (Tables 1 and 2 ). We recalculated sample size for those groups using the power of 80 %, probability of type 1 error 0 .05 , and the achieved difference.We used those parameters as they were the most commonly used amongst the studies.The parameters we used were two independent groups, dichotomous outcomes. In group 1 we have put the rate reported by the study of the intervention drug, and in group 2 we have put the rate of the placebo.

    The small lest MCID that was reported by the studies was 10 %, thereby, we decided to not reproduce PC for those studies with the achieved difference of less than 10 %.We also calculated the mean sample deficit in percentage based on the target sample size and achieved sample size reported by the studies.

    After receiving the sample size of participants, we made a decision whether the study is underpowered, and if yes, then by how many people.

    Data synthesis

    We produced descriptive statistics regarding the sample sizes for the studies grouped according to the interventions (Tables 1 and 2 ).

    Ethical statement

    As all data included already existed within the published scholarly output, no ethical approval was sought.

    Table 1 Overall summary of power calculations and sample size deficits

    RESULTS

    A total of 7451 potential citations were screened and 308 full texts assessed for eligibility. There were 209 texts excluded, 106 because they were published prior to the release of the CONSORT statement and 103 because they did not match our inclusion outcome. This left a total of 99 trials included, with 60 pertaining to CD and 39 to UC.The full details are shown in Figure 1 .

    The mean proportion of patients achieving clinical remission reported within the placebo groups of induction studies was 34 .34 % in CD trials and 26 .79 % for UC. For endoscopic remission, 0 % in CD and 29 .6 % for UC. The mean proportion of patients achieving clinical relapse for maintenance studies were 55 % for CD and 46 .79 % for UC. For endoscopic relapse, 78 .85 % in CD, and 28 .7 % in UC.

    Within CD induction studies, 26 out of 41 (63 .4 %) reported a PC and 19 of 26 (73 .1 %)in maintenance studies. Within UC induction studies, 22 out of 31 (71 %) reported a PC and 10 of 17 (58 .8 %) in maintenance studies.

    When considering the MCID that those studies reporting a PC employed for this calculation, within CD induction studies the mean difference was 33 % (range 20 %-50 %) and 27 % difference for maintenance studies (15 %-40 %). Within UC induction studies the mean was 26 % (range 19 %-40 %) and 27 % for maintenance studies (18 %-40 %). The MCIDs these studies reported rarely matched the actual differences achieved by these studies. In fact, the discrepancy between this estimated figure for the MCID used for the PC and the actual differences seen were a mean of 22 .8 % higher in CD induction studies, 13 .8 % higher in maintenance studies, 15 .7 % higher in UC induction studies, and 10 .2 % higher in maintenance studies.

    These discrepancies are proportionally large and in the context of PCs are clearly substantial and led to large numbers of studies being underpowered. These are summarised in Table 1 . Study specific data with further details is available upon request.

    Table 2 gives the results of our sample size calculations at the intervention specific level that employed the actual achieved clinical differences from previous studies,using the power of 80 % and the probability of type 1 error 0 .05 . This shows the minimum sample sizes that would be indicated for RCTs compared with placebo to use. Within comparisons where the mean difference was less than 10 %, no calculation has been given as this would be a very high indicative figure.

    DISCUSSION

    Within this review, it has been demonstrated that there is no clear basis or accepted standard for current practice for MCID estimation when producing a PC for a primary RCT within IBD. This has led to huge variations in suggested figures for recruitment.These trials present practical and logistical challenges to organisers, with potential inconvenience to patients, as well as the cost to those funding such research. Having an accurate figure for calculations is important to ensure this investment of resource is used most efficiently and effectively. It is key to note that we are not commenting atthe individual study level. It is inappropriate to look at the projected MCID and PC for a project, if calculated on a reasonable basis, to then retrospectively suggest that the findings of a lesser MCID mean it is underpowered. This not just statistically inappropriate, but methodologically flawed. However, these findings propose that the basis for such MCID estimations is at worst unclear and often can be seen as flawed.

    TabIe 2 ProposaIs for minimum cIinicaIIy important difference and associated power caIcuIations for future studies

    Outcome-endoscopic relapse Interventional diet vs Control diet-2 .5 %NA Vedolizumab vs Placebo-3460 Antibiotics vs Placebo -14 .6 %360 Methotrexate vs Placebo -24 .2 %1285 -ASA vs Placebo -16 .4 %290 Methotrexate vs Placebo -24 .2 %128 Outcome-endoscopic relapse 5 -ASA vs Placebo 2 .7 %NA Azathioprine vs Placebo -23 %1306 -MP vs Placebo -3 .8 %NA Antibiotics vs Placebo 6 .6 %NA Induction studies Outcome-clinical remission Outcome-clinical remission Vedolizumab vs Placebo 14 .8 %190 Glutamine-enriched diet vs Placebo-11 .1634 Azathioprine vs Placebo -3 .6 %NA 6 -MP vs Placebo 5 %NA Fecal Transplant vs Control 20 .3 %1506 -MP vs Placebo 5 %NA Budesonide vs Placebo 6 .5 %NA Interventional diet vs Control diet 20 .9 %160 Type 1 IFNs vs Placebo 5 .9 %NA Elemental diet vs Non elemental diet 1 .6 %NA Etrolizumab vs Placebo 13 .4 %140 N6 /N9 rich feeds vs non N6 /N9 rich food-1 .1 %NA Low dose naltrexone vs Placebo 9 %NA 5 -ASA vs Placebo 11 .8 %422 GM-CSF vs Placebo 7 .8 %NA Outcome-endoscopic remission Brakinumab vs Placebo 8 .5 %NA Vedolizumab vs Placebo 37 .7 %182 Ustekinumab vs Placebo 8 .6 %NA Natalizumab vs Placebo 14 .8 %310 Fecal Transplant vs Control 26 .4 %160 Methotrexate vs Placebo -14 .8 %350 Budesonide vs Placebo 13 .9 %NA Antibiotics vs Placebo 10 %780 Methotrexate vs Placebo 46 .7 %NA Outcome-endoscopic remission Etrolizumab vs Placebo 7 .7 %NA Low dose naltrexone vs Placebo 22 .2 %605 -ASA vs Placebo 53 .7 %306 Maintenance studies Outcome-clinical relapse Outcome-clinical relapse 5 -ASA vs Placebo -16 .4 %2905 -ASA vs Placebo,medically induced 3 .1 %NA Vedolizumab vs Placebo-27 .4845 -ASA vs Placebo,surgically induced-5 .4 %NA Interventional diet vs Control diet-3 .6 %NA Anti-TB vs Placebo -23 %130 Probiotics vs Control-16 .7154 Azathioprine vs Placebo,medically induced-9 .9 %NA

    Azathioprine vs Placebo-22 .4154 Azathioprine vs Placebo,surgically induced-17 .3 %254 Methotrexate vs Placebo 19 .9 %1946 -MP vs Placebo,surgically induced-10 .9 %646 Rectal 5 -ASA vs Placebo-29 %90 Omega -3 fatty acids diet vs Control diet-8 .5 %NA Curcumin vs Placebo-9 .6 %NA Elemental diet vs No supplemets-29 .4 %88 Outcome-endoscopic relapse Interventional diet vs Control diet-2 .5 %NA Vedolizumab vs Placebo-3460 Antibiotics vs Placebo -14 .6 %360 Methotrexate vs Placebo -24 .2 %1285 -ASA vs Placebo -16 .4 %290 Methotrexate vs Placebo -24 .2 %128 Outcome-endoscopic relapse 5 -ASA vs Placebo 2 .7 %NA Azathioprine vs Placebo -23 %1306 -MP vs Placebo -3 .8 %NA Antibiotics vs Placebo 6 .6 %NA NA is put when the difference achieved is less than 10 % (which is the least Minimal Clinically Important Difference used by the studies).

    Figure 1 Study flow diagram. UC: Ulcerative colitis; CD: Crohn’s disease.

    There are further ethical issues these problems raise, such as being forced to give treatments to people without having a statistically proved effect or a high certainty result within the Grading of Recommendations Assessment, Development and Evaluation analysis (due to reasons of imprecision from statistical sampling issues).The power of a study, therefore, has huge implications on the precision of estimates in the future analysis of data and in turn clinical practice guidelines. Within this review,30 % of studies appeared to be underpowered based on actual achieved clinical differences within the wider comparable evidence base, with mean sample size deficits up to 79 patients per trial. This does impact the overall certainty of the global evidence base within IBD, with precision a key limitation downgrading many outcomes within key guidelines across dozens of interventions.

    Within this review, we present a resource for SSE not just for future study authors,but for study peer reviewers and most importantly professionals and the patients. This table gives an estimated PC result for a minimum sample size based on all existing studies within this period. Rather than being based on just single studies or clinical judgement, these represent estimates based on actual achieved clinical data and to our knowledge are the first time such a resource has ever been provided for researchers in the field or indeed for readers of future research. Additionally, for those wishing to calculate key statistics and measures of outcome from their primary studies, this paper provides a systematic and objective resource for baseline risk. This could be used for calculating numbers needed to treat or harm, for example.

    This resource can be used by study designers to prevent PCs based on studies that offer a high MCID and as such a lower minimum sample size than is actually warranted. Conversely, it prevents unnecessary over recruitment. Funders can use this to appropriately budget and ensure viability of studies. Ethics boards and other governance groups will be able to consult this resource to support their consideration of research proposals.

    There were a number of comparisons where the difference in practice was below 10 % and it was deemed inappropriate to make a calculation in such cases, as no previous study has ever indicated an MCID below 10 % as clinically significant to patients or practice. In these cases, consideration should be given to the overall figures presented in Table 2 or minimum sample size and MCID in practice in a similar context.

    We would also recommend that in practice, patients and key stakeholders should be involved in deciding on an MCID for a given intervention prior to a new study. They may indicate that in spite of any existing MCID evidence that such a difference is not significant enough to matter to those who are most impacted by the findings and such views must be reflected in the process of SSE. It is also worth noting that there will always be settings and contexts when deviation may be warranted, thereby, a resource is not prescriptive but rather presented as evidence-based guidance. We would,however, propose that such deviations can and should be justified to support transparency for the readings these trials report.

    There are weaknesses and exceptions to these approaches. The search methods used limited the parameters of the search for pragmatic reasons. However, this does not represent any systematic bias, hence we do not believe it invalidates the findings, and in the future this resource can be updated prospectively. When the achieved difference was less than 10 %, rather than reporting extremely large sample size calculations, no such calculation was made. Additionally, in studies comparing active agents, accurate estimates are needed based on the contexts as the hypothesis may not be of the inferiority or superiority but of no difference, which requires a different approach to calculations.

    There were some limitations to this review. There are obvious issues of heterogeneity limiting the appropriateness of pooling the data, however, the only way to obtain the previously used MCID was through looking at the past studies. These are mainly related to missing or unclear information in primary studies regarding SSE and as authors were not contacted, assumptions were made for the basis of these calculations which could confer some inaccuracy in our estimations. We also limited our studies to those from after the CONSORT statement release as we felt this was a fair time from which to expect SSE to occur, but earlier studies could potentially have offered more insight. Finally, we have focussed on studies comparing treatment with placebo or no intervention. This was a pragmatic decision as many studies of agents choose to make this comparison, although often these do not reflect current standard clinical practice. In the cases of such comparisons, SSE may not have to be based on a MCID but instead assume clinical equivalency and therefore be informed differently.In essence, this guidance may not be relevant for these scenarios, although may inform statistical considerations within similar contexts. Finally, such a resource of course is likely to become inaccurate rapidly, with the need for updates, but as often no such resource is employed, we believe this is still an improvement on current practices.

    Future researcher is needed to potentially validate the calculations with clinical and patient input to ensure the SSE and MCID that the data informs has clinical, as well as statistical relevance. This could lead to a more triangulated resource that is statistically and evidentially sound, but also clinically sound and patient informed. This could conceivably lead to increases or decreases in minimally important differences to reflect complexity in specific clinical scenarios and interventional contexts.

    CONCLUSION

    In conclusion, a third of intervention IBD studies within the last 25 years are underpowered, with large variations in the approaches to calculating sample sizes and the minimum clinically important differences. The authors present a sample size estimate resource based on the published evidence base for future researchers and other key stakeholders within the IBD trial field.

    ARTICLE HIGHLIGHTS

    少妇的逼好多水| 欧美日韩国产mv在线观看视频| 久久久久精品性色| 久久久久久久国产电影| 欧美激情极品国产一区二区三区 | 一边亲一边摸免费视频| 精品第一国产精品| 午夜免费鲁丝| 大片免费播放器 马上看| 亚洲国产最新在线播放| 中文乱码字字幕精品一区二区三区| 欧美精品亚洲一区二区| 少妇 在线观看| 啦啦啦啦在线视频资源| 97在线人人人人妻| 久久婷婷青草| kizo精华| 欧美日本中文国产一区发布| 大香蕉久久网| 欧美日韩一区二区视频在线观看视频在线| 国产女主播在线喷水免费视频网站| 成人手机av| 91aial.com中文字幕在线观看| 国产一区二区在线观看日韩| 99热网站在线观看| 18禁裸乳无遮挡动漫免费视频| 桃花免费在线播放| 一区二区三区四区激情视频| 99久久综合免费| 欧美日韩国产mv在线观看视频| 午夜老司机福利剧场| 国产亚洲精品久久久com| 热99国产精品久久久久久7| 秋霞在线观看毛片| 51国产日韩欧美| 欧美精品一区二区免费开放| 成人毛片a级毛片在线播放| 久久女婷五月综合色啪小说| 纵有疾风起免费观看全集完整版| 男女边吃奶边做爰视频| 免费观看性生交大片5| 久久久国产一区二区| 少妇被粗大的猛进出69影院 | 亚洲av在线观看美女高潮| 99国产精品免费福利视频| av网站免费在线观看视频| 少妇的丰满在线观看| 久久 成人 亚洲| 在线观看www视频免费| 午夜免费观看性视频| 免费女性裸体啪啪无遮挡网站| 精品一区二区三区四区五区乱码 | 99九九在线精品视频| 欧美 日韩 精品 国产| 18+在线观看网站| 精品人妻偷拍中文字幕| 激情五月婷婷亚洲| 麻豆精品久久久久久蜜桃| 亚洲精品456在线播放app| 久久久a久久爽久久v久久| 国产成人精品在线电影| 亚洲av男天堂| www日本在线高清视频| 又黄又爽又刺激的免费视频.| 99国产综合亚洲精品| 十分钟在线观看高清视频www| 国产免费一区二区三区四区乱码| 亚洲国产毛片av蜜桃av| 久久人妻熟女aⅴ| 欧美精品国产亚洲| 秋霞在线观看毛片| 久久久久国产网址| 免费不卡的大黄色大毛片视频在线观看| 国语对白做爰xxxⅹ性视频网站| av在线app专区| 老司机影院毛片| 国产成人91sexporn| 一级毛片我不卡| 日本91视频免费播放| 国产有黄有色有爽视频| 日本猛色少妇xxxxx猛交久久| 下体分泌物呈黄色| 伦精品一区二区三区| 午夜av观看不卡| 人人妻人人添人人爽欧美一区卜| 乱人伦中国视频| 99国产综合亚洲精品| 爱豆传媒免费全集在线观看| 少妇人妻精品综合一区二区| 亚洲,欧美精品.| 国产精品偷伦视频观看了| 国产综合精华液| 黄色 视频免费看| 亚洲国产日韩一区二区| 亚洲综合色惰| 热99国产精品久久久久久7| 精品一品国产午夜福利视频| 伊人亚洲综合成人网| 亚洲精品国产色婷婷电影| 久久精品久久久久久久性| 欧美激情国产日韩精品一区| 日韩伦理黄色片| 91精品国产国语对白视频| 久久精品国产a三级三级三级| 在线天堂最新版资源| 五月玫瑰六月丁香| 少妇熟女欧美另类| 欧美最新免费一区二区三区| xxx大片免费视频| 日韩 亚洲 欧美在线| 18+在线观看网站| 欧美日韩视频精品一区| 亚洲综合精品二区| 国产免费又黄又爽又色| 中文欧美无线码| 国产av国产精品国产| 国产乱人偷精品视频| 日本免费在线观看一区| 中文字幕最新亚洲高清| 亚洲伊人色综图| 你懂的网址亚洲精品在线观看| 各种免费的搞黄视频| 亚洲欧美中文字幕日韩二区| 亚洲国产日韩一区二区| 成人国产av品久久久| 国产精品免费大片| 中文字幕亚洲精品专区| 99视频精品全部免费 在线| av又黄又爽大尺度在线免费看| 97人妻天天添夜夜摸| 尾随美女入室| 久久精品国产自在天天线| 日韩欧美精品免费久久| 国产精品不卡视频一区二区| 国产精品秋霞免费鲁丝片| 春色校园在线视频观看| 18禁国产床啪视频网站| 亚洲av.av天堂| 成年人午夜在线观看视频| 少妇的逼水好多| 91国产中文字幕| 男男h啪啪无遮挡| 亚洲第一av免费看| 哪个播放器可以免费观看大片| 91精品伊人久久大香线蕉| 久久久久久久亚洲中文字幕| 一区在线观看完整版| 免费观看性生交大片5| 激情视频va一区二区三区| 美女中出高潮动态图| 久久 成人 亚洲| 三级国产精品片| 亚洲伊人色综图| 女人久久www免费人成看片| freevideosex欧美| 国产激情久久老熟女| 熟女电影av网| 日本免费在线观看一区| 亚洲av欧美aⅴ国产| 国产黄色免费在线视频| 日本午夜av视频| 日韩不卡一区二区三区视频在线| 国产精品一国产av| 久久久久人妻精品一区果冻| 亚洲人与动物交配视频| 激情视频va一区二区三区| 丰满乱子伦码专区| 9191精品国产免费久久| 侵犯人妻中文字幕一二三四区| 男女无遮挡免费网站观看| 全区人妻精品视频| www.色视频.com| 一二三四中文在线观看免费高清| 国产69精品久久久久777片| 人人妻人人澡人人爽人人夜夜| 大片电影免费在线观看免费| 国产一级毛片在线| 永久免费av网站大全| 综合色丁香网| 日韩一区二区视频免费看| 99视频精品全部免费 在线| 精品一区在线观看国产| 免费黄频网站在线观看国产| 久久99精品国语久久久| 久久 成人 亚洲| 国产又爽黄色视频| 精品国产乱码久久久久久小说| av不卡在线播放| 人妻一区二区av| 日本vs欧美在线观看视频| 国产成人aa在线观看| 欧美日本中文国产一区发布| 欧美另类一区| 国产在线一区二区三区精| 男的添女的下面高潮视频| 一区二区三区四区激情视频| 热99久久久久精品小说推荐| 亚洲精品色激情综合| 欧美xxxx性猛交bbbb| 少妇高潮的动态图| 国产一区二区在线观看av| 亚洲人与动物交配视频| 你懂的网址亚洲精品在线观看| 成人18禁高潮啪啪吃奶动态图| av线在线观看网站| 亚洲激情五月婷婷啪啪| 欧美 亚洲 国产 日韩一| 熟女av电影| 色吧在线观看| 黄色 视频免费看| 日本黄大片高清| 天美传媒精品一区二区| 久久精品aⅴ一区二区三区四区 | 伊人亚洲综合成人网| 一二三四中文在线观看免费高清| 日韩成人伦理影院| 久久人人爽人人爽人人片va| 中文字幕免费在线视频6| 母亲3免费完整高清在线观看 | 男人爽女人下面视频在线观看| 宅男免费午夜| 亚洲精品色激情综合| 美女视频免费永久观看网站| 亚洲精品视频女| videossex国产| a级片在线免费高清观看视频| 亚洲av男天堂| 婷婷成人精品国产| 大话2 男鬼变身卡| 亚洲婷婷狠狠爱综合网| 久久久久精品人妻al黑| 国产高清国产精品国产三级| 欧美97在线视频| 国产一区二区在线观看日韩| 熟女人妻精品中文字幕| 免费女性裸体啪啪无遮挡网站| 日韩成人av中文字幕在线观看| 日本欧美视频一区| 精品久久久久久电影网| 99热这里只有是精品在线观看| 免费女性裸体啪啪无遮挡网站| 日韩成人av中文字幕在线观看| 欧美97在线视频| 国产国语露脸激情在线看| 2021少妇久久久久久久久久久| 精品视频人人做人人爽| 涩涩av久久男人的天堂| 久久狼人影院| 精品人妻偷拍中文字幕| 久久久久久久精品精品| 丝袜喷水一区| 在线观看免费日韩欧美大片| 久久午夜福利片| 久久狼人影院| 9191精品国产免费久久| 久久久久久人人人人人| 国产免费现黄频在线看| 亚洲伊人久久精品综合| 热re99久久国产66热| 少妇 在线观看| 制服诱惑二区| 日韩成人av中文字幕在线观看| 18禁观看日本| 精品熟女少妇av免费看| 激情五月婷婷亚洲| 欧美 日韩 精品 国产| 香蕉丝袜av| 多毛熟女@视频| 亚洲精品456在线播放app| 精品国产露脸久久av麻豆| 精品久久蜜臀av无| 国产成人免费无遮挡视频| 久久久久国产精品人妻一区二区| 成年动漫av网址| 男女免费视频国产| 老司机影院成人| 色94色欧美一区二区| 天天影视国产精品| 国产免费又黄又爽又色| 欧美bdsm另类| 久久久亚洲精品成人影院| 母亲3免费完整高清在线观看 | 久久99热6这里只有精品| 欧美国产精品va在线观看不卡| √禁漫天堂资源中文www| 日韩欧美精品免费久久| 亚洲精品一区蜜桃| 国产精品久久久av美女十八| 午夜免费男女啪啪视频观看| 一区二区日韩欧美中文字幕 | 久久精品aⅴ一区二区三区四区 | 中文字幕精品免费在线观看视频 | 极品少妇高潮喷水抽搐| 黑人巨大精品欧美一区二区蜜桃 | 国产成人免费观看mmmm| 精品一区在线观看国产| 久久久久国产精品人妻一区二区| 日韩,欧美,国产一区二区三区| 十分钟在线观看高清视频www| 免费看av在线观看网站| 亚洲精品,欧美精品| 热99国产精品久久久久久7| 久久精品aⅴ一区二区三区四区 | 建设人人有责人人尽责人人享有的| 欧美3d第一页| 夜夜爽夜夜爽视频| av有码第一页| 亚洲欧美成人综合另类久久久| 99九九在线精品视频| 久久精品国产鲁丝片午夜精品| 免费人成在线观看视频色| 成人综合一区亚洲| 18在线观看网站| 亚洲av免费高清在线观看| 色94色欧美一区二区| 精品少妇久久久久久888优播| av视频免费观看在线观看| 日日撸夜夜添| 欧美xxxx性猛交bbbb| 免费女性裸体啪啪无遮挡网站| 亚洲欧洲精品一区二区精品久久久 | 三上悠亚av全集在线观看| 18在线观看网站| 精品一区二区三区视频在线| 亚洲欧美一区二区三区黑人 | 亚洲国产精品国产精品| 国产精品秋霞免费鲁丝片| 亚洲精品第二区| 22中文网久久字幕| 丝袜脚勾引网站| 国产免费福利视频在线观看| 99久国产av精品国产电影| 免费高清在线观看日韩| 欧美日韩国产mv在线观看视频| 欧美变态另类bdsm刘玥| 少妇被粗大猛烈的视频| 久久国产亚洲av麻豆专区| 国产精品久久久久久精品古装| 国产精品不卡视频一区二区| 男女边摸边吃奶| 高清av免费在线| 丝袜脚勾引网站| 午夜免费男女啪啪视频观看| 久久精品国产自在天天线| 国产亚洲一区二区精品| 免费观看av网站的网址| 精品第一国产精品| 丝袜脚勾引网站| 18禁动态无遮挡网站| 另类亚洲欧美激情| 亚洲国产精品一区二区三区在线| 成人国产av品久久久| 亚洲精品乱码久久久久久按摩| 91在线精品国自产拍蜜月| 乱码一卡2卡4卡精品| 成人毛片60女人毛片免费| 中国国产av一级| 国产 精品1| 又黄又爽又刺激的免费视频.| 99视频精品全部免费 在线| 少妇人妻久久综合中文| 亚洲国产最新在线播放| 精品国产一区二区三区四区第35| 男女下面插进去视频免费观看 | 国产亚洲av片在线观看秒播厂| 视频在线观看一区二区三区| 久久ye,这里只有精品| 亚洲综合精品二区| 亚洲伊人色综图| videosex国产| 亚洲av男天堂| 香蕉国产在线看| 最后的刺客免费高清国语| 日韩欧美一区视频在线观看| 日本av免费视频播放| 黄网站色视频无遮挡免费观看| 这个男人来自地球电影免费观看 | 91久久精品国产一区二区三区| 国产日韩欧美视频二区| 精品一品国产午夜福利视频| 免费观看av网站的网址| 国产一区亚洲一区在线观看| 久久久久精品性色| 欧美激情 高清一区二区三区| 亚洲欧洲国产日韩| 好男人视频免费观看在线| 夜夜爽夜夜爽视频| 大片电影免费在线观看免费| 久久狼人影院| 久久这里只有精品19| 最近的中文字幕免费完整| 国产精品人妻久久久久久| 亚洲精品视频女| 91久久精品国产一区二区三区| 国产无遮挡羞羞视频在线观看| 九草在线视频观看| 国产麻豆69| 免费黄色在线免费观看| 少妇高潮的动态图| 成人国产av品久久久| 精品一区二区免费观看| 亚洲国产精品成人久久小说| 国产精品 国内视频| 欧美精品亚洲一区二区| 亚洲精品乱码久久久久久按摩| 亚洲欧美日韩另类电影网站| 日本与韩国留学比较| 黄色 视频免费看| av福利片在线| 秋霞在线观看毛片| 少妇高潮的动态图| 亚洲国产av新网站| 嫩草影院入口| 亚洲精品久久成人aⅴ小说| 一级,二级,三级黄色视频| 国产综合精华液| 丝袜喷水一区| 国产成人精品无人区| 男人爽女人下面视频在线观看| 制服丝袜香蕉在线| 秋霞在线观看毛片| 最黄视频免费看| 黑人巨大精品欧美一区二区蜜桃 | 精品视频人人做人人爽| 精品一区在线观看国产| 日本黄色日本黄色录像| 大片免费播放器 马上看| 亚洲成人av在线免费| 热re99久久国产66热| 在线天堂最新版资源| 老司机影院成人| 91午夜精品亚洲一区二区三区| 欧美日韩av久久| 蜜臀久久99精品久久宅男| 在线观看www视频免费| 欧美bdsm另类| 国产精品麻豆人妻色哟哟久久| av免费在线看不卡| 两个人免费观看高清视频| 久久久精品94久久精品| 久久鲁丝午夜福利片| 国产免费视频播放在线视频| 女性生殖器流出的白浆| 视频中文字幕在线观看| 男人添女人高潮全过程视频| 超色免费av| 中文字幕av电影在线播放| 久久久久久人妻| 中文字幕人妻丝袜制服| 亚洲精品国产色婷婷电影| 极品少妇高潮喷水抽搐| 亚洲精品乱码久久久久久按摩| 美国免费a级毛片| 高清视频免费观看一区二区| 啦啦啦中文免费视频观看日本| 9色porny在线观看| 在线观看www视频免费| 精品国产乱码久久久久久小说| 亚洲av在线观看美女高潮| 久久久久视频综合| 欧美变态另类bdsm刘玥| 亚洲欧美日韩卡通动漫| 中文字幕另类日韩欧美亚洲嫩草| 亚洲国产精品成人久久小说| 日产精品乱码卡一卡2卡三| 熟女人妻精品中文字幕| 大话2 男鬼变身卡| 日韩欧美精品免费久久| 99re6热这里在线精品视频| 国产激情久久老熟女| 国产爽快片一区二区三区| 亚洲精品日韩在线中文字幕| 日韩欧美精品免费久久| 99国产精品免费福利视频| 国产精品三级大全| 亚洲精品国产av蜜桃| 免费观看a级毛片全部| 侵犯人妻中文字幕一二三四区| 欧美日韩成人在线一区二区| 欧美成人午夜免费资源| 国产男女内射视频| 国产在线视频一区二区| 夜夜骑夜夜射夜夜干| 久久免费观看电影| 香蕉精品网在线| 日韩大片免费观看网站| 免费看不卡的av| 国产1区2区3区精品| 永久网站在线| a级毛色黄片| 男人操女人黄网站| 久久99热6这里只有精品| 最近最新中文字幕大全免费视频 | 欧美少妇被猛烈插入视频| 国产亚洲av片在线观看秒播厂| 69精品国产乱码久久久| 国产黄色视频一区二区在线观看| 99视频精品全部免费 在线| 久久久久久久精品精品| 少妇被粗大的猛进出69影院 | 内地一区二区视频在线| 久久久久视频综合| 国产成人一区二区在线| 丰满少妇做爰视频| 18在线观看网站| 老熟女久久久| 男女国产视频网站| 看十八女毛片水多多多| a级毛片黄视频| 街头女战士在线观看网站| 高清毛片免费看| 一级a做视频免费观看| 国产欧美亚洲国产| www日本在线高清视频| 欧美精品一区二区免费开放| 老女人水多毛片| av一本久久久久| www.av在线官网国产| 亚洲久久久国产精品| 好男人视频免费观看在线| 久久久亚洲精品成人影院| 免费黄网站久久成人精品| 一级a做视频免费观看| 欧美激情极品国产一区二区三区 | 免费人妻精品一区二区三区视频| 久久精品国产a三级三级三级| 国国产精品蜜臀av免费| 亚洲性久久影院| 国产av国产精品国产| 九草在线视频观看| 久久午夜综合久久蜜桃| 18禁观看日本| 国产精品成人在线| 99久国产av精品国产电影| 久久国产精品大桥未久av| 亚洲精品久久午夜乱码| 国产毛片在线视频| 男女边吃奶边做爰视频| 在线观看免费视频网站a站| 国产精品三级大全| 国产精品人妻久久久久久| 18禁在线无遮挡免费观看视频| 亚洲精品视频女| 日日啪夜夜爽| 国产视频首页在线观看| 久久国产精品大桥未久av| 欧美成人午夜精品| 最近最新中文字幕免费大全7| 午夜福利,免费看| 美女内射精品一级片tv| 国产精品国产三级专区第一集| 国产亚洲精品第一综合不卡 | 欧美日本中文国产一区发布| 9热在线视频观看99| 亚洲欧美成人综合另类久久久| 赤兔流量卡办理| 午夜福利视频精品| 日韩av在线免费看完整版不卡| 亚洲美女搞黄在线观看| 免费久久久久久久精品成人欧美视频 | 日韩av在线免费看完整版不卡| 国产在线一区二区三区精| 中国国产av一级| 免费观看av网站的网址| 亚洲国产色片| 婷婷色麻豆天堂久久| 三级国产精品片| 亚洲熟女精品中文字幕| 国产欧美日韩一区二区三区在线| 草草在线视频免费看| 国产深夜福利视频在线观看| 久久这里只有精品19| 久久精品国产鲁丝片午夜精品| 99热网站在线观看| 亚洲少妇的诱惑av| 最近最新中文字幕免费大全7| 国产高清三级在线| 又粗又硬又长又爽又黄的视频| 国产免费又黄又爽又色| 亚洲欧洲日产国产| 日韩在线高清观看一区二区三区| 精品少妇久久久久久888优播| 国产精品久久久久久久电影| 久热久热在线精品观看| 免费久久久久久久精品成人欧美视频 | 欧美精品一区二区大全| 男人爽女人下面视频在线观看| 男女下面插进去视频免费观看 | 一级片免费观看大全| 亚洲精品成人av观看孕妇| 亚洲美女黄色视频免费看| 国产成人欧美| 精品一区二区三区四区五区乱码 | 国产女主播在线喷水免费视频网站| 久久久久久久国产电影| 夫妻午夜视频| 最近中文字幕2019免费版| 国产一级毛片在线| 国产精品三级大全| 插逼视频在线观看| 18禁动态无遮挡网站| 伦理电影免费视频| 亚洲成色77777| 国产无遮挡羞羞视频在线观看| 国产男女内射视频| 99视频精品全部免费 在线| 国产精品久久久久久久久免| 欧美少妇被猛烈插入视频| av.在线天堂| 天天躁夜夜躁狠狠躁躁| 成人影院久久| 欧美日韩一区二区视频在线观看视频在线| 欧美日韩亚洲高清精品| 制服人妻中文乱码| 永久免费av网站大全|