Live streaming commerce as a popular marketing method has attracted wide attention, but little is known about why consumers continue to watch live streaming. To fill this research gap, this study draws on social presence theory to examine the impact of sense of community, emotional support, and interactivity on viewers’ social presence, which, in turn, influences their live streaming watching. Furthermore, the moderating role of streamer attractiveness is also investigated. The authors collected survey data from 386 live streaming viewers and used the structural equation model to test the research model. The results reveal that sense of community, interactivity, and emotional support positively affects viewers’ social presence, leading to viewers’ watching live streaming. Furthermore, streamer attractiveness plays a significant moderating role between social presence and live streaming watching. This study provides a unified theoretical framework to explain the intention to watch live streaming based on social presence theory. Sense of community, interactivity and emotional support positively influence viewers’ social presence, and in turn, social presence influences watching intention. The results of the moderation test show that streamer attractiveness positively moderated the relationship between social presence and watching intention.Therefore, we examine how these three variables affect social presence in live streaming. In addition, there is another critical factor in live streaming: the streamer. The streamer engages the viewers by organizing and conveying the content. Although we explore the formation of social presence from the viewer experience perspective, it is inevitably influenced by the streamer. Attractiveness embodies streamers’ charm and comprehensive ability . TherefoThis study has the following three theoretical contributions. First, we contribute to the literature explaining intention to watch live streaming by focusing on viewer social presence in the live streaming. Second, we explain the antecedents of social presence based on viewers’ experience and combined with social presence theory. Third, we verify the moderating role of streamer attractiveness in social presence and watch intention, explaining the impact of streamer attractiveness on viewers’ perception. Finally, this study has practical value by investigating viewers’ live streaming from a social presence theory perspective and giving new insights for live streaming commerce.Live streaming is online and real-time dissemination on the Internet where video information can be captured, published, and viewed simultaneously . It has Live streaming has become a novel way and method of e-commerce. Live e-commerce has social and e-commerce attributes . Live stScholars have studied the motivation of viewers in watching live streaming from different perspectives, and various theories concentrate on motivational drivers such as emotional  cognitivSocial presence refers to the extent to which viewers perceive that they are connected and interacting with others as independent and genuine individuals in the use of media products . Social There is research on the motivation of live streaming intention from social presence. Based on social presence theory, we take emotional support, sense of community, and interactivity as the variables that affect social presence studies and then explore viewers’ watching intention see . In addiSense of community is a person’s perception of being a part of a community . NumerouLive streaming communities are different from general communities in that they pursue more participation, interaction and communication among members . In addiLive streaming viewers meet their own needs through community participation, interaction, and socialization  and incrH1 Sense of community positively influences social presence.Emotional support is about allowing people to listen, care, empathize, provide reassurance, and make people feel valued, loved, and cared for In social media, viewers can satisfy their needs through emotional support and become attached to social media . EmotionH2 Emotional support positively affects social presence.Interactivity refers to interaction in communication . In sociInteraction between viewers in live streaming can satisfy interpersonal needs, reduce loneliness and psychological distance, reduce perceived risk, enhance viewers’ perception of usefulness and the self-connection with the streamer , and proH3 Interactivity positively affects social presence.Social Presence may increase live streaming watching in several ways. First, social presence enhances viewers’ enjoyment  and posiH4 Social presence positively affects watching intention.People spontaneously identify with streamers with particular appeal and see them as role models . AttractH5 Streamer attractiveness has a positive moderating effect on the relationship between social presence and watching intention.We adopted a survey approach to test our framework and established measurements of constructs in previous studies used in the survey. We adapted the measurement items into live streaming context to generate an appropriate questionnaire. The measure of emotional support was primarily referenced to t-tests and found no significant differences between them.We use Credamo, a professional online questionnaire platform, to distribute the online questionnaire. As mentioned before, we tested our hypothesis by sending questionnaires to the viewers’ who have watched the live streaming before. The collection of questionnaire data relies on Credamo’s sampling service. We collected 413 questionnaires and some were removed because of obvious logic inconsistency, remaining 386 valid ones with a valid response rate of 93.46%. The sample size was approximately 25 times the number of constructs. Respondents were mainly from two famous live-streaming platforms in China, Tmall, and Sina. We conducted independent sample As per Finally, reliability and validity also were tested. In this study, the Cronbach’s α coefficient was used to assess the internal consistency of the data, and the mean refined variance method was used to evaluate the convergent validity and discriminant validity. The data test results showed that the Cronbach’s α values of all the constructs were above 0.819. Furthermore, according to the study results, the reliability was significant when the Cronbach’s α coefficient exceeded 0.8 , which iCommon method bias is a common problem in survey research. Therefore, this study followed We conducted a multicollinearity test based on variance inflation factor (VIF) . The res2/df = 2.128, RMSEA = 0.0543, NFI = 0.904, CFI = 0.913, IFI = 0.908, TLI = 0.894. The RMSEA was below the critical value of 0.06. And the model fit was acceptable , emotional support , and interactivity  all positively influenced social presence. Therefore, H1, H2, and H3 are supported. The results of the data analysis show that social presence positively influences viewing intention . Therefore, H4 is supported. The results are shown in p < 0.01), emotional support , and interactivity  all have indirect effects on watching intention.According to the results o, the standardized path coefficients between the elements of each variable were more significant than 0.384, which passed the significance test . TherefoHowever, the variation of the standardized path coefficients between different variables is significant. Among the factors influencing viewers’ social presence, interactivity has the most significant effect on the social presence (0.516), followed by the impact of sense of community on the social presence (0.423), whereas emotional support has a lower effect on the social presence (0.384). Although the results of data analysis and literature studies  suggest To test the moderating effect of group streamer attractiveness on the hypothetical model, we divide the collected sample data into groups with lower streamer attractiveness and higher streamer attractiveness levels. In this study, the sample data were split into groups of lower streamer attractiveness and higher streamer attractiveness according to the mean of streamer attraction . A total2 (Δχ2) with a degree of freedom (df) of 1 is more significant than the critical value of 3.84. As shown in 2 = 5.299, p < 0.01). And the moderating effect is positive from different grouping path coefficients. Therefore, streamer attractiveness has a positive moderating effect on the relationship between social presence and watching intention. So, hypothesis H5 is supported.This study constructed a basic model without any constraints and a restricted model with equal weights of the limited test path structure. A Chi-square test was conducted to test and derive the differences in the path coefficients between different levels of streamer attractiveness. According to First, live streaming is a new research topic. Although it has been studied by scholars from different perspectives , only a Second, we reveal the formation mechanism of social presence in live streaming from the perspective of the viewer experience, which provides new theoretical support and perspective to live streaming work and managers. Most previous studies on live streaming intention under social presence theory have taken three dimensions: communication, emotion, and coexistence . There aThird, we verify the moderating role of streamer attractiveness in social presence and watch intention, explaining the effect of streamer attractiveness on viewers’ perception. A literature review reveals that most studies only consider a single cognitive and affective mechanism  not bettFirst, firms should cultivate the viewers’ sense of community to create a high-quality live community. The viewers’ sense of community can improve social presence and generate positive intention. Therefore, firms should strengthen the cultivation of the sense of community of live streaming. Specifically, firms cultivate sense of community based on different types of live streaming. For example, in the live e-commerce context, firms can develop a sense of community among viewers through product sharing. And in the live game context, game strategy sharing, group play, etc., are good means. In a word, firms should build a high-quality live streaming community through useful content production. Furthermore, excellent streamers should be cultivated to enrich community content and emotional ties strengthen the sense of community.Second, firms should improve the skills of streamers and enhance the empathy between streamers and viewers. The two most direct and significant receptors in live streaming activities are viewers and streamers. The key to the effectiveness of live streaming depends on the skills and quality of streamers. Hence, firms need to provide regular training and skill quality training for the streamer group according to their personal attributes to develop different skills, such as communication style, humor, and physical attractiveness. Firms should focus on streamer image management to improve the attractiveness of streamers, thereby attracting faithful and loyal fans for the live streamer.Finally, firms should strengthen the interaction and communication in the live streaming community. The rapid development of live streaming cannot be separated from people’s intrinsic motivation to reduce loneliness. Therefore, firms should strengthen the interaction between streamers and viewers. For example, streamers can get prizes if they answer streamers’ questions. Firms can also create identity tags and status symbols unique to highly interactive fans. In addition, firms need to actively care about viewers’ emotional state communicate and interact more with viewers.This article has limitations and can be extended in several ways. First, given the different types of live streaming  that meet viewers’ varying needs, future research can subdivide live streaming into different groups to generalize and obtain more fine-grained findings in different live streaming contexts. Second, this paper is mainly based on online questionnaire data. Third, in the future, researchers can obtain viewers’ longitudinal live streaming watching data to explore the dynamic drivers of viewers’ watching behaviors. Finally, the relationship between live streaming watching and purchase behaviors is an interesting research topic worthy of future research.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JC and JL worked together on the manuscript. JC was responsible for writing and data analysis. JL was responsible for project management and revision of the edited 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. We identified 3778 reports, 35 related to cataract guidelines, four of which met the inclusion criteria . The recommendations across the four guidelines covered pre-operative (43%), intra-operative (37%), and post-operative interventions (20%). Most ‘strong’ recommendations were supported by good quality evidence. Differences in recommendations across guidelines may be attributable to time of publication or regional differences in surgical practice. Few guidelines met the quality criteria, and only three countries were represented. The results of this step of the PECI development process will inform subsequent phases for development of the WHO’s package of evidence-based eye care interventions for cataract.The World Health Organization (WHO) is developing a Package of Eye Care Interventions (PECI) to facilitate the integration of eye care into Universal Health Coverage. This paper presents the results of a systematic review of clinical practice guidelines for cataract in adults, to help inform PECI development. We searched academic and guideline databases, and websites of professional associations, for guidelines published between January 2010 and April 2020. Guidelines were excluded if there was commercial funding or unmanaged conflicts of interest. Quality appraisal was conducted using the  World report on vision in 2019, the World Health Organization (WHO) recommended that eye care should be integrated into Universal Health Coverage (UHC) to improve access to eye care services and strengthen eye care in health systems globally . Th. Th11]. Eligibility Criteria: We included CPGs relating to cataract, from any country, published after 2010 in the English language. Full exclusion criteria for each stage of selection of the CPGs are provided in Information Sources and Search: Systematic literature searching of MEDLINE, Embase, CINAHL, Global Health, Global Index Medicus was conducted by an experienced Cochrane Eyes and Vision information specialist (IG) in April 2020. The full search strategy can be found in Selection of Sources of Evidence and Appraisal: Titles and abstracts were independently screened by two investigators (GL/SS), with the aid of a web-based organization tool ). Any conflicts were resolved by discussion between a WHO (SK) and Cochrane Eyes and Vision (JE) representative. Full texts were then independently screened by two investigators (JZ/JR and JZ/CNL). Any conflicts were resolved by discussion; if the two investigators could not come to a consensus, the conflict was resolved by discussion with a third investigator (SK). Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool [strongly disagree to strongly agree), so the maximum possible total score for all 9 items was 63. If the scores given by the two investigators differed by more than 2, the conflict was resolved by discussion between the two investigators, or with a third investigator. CPGs were excluded if: (1) the average score between the two investigators was less than 3 for items 4, 7, 12, or 22; or (2) the sum of the average score of the two investigators was less than 45 for items 4, 7, 8, 10, 12, 13, 15, 22, and 23. Quality appraisal of CPGs was conducted independently by two investigators (JZ/JR) using the II) tool . SpecifiII) tool , and in II) tool  (items 4Data Charting and Data Items: Data were charted using a standardized form. Data from each CPG were extracted by a single investigator (JZ) and verified by a second investigator (JR). Any conflicts were resolved by discussion with a third investigator (SK). The following data items were extracted:Title of the CPG;Sponsoring organization ;Publication year;Title of the chapter to which the recommendation refers to;Page number, title and numbering of the section in which the recommendation is stated;Intervention target;Intervention category;Intervention name;Who usually provides the intervention;Dosage or frequency of the intervention;The specific recommendation copied and pasted from the relevant paragraph in the CPG;Recommendation strength, and the name or description of the classification system used;Quality or level of evidence relating to the recommendation, and the name or description of the classification system used;Any other remarks on the recommendation that the investigator believes to be relevant.Synthesis of Results: Recommendations of eye care interventions were tabulated, and categorized into pre-operative, intra-operative, and post-operative recommendations. For each intervention tabulated, the corresponding CPG(s) that recommended that intervention was listed, alongside judgements on the quality of evidence and strength of recommendation. As the CPGs used different frameworks for assessing the quality of evidence and strength of recommendation, we present the results narratively for each CPG. Ethics and Dissemination: As this study only included freely available CPGs, ethics approval was not sought. Results will be widely disseminated after the WHO, supported by a Technical Advisory Group of experts, have agreed on which interventions should be included in the final PECI (Phase 3), and after the peer review process (Phase 4).After combining all searches , 3778 reports were identified. Then, 177 duplicates were removed, and 3132 were excluded after title and abstract screening. Finally, 469 full text reports were retrieved, of which 35 were related to cataract. Of the 35 reports, 26 were excluded after full text screening, and nine CPGs went through to the appraisal stage, five of which were excluded ; Table 3National Institute for Health and Care Excellence (NICE), 2017, Cataracts in adults; management .American Academy of Ophthalmology, 2016, Cataract in the Adult Eye Preferred Practice Pattern .Rajavi et al., 2015, Customized clinical practice guidelines for management of adult cataract in Iran .The Royal College of Ophthalmologists and Clinical Council for Eye Health Commissioning, 2018, Commissioning guide: Adult cataract surgery .The following four CPGs were included:CPGs 1 and 4 were published by organizations based in the United Kingdom, CPG 2 is from the United States, and CPG 3 is from Iran. CPGs 1 and 2 drew evidence directly from original research , whereas CPG 3 drew evidence from other CPGs . CPG 4 drew evidence from a mixture of original research and other organizations’ CPGs (such as NICE guidelines). Only CPGs 1–3 reported the quality of evidence supporting their recommendations . CPGs 1 strong, and the other one quarter of their recommendations were discretionary (where the trade-offs between benefits and risks were less certain). For CPG 2, 97% of the recommendations were strong, with only 3% reported as discretionary. Only CPGs 1 and 2 reported the strength of recommendation . For CPGA summary of the eye care intervention recommendations from the four CPGs are presented in Most of the strongly recommended interventions had good quality evidence supporting them, for example, weighing up risks and benefits of surgery with the patient, use of appropriate biometry, small incision surgery, prepping with povidone-iodine, and appropriate counselling of the patient regarding complications and post-operative care. A minority of interventions were strongly recommended without high quality evidence. For example, no evidence was identified for the recommendation to offer eye protection for patients whose eye shows residual effects of anesthesia at time of discharge after surgery.There are instances where the CPGs make recommendations that do not align. For example, CPGs 1 and 4 indicate that immediate sequential bilateral cataract surgery (ISBCS)  can be considered in low-risk patients; whereas CPG 3 recommends that surgery should be performed in separate sessions in patients with bilateral cataract.Our systematic review found four CPGs relating to cataract that met our inclusion criteria. In the three CPGs where quality of evidence was evaluated, high-quality evidence was available for 18% (CPG 2), 86% (CPG 1) and 38% (CPG 3) of the interventions recommended. In the two CPGs where strength of recommendation was presented (CPGs 1 and 2), 75% and 97% of interventions were strong recommendations, respectively. The recommendations were broad in scope, covering pre-operative (43%), intra-operative (37%), and post-operative interventions (20%). A minority of interventions were strongly recommended without high quality evidence. However, in some cases, conducting a study might be unethical or impractical. For example, it would be unethical to randomize patients to a study arm where they are not offered eye protection, as this could lead to complications such as corneal abrasions. Since eye protection  is inexpensive, has minimal risk of causing harm and could avert complications, it seems reasonable to make a strong recommendation for eye protection despite the lack of evidence. Additionally, it would be unethical to perform a trial comparing cataract surgery versus no cataract surgery . Therefore, while there are research and trial data comparing different cataract procedures, there is no evidence from randomized controlled trials for cataract surgery per se. The four included CPGs were published between 2015 and 2018. However, CPG 3 itself sourced its recommendations from four other CPGs that were published between 2006 and 2011 : the AmeThere was a consistent view across the CPGs that, pre-operatively, patients should be given adequate information to help them weigh up the risks and benefits of cataract surgery, and the patient’s individual preferences and needs should be considered. Use of biometry and keratometry prior to cataract surgery was emphasized by three of the four CPGs. Intraoperatively, there was a consistent view that the preferable method for cataract surgery is small incision surgery under local anesthesia, and the patient’s eyes should be prepped with povidone-iodine. Post-operatively, it was recommended that patients are given adequate information regarding their post-operative care, and topical steroids or non-steroidal anti-inflammatory drugs should be offered to reduce post-operative inflammation, particularly in patients at risk of cystoid macular oedema. Two CPGs also recommended that providers of cataract services should be able to provide commissioners with data to monitor quality, outcomes, and adverse events. Finally, counselling patients regarding the risk factors for developing cataracts, such as smoking, sun exposure, and long-term steroid use, was recommended by two CPGs. There are other instances where the CPGs make recommendations that are somewhat conflicting. For example, there are conflicting recommendations regarding ISBCS. Whilst there is evidence supporting ISBCS ,23, surgAppraisal of Guidelines for Research and Evaluation II (AGREE II) tool [Very few CPGs met the inclusion criteria, which is a surprising finding given that cataract is such a common condition, and in many settings, cataract surgery is one of the most frequently performed operations . Four CPII) tool , to ensuA limitation of our methodology is that we restricted our search to English language papers only, and thus may have missed CPGs that are published in non-English speaking settings. This decision was due to feasibility considerations, including the labour-intensive nature of screening and translation of CPGs in all official WHO languages. Another limitation is that some CPGs were excluded based on an absence of information regarding author affiliation, as lack of author affiliation does not necessarily mean that a conflict of interest is present. Additionally, the publication year of the CPG may not reliably reflect how up-to-date the cited evidence was. For instance, CPG 3 drew on evidence from other published CPGs, half of which were published prior to 2010. Given that cataract surgery is a long-standing, well-established and cost-effective intervention, this may limit the amount of new evidence in this field. As only four CPGs were identified, and only one was from a low/middle-income country (LMIC), the recommendations drawn from these four CPGs may only be applicable in certain settings. Due to timeline constraints for the development of the PECI, the literature search was conducted in April 2020, so CPGs published subsequently were not included in this study. We may have missed more recent guidelines that can be considered in future updates to the PECI, such as “Cataract—Treatment of Adults, Ministry of Health British Columbia, 2021” , and “CaAmong the cataract CPGs from LMIC settings, only one CPG from Iran met the inclusion criteria for our review. Cataract recommendations in LMIC settings may differ from those in high-income settings; for example, resource constraints in some countries may mean that recommendations cover how to prioritize patients for cataract surgery according to level of need. To address this, a broad range of public health, academic and clinical professionals from all WHO regions, with a particular focus on LMIC settings, were involved in all stages of development of the PECI. There is a pressing need for more high-quality CPGs from LMIC settings, particularly as cataract is highly prevalent in these regions.The results presented in this paper will assist in informing Phases 3 and 4 of the PECI development process, with the ultimate goal of developing a package of evidence-based eye care interventions for cataract .


Estrogen and progesterone receptors being present or not represents one of the most important biomarkers for therapy selection in breast cancer patients. Conventional measurement by immunohistochemistry (IHC) involves errors, and numerous attempts have been made to increase precision by additional information from gene expression. This raises the question of how to fuse information, in particular, if there is disagreement. It is the primary domain of Dempster–Shafer decision theory (DST) to deal with contradicting evidence on the same item (here: receptor status), obtained through different techniques. DST is widely used in technical settings, such as self-driving cars and aviation, and is also promising to deliver significant advantages in medicine. Using data from breast cancer patients already presented in previous work, we focus on comparing DST with classical statistics in this work, to pave the way for its application in medicine. First, we explain how DST not only considers probabilities (a single number per sample), but also incorporates uncertainty in a concept of ‘evidence’ (two numbers per sample). This allows for very powerful displays of patient data in so-called ternary plots, a novel and crucial advantage for medical interpretation. Results are obtained according to conventional statistics (ODDS) and, in parallel, according to DST. Agreement and differences are evaluated, and the particular merits of DST discussed. The presented application demonstrates how decision theory introduces new levels of confidence in diagnoses derived from medical data. Biomarkers gain importance in selecting treatments optimized and personalized to the individual needs of patients, as envisaged in personalized medicine ,2,3,4. BFor breast cancer, the HER2-status  of a patient is one of the most important prognostic factors ,28. The Among HER2-negative patients, the hormone receptor status of estrogen (ER) and progesterone (PGR) are of focal importance. Clinically, patients are considered receptor-positive if at least one of both receptors (ER or PGR) is found positive. Since hormone receptors play a role in promoting cancer, hormone therapy has to be part of an effective treatment. In patients without metastases, hormone therapy may even render chemotherapy unnecessary.However, if the receptor status is accidentally estimated as false positive, hormone treatment will not work and the patient may be deprived of life-saving chemotherapy. Therefore, numerous studies have evaluated the quality of receptor assessment ,39 and rOne possibility is adding information from gene expression. Some approaches merely used visual inspection to set cut-points between positive and negative , some usDempster–Shafer decision Theory (DST) [We have elaborated and improved the above approaches ,59 by inry (DST)  into perry (DST) . This isry (DST) ,62,63, ory (DST) ,65 and ary (DST) , diagnosry (DST)  and breary (DST) . The speIn the present work, we draw on data from our previous paper  and elabDST is a general theory for reasoning with uncertainty . It stard, is being measured . Conventional statistics would derive a single number from d, the probability p for the receptor being positive, given the measured value of d. Consequently, 1 − p would be the probability for being negative.Suppose some continuous variable, two numbers to characterize possible predictions based on measuring d:α(d), gives the probability (weight) that, upon measuring this particular value of d, the prediction ‘positive’ can be made based on the quality of measurement (classification ‘with full right’).The belief θ(d), characterizing the probability (weight), that the prediction ‘positive’ could root in chance and not in quality of measurement. Belief and uncertainty taken together yield the total probability (termed ‘plausibility’) to obtain the prediction ‘positive’, given the measured value of d (α + θ = pl).The uncertainty β(d) for yielding the prediction ‘negative’ by quality of measurement, given d. We always have: α + θ + β = 1; hence, β can be computed from α and θ.Finally, a third number can be computed from belief and uncertainty, the probability DST provides α, β, θ) is equivalent to a piece of ‘evidence’. DST not only yields probabilities for a positive versus negative outcome, but, additionally, incorporates the uncertainty of prediction [In the special case of only two statuses, as considered here, the triple (ediction . This re○Receptor status predicted from expression of the receptor gene○▪DCombining above evidence by Dempster evidence combination rule ⊕Receptor status predicted from expression of a co-gene○▪YCombining evidence from gene expression and IHC by Yager evidence combination rule ⊕Receptor status predicted from IHCFor estrogen (ER)○Receptor status predicted from expression of the receptor gene○▪DCombining above evidence by Dempster evidence combination rule ⊕Receptor status predicted from expression of a co-gene○▪YCombining evidence from gene expression and IHC by Yager evidence combination rule ⊕Receptor status predicted from IHCFor progesterone (PGR)Hormone receptor status is finally obtained by combining the statuses of estrogen and progesterone using a multiplicative combination rule ⊗A second advantage of DST is its capability of merging evidence from different sources  as follows: The responsibility function for positive receptor status, xExpr. Likewise, r+ for positive estrogen (red dashed curve). r−, for negative estrogen (blue dashed curve), is based on the same regression coefficients, see Equation (1). A similar analysis was performed for progesterone, see Receptor status is related to gene expression .Based on logistic regression, gene expression measurements lend themselves to derive evidence of receptor status according to Dempster–Shafer decision theory . In the xExpr, is prognostic for receptor status. Given a measurement of xExpr, DST attributes two independent numbers, as outlined below:Assume the variable gene expression, xExpr; ibility’ ) for recβExpr: the belief (probability) for receptor status being non-positive  on good grounds or by quality of the measuring method;θExpr is a third quantity considered: the probability that the receptor status is uncertain.α, β and θ are also called ‘masses’ of the respective outcomes. They are by definition larger than or equal to zero (be found . Masses be found :(2)αExprHence a third number is in fact redundant . Decision theory even considers a fourth quantity, called plausibility; it is also redundant but intuitive and useful:xExpr as is. The plausibility of a given outcome sums up everything either supportive or neutral, but excludes everything advocating the opposite outcome. The exactly opposite outcome is represented by βExpr.xExpr,) of a gene ; data in The output of above procedure is the evidence αExpr, and negative, βExpr, may be obtained from gene expression alone, xExpr, as demonstrated above. Doing so, maximum expression corresponds to a responsibility function r+(xExpr) close to 1, see αExpr, actually must be less than 1.The beliefs in receptor positive, We chose to model this fact by a factor, All in all we obtain the belief in receptor positivity after measuring αExpr is represented by the increasing solid red curve in βExpr by the declining blue one. The remaining uncertainty, θExpr, is easily computed from reformulating Equation (2)αExpr, βExpr) are collectively called ‘evidence’ of receptor status, given a measurement of the continuous variable ‘gene expression’, xExpr. They enrich the information given by a single number, the probability p, known from conventional statistics, quantifying the chances of receptor statuses, a similar procedure applies to the receptor gene of progesterone, see αExpr, βExpr) and evidence from IHC  are combined by so-called ‘evidence combination rules’ (ECR). DST offers several such rules [D, and the Yager ECR, ⊕Y [To further increase precision of receptor status diagnostics, evidence from gene expression . In that case the belief in positive surmounts the sum of both other beliefs (β + θ ≤ 0.5) and dominates. Hence, the dotted line α = 0.5 represents a decision border and will be analogously outlined in the following figures.A definite decision for positive receptor status is obtained if the combined evidence exceeds 0.5 , points of all samples lie within a single plane (of evidence), see https://en.wikipedia.org/wiki/Orthographic_projection (accessed on 26 March 2022)) which still contains all information but fits into two dimensions and is called ‘ternary plot’, see Note that belief, plausibility and uncertainty are not independent but always sum up to unity for a given sample, see Equation (2). This mathematical property allows for a special graphic display, called ‘ternary plot’, as follows. When plotting these data in an ordinary 3-dimensional scatter plot with coordinates  add up to a constant, for each individual considered. For example, a biological fluid (say milk) may be composed of water, protein and fat (three components) and nothing else. Clearly, the percentages of water, protein and fat must then add up to 100%. For a set of milk samples, these percentages may be visualized by points in a 3D scatter plot, such as α, β and θ, since they also add up to unity due to Equation (2). Hence, points of evidence  for any single patient, lie within the same  plane in 3D. This plane always lies in the same, specific position and orientation, for the following reason: the point , represents a valid point of evidence (adding up to unity) and must be part of the plane. Therefore, the plane cuts the α–axis at α = 1, see β = 1 and θ = 1, respectively. This uniquely defines an equilateral triangle in the 3D coordinate system, see What is true for three components of a substance (milk) is also true for evidence composed of three numbers, Even though the plane of evidence lies embedded in a 3D coordinate system, it is by itself just a 2-dimensional object, as every flat plane is. Therefore, without any loss of information regarding the location of points (representing evidence) we may perform an orthogonal projection along the heavy arrow shown in A ternary plot does not have its axes at right angles, as ordinary plots do. To read off the coordinates of a point from such a ternary plot, several methods are available, out of which we propose the following , illustrated in α, the ‘belief in positive’, has its own scale, see the dashed heavy line in orange; it starts on the left with α = 0 at a right angle from a triangle’s left side and runs towards the opposing corner, where α = 1 (indicating ‘surely positive’). See also the scale with numerical values aside. The two other scales, for β and θ, are defined analogously (not shown for simplicity).Each of the three components of evidence, e.g., α, β, θ) can be read off as follows. Note the lines being drawn perpendicular to each side of the triangle —they represent the axes for quantification. Values α, β, θ  can be read off from the corresponding axis’ scale. In this example  discriminates points with α ≤ 0.5 (left upper) from those with α > 0.5 (towards lower right corner), and hence represents a decision border; points right of this border are predicted ‘positive’, since their evidence for positive is greater than for all other options (‘negative’ and ‘uncertain’) taken together.Parallel lines at right angles with one axis represent constant values for the respective variable (as with ordinary right-angle axes). In particular, the line crossing the α = 0.5 (shaded light red) comprise samples predicted positive. Similarly, the subsets of negative and uncertain samples may be defined, see Decision borders segregate subsets of samples. For example, all samples within the triangle in the lower right of α = 1: ‘surely positive’; β = 1: ‘surely negative’ and θ = 1: ‘totally uncertain’).In each corner one piece of evidence totally dominates, assuming a value of unity (α = 0) means that there is no indication whatsoever for the prediction at opposing corner. For example, α = 0 along the left side of the triangle, means that there is no indication whatsoever for a ‘positive’ prediction. All evidence is shared between ‘negative’ and ‘uncertain’ (β and θ). In this case β + θ = 1.Conversely, the footing point of each axis  towards α = 1 (right): for each sample along this line uncertainty θ equals zero, and all evidence is shared between belief in positive (α) and belief in negative (β), e.g., α = 0.6 and β = 0.4, while θ = 0. One may legitimately ask: “Does this mean that the prediction was made for sure?”. Since α > 0.5 and dominates both other options, we consider this prediction clearly positive. However, α = 0.6 is no more than a probability and not that much larger than the probability of the opposite outcome, β = 0.4. In reality, the outcome may well result in a negative prediction. If θ = 0, evidence masses revert back to ordinary probabilities: p+ = 0.6 for positive and hence p− = 0.4 for negative, without indicating any uncertainty about the estimates of these two numbers. Thus, for θ = 0, decision theory’s evidence coincides with ordinary probabilities. In DST terminology the evidence is said to turn ‘Bayesian’ [A special role is played by the triangle’s bottom edge, running from ayesian’ .θ > 0, decision theory not only gives estimates for probabilities  but additionally indicates the uncertainty of those (θ). It hence offers a wider scope of evidence, valuable in particular for personalized medicine.In general, for Note also the following intriguing features of this ternary plot:location of the point indicates the prediction according to DST shown by the respective area: red triangular area for positive (+), blue for negative (-) and the white, kite-shaped area for inconclusive (inc).The coloring of points indicates prediction according to ODDS. For most samples, both predictions match. For some samples however, they differ, thus perfectly outlining the contrast between the two prediction methods.At the same time, Ternary plots allow for a highly transparent comparison of our two classification methods (ODDS versus DST) for each single sample:three variables in two dimensions, provided their sum is constant, which is true for evidence and many other variables. We think it worth the effort to introduce ternary plots into the field of personalized medicine. They are the most adequate tool for quantitatively presenting evidence, and may in the future represent a cornerstone of personalized medicine.Although ternary plots may seem somewhat unusual for medical application, they offer the unique capability to display In First, we supplement estrogen expression evidence Numerical results of the logistic regression for progesterone are shown in Next, evidence from genes and co-genes are combined by the Dempster Evidence Combination Rule . The very same is done for progesterone, yielding .As outlined in OR’ the progesterone receptor (or both) is/are positive, and treatment is assigned accordingly. Corresponding decision borders will be shown below  and progesterone  may be combined to obtain evidence for the overall hormone status  as follows [In the step to follow, evidence for different targets—estrogen and progesterone—will be combined. Clinically, a breast cancer patient is considered receptor positive, if either the estrogen ‘wn below . While c follows :(9)αH=αEPredictions via conventional statistics (ODDS) and decision theory (DST) are directly compared for the whole patient cohort in In the left panels, samples are geometrically located according to ODDS scores, but color-coded according to DST prediction.Decision borders in ODDS can be directly displayed in an orthogonal, 2-dimensional plot of ‘scores’, see ODDS scores incorporate IHC evidence in an additive fashion. Each of the nine possible IHC statuses  merely differ in shifts along the respective ODDS coordinate . ODDS decision borders are, hence, valid for any combination of IHC statuses.In the right panels, samples are geometrically located according to DST evidence, but color-coded according to ODDS.α = 0.5 and β = 0.5, respectively, which appear as straight lines in a ternary plot. DST evidence also incorporates IHC information, and decision lines, hence, also represent unique borders in the ternary plot, valid for any combination of IHC statuses .Decision borders in DST are most appropriately displayed in ternary plots of evidence, see In the ternary plot, DST evidence for subsets of patient samples appear in polygonal areas. In fact, these areas root in respective combinations of IHC statuses for estrogen and progesterone , as will be scrutinized in the appendix, for those interested in mathematical details. Indeed, these polygonal areas are generalizations of those simple straight lines already seen with single gene expression data . For example, if such a subset of samples crosses from inconclusive to decided, this indicates that IHC on its own was inconclusive, but adding evidence from (increasing) gene expression finally rendered a decision:○A stripe of red points originates within the DST-inconclusive, kite-shaped area and protrudes into the positive triangle.○The stripe of blue points originates in the DST-inconclusive, kite-shaped area and protrudes into the negative triangle.ion data . Since eNote the following features in Crossing decision borders for given IHCs underpins the importance of information from gene expression being added.κ = 0.9287 [Agreement and divergence between ODDS and DST are summarized in = 0.9287 .For 10 patients, DST predicted a positive receptor status, whereas ODDS had predicted ‘undecided’. Based on the additional information provided by DST, these patients may, upon careful reassessment, be candidates for milder therapies, possibly without chemotherapy (chemo). We, therefore, labelled this group with ‘adding information’ in For 40 patients, DST predicted ‘undecided’, whereas ODDS had predicted ‘positive’. ‘Undecided’ severely questions abstaining from chemo and calls for a re-assessment at least. We, therefore, labelled this group with ‘increasing safety’ in Besides good overall agreement, possible advantages of DST may be seen twofold, cf. the cells outlined with bold face in Hormone receptor diagnostics—in comparison with ODDS and DST—was evaluated regarding its impact on survival. OR progesterone, see p = 0.03). Since all patients considered in our study were actually treated according to conventional, clinical ‘IHC+’, we might speculate as follows: this actual, former treatment as ‘IHC+’ was confirmed post hoc in our study (by pos/pos) as correct and, hence, these patients experienced much better survival.For comparison, the IHC+ group was also evaluated, incorporating patients receptor positive either for estrogen Over the years, hormone receptor status has become the most important predictive parameter, which allows for an identification of endocrine-sensitive invasive tumors. The use of hormone-receptor-targeted treatment strategies is associated with an approximately 50% reduction in recurrences and a reduction in breast-cancer-attributed deaths by approximately 30%, and receptor status assessment has, therefore, become the single most important biomarker in early and advanced breast cancer. A correct classification of endocrine sensitivity by receptor measurement is, therefore, critical for individualized treatment, since falsepositive results lead to overtreatment and therapy-associated side effects, which range from menopausal symptoms, infertility and depression, to bone loss and an increase in fractures, and other significant side effects. False negative results, on the other side, subject patients to under-treatment and a profound worsening of the long-term outcome. These profound clinical consequences are contrasted by a number of technical uncertainties: the hormone receptor status is presently assessed by immunohistochemistry, and different standards in tissue fixation, varying protocols, the myriad of commercially available antibodies, inter-observer variability and other technical issues compromise an objective assessment. Moreover, while some labs use a cut-off of 10% of hormone receptor positive cells, others prefer a cutoff of 1%, thus, limiting the value of the current gold standard in receptor assessment. Within this context, prediction models, such as DST and ODDS, can add to further ascertainment of the receptor status. The decision of which model to use could be factored into the decision tree and allow for a more personalized treatment, in the sense that the more conservative DST could be applied in older and frail patients, in whom the significant side effects of endocrine therapy need to be balanced against competing mortalities and might lead to an omission of endocrine therapy, and an additional IHC, performed by an independent laboratory could be helpful in decision making and in potentially sparing patients from therapy-associated side effects. By contrast, ODDS with 0.4% inconclusive rates might be more appropriate in mainstream assessment, since the need for independent reassessment can be reduced.coded by location versus predictions coded by color in Within the plane of ODDS scores (left panel), the L-shaped area (colored faint red) denotes samples definitely predicted positive by ODDS (according to location). However, some of them are inconclusive according to DST (colored beige); in fact, 40 DST-inconclusive samples invade the positive, and the other 45, the negative domain of ODDS scores, see Conversely, the uncolored L-shaped area accommodates samples predicted inconclusive according to ODDS (according to location). However, 10 are colored red, i.e., according to DST, decided positive. In fact, these samples, definitely predicted positive by DST, invade the inconclusive region of ODDS scores and are labelled ‘adding information’, see Within the ternary plot of DST evidence (right panel), the triangular shaped areas denote samples predicted negative (faint blue) and positive (faint red), respectively, according to DST (by location). However, some samples are color-coded beige, i.e., they were rendered inconclusive by ODDS. Note that the very same samples appear in dual roles along ODDS scores and ternary evidence, respectively (left and right panel).Conversely, the uncolored kite-shaped area denotes samples predicted inconclusive according to DST (by location). However, some of them are color-coded red or blue, i.e., definitely predicted as positive or negative according to ODDS. In fact, 40 samples definitely classified positive through ODDS intrude into the ‘inconclusive’ region of DST and have been labelled as ‘increasing safety’, see panel (d). Another 45 definitely predicted negative through ODDS intrude into the ‘inconclusive’ region of DST.As noted above, definite predictions were never seen contradicting between ODDS and DST. However, decisions deemed definite in ODDS were rendered inconclusive by DST and vice versa. This becomes evident by contrasting predictions All in all, differences in prediction only occur with samples on the brink of predictability. While one method yields positive or negative, the other may yield ‘inconclusive’. These differences turn up in the off-diagonal elements of Moreover, visual inspection of the ternary plot in Dempster–Shafer Decision Theory (DST) has been made available for the personalized therapy of breast cancer in a previous paper , in partp = 0.03) than those conventionally diagnosed positive, see the red versus the light blue curves in In addition, we compared patients considered receptor positive according to up-to-date clinical standards  with those considered positive  according to both of our proposed methods, ODDS and DST. Patients positive according to the new methods experienced significantly better survival  and demonstrate how to:In a second step, we demonstrate how to create evidence from co-genes and join them with evidence of receptor genes and IHC .In the third step we demonstrate how to join evidence from estrogen with that from progesterone, using a formula imitating the clinical criterion ‘positive ER or positive PGR’ for ‘receptor positivity’, in terms of Dempster–Shafer mathematics.This stepwise approach allows for a detailed introduction into ternary plots, demonstrating their applicability to clinical decision making, based on evidence. It becomes clear that evidence not only provides more information about the outcome of a measurement than conventional probability does, but that probabilities are supplemented by uncertainty. Evidence also has the property of three numbers summing up to unity for each single sample considered, and may be advantageously displayed in ternaries. Groups of patients (different IHC statuses) are segregated by the method itself (being either positive or negative).Data quality is a crucial aspect of personalized medicine. In this work, we have never let gene expression overrule IHC. Technically, this was achieved by selecting the constants At first glance, this statement may seem paradoxical. However, DST—in comparison to ODDS—supports this concept, as can be seen from a vivid comparison:p and the probability 1 − p for its opposite.Suppose we have a ballot between two options . If the voter turnout was 100%, we might obtain 75% for pro and 25% for contra (3:1), and with full right, consider this a clear decision. The option ‘pro’ would clearly be implemented, having the majority of voters on its side, see the top bar in Now suppose the voter turnout was only 80%, with exactly the same distribution between pro and contra, i.e., 60%:20% = 3:1, see the second bar in Finally, suppose a voter turnout of just 40%, again with the same ratio between pro and contra of 30%:10% = 3:1, see the third bar in Analog concepts hold for medical diagnostics. As DST introduces uncertainty as the third part of evidence ,83, bordTo allow for evidence-based decisions, the explicit quantification of uncertainty seems utmost desirable.The approach presented here may be expanded by considering more than one co-gene, since DST allows us to combine more than two items of evidence. Considerable increases in stability can be expected if such expanded markers are applied to new incoming data.Another possible extension refers to combination rules.One basic concept for combining evidence from different sources was introduced by Dubois , hence, In the present work, we only used the Dempster Evidence Combination Rule (ECR) and the Yager rule . HoweverThe Dempster Evidence Combination rule advocates fierce decisions—leaving little uncertainty in the conclusions—even if both pieces of input evidence concede considerable uncertainty. As opposed, given the same input evidence, the Yager rule follows a much softer strategy, transmitting larger uncertainty into its conclusion. We illustrate this by a specific example.α = 0.8, β = 0.1, θ = 0.1), strongly favors ‘positive’, via large α and small β. Moreover, it claims to be quite ‘sure’ in terms of small θ. The second piece of evidence, from IHC , favors ‘negative’, with some larger uncertainty θ = 0.3. Obviously, these pieces of evidence contradict each other quite strongly, and one may legitimately ask ‘what should be the synthesis of these two?’ The answer can be precisely modelled by decision combination rules, according to Dempster (⊕D) or Yager (⊕Y), which also exemplifies their difference in approach.Suppose we have two items of evidence for receptor status: The first piece of evidence, from gene expression , expressing a quite ‘sharp’ contradiction , without admitting much uncertainty . On the contrary, the Yager rule, Equation (6), yields combined evidence EY = , expressing only ‘soft’ contradiction , with quite a lot of uncertainty (large θ).For the current example, the Dempster rule (Equations (7) and (8)) yields as combined evidence How can these features be exploited for personalized medicine?Clinical experts have always been looking for the most beneficial balance in decision making, based on SOPs, their personal experience, and also skill, or even educated guessing, in particularly difficult cases. It has always been the strength and fame of top clinicians to decide correctly in a percentage of cases far above average. However, it may not be fully transparent how such an outstanding clinical performance comes about and could be transferred to young doctors in training. Decision theory tries to bring such ‘clinical expert competence’ down to more formally applicable rules. Of course, it will remain the task of top clinicians to help define and select those rules, based on sound statistical evaluations of clinical studies. Such decision rules, once established, may be incorporated in SOPs and will improve their performance significantly.While this work exemplifies the use of DST in personalized medicine, related to the very specific field of breast cancer receptor diagnostics, the methods described are universal. Decision theory, in particular, the fusion of diverging evidence , as well as the professional incorporation of uncertainty into biomarker research, seem valuable for all fields of personalized medicine and medicine in general.


Diabetic neuropathy (DN) is a common complication of diabetes that is becoming an increasing concern as the prevalence of diabetes rapidly rises. There are several types of DN, but the most prevalent and studied type is distal symmetrical polyneuropathy, which is the focus of this review and is simply referred to as DN. It can lead to a wide range of sensorimotor and psychosocial symptoms and is a major risk factor for diabetic foot ulceration and Charcot neuropathic osteoarthropathy, which are associated with high rates of lower limb amputation and mortality. The prevention and management of DN are thus critical, and clinical guidelines recommend several strategies for these based on the best available evidence. This article aims to provide a narrative review of DN prevention and management strategies by discussing these guidelines and the evidence that supports them. First, the epidemiology and diverse clinical manifestations of DN are summarized. Then, prevention strategies such as glycemic control, lifestyle modifications and footcare are discussed, as well as the importance of early diagnosis. Finally, neuropathic pain management strategies and promising novel therapies under investigation such as neuromodulation devices and nutraceuticals are reviewed. Diabetes is a major global health problem affecting half a billion people worldwide. Its global prevalence is rising at an alarming rate and has been forecast to reach 700 million by 2045 . DiabetiDN is an insidious and often disabling disease. Sensory symptoms are diverse, ranging from numbness to dysesthesia, pain and allodynia, and typically begin in the feet and spread proximally. Motor function can also be affected, resulting in weakness, atrophy, gait disorder and loss of coordination, preventing patients from engaging in activities of daily living. More recently, the considerable psychosocial and quality of life (QoL) impacts of DN have been recognized . FurtherThe pathophysiology of DN is characterized by peripheral nerve fiber and microvessel dysfunction. This is primarily driven by hyperglycemia and other metabolic factors, such as hyperlipidemia and impaired insulin signaling, which lead to a variety of downstream pathogenic pathways. In particular, hyperglycemia leads to overactivation of the polyol, glycation, protein kinase C, poly (ADP-ribose) polymerase (PARP) and hexosamine pathways, all of which contribute to oxidative stress in nerves and microvessels. The complexities of these pathways are beyond the scope of this article, but we refer the reader to relevant recent review articles ,8,9.These pathogenic pathways influence nerve structure and function. The myelin sheath is disrupted, and Schwann cells dissociate from both myelinated and unmyelinated nerve fibers, produce less neurotrophic factors and undergo apoptosis ,11,12,13In the closely connected microvasculature, there are changes in basement membrane density, pericyte function, endothelial cell function and the formation of arteriovenous shunts occur, all signifying ischemic damage ,24,25,26Instead, national and international clinical guidelines recommend several prevention and management strategies for DN based on the best available evidence. Prevention strategies aim to address DN before symptoms develop, or to prevent the progression of DN, whereas management strategies treat symptoms of DN that patients already have. These guidelines focus on prevention through glycemic control, lifestyle modifications and footcare, all of which can be difficult to achieve for a variety of reasons. For people with painful DN, management through pharmacotherapies is recommended; however, this is frequently sub-optimal and does not target the approximately 70% of people with DN who do not experience pain ,31. The The aim of this article is to provide a narrative review of DN prevention and management strategies. First, the epidemiology of DN and its risk factors will be briefly summarized, discussing differences between diabetes subtypes. The diverse clinical manifestations will be described, with a focus on sensorimotor and psychosocial symptoms, and further foot complications. Prevention strategies recommended by clinical guidelines will be discussed and the diagnostic evaluation of DN will be briefly reviewed. Finally, neuropathic pain management strategies and promising novel therapies under investigation will be discussed.Previous research has suggested that the prevalence of DN is higher in people with type 2 diabetes (T2DM) than in people with type 1 diabetes (T1DM) . This ha= 1441) were followed-up for 14 years. The cases of DN had increased significantly from 6% at baseline to 30% at final follow-up, implicating age, duration of diabetes and chronic hyperglycemia as risk factors [These pioneering studies also identified risk factors for DN. In the DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) studies, the T1DM cohort , a condition that causes gradual bone and soft tissue destruction and deformity. Despite diabetes being the leading cause of Charcot foot in the northern hemisphere , the ratCurrent prevention strategies for DN focus on glycemic control, lifestyle modifications and footcare. p = 0.033) [Achieving glycemic control to prevent DN is recommended in several clinical guidelines ,4,90,91.= 0.033) ,94. The = 0.033) .p < 0.00001). The risk was also reduced in people with T2DM ; however, this did not reach statistical significance [p = 0.002) but not DN  at 8 years follow-up [These observed differences in the efficacy of glycemic control when comparing T1DM and T2DM have been further examined in a Cochrane systematic review and meta-analysis . The autificance . This coificance . Interesollow-up . Glycemic control can now be assessed more readily with flash glucose monitors (FreeStyle Libre) and continuous glucose monitoring (CGM). A recent meta-analysis found that CGM tools significantly improve glycemic control. Fifteen RCTs (n = 2461) comparing the effects of CGM versus standard care  on glycemic control were identified, and pooled analysis revealed that CGM significantly increased time in target range while decreasing time above and below range, as well as glucose variability . ClinicaTo reduce the risk of DN, prevent disease progression and minimize cardiometabolic risk factors, some clinical guidelines recommend lifestyle modifications such as regular exercise and a balanced diet ,4,91. ThExercise has a moderate level of evidence for the prevention and treatment of DN. A recent meta-analysis  found that exercise interventions may improve balance, peripheral nerve conduction velocity and glycemic control in patients with DN, with a combined endurance and sensorimotor training program being the most beneficial . For exaIn people with pre-diabetes, the level of evidence for exercise is low and requires further investigation. Only one completed study has been identified in people with prediabetes, which found that after one year of individualized exercise (150 min per week) and dietary advice, intraepidermal nerve fiber density increased significantly, as measured by nerve biopsy at the lower limb. This increase was also associated with improved electrophysiological and pain outcomes, validating intraepidermal nerve fiber density as a surrogate measure for small fiber neuropathy. The study, however, was not powered or designed to investigate efficacy . A powerThere is a paucity of studies investigating diet alone in the context of DN because most studies include diet as part of a multifactorial lifestyle intervention. Nonetheless, the American Diabetes Association advises to reduce calorie and processed food intake while increasing polyunsaturated fats and antioxidant rich foods in order to minimize risk factors and improve outcomes . NourishWith physical activity and improved diet being cornerstones of prevention guidelines, psychological and behavioral change interventions may help people with diabetes improve compliance with such lifestyle modifications. Currently, there are no guidelines that recommend counselling for the prevention of DN, despite its considerable psychosocial burden (including pain). A previous systematic review of 25 RCTs found improved long-term glycemic control in people with T2DM following psychological therapies and commented positively on less “psychological distress”, though improvements in body weight and blood glucose levels were not found . A more Clinical guidelines in the USA recommend that people with T1DM have a foot assessment five years after diagnosis and then annually thereafter, and that people with T2DM have foot assessments both at diagnosis and on an annual basis ,90. AlteThe ‘Putting Feet First’ framework exists to outline the minimum diabetic footcare required in the UK. It emphasizes the importance of a multidisciplinary approach involving diabetology, podiatry, vascular surgery, orthopedics and other specialties, as well as a pathway to ensure timely footcare and urgent referral . For exaThe level of evidence for footcare in preventing further foot complications is low. A systematic review identified 19 studies that evaluated the impact of multidisciplinary care on diabetic foot outcomes. Although amputation severity, mortality rates and length of hospital stay were reduced, the studies reviewed were of low-quality . FurtherSeveral guidelines include recommendations for diagnostic evaluation of DN. They emphasize the importance of accurate diagnosis, which excludes other causes of peripheral neuropathy, as well as regular evaluation so that DN is detected early, allowing for advanced implementation of strategies to prevent disease progression ,4,90,91.There are numerous diagnostic and screening tools for DN available; though many focus on symptomatology and may overlook people with early DN. The Michigan Neuropathy Screening Instrument, for example, is a validated screening tool for DN that includes a patient questionnaire and separate clinical examination of the feet . At valiThe gold standard for diagnosing DN is nerve conduction studies, though there are inconsistencies in how these are undertaken and interpreted. Dyck et al.  developeThe gold standard for assessing small fiber function is intraepidermal nerve fiber density, but this requires an expensive, invasive skin biopsy. The procedure can be unsettling for patients and results in a small wound, raising safety concerns due to an increased risk of foot ulceration in this patient group. As a result, non-invasive alternatives have emerged such as Quantitative Sensory Testing (QST), a measure of sensory function that includes sensation involving small fibers. The German Research Network on Neuropathic Pain has developed a valid, comprehensive, standardized protocol for QST , which iSeveral novel diagnostic evaluation tools are under investigation. The most notable is corneal confocal microscopy, a noninvasive imaging technique that assesses small (C) fiber damage in the cornea, the body’s most densely innervated tissue . A systeAs the management strategies for people with insensate or painless DN are limited, current guidelines focus on strategies for painful DN. These include pharmacotherapies such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), opioids, topical analgesics and intravenous (IV) medications. Pregabalin and gabapentin are recommended first- or second-line treatments for painful DN ,99,100. The level of evidence for these medicines as a treatment for painful DN is moderate. A recent Cochrane systematic review found that pregabalin 300 mg significantly reduced pain intensity by at least 30%  and 50%  versus placebo . The resThe exact mechanism by which pregabalin and gabapentin act are unknown. They bind to the α2δ subunit of calcium channels, which appears to result in analgesic effects; however, they are associated with tachyphylaxis. Typical side effects for both include drowsiness, dizziness, headache, diarrhea and nausea ,132. In Duloxetine is also recommended as a first- or second-line treatment for painful DN ,99,100. The level of evidence for duloxetine is also moderate; a previous Cochrane systematic review  found that 60 to 120 mg is efficacious in treating painful DN, while lower doses are not . Since tVenlafaxine, an SNRI and selective serotonin reuptake inhibitor (SSRI), is recommended as a first- or second-line treatment for painful DN by the European Federation of Neurological Societies Task Force and the American Academy of Neurology ,100, butThe level of evidence for venlafaxine is low. A previous Cochrane systematic review  found little convincing evidence to support the use of venlafaxine in the treatment of painful DN. Although doses ranging from 150 to 225 mg showed some benefit, these studies were compromised by a large placebo effect . There hAlternatively, amitriptyline is recommended as a first- or second-line treatment for painful DN ,99,100. The level of evidence for amitriptyline is low. Although several RCTs have indicated a reduction in DN pain with amitriptyline ,172,173,The exact mechanism by which amitriptyline acts is unknown, though it is known that the antidepressant and analgesic actions are distinct. It inhibits noradrenaline and serotonin reuptake at nerve terminals, as well as sodium, potassium and N-methyl-D-aspartate (NMDA) channels in the central nervous system, which are known to be involved in neuropathic pain . A startDesipramine and nortriptyline have also been investigated for their efficacy in the treatment of painful DN. Multiple RCTs have shown that desipramine significantly reduced symptoms of painful DN ,175,176,Some clinical guidelines recommend considering opioids for the treatment of painful DN ,100, or Tramadol is licensed in the USA and UK for moderate to severe pain rather than specifically neuropathic pain ,150. It Overall, the level of evidence for tramadol is low. Two major RCTs have shown that tramadol significantly reduces pain in people with DN versus placebo ,149. A sTapentadol is licensed specifically for neuropathic pain in the USA but not in the UK . The anaOther opioids, such as methadone and oxycodone have insufficient evidence to support their use in the treatment of neuropathic pain ,187. FurSome clinical guidelines recommend considering topical analgesics for painful DN ,99,100, The level of evidence for topical capsaicin ranges from moderate to low based on the strength applied. An RCT investigating 0.025% capsaicin gel demonstrated no significant effect in reducing pain versus placebo in people with painful DN . MeanwhiA recent meta-analysis (25 RCTs) of 8% capsaicin in the treatment of painful DN found that the patch is more efficacious in achieving ≥ 30% pain reduction versus placebo. Furthermore, it may be more beneficial than anticonvulsants and have a similar efficacy profile to duloxetine . A recenThe level of evidence for other topical analgesics, such as topical lidocaine and topical ketamine, are very low as there are no high-quality RCTs demonstrating that these agents have efficacy for DN ,193,194.Clinical guidelines do not currently recommend IV medications for painful DN, though there is some low-quality evidence to suggest these may be beneficial and warrant further investigation. A recent systematic review (26 studies) found that IV lidocaine is effective in reducing neuropathic pain in the short term . Since tIV ketamine produces analgesia and anti-hyperalgesia when administered at sub-anesthetic dosages . A recenNeuromodulation devices such as spinal cord stimulation (SCS), frequency-modulated electromagnetic neural stimulation (FREMS), transcutaneous electrical nerve stimulation (TENS) and neuromuscular electrical stimulation (NMES) are among the novel therapies under investigation. In addition, nutraceuticals such as α-lipoic acid (ALA), vitamin B12 and acetyl-L-carnitine (ALC) are being increasingly investigated for their safety and efficacy in DN as per recommendations from the American Academy of Neurology . The AmeSCS is recommended by some clinical guidelines for severe painful DN ,91. TherThe level of evidence for SCS is low. A recent systematic review identified only two multi-center RCTs investigating SCS for painful DN . AlthougRecently, dorsal root ganglion stimulation has also been proposed as an alternative nonpharmacological treatment for painful DN ,206, butClinical guidelines do not recommend FREMS as a treatment for DN as the level of evidence is very low. A preliminary RCT (n = 31) demonstrated that two rounds of ten FREMS sessions significantly reduced pain levels and vibration thresholds and improved sensory tactile perception and motor nerve conductivity, whereas no significant changes were seen with the placebo device . A subseAlthough TENS is a nonpharmacological treatment option for chronic pain, no clinical guidelines recommend its use in painful DN. The level of evidence for TENS is low; a meta-analysis found that TENS significantly reduces pain scores by −0.44 (95% CI −0.79 to −0.09), but the studies included were of low methodological quality . There hA modality very similar to TENS is electrical stimulation via percutaneous needles known as PENS . Despite the American Academy of Neurology previously recommending PENS as a treatment for painful DN , the levNMES has the potential to be a nonpharmacological adjuvant treatment for DN. It differs from other peripheral nerve stimulation modalities, such as TENS, in that it is applied at a sufficient intensity to depolarize neurons and evoke muscle contraction, simulating exercise. A double-blind RCT investigating NMES in DN is currently ongoing .The most promising nutraceutical in the treatment of DN is ALA, though its potential has only been recognized in some clinical guidelines ,91. ALA The level of evidence for ALA is low. A previous meta-analysis (15 RCTs) found motor and sensory nerve conduction velocities to be significantly improved in intervention groups administering 300 to 600 mg per day IV ALA compared to control groups. However, many of the included studies were low-quality and subject to a high risk of bias . Oral ALp < 0.0001) and lower vitamin B12 levels  compared to people taking other diabetes treatments [There are important links between vitamin B12 deficiency, peripheral neuropathy and the treatment of diabetes. Firstly, vitamin B12 deficiency is an independent cause of peripheral neuropathy, and its exclusion is required for a diagnosis of DN . Second,eatments . Thus, teatments . These reatments . Vitamineatments ,220,221.The level of evidence for vitamin B12 is low. Vitamin B12 can be administered by injection or orally, but the latter has been investigated in most studies. A notable double-blind RCT that included people with DN and autonomic neuropathy who had been taking metformin for at least four years investigated the effects of oral vitamin B12 (1000 μg/day) versus placebo after one year. Compared to baseline, participants in the intervention group (n = 44) had significantly improved neuropathy symptoms, pain outcomes, vibration perception threshold, QoL, sural nerve conduction velocity and action potential amplitude and skin conductance in their feet, while cardiovascular autonomic reflex texts and neuropathy clinical examination scores were non-significantly improved. In addition, no participants reported any suspected or related adverse effects . This stPresently, vitamin B12 is only indicated for people who have a deficiency, so it is not suitable for everyone with DN . There iALC has been proposed as a treatment for DN because of its role in nerve glucose and lipid metabolism. It promotes long-chain fatty acid transport, which is especially important in hyperglycemic and hyperlipidemic conditions to keep mitochondrial function efficient . The levThe rise in DN and its serious consequences for patients is both concerning and costly. More than 50% of people with diabetes will develop DN, causing symptoms ranging from numbness to unsteadiness and pain, as well as complications such as foot ulceration and Charcot foot. More recently, the psychosocial consequences of DN and their contribution to high levels of morbidity have also been recognized. Guidelines currently recommend two types of strategies: prevention, which aims to address DN before symptoms develop, or to prevent the progression of DN; and management, which investigates and treats symptoms patients already have while often failing to address the underlying cause. These established and novel strategies consist of pharmacological and nonpharmacological interventions .The focus of DN prevention is glycemic control, lifestyle modification and footcare. Glycemic control can be achieved by a variety of different interventions such as insulin, antidiabetic medications, lifestyle modifications, pancreas transplant and bariatric surgery. In people with T1DM, glycemic control is an effective disease-modifying strategy; however, in people with T2DM, other cardiometabolic risk factors may also need to be targeted. Lifestyle modifications, such as supervised exercise programs, may improve DN outcomes and reduce the risk of DN and DFUs. Several different supervised exercise programs have been developed ; each are beneficial, but they are difficult to implement in underfunded healthcare systems. A combination of endurance and sensorimotor training has been proposed as the most effective program; however, these types of programs frequently have low compliance. Personalized programs tailored to the individual may be more appealing. For example, balance training has been shown to be especially effective in treating psychosocial problems. Furthermore, offering diabetes and diet counselling may facilitate compliance with exercise programs, as well as assisting with glycemic control and weight management. To prevent further foot complications, multidisciplinary and self-led footcare through education are recommended, with multidisciplinary care including surgical and infection expertise the best approach for limb salvage; however, these services are currently underperforming, leaving patients confused and often being cared for in the community.Screening and early diagnosis are critical for ensuring advanced implementation of strategies that prevent disease progression. There are numerous screening and diagnostic evaluation tools available, but many do not detect people with early DN because they are focused on symptoms or large fiber function. This is even true for nerve conduction studies, which are the current gold standard for diagnosing DN but are unable to assess small fibers that are targeted before large fibers. Although techniques for assessing small fiber function are available, they also have limitations. There are safety concerns around intraepidermal nerve fiber density, which is considered the gold standard for assessing small fibers, as it requires a skin biopsy leaving a wound in patients who are already at high risk of ulceration. Alternatively, QST is a noninvasive diagnostic modality including the assessment of small fiber function, but it is time consuming, expensive and requires training. Novel techniques, such as corneal confocal microscopy are being investigated and may provide an easy and accurate test for detecting early DN, but further high-quality research needs to be undertaken to strengthen its evidence for regulator review. There are few management strategies for people with insensate or painless DN. For people with painful DN, anticonvulsants, SNRIs and TCAs are recommended first- and second-line pharmacotherapies. These pharmacotherapies have moderate- to low-quality evidence and are associated with a variety of side effects. In some cases, opioids are recommended as third-line pharmacotherapies. New guidance, however, advises against their use entirely due to significant risks. The level of evidence for topical analgesics is moderate to low, but recent studies of 8% topical capsaicin show efficacy for painful DN. IV medications are not currently recommended and are limited to use in refractory cases and warrant further study.Neuromodulation devices are novel, nonpharmacological therapies for DN that have the potential to improve pain outcomes and nerve conductivity. SCS has been recently approved for severe painful DN despite a level of low-quality evidence and its associated procedural risks. Other noninvasive neuromodulation devices such as TENS and NMES are being investigated, but there is a lack of data to determine their efficacy. Other innovative disease-modifying nutraceuticals have been explored, such as ALA, vitamin B12 and ALC, but none have received sufficient evidence for approval in the USA or UK and there are increasing concerns with their safety due to their lack of regulations.


Endometrial biopsy is generally performed with a metal uterine curette sonde; however, recently, many types of vacuum aspirators are available, including the manual vacuum aspiration (MVA) system. We used the women's MVA system for endometrial sampling and evaluated its effectiveness in determining the presence of endometrial malignancy.Forty‐seven samples were examined using the following procedures after measuring endometrial thickness by transvaginal ultrasonography: fractional curettage biopsy , total curettage under general anesthesia , and MVA (14 samples). The quality of the endometrial samples was classified into four types: 1–4, where 1 denoted poor and 4, good quality.p = 0.0065). No differences were observed between the MVA and total curettage groups (p = 1.00). When patients were divided into two groups according to endometrial thickness (<10 mm or ≥10 mm) and analyzed, both the MVA and T/C groups did not show a significant difference in their scores compared to the Bx group when the endometrial thickness was <10 mm. However, when the endometrial thickness was ≥10 mm, the MVA and T/C groups had significantly better scores than the Bx group . Vagal reflex, as an adverse event, was observed only in two patients in the Bx group .The mean score of the MVA group was significantly higher than that of the partial curettage biopsy group (Considering its quality and safety, Karman‐type MVA for endometrial sampling could be an alternative to fractional curettage using a metallic uterine curette sonde. The incidence of uterine cancer has increased in many countries in recent years, including Japan. In 2018, the number of endometrial cancer cases was 17 089, which is the largest number for a gynecologic malignancy, surpassing 10 978 for cervical cancer and 13 049 for ovarian cancer. The age‐standardized mortality rate of endometrial cancer in 2019 was 1.5 (per 100 000). Endometrial cells and tissues can be collected from patients with abnormal uterine bleeding in outpatient clinics.Conventionally, endometrial tissue collection is often performed by sharp curettage involving the use of a uterine curette sonde, and the rate of false results due to the location of the disease is high. The use of fractional curettage, which involves repeated tissue collection in four directions, is, thus, recommended.However, fractional curettage is sometimes very painful and may cause a decrease in blood pressure due to vagal reflex. Furthermore, it is not always easy and safe to carry out the procedure because of the risk of complications, such as uterine perforation due to blind operation with a thin and hard instrument.Endometrial tissue samples obtained by MVA are already being used for diagnostic purposes overseas, and many reports on the diagnostic accuracy and safety have been published.Forty‐seven patients whose endometrial tissue was collected from May 2018 to August 2021 at the University of Tokyo Hospital and Tokyo Metropolitan Bokutoh Hospital under informed consent were selected and analyzed with the approval of the ethics committee (No. 3084‐(3) University of Tokyo Hospital; No. 03‐004 Bokutoh Hospital). The clinical diagnoses and suspicions that required endometrial sampling included endometrial cancer and atypical endometrial hyperplasia.Three collection methods were compared: fractional curettage biopsy , total curettage under general anesthesia , and MVA (14 samples). Before carrying out the sampling procedures, we measured the endometrial thickness in all the patients by transvaginal ultrasonography.T/C were performed to those who required them according to the conventional treatment policy. Regarding Bx, with few exceptions, whether to use curette sonde or MVA was determined by the period in which the procedure was performed. The test period was 6 months from May to October 2018 for The University of Tokyo Hospital, and 2 months from July to August 2021 for the Tokyo Metropolitan Bokutoh Hospital.Bx was performed in the outpatient setting with a 3 mm sized metal uterine curette sonde Figure  in four The metal uterine curette sonde was 3 mm in thickness, which was the same as the harder type of cannula of the MVA. Therefore, there was no case in which we could only collect endometrial tissue with a metal sonde.Tissue analysis was carried out using pathological slides prepared from the collected endometrial tissue, and the amount and quality of the slides was scored according to the criteria shown in Figure H‐test and Mann–Whitney U‐test with Bonferroni correction were used for statistical analyses, and statistically significant differences were considered at p values lower than 0.05. Statistical analyses were performed using Excel® Statistical Program File ystat2008.xls for Windows/Macintosh programed by Shinya Yamazaki DDS, PhD, and GraphPad PRISM version 5.0c.The Kruskal–Wallis The background characteristics of the 47 patients are shown in Table Table p = 0.0065; Figure p = 1.00). When the data were analyzed according to endometrial thickness of 10 mm or more and less than 10 mm, there was a significant difference in the scores between the Bx and MVA or T/C of thick endometrial group . However, in the thin endometrial group, no significant differences were observed between Bx and MVA or T/C  . Decreased blood pressure and nausea due to vagal reflex were observed in one patient, and decreased blood pressure was observed in one patient. The patients recovered after a short rest with no additional medication. The two patients with side effects were both nulliparous and premenopausal patients. In contrast, no adverse events were observed in the MVA group. No uterine perforation was observed during any of the procedures.We found that the quality of endometrial tissue collected by MVA was comparable to that collected by T/C. The effectiveness of MVA has been reported in many papers. Tansathit et al. examined the diagnostic efficacy of endometrial aspiration histology (Karman‐type cannula = women's MVA) with a study sample of 226 patients with abnormal bleeding.In the study by Sirimai et al., endometrium samples were collected using both conventional metal curettage and MVA from 132 patients with abnormal bleeding, and the pathological results were compared. The diagnostic concordance rate among the 123 evaluable samples was 64.2%. Atypical proliferation (one case) and cancer (five cases) could be diagnosed consistently using either method.Regarding the cannula size, the size of 3 mm was selected for patients whose uterine ostium and cervical canal were narrow. For patients with a wide uterine ostium/lumen and with a complicated direction of the endometrium, the size of 4 mm was selected. Thus, smooth tissue collection was possible. In addition, while the safety of MVA was not inferior to that of conventional fractional curettage, this needs to be investigated in future studies with larger sample sizes. Once accustomed to the procedure, both the practitioner and the caregiver took almost the same amount of time and effort for MVA as they did for fractional curettage.Notable complications of endometrial fractional curettage include uterine perforation and vagal reflex. The risk of uterine perforation due to fractional curettage or dilatation and curettage (D&C) is estimated to be up to 1%, with an incidence of 0.16%–0.9%,The limitation of this study would be the small number of samples, which might result in no significant difference in analyses of thin endometrial patients. Further study with more samples would be needed to evaluate the precise advantage, adverse events, and pathology quality, for example, by following patients' conditions after leaving the hospital. Furthermore, it would also be necessary to consider the impact of MVA on cost‐effectiveness.Some studies have reported that D&C is more accurate than aspiration biopsy for patients with endometrial hyperplasiaThe authors have no conflict of interest to declare.