Based on the authors' clinical experience, the acupuncture treatment of non-alcoholic fatty liver disease mainly includes the following three aspects. (1) The etiology and pathogenesis of non-alcoholic fatty liver disease are based on “deficiency in origin and excess in superficiality.” The deficiency in origin means deficiency of the spleen and stomach, and the excess in superficiality is caused by hepatobiliary disorders. (2) The application of the theory of strengthening the spleen and mobilizing transportation should be considered for the treatment of non-alcoholic fatty liver disease by acupuncture and moxibustion. Therefore, the use of “treatment from the spleen” often has miraculous effects. (3) Skillful use of acupuncture, shallow acupuncture, acupoint thread embedding, and other traditional Chinese medicine therapies are used to regulate the liver and spleen. In addition, warm acupuncture is reused to warm the Yang and strengthen the body. Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction-associated fatty liver disease (MAFLD), refers to the exclusion of alcohol and other clear liver damage factors. Clinicopathological syndromes in which diffuse hepatocyte bullous fat becomes the main feature include simple fatty liver disease and its evolution of steatohepatitis, fatty liver fibrosis, and cirrhosis . StudiesThe etiology and pathogenesis of non-alcoholic fatty liver disease are based on the “deficiency in origin and excess in superficiality”: the deficiency in origin refers to deficiency of the spleen and stomach, and the excess in superficiality is caused by stagnation of the liver and Qi .Spleen and stomach are the acquired foundation. The spleen and stomach are weak in transporting water and grains, and the circulation of Qi and blood is not smooth, which leads to the deposition of phlegm and dampness in the liver and blood stasis in the liver. In disorders of the spleen and stomach, the turbidity is cleared without distinction, condensing the “cream” and forming fatty liver; hyperlipidemia occurs when turbid Qi enters the blood. Modern research has also shown that gastrointestinal function is closely related to NAFLD . ResearcThe liver is responsible for dredging and drainage. With the onset of disease, the liver is unbalanced, the Qi does not run smoothly, the Qi is blocked by phlegm, and bile excretion is not smooth. This worsens fatty liver. Modern medical research has also confirmed that disorders of lipid metabolism and hepatocyte steatosis are related to NAFLD , 7. HumaThe pathogenesis of non-alcoholic fatty liver disease is led by spleen deficiency. Although the disease is located in the liver, it is inseparable from the spleen. Physiologically, the movement and transformation of the spleen depend on the maintenance of the Qi of the liver, and the dispersion of the liver and blood storage needs the spleen and stomach to metabolize and produce essence for nourishment. This reflects the roles and relationship of the liver and spleen in the function of dispersion and transportation and in blood production and blood storage. Regarding the meridian and collaterals, the “Lingshu·Meridian” points out that the spleen meridian “traces the tibia, then detours to the front of the Jueyin meridian,” and the liver meridian “is eight inches above the ankle and then detours to the back of the Taiyin meridian.” The Foot Taiyin Spleen Meridian and Foot Jueyin Liver Meridian cross and circulate on the inner side of the calf. The two meridians influence each other, which also fully reflects the close relationship between liver and spleen functions. In terms of pathology, Dongyuan Li mentioned in “Spleen and Stomach Theory” that “[with] internal injury to the spleen and stomach, all diseases arise.” If the spleen and stomach show insufficiency and dysfunction of transportation and chemistry, water dampness and turbid phlegm are inevitable; it can also affect liver failure and release, leading to the syndrome of “Tuyong Muyu.” Reflecting the pathological importance of the spleen, the signs and symptoms of NAFLD are mostly the manifestations of splenic failure. In the treatment of NAFLD, spleen strengthening should be the entry point , 11. TheThe authors believe that acupuncture and moxibustion are effective in treating NAFLD, and they chose unique therapies—shallow acupuncture, acupoint embedding, and warm needle moxibustion. At the same time, the unique selection of acupoints can be effective .Treatment Method. (1) Acupoint selection: Danzhong point. Point selection basis: Danzhong acupoint is the mu acupoint of the pericardium (the place where the Qi of the pericardium meridian gathers), the Qihui acupoint (the place where the Qi gathers), and the rendezvous point of the Ren channel, foot taiyin, foot shaoyin, hand taiyang, and hand shaoyang. The Danzhong point can regulate qi, activate blood and dredge the collaterals, and regulate the function of the Qi of the whole body. (2) Operation: the thumb is used to press the needle tail, the index finger and the middle finger to hold the needle handle, and the needle tip to press on the meridian skin. Use your middle finger nail to make continuous up and down movements on the needle handle. Reducing method: (a) the needle body is not perpendicular to the plane of the meridian points ; (b) the middle finger nail is scraped up the needle handle with a strong force, but the downward force is small . Push gently. (c) After completing the stimulation of each meridian point, the thumb leaves the tail of the needle, while the middle finger keeps clamping the needle handle, and the needle tip is kept on the acupuncture point. Rotate six times in a counterclockwise arc. (3) Precautions: during the entire operation, the thumb should be kept lightly against the tail of the needle, so as not to increase the pressure involuntarily when the stimulation is applied and cause the needle to pierce the skin and cause pain. At the same time, when the middle finger nail is scraped and pushed on the needle handle, always keep the needle handle still in order to avoid irregular beating. The amplitude of the scraping and pushing should be large , and the finger force must be soft and even; the speed should not be too fast or slow. The punctured part should always maintain a soft and even slight tremor, so that the patient can feel acupuncture and feel comfortable.“Binghuang Wu's shallow acupuncture” has been included in the protection of intangible heritage. Shallow acupuncture can treat a variety of diseases, and its method of flattening, replenishing, and reducing is unique in the treatment of NAFLD. The principle of shallow acupuncture is to stimulate the meridian blood circulation through the physical stimulation of the meridian points by the needle tip, adjust the functional balance of the meridians and viscera, and play the role of strengthening the body, eliminating pathology and curing diseases , 13. ThiTreatment Method. (1) Acupoint selection: Zhongwan, Zusanli, Sanyinjiao, Fenglong, and Taichong. Point selection basis: Zhongwan is the mu point of the stomach meridian and the Fuhui of eight influential points. Zhongwan has the effect of regulating the spleen and stomach. Zusanli is the point of the stomach meridian. Zusanli can regulate the spleen and stomach and, when combined with Sanyinjiao, it can relieve the dampness of the Yangming Meridian and Taiyin Meridian and support the function of spleen and stomach transportation and transfusion. The Fenglong point is the luo point of the foot Yangming stomach meridian, and the point is also connected to the foot Taiyin spleen meridian. Therefore, this point can treat the two meridian disorders of the spleen and stomach and regulate Qi of the spleen and stomach meridian to ensure that the Qi is running and the body fluid is spreading. The spleen meridian governs transportation and transformation, and crosses out the wet and phlegm. The Taichong point is the original point of the liver meridian. It can soothe the liver, regulate the Qi, and regulate the channels of Qi. (2) Operation: the patient takes the supine position, the skin of the abdomen and lower limbs is fully exposed, and the acupoints are disinfected with Aner iodine or 75% alcohol. After washing and disinfecting the hands, the doctors put on sterile gloves. Needle selection: No. 7 injection needle (specification 0.7 mm × 32 mm) is used as a cannula, and an acupuncture needle (specification 0.30 mm × 50 mm) has the needle cut off as a needle core to make a simple embedding needle. Use sterile forceps to take the sterilized collagen thread with a length of 2 cm, place the needle tip into the injection needle, pierce the needle with the protein thread into the acupuncture point, push in the needle core, withdraw the needle tube, and pull the collagen thread. Embed the acupuncture points, put pressure on the needle hole with a cotton swab for a while after the needle is taken out, and then apply a sticking plaster to the needle hole. This is usually done once a week, for a total of 3 months of treatment. (3) Precautions: keep the needle eye position dry for 24 hours after embedding the thread to prevent infection.The authors often use catgut embedding at acupoints to treat NAFLD, and the effect is stronger. Acupoint embedding therapy involves placement of absorbable surgical sutures into the viscera, meridians, and collaterals to infuse the Qi into a special part of the body surface, to produce continuous stimulation to the human body, so as to achieve the purpose of preventing and curing diseases. Treatment Method. (1) Acupoint selection: Dazhui, Pishu, and Weishu. Point selection basis: Dazhui point is the meeting of the three Yang of the hands and feet and the governor channel, and it controls the Yang Qi of the whole body. Pishu is the beishu point of the spleen and Weishu is the beishu point of the stomach. They are the main points for the treatment of spleen and stomach diseases. Both belong to the tai Yang of the feet bladder meridian, so that they have a good effect of nourishing Yang. (2) Operation: the patient lies in the prone position, the skin on the back is exposed, and the acupuncture points are thoroughly disinfected. Routinely insert the needle, insert and twist, using the replenishing and reducing method; take a 2 cm long (one strong) moxa section, insert it on the needle, and light it. Moxibustion is performed for two strong moxibustions each time, and the needles are retained for 30 minutes. (3) Precautions: protect the skin with a piece of hard paper to prevent skin burns. If burned, apply moist scald cream  of 28.4 kg/cm2. Previous physical examination revealed fatty liver for more than 1 year; the patient denied a history of viral hepatitis and other medical history and had no history of drinking alcohol. The tongue is pale, there are tooth marks on the sides, the fur is white and greasy, and the pulse is smooth. Western medicine diagnosis was non-alcoholic fatty liver disease; Chinese medicine diagnosis was liver pi . Treatment method: invigorate the spleen and stomach and transport and resolve phlegm and dampness. Acupuncture methods used were shallow acupuncture, acupoint embedding, and warm needle moxibustion. Symptoms improved after 3 weeks, and after more than 3 months of treatment, the symptoms improved significantly, and the patient's weight decreased to 64.2 kg.Acupuncture treatment of non-alcoholic fatty liver disease is simple and effective. The authors have conducted research on the treatment of NAFLD with acupuncture. The etiology and pathogenesis of NAFLD are based on “deficiency in origin and excess in superficiality”: deficiency in origin means deficiency of the spleen and stomach, and excess in superficiality is caused by hepatobiliary disorders.Given that the spleen and stomach are the foundation of the acquired nature and that spleen deficiency and loss of transport are the internal basis of the disease, “treatment from the spleen, seeking the root of the disease” can show a miraculous effect. Acupuncture can regulate the Qi of the meridians and viscera to restore normal physiologic function. We summarize the characteristic therapies of traditional Chinese medicine acupuncture on the basis of our long-term clinical experience. We make good use of shallow acupuncture and acupoint embedding therapy to regulate the spleen and stomach, dredging the Qi of the whole body. Additionally, we reuse warm acupuncture for warming Yang, strengthening the spleen, and improving immune function. This study provides a reference for clinical treatment and provides a basis and foundation for the clinical promotion of acupuncture and moxibustion in the treatment of NAFLD.


The present study aimed to develop a comprehensive applied framework for EBDM.Scientific evidence is the basis for improving public health; decision-making without sufficient attention to evidence may lead to unpleasant consequences. Despite efforts to create comprehensive guidelines and models for evidence-based decision-making (EBDM), there isn`t any to make the best decisions concerning scarce resources and unlimited needsThis was a Best-Fit Framework (BFF) synthesis conducted in 2020. A comprehensive systematic review was done via six main databases including PUBMED, Scopus, Web of Science, Science Direct, EMBASE, and ProQuest using related keywords. After the evidence quality appraisal, data were extracted and analyzed via thematic analysis. Results of the thematic analysis and the concepts generated by the research team were then synthesized to achieve the best-fit framework applying Carroll et al. (2013) approach.Four thousand six hundred thirteen studies were retrieved, and due to the full-text screening of the studies, 17 final articles were selected for extracting the components and steps of EBDM in Health System Management (HSM). After collecting, synthesizing, and categorizing key information, the framework of EBDM in HSM was developed in the form of four general scopes. These comprised inquiring, inspecting, implementing, and integrating, which included 10 main steps and 47 sub-steps.The present framework provided a comprehensive guideline that can be well adapted for implementing EBDM in health systems and related organizations especially in underdeveloped and developing countries where there is usually a lag in updating and applying evidence in their decision-making process. In addition, this framework by providing a complete, well-detailed, and the sequential process can be tested in the organizational decision-making process by developed countries to improve their EBDM cycle. Publt wastes . At the t wastes .Evidence suggests that health systems often fail to exploit research evidence properly, leading to inefficiencies, death or reduced quality of citizens’ lives, and a decline in productivity . DecisioUsing the evidence in health systems’ policymaking is a considerable challenging issue that many developed and developing countries are facing nowadays. This is particularly important in the latter, where their health systems are in a rapid transition . For insSince the use of EBDM is fraught with the dilemma of most pressing needs and having the least capacity for implementation especially in developing countries , effortsThis was a Best Fit Framework (BFF) synthesis conducted in 2020 to develop a comprehensive framework for EBDM in HSM. Such a framework synthesis is achieved as a combination of the relevant framework, theory, or conceptual models and particularly is applied for developing a priori framework based on deductive reasoning . The BFFIn order to achieve this aim the following methodological steps were conducted as follows:In this step, we aimed to look for the relevant models and frameworks related to evidence-based decision-making in health systems management. The main research question was “what is the best framework for EBDM in health systems?” after defining the research question, the researchers searched for published studies on EBDM in HSM in different scientific databases with relevant keywords and constraints as inclusion and exclusion criteria from 01.01.2000 to 12.31.2020  for assessing the quality of qualitative researches , Scale fAfter searching the studies from all databases and removing duplicates, the studies were independently reviewed and screened by two members (TS and MRAM) of the research team in three phases by the title, abstract, and then the full text of the articles. At each stage of the study, the final decision to enter the study to the next stage was based on agreement and, in case of disagreement, the opinion of the third person from the research team was asked (PB). Mendeley reference manager software was used to systematically search and screen relevant studies. The data from the included studies were extracted based on the study questions and accordingly, a form of the studies’ profile including the author's name, publication year, country, study title, type of study, and its conditions were prepared in Microsoft Excel software Table 4-.In this step, a thematic analysis approach was applied to extract and analyze the data. For this purpose, first, the texts of the selected studies were read several times, and the initial qualitative codes or thematic concepts, according to the determined keywords and based on the research question, were found and labeled. Then these initial thematic codes were reviewed to achieve the final codes and they were integrated and categorized to achieve the final main themes and sub-themes, eventually. The main and the sub-themes are representative of the main and sub-steps of EBDM. At the last stage of the synthesis, the thematic analysis was finalized with 8 main themes and all the main and the sub-themes were tabulated Table 5-.For BFF synthesis in the present study, we compared the existing models and tried to find a model that fits the best. Three related models that appeared to be relatively well-suited to the purpose of this study to provide a complete, comprehensive, and practical EBDM model in HSM were found. According to the BFF instruction in Carroll et al. (2013) study , we deciIn order to assess the differences between the priori framework and the new conceptual framework, the authors tried to ask some experts’ opinions about the validity of the synthesized results. The group of experts has included eight specialists in the field of health system management or health policy-making. These experts have been chosen considering their previous research or experience in evidence-based decision/policy making performance/management Table . This paTo prevent bias, two individuals carried out all stages of the study such as screening, data extraction, and data analysis. The overall research project related to this manuscript was approved by the medical ethics conceal of the research deputy of Shiraz University of Medical Sciences with approval number IR.SUMS.REC.1396–01-07–14184, too.The initial search across six electronic databases and the Cochrane library yielded 4613 studies. After removing duplicates, 2416 studies were assessed based on their titles. According to the abstract screening of the 1066 studies that remained after removing the irrelevant titles, 291 studies were selected and were entered into the full-text screening phase. Due to full-text screening of the studies, 17 final studies were selected for extracting the components and steps of EBDM in HSM . A significant number of those models were proposed for the scope of public health and evidence-based practice, and only a limited number of them focused exactly on the scope of management and policy/decision making in health system organizations.Given that the designed model is a comprehensive 10-step model, it can be used in some way at all levels of the health system and even in different countries. However, there will be a difference here, given that this framework provides a practical guide and a comprehensive guideline for applying evidence-based decision-making approach in health systems organizations, at each level of the health system in each country, this management approach can be applied depending on their existing infrastructure and the processes that are already underway , and at the same time, with a general guide, they can provide other infrastructure as well as the prerequisites and processes needed to make this approach much more possible and applicable.It is true that evidence-based management is different from evidence-based medicine and even more challenging . Still, the general framework provided in this article can be used to help organizations that really want to act and move forward through this approach.Furthermore, based on the findings, most of the previous studies only referred to some parts of the components and steps of the EBDM in health organizations and neglected the other parts or they were not sufficiently comprehensive –40. MostLikewise, the models presented by Brownson (2009) and Janati (2018) were only limited to the six or seven key steps of the EBDM process, and they did not mention the details required for doing in each step, too , 4, 42. In the present study, the framework of EBDM in HSM was developed in the form of four general scopes of inquiring, inspecting, implementing, and integrating including 10 main steps and 47 sub-steps. These scopes were discussed as follows:In the first step, “situation analysis and priority setting”, the most frequently cited sub-step was identifying and prioritizing the problem. Accordingly, Falzer (2009), emphasized the importance of identifying the decision-making conditions and the relevant institutions and determining their dependencies as the first steps of EBDM . Aas  pointed to the use of library services in EBDM . AppraisFurthermore, the sixth step, “analysis, synthesis, and interpretation of data”, was mentioned in many included studies , 59, 72.The third scope consisted of the seventh and eighth steps of the EBDM process in HSM. In the seventh step, “developing evidence-based alternatives”, the issue of involving stakeholders in decision-making and subsequently, planning to design and implementation of the process and evaluation strategies had been focused by the previous studies , 63, 73.“Pilot-implementation of selected alternatives” was the eighth step of the framework. Some key sub-steps of this step were resources allocation , Pre-impThis last scope consists of the ninth and tenth steps. The main sub-step of the ninth step, “evaluating alternatives”, was to evaluating process and outcomes and revise. After a successful implementation of the pilot, this step can be assured that the probable outcomes may be achieved and this evaluation will help the decision and policymakers to control the outcomes, effectively. Also, it impacts the whole target program and proposes some correcting plans through an accurate feedback process, too. Pagoto (2007) explained that a facilitator for EBDM would be an efficient and user-friendly system to assess utilization, outcomes, and perceived benefits .Also, the tenth step, “integrating and maintaining change in practice”, was not considered as a major step in previous models, too, while it is important to maintain and sustain positive changes in organizational performance. In this regard, Ward (2011) also suggested several steps to maintain and sustain the widespread changes in the organization, including increasing the urgency and speed of action, forming a team, getting the right vision, negotiating for buy-in, empowerment, short-term success, not giving up and help to make a change stick . FinallySome previous findings showed that about half and two-thirds of organizations do not regularly collect related data about the use of evidence, and they do not systematically evaluate the usefulness or impact of evidence use on interventions and decisions . The resIn contrast, results of Lavis study (2008) on organizations that supported the use of research evidence in decision-making reported that more than half of the organizations  may use the evidence in their process of decision-making , so applOne of the limitations of the present study was the lack of access to some studies  related to the subject in question that we tried to access them by manual searching and asking from some articles’ authors and experts. In addition, most of the existing studies on EBDM were limited to examining and presenting results on influencing, facilitating, or hindering factors or they only mentioned a few components in this area. Consequently, we tried to search for studies from various databases and carefully review and screen them to make sure that we did not lose any relevant data and thematic code. Also, instead of one model, we used four existing models as a basis in the BFF synthesis so that we can finally, by adding additional codes and themes obtained from other studies as well as expert opinions, provide a comprehensive model taking into account all the required steps and details. Also, the framework developed in this study is a complete conceptual model made by BFF synthesis; however, it may need some localization, according to the status and structure of each health system, for applying it.The present framework provides a comprehensive guideline that can be well adapted for implementing EBDM in health systems and organizations especially in underdeveloped and developing countries where there is usually a lag in updating and applying evidence in their decision-making process. In addition, this framework by providing a complete, well-detailed, sequential and practical process including 10 steps and 56 sub-steps that did not exist in the incomplete related models, can be tested in the organizational decision-making process or managerial tasks by developed countries to improve their EBDM cycle, too.


Time-saving formats of evidence syntheses have been developed to fulfill healthcare policymakers’ demands for timely evidence-based information. A discrete choice experiment (DCE) with decision-makers and people involved in the preparation of evidence syntheses was undertaken to elicit preferences for methodological shortcuts in the conduct of abbreviated reviews.D-efficient scenarios, each containing 14 pairwise comparisons, were designed for the DCE: the development of an evidence synthesis in 20 working days (scenario 1) and 12 months (scenario 2), respectively. Six attributes  with 2 to 3 levels each were defined. These were presented to the target population in an online survey. The relative importance of the individual attributes was determined using logistic regression models.Scenario 1 was completed by 36 participants and scenario 2 by 26 participants. The linearity assumption was confirmed by the full model. In both scenarios, the linear difference model showed a preference for higher levels for “number of reviewers during data extraction”, followed by “number of reviewers during screening” and “full-text analysis”. Subgroup analyses showed that preferences were influenced by participation in the preparation of evidence syntheses.The surveyed persons expressed preferences for quality standards in the process of literature screening and data extraction.The online version contains supplementary material available at 10.1186/s13643-021-01647-z. Healthcare policymakers require evidence-based information for their decision-making processes . Health New and abbreviated formats of evidence syntheses are up for discussion which are conducted within shorter timeframes and may be less expensive . FrequenWhile rapid reviews aim to fulfill the demands of healthcare decision-makers in a timely manner, the resulting methodological shortcuts bear the risk that results may be less reliable than those of systematic reviews . Despiten=36=729 possible combinations. To deal with this problem, optimal designs can be used in which, based on certain quality criteria, an appropriate subset  is selected from the set of theoretically possible stimuli. Thus, a reduced number of comparisons is required [One of the challenges in DCEs is their complexity related to the number of tasks. In so-called full factorial designs, combinations of all attribute levels are used. In practice, these designs are often not feasible as the number of evaluations required from each respondent becomes prohibitively large. For example, an experimental design consisting of six attributes with three levels each would result in required . The preA key stage in the conduct of this study was to ensure that relevant attributes and levels were included in the DCE. Therefore, websites of organizations producing abbreviated evidence syntheses were searched for methodological guidance of rapid reviews. A list of organizations is shown in Sup. Table A sample of decision-makers in healthcare and people involved in the preparation of evidence syntheses was generated via the network of contacts of the Institute for Healthcare Management and Research. Eligible persons were contacted by e-mail and asked to participate in the online survey. A three-wave e-mail schedule was followed. First, an announcement e-mail was sent to 204 eligible individuals in June 2019, containing general information on the aim and purpose of the survey. A week later, the individuals received an e-mail containing a link to the web-based survey. Three weeks later, a follow-up e-mail was sent and after five weeks, the survey was deactivated. The web-based survey was accessible on the QuestionPro Survey  platform. The questionnaire contained questions on age, sex, company affiliation, managerial responsibility, and usage of evidence syntheses. The participants were then asked to complete the pairwise comparisons. Finally, the participants were asked to rate the importance of 11 aspects of an evidence synthesis on a five-point scale .n = number of respondents, t = number of tasks, a = number of alternatives per task, and c = the largest number of levels for any one attribute [Currently, no standard exists for the determination of the minimum sample size in DCEs. Johnson and Orme have recommended a rule-of-thumb: nta/c ≥ 500, where ttribute . In the Two scenarios on the basis of German regulations were defined, namely: (i) It has to be evaluated if a telemedical service should be implemented as a new medical examination and treatment method. Therefore, a rapid review has to be elaborated within 20 working days. (ii) The necessity, efficiency, and expediency of laboratory and human genetic services in the outpatient sector have to be evaluated. Within 12 months, a rapid review has to be elaborated. D-efficient choice sets were developed within QuestionPro Survey Software. As the scenarios address different timeframes for the conduct of rapid reviews, the number of levels assigned to the attributes was different. Therefore, distinct choice sets had to be developed  no full-text analysis, (ii) full-text analysis only for easily obtainable literature, and (iii) full-text analysis. The individual levels are mutually exclusive. An overview of the attributes and their levels for scenarios 1 and 2 is shown in Table Descriptive statistics were used to summarize demographic characteristics of the first five survey questions. Responses to the DCE were analyzed using logistic regression models in SAS 9.4 . Full models were used to check the linearity of the linear difference model. In full models, no linear order is presupposed and thus, they were applied to investigate whether the order of levels corresponds to their predefined order and whether the distances between levels can be regarded as uniform. If this was the case, the further analysis was based on linear difference models. These parsimonious models were used to assess the relative importance of the individual attributes assuming uniform distances between levels. The Wald test was used to test the statistical significance of the individual regression coefficients. Additionally, descriptive subgroup analyses were performed by repeating the main analysis for a selected population. Due to an expected small sample size, the importance of the respective subgroup was not assessed . Consequently, the analysis was carried out in an exploratory manner and therefore has to be interpreted with caution. The regression coefficients and odds ratios (OR) with their respective 95% confidence intervals (CI) are reported.The descriptive analysis of the last question dealing with 11 aspects of an evidence synthesis was performed in SPSS . As this question deals with general characteristics of evidence synthesis and is not related to scenario 1 or 2, a combined analysis was undertaken.A total of 62 persons participated and completed a total of 868 pairwise comparisons. Of these, 36 persons participated in scenario 1 and 26 persons participated in scenario 2. The response rate was 30.4%. The participants needed 15 minutes to complete the survey, on average. Participants’ characteristics are shown in Table Overall, 63% of respondents were male, 39% were aged between 55 and 64 years, and a further 34% were between 45 and 54 years of age. About 15% were employed at a statutory health insurance, 8% at the National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung), 8% worked for a private health insurance, and a further 5% was employed at the Medical Review Board of the Statutory Health Insurance Funds (Medizinischer Dienst der Krankenkassen). Twenty-seven percent of respondents had no managerial responsibility, a further 27% had managerial responsibility for ≤ 10 employees, and 19% had managerial responsibility for > 50 employees. About half (55%) of respondents stated to use evidence synthesis for informational purposes. A further 19% of the respondents were involved in the preparation of evidence syntheses, and 15% of the respondents used evidence syntheses as a basis for decision-making. In both scenarios, participants’ characteristics in terms of sex and affiliation do not deviate significantly from the originally generated sample of 204 persons and thus, no participation bias is suspected.The respondents completed a total of 504 pairwise comparisons in scenario 1 (preparation of rapid review within 20 working days). In the full model, the coefficients of level 2 were consistently classified between level 1 and level 3. However, distances from zero were not uniform for the attributes “number of reviewers during screening”, “types of HTA domains”, and “number of databases”, i.e., perfect linearity cannot be assumed for these attributes . Similar to scenario 1, the coefficients of level 2 were consistently classified between level 1 and level 3. Distances from zero were basically uniform with the exception of “number of databases”. Concerning the latter, level 1 and level 2 were essentially rated as equal. However, level 3 of “number of databases” was significantly different from zero. Results of the linear difference model showed preferences for higher levels for “number of reviewers during data extraction”, followed by “number of reviewers during screening”, “full-text analysis”, and “types of HTA domains”. The attributes “number of databases” and “publication period to be considered” did not reach statistical significance . Full-text analysis was given a lower preference by respondents who did not participate in the preparation of evidence syntheses themselves . Due to the rather small number of participants in the subgroups, the generalizability of these findings is very limited. The full results of the explorative subgroup analyses are shown in the supplementary material   and therefore include different numbers and definitions of levels. Nevertheless, for both scenarios, performing the data extraction by two persons in conjunction with quality assurance is very relevant. Similarly, screening by two persons with consensus and a full-text analysis of the literature are of great importance for the respondents. In scenario 2, the inclusion of several domains  shows a stronger preference than in scenario 1. It is conceivable that with the longer working time in scenario 2, participants ascribe importance to the consideration of several domains. However, the higher relevance of the additional domains to be included could have also been influenced by the fact that scenarios 1 and 2 deal with different topics. The attributes “searches in several databases” and “publication period to be considered” show comparatively low preferences in both scenarios.Potential for improvement of existing formats can be derived from the fact that decision-makers clearly expressed preferences for formats in which the process of screening and data extraction was performed by two persons and specific quality standards were attained. Based on these preferences, financial and temporal savings should not be realized by reducing the number of people involved in screening and data extraction. According to the participants of this survey, preferable methodological shortcuts involve restrictions in the number of databases, a consideration of a smaller number of HTA domains, or a shorter publication period. Presumably, the absence of trade-offs is reflected in the answers to the final question on 11 attributes of an evidence synthesis. Even though the data extraction by two persons was also rated as most important, the other individual attributes were rated comparably high, so no clear results can be derived.The present study has several limitations. First, due to the aggregation of the originally defined 11 attributes to six attributes, only a selection of attributes could be examined and thus, preferences could not be derived for all steps in the preparation of rapid reviews. However, this reduction of attributes was deemed necessary to enhance the feasibility of the DCE. Second, the rather small number of 36 persons participated in scenario 1, and only 26 persons participated in scenario 2. However, statistically significant findings could be reported for the majority of attributes in scenario 1 and scenario 2, indicating their relevance. Third, one could argue the usage of the linear difference model. Though some of the attributes do not show a perfect linear relationship, the order of the levels was still preserved, i.e. the lower and higher levels lie on different sides of the medium level throughout. As a ranking of attributes was the major goal of this analysis rather than an interpretation on level basis, it was decided to use the more parsimonious model. Fourth, our sample consisting of decision-makers and people involved in the development of evidence syntheses is not a representative sample in a statistical sense. Fifth, there is some evidence for a higher proportion of employees in statutory health insurance in scenario 1 than in scenario 2 and it cannot be ruled out that the results were influenced by these differences. This unequal distribution may be due to the fact that (i) these employees have felt an affinity to scenario 1 and (ii) that the link to the survey might have been shared among colleagues.Finally, the fact that the three attributes “number of reviewers during data extraction”, “number of reviewers during screening”, and “full-text analysis” have a similarly strong preference in the two scenarios suggests a generalizability. However, it must be taken into account that the importance of the individual work steps in practice depends on the respective research question. For example, the benefit of including further databases might be small for certain research questions. In the case of very short-term inquiries, it might be useful to focus on the clinical domains of safety and efficacy, and the economic assessment may be conducted at a later stage. Furthermore, a possible link between the attributes should be considered. Although, as described, the attributes do not overlap as such, they are part of a sequence in which alterations might affect process steps occurring later in time. For example, there might be little point to restrict the number of databases, in order to ultimately examine a large number of domains. The analysis principally reflects the view of German users and developers of evidence syntheses.Concluding, the present paper shows that the method of DCE can be applied to determine preferences for methodological aspects of rapid reviews. Our findings that decision-makers and researchers preparing evidence syntheses clearly expressed preferences for certain quality standards related to the process of literature screening and data extraction provides important insights. Current methodological approaches with a reduced number of people involved in screening and data extraction should be critically evaluated. Especially in times of global public health crises, such as the COVID-19 pandemic, rapid reviews gain importance. It must be ensured that rapid reviews are of acceptable quality to maximize their credibility and impact. Future research needs to further explore the impact of certain methodological alterations in the conduct of rapid reviews with the ultimate aim to develop formats which fulfill decision-makers’ preferences and expectations regarding the validity of rapid reviews.Additional file 1: Sup. Table 1. List of organizations. Sup. Table 2. Attributes and levels for scenario 2. Sup. Table 3. Results of the full model for scenario 1. Sup. Table 4. Results of the full model for scenario 2. Sup. Table 5. Results of the subgroup analyses. Sup. Table 6. Results for the question on 11 attributes of an evidence synthesis. Sup. Figure 1. Exemplary choice task (translated).


Patient decision aids (PDAs) should provide evidence‐based information so patients can make informed decisions. Yet, PDA developers do not have an agreed‐upon process to select, synthesize and present evidence in PDAs.To reach the consensus on an evidence summarization process for PDAs.A two‐round modified Delphi survey.A group of international experts in PDA development invited developers, scientific networks, patient groups and listservs to complete Delphi surveys.We emailed participants the study description and a link to the online survey. Participants were asked to rate each potential criterion  and provide qualitative feedback.Criteria in each round were retained if rated by >80% of participants as desirable or essential. If two or more participants suggested rewording, reordering or merging, the steering group considered the suggestion.Following two Delphi survey rounds, the evidence summarization process included defining the decision, reporting the processes and policies of the evidence summarization process, assembling the editorial team and managing  their conflicts of interest, conducting a systematic search, selecting and appraising the evidence, presenting the harms and benefits in plain language, and describing the method of seeking external review and the plan for updating the evidence .A multidisciplinary stakeholder group reached consensus on an evidence summarization process to guide the creation of high‐quality PDAs.A patient partner was part of the steering group and involved in the development of the Delphi survey. Evidence summarization processes for other resources have become increasingly standardized, which promotes transparency and rigour, while minimizing the risk of bias in the end product.The aim of the study was to reach consensus, using a modified Delphi survey, on a process, related steps and criteria for selecting and summarizing evidence for PDAs. This will, in turn, assist PDA developers in improving the transparency and rigour, while minimizing the risk of bias in the evidence summarization processes used in PDA development.22.1Our study protocol was published, and a summary is presented here.2.2To maximize the generalizability and applicability of the criteria, we invited the following groups to complete the surveys: (1) the Global Inventory of Patient Decision Support Developers, which includes all known developers of PDAs who created or updated a tool within the last five calendar years (the inventory was last updated 4 October 2019), (2) all members of the IPDAS group, (3) the shared decision‐making listserv, (4) the Society for Participatory Medicine listserv, (5) an overdiagnosis Google Group, (6) the evidence‐based health‐care listserv, (7) the Society for Medical Decision Making, (8) the Society of Behavioural Medicine , (9) the HTAi‐ISG patient involvement listserv, (10) the GRADE working group, (11) the Guidelines International Network, (12) a convenience sample of policymakers with interest and expertise in PDA certification, (13) the BMJ patient group and (14) the ProPublica Patient Safety Community. Membership in one of the groups listed above was the only criterion for inclusion in our study.2.3We convened a steering group to oversee the project and make strategic decisions about the study design, data collection and analysis processes, as well as agree on a final set of steps and criteria. The steering group also generated an initial set of criteria for the Delphi process and managed the distribution of the survey.An invitation to join the steering group was posted in the Shared@Shared Decision Making Network Facebook group (745 members) on 30 June 2017. The post invited all members in the Facebook group to join an in‐person meeting about evidence summarization during the International Shared Decision Making (ISDM) conference held in Lyon, France, between 2 and 5 July 2017. Following the conference, a summary of the meeting was posted on Facebook for those who expressed interest in evidence summarization of PDAs but could not attend.The steering group convened by videoconference in September 2017. It included 9 international experts in the areas of PDA development, evaluation and implementation, evidence summarization and clinical practice guidelines. The experts were based in the United States (n = 6), Canada (n = 1), Australia (n = 1) and Spain (n = 1), all of whom are authors of this study. The steering group also included 1 patient representative. To avoid contaminating Delphi results or duplicating their views, the steering group members unanimously decided not to complete the Delphi surveys.2.4At the first meeting of the ISDM conference in Lyon, France, the steering group developed a spreadsheet that detailed the evidence summarization process inherent to PDA development. The first draft of the process included 18 criteria. The 18 criteria were combined with the 8 existing standards for the summarization of clinical practice guidelines as outlined by the National Academy of Medicine and US Preventive Services Task Force Standards.2.52.5.1The round 1 survey invitation  or in the higher two categories , we considered consensus as having been reached and the criterion was removed or retained accordingly. Following the round 1 survey, a consensus meeting involving the steering group was held. The steering group reviewed and discussed the ratings and qualitative feedback, including rewording suggestions, suggestions to add new phases, steps or criteria, and more general comments or questions. The wording or order of the phases, steps or criteria were revised if two or more respondents suggested it or if the steering group members agreed that the phase, step or criterion would benefit from rewording, reordering or merging. The same process was conducted following the round 2 survey.Only fully completed surveys were included in the analysis. Based on the round 2 results and feedback, the steering committee deemed it unnecessary to conduct a third Delphi round. This method to determine the number of survey rounds was implemented successfully in the past to develop a measure of organizational readiness for patient engagement.33.1In the first Delphi round, 50% n = 131/260) of participants who started the survey completed it. The majority, 58% (n = 76), of respondents were female. Overall, 26 countries were represented  completed it. Similar to round 1, the majority, 59% (n = 67), were female. Overall, 18 countries were represented in this round , the outcomes and the patient concerns. Participants felt that the four criteria on the evidence summarization process in step 2 were redundant. We therefore merged them into one criterion for the round 2 survey. Similarly, participants felt that the four criteria in step 4, each listing a different stakeholder group that should be part of a team that develops a PDA, should be merged into one criterion. Participant feedback in step 3 suggested spelling out the COI abbreviation, and adding a fifth criterion to report all current and potential conflicts of interest. The general comments also led to the reordering of step 3 and step 4 for the round 2 survey. Also, the following three criteria in step 5 were rated as essential or desirable by 80% or less of participants: (i) there is a systematic process to reduce bias in the definition of the population for the PDA; (ii) there is a systematic process to reduce bias in the definition of the options for the PDA; and (iii) there is a systematic process to reduce bias in the definition of the outcomes or patient concerns for the PDA. The ratings and qualitative feedback led to the removal of step 5 in the round 2 survey. Lastly, participants suggested adding examples to clarify many of the criteria in each step of Phase 1. We added the following example for the first criteria in step 1: ‘3.3.2Between 86% and 100% of participants rated the ten criteria in Phase 1 as desirable or essential.Based on qualitative feedback, the criteria in step 3 (‘Assemble the team’) should include a larger stakeholder group to ensure multiple voices prevent the development of a biased PDA. General comments in step 4 (‘Manage conflicts of interest’) explained how PDAs should report a clear, succinct conflict of interest statement. For research teams that develop a suite of PDAs, it may be more practical to have a blanket conflict of interest statement or have the statement be available upon request from the authors. Participants also suggested merging the five criteria in step 4, so that it reads: ‘collect, manage, monitor, and report conflicts of interest’ to avoid repetition.3.43.4.1For example, you may use The Cochrane Risk of Bias Tool.Between 79% and 94% of participants rated the 12 criteria in Phase 2 as desirable or essential. The majority of the participant qualitative feedback focused on rewording the criteria in steps 1 and 2 to be more concise. The five criteria in step 3 (‘Appraise the evidence’) were considered redundant and, based on feedback, were merged into two criteria for the round 2 survey: (a) critically appraise for risk of bias at study level, and (b) critically appraise quality or certainty of the body of evidence. Examples, where suggested by participants, were inserted to help clarify criteria. For instance, participants wanted an example of how to account for risk of bias in study design, so we added the following to the second criteria in step 7: 3.4.2Between 86% and 100% of participants rated the nine criteria in Phase 2 as desirable or essential. To avoid redundancy, participants suggested merging two of the criteria in step 2 so that it reads: ‘Systematically select evidence about benefits and harms of each option’. Overall, the qualitative feedback indicated that participants wanted more detail on the hierarchy, grading and sources of evidence. Evidence embedded in PDAs should be derived from systematic reviews. GRADE should be followed to rate the quality of evidence as determined by systematic reviews. The certainty or quality of the evidence should also be critically appraised. Grey literature and social media sources should be avoided unless patient‐relevant harms and benefits and concerns are not sufficiently covered in biomedical databases of published literature.3.53.5.1For example, the IPDAS chapter on communicating evidence may be used.Between 74% and 98% of participants rated the 14 criteria in Phase 3 as desirable or essential. The majority of the qualitative comments focused on the redundancy of the criteria in this phase. We therefore reworded the first four criteria in step 1 to be more concise, and we removed the last two criteria for the round 2 survey to avoid redundancy. Furthermore, the three criteria in step 2 (‘Manage COI’) were considered by participants to be too similar to the criteria in step 3 of Phase 1, so we removed them for the round 2 survey. Based on participant feedback, two of the four criteria in step 3 (‘Report’) were removed to avoid redundancy, and the remaining criteria were reworded for the round 2 survey: (a) report the methods used to represent the evidence, and (b) report the evidence summarization process publicly and in a way that is easy to understand. Examples, where suggested by participants, were inserted to help clarify criteria. For instance, participants wanted some guidance on how to present evidence in a way that is easy to understand, so we provided an example in the third criteria of step 8: 3.5.2how to present risk information in a balanced fashion considering the difficulty of this task. PDAs should use absolute risks instead of relative risks. Also, participants sought more detail on the external group in step 3. The criteria should be explicit on the make‐up of the external group, which should include patients to assess how to best present the evidence.Between 84% and 96% of participants rated the seven criteria in Phase 3 as desirable or essential. Based on qualitative feedback, participants wanted more information in step 1 on 3.63.6.1Update the evidence’ and the criterion was reworded for the round 2 survey so that it reads: ‘specify process for updates when new evidence becomes available’. Participants suggested that we add an example to the final step and criteria to clarify what is meant by ‘updating the evidence’. We added the following: For example, the evidence will be updated every year or whenever new relevant evidence is published.Step 1 (‘Update’) had one criterion that was rated desirable or essential by 90% of participants: the PDA content is updated when new evidence becomes available. Based on qualitative feedback, the step 1 title was reworded to ‘3.6.2when and who updates the evidence. Relatedly, to increase feasibility, participants felt that a benchmark should be established to update the evidence of PDAs (eg updates are required every three years). Participants also suggested including publication dates on PDAs.The criterion was rated as desirable or essential by 90% of participants. Qualitative feedback indicated that participants were concerned about the practicality of updating the PDA every time new evidence becomes available. Updating the evidence is a time‐ and resource‐intensive process that requires funding. Guidelines should also be developed to identify 3.7Overall, the process for selecting and summarizing evidence for PDAs went from five phases consisting of 13 steps and 48 criteria (Round 1) to four phases consisting of 11 steps and 31 criteria Round 2). Oversight at the beginning of the Delphi process led to the omission of a criterion about the systematic search for the evidence about the effects on the outcomes for each option in the PDA. This oversight was only realized after the completion of the second round of the Delphi survey. At the conclusion of the Delphi process, this criterion was added based on unanimous consensus by the steering group members. An editorial process was undertaken by the steering group to summarize the evidence summarization process for an external audience. The brief, easy‐to‐read summary is presented in Table . Oversig44.1Based on two rounds of a modified Delphi survey, we have developed a process for selecting and summarizing evidence for PDAs that now consists of four phases, 11 steps and 31 criteria. Based on the stakeholders’ feedback, the number of steps was reduced from 13 to 11, and the criteria from 48 to 31 by merging or deleting redundant criteria. The qualitative feedback also informed the rewording of criteria and the addition of examples to improve the clarity of the process for PDA developers. The final 31 criteria were rated as desirable or essential by 84% to 100% of participants.4.2Our use of the Delphi method to obtain feedback from a multidisciplinary stakeholder group to develop the PDA evidence summarization process is a strength, and the use of this method is supported when evidence is weak or uncertain. There is a dearth of empirical evidence for an evidence summarization process specific to PDA development. This group included patients in each round of the Delphi survey, ensuring that the patient perspective is included in the evidence summarization process. We believe that a major strength of our evidence summarization process is that it encourages the involvement of patients throughout the process and can be used to develop tools for all patient populations, including those who are underrepresented. In terms of limitations, the high attrition rate in the Round 1 survey decreased the size of our sample and may have led to a non‐response bias. Also, we do not know the total number of participants invited to the Round 1 survey because we are unable to determine the total number of potential participants from each listserv. The consistent ‘desirable or essential’ ratings suggest a ceiling effect, which could be reduced in future Delphi studies by substituting a 4‐point scale with a 5‐point scale that includes 3 positive and 2 negative choices.4.3et al, further guidance is needed on how to present evidence, and how to communicate the uncertainty of evidence.Our study addresses a significant gap in PDA development guidance by presenting the first process for selecting, summarizing and reporting evidence in PDAs. Prior to the development of this process, the following five items in the IPDAS checklist were the only source of guidance for the selection and summarization of evidence to be included within PDAs: the PDA provides citations to the studies selected, describes how research evidence was selected or synthesized, provides a production or publication date, provides information about the proposed update policy, and describes the quality of the research evidence used.4.4Without a transparent and articulated process for summarizing and presenting evidence, PDAs may not contain an accurate and up‐to‐date summary of the appropriate evidence or present information about evidence quality and certainty. This has implications on the decision‐making process, as the evidence that is included in PDAs can influence the decisions that patients make. Having a process in place may help address frequent concerns from clinicians that important information is missing from PDAs and that numerical data are poorly presented.5Ratings and qualitative feedback from over 100 multidisciplinary stakeholders across 28 countries in two Delphi survey rounds led to the development of a set of criteria for selecting, summarizing, reporting and updating evidence in PDAs. PDAs are promoted as tools that provide evidence‐based, trustworthy information. Widespread adherence to the proposed criteria will help ensure that these tools fulfil that promise.Shared Decision Making (Oxford University Press) and Groups (Radcliffe Press). Dr Elwyn's academic interests are focused on shared decision making and coproduction. He owns copyright in measures of shared decision making and care integration, namely collaboRATE and integRATE (measure of care integration), consideRATE (patient experience of care in serious illness), coopeRATE , toleRATE (clinician attitude to shared decision making), and Observer OPTION‐5 and Observer OPTION‐12 (observer measures of shared decision making). He has in the past provided consultancy for organizations, including the following: (a) Emmi Solutions, LLC who developed patient decision support tools; (b) National Quality Forum on the certification of decision support tools; (c) Washington State Health Department on the certification of decision support tools; and (d) SciMentum LLC, Amsterdam (workshops for shared decision making). He is the founder and director of &think LLC, which owns the registered trademark for Option Grids™ patient decision aids; and founder and director of SHARP NETWORK LLC, a provider of training for shared decision making. He provides advice in the domain of shared decision making and patient decision aids to: (a) Access Community Health Network, Chicago ; (b) EBSCO Health for Option Grids TM patient decision aids (Consultant); (c) Bind On‐Demand Health Insurance (Consultant), (d) PatientWisdom, Inc (Adviser); and (e) Abridge AI Inc . Marie‐Anne Durand receives consulting income from EBSCO Health and may receive royalties in the future. She was also a consultant for ACCESS Community Health Network until 2019. All other authors have no conflicts of interest to declare.Professor Glyn Elwyn has edited and published books that provide royalties on sales by the publishers: the books include CHS, MD, AMCG, BSA, TH, LPP, MAD and GE initiated the study. CHS, MD and PS created the surveys and facilitated recruitment. PS analysed the data and wrote the first draft of the manuscript. All authors contributed to the writing of the manuscript and approved the final version.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.Appendix S3Click here for additional data file.Appendix S4Click here for additional data file.Appendix S5Click here for additional data file.


Tetragenococcus (40.65%), Lentibacillus (9.23%), Vagococcus (2.20%), Psychrobacter (1.80%), Pseudomonas (0.98%), Halomonas (0.94%) and Staphylococcus (0.16%) were the dominant microflora in fish sauce. The content of BAs gradually increased as the fermentation progressed. After 12 months of fermentation, the histamine content (55.59 mg/kg) exceeded the toxic dose recommended by the Food and Drug Administration (FDA). Correlation analysis showed that dominant microorganisms have a great contribution to the accumulation of BAs. By analyzing the BA production capacity of dominant isolates, the accumulation of BAs in fish sauce might be promoted by Tetragenococcus and Halomonas. Moreover, four strains with high BA reduction ability were screened out of 44 low BA-producing dominant strains, and their influence on BA accumulation in fermented foods was determined. Results demonstrated that Staphylococcus nepalensis 5-5 and Staphylococcus xylosus JCM 2418 might be the potential starters for BA control. The present study provided a new idea for the control of BAs in fermented foods.In this study, high-throughput sequencing and culture-dependent and HPLC methods were used to investigate the contribution and regulation of biogenic amines (BAs) by dominant microorganisms during fish sauce fermentation. The results showed that the microbial composition constantly changed with the fermentation of fish sauce.  Fish sauce, a seasoning with a unique flavor, is spontaneously fermented from anchovies and salt in a certain proportion, and the fermentation time was more than 6 months ,2. Fish BAs are small molecule nitrogen-containing compounds which are formed by the decarboxylation or transamination of amino acids by microorganisms . AlthougS. xylosus NO.0538 was 16.0% lower than that in the control group. From this perspective, evaluating bacterial BA production and reduction ability is critical in understanding the BAs accumulation mechanism. Therefore, compared with previous studies, our study not only analyzed the role of microorganisms in BA accumulation, but also identified the strains that can reduce BAs on this basis, which were successfully applied to fish sauce and other fermented foods.The microbial community in naturally fermented fish sauce is complex, but it is a significant factor in determining product quality and safety . TherefoThe fish sauce factories in northern China are concentrated in Shandong, and the fish sauce factory that provided samples for us is the largest factory in Shandong, with a complete and representative fermentation process. In this study, the fish sauce samples at different fermentation stages from Rongcheng  were characterized by BAs assays, high-throughput sequencing analysis of bacterial diversity and cultural isolation of dominant bacteria. The microbial community information was used to clarify the contribution of microorganisms to the accumulation of BAs. Candidate starters isolated from fish sauce to control BA accumulation were screened. This research provides new ideas for improving the quality of fish sauce and reducing the risk of eating fish sauce.The fish sauce samples were collected from the Rongcheng Baozhiyuan fish sauce factory . Fish sauce is made by the natural fermentation of anchovies and salt at a ratio of 7:3 for more than 12 months . The ann600 = 0.4) was inoculated into the above-mentioned fermented foods (50 g) with an inoculum of 5% (v/v), and the fermentation was continued for 7 days at 37 °C. The control group was inoculated with 5% (v/v) sterilized water in different fermented foods. All experiments were performed in triplicate.Fish sauce samples fermented for 9 months and shrimp paste, Doujiang and Sufu, purchased at the market, were selected as the raw materials to determine the effect of strains on the accumulation of BAs in different fermented foods. The isolated strain  according to the manufacturer’s instructions, and was run on the Miseq Illumina platform at Majorbio Bio-Pharm Technology Co., Ltd.  [To further analyze the changes in microbial composition in the fish sauce during fermentation, the fish sauce samples were subjected to high-throughput sequencing analysis. Primer pairs 338F and 806R were used to amplify the hypervariable V3–V4 region of bacterial , China) .v/v) was added to 10 g fish sauce sample, and the mixture was shaken at 37 °C at 150 rpm for 30 min. The mixtures were serially diluted (10−1 to 10−5) with the sterile normal saline, and 100 µL of each dilution was plated onto the above medium. The single colony was isolated and purified on the corresponding medium at least 4 times to obtain the pure isolates. For the identification of bacteria, the Gen-EluteTM Kit  was used to extract the genomic DNA of the bacteria. The bacterial 16S rDNA gene was amplified with the universal primer pairs 27F and 1492R. The PCR programswere carried out as follows: pre-denaturation at 94 °C for 5 min, followed by 30 cycles at 94 °C for 30 s, 56 °C for 30 s, 72 °C for 1 min and elongation at 72 °C for 10 min. The amplified fragments were then sent to sequencing . The pure isolates were stored at −80 °C in the corresponding liquid culture medium containing 32% (v/v) glycerin [Luria-Bertani (LB) medium with 15% NaCl, de Man Rogosa and Sharp (MRS) medium with 15% NaCl and Plate Count Agar are the main media used in this study. A total of 90 mL of sterile normal saline , and derivating agent ) were purchased from Sangon Biotech  and Meilun biotech .3, and 800 μL dansyl chloride solution (10 mg/mL in acetone) to 400 μL pretreated sample. The mixtures were incubated in water at 45 °C for 40 min. A total of 550 uL of acetonitrile was added to the mixture to dissolve the residue and then the mixture was centrifuged at 3000× g for 5 min at 4 °C. The supernatant was filtered through the 0.22 filter for three times. The quantification of BA was carried out using a Huapu S6000 HPLC unit  which consisted of an ACCHROM Tnature C18 (4.6 × 250 mm) column coupled to a quaternary pump and a diode array detector. Two elution solutions are (A) ultrapure water and (B) acetonitrile. A 10 µL sample was injected into the column at a flow rate of 1.0 mL/min. The gradient elution program was carried out as follows: 0–10 min, 45% A; 10–15 min, 35–45% A; 15–20 min, 20–35% A; 20–25 min, 20% A; 25–30 min, 10–20% A; 30–33 min, 10% A; 33–35 min, 10–45% A; 35–40 min, 45% A. During analysis, the column temperature was lower than 35 °C, and the absorbance was monitored with a UV detector at 254 nm. Each BA was quantified with a calibration curve generated by analyzing standard BA mixed solution. The experiment was carried out in triplicate.The BA content in each sample was assessed according to the method developed by Sang et al. . In detag for 10 min at 4 °C. An equal volume of 10% TCA was used to extract the remaining BA in the supernatant again. The obtained mixture was centrifuged at 3000× g for 10 min at 4 °C. The BA in the samples was determined according to the method described in After adding 20 mL of 10% trichloroacetic acid (TCA)  to 5 g of sample to extract biogenic amines, the mixture was left at 4 °C for 2 h. The mixture was centrifuged at 8000× w/v) histidine, tyrosine, ornithine hydrochloride and lysine . The BA concentrations after 48 h of incubation were determined to evaluate the BA production ability of the strains. The strain was incubated at 37 °C for 12–24 h and then centrifuged at 6000× g for 5 min to collect bacterial pellets. The bacterial pellets were washed twice with 0.05 mol/L phosphate buffer , and then centrifuged at 6000× g for 5 min. We added 0.05 mol/L PBS containing putrescine, cadaverine and histamine (100 mg/L) to the bacterial pellet until the OD600 of the mixture reached 0.4. The mixture was then cultured at 37 ◦C for 48 h and the residual BAs in the suspension were determined. Sterile PBS  was used as a control. The BA reduction efficiency was calculated as:The strains were cultured in a 5 mL medium containing 0.5% . For the data of high-throughput sequencing, raw data were quality-filtered by Fastp (version 0.20.0). Operational taxonomic units (OTUs) were clustered with 97% similarity cutoff using Uparse (version 7.1) . The taxonomy of each 16S rRNA gene sequence was analyzed by RDP Classifier (version 2.2) algorithm  against the Silva 128/16s_bacteria, using a confidence threshold of 0.7.The statistical software SPSS 26 was used to analyze the significance of the difference by one-way ANOVA method. The high-throughput sequencing analysis was performed using the free online platform of the Majorbio I-Sanger Cloud Platform  database (Accession Number: SRR15851749).The content of BA in fish sauce samples at different fermentation stages was shown in Firmicutes predominated during the entire fermentation, particularly in 18-month samples with up to 94.29% of the total sequences. The species abundance of Cyanobacteria was high during the process from 3 months to 12 months of fermentation, especially in 12-month samples (21.10%), while after 18 months of fermentation, the abundance of Cyanobacteria dropped sharply to 0.01%. Proteobacteria and Actinobacter rose rapidly between 3 and 12 months of fermentation, and the abundance reached 19.14% and 15.13%, respectively. The abundance of these two phyla decreased significantly after fermentation to 18 months. (Lentibacillus (approximately 45.90%) was the most dominant bacteria in the early phase of fish sauce fermentation. Then, Tetragenococcus (9.15–45.78%) rapidly replaced Lentibacillus as the dominant genus at the 6th month of fermentation. In the 18th month of fermentation, Tetragenococcus became the most dominant bacteria (approximately 91.99%), and Halomonas became the second most dominant genus with an abundance of 2.74%. The genus Pseudomonas appeared as the dominant genus during the late fermentation period (9–18 month), especially in the 12-month samples, and the abundance reached 3.69%  was used to qualitatively examine the differences in bacterial composition, and the results showed the clear cluster pattern of the five samples, and the microbiological composition of samples fermented for 6 months was more similar to that at 9 months A. ANOSIMectively C.Tetragenococcus and Lentibacillus had the strongest correlation with BAs. Tetragenococcus is positively correlated with BAs, while Lentibacillus is negatively correlated with BAs. The correlation network analysis between species and BAs shows that most genera were negatively related to BAs. However, some bacterial genera still exhibited as being positively related to BAs  analysis among BAs, fermentation time and dominant microorganisms are shown in d to BAs B. For exwith BAs C.Tetragenococcus strains, 45.83% Staphylococcus strains, 33.33% Lentibacilluis strains and all strains of Psychrobacter and Pseudomonas had a high ability to produce BAs. These strains may be the main factor causing the large accumulation of BAs in fish sauce. The analysis of the correlation between dominant bacteria with BAs and the determination of BA production ability of the dominant isolates showed that Tetragenococcus, Lentibacillus, Psychrobacter, Pseudomonas and Staphylococcus and other bacteria had a regulatory effect on the accumulation of BAs in fish sauce fermentation. For example, Tetragenococcus positively regulated BAs and promoted the accumulation of BAs, while Lentibacillus negatively regulated BAs and inhibited the accumulation of BAs.In order to better illustrate the role of dominant bacteria on the accumulation of BAs, we evaluated the ability of producing the BAs of 100 dominant strains isolated from fish sauce . A totalS. nepalensis, had the best ability to reduce BAs. The reduction efficiencies of S. nepalensis 5-5 on putrescine, cadaverine and histamine were significantly higher than other strains, which were 17.64%, 19.80% and 16.77%, respectively. The isolated Lentibacillus strains also showed a high ability to reduce BAs. The ability to reduce the histamine of Lentibacillus salicamp SF-20 was higher than that of Lentibacillus amyloliquefaciens LAM0015. Tetragenococcus halophilus NBRC 12172 and Tetragenococcus muriaticus LMG 18498 had a low ability to reduce BAs, especially histamine. Strains with high BA reduction ability can be used as candidates for reducing BAs in fermented foods.Due to the regulation of microbes on the accumulation of BAs, it is feasible to select microorganisms to reduce the content of BAs in fish sauce. Therefore, eight strains with the lowest BA production capacity  were screened from the genera and their BA reduction ability was determined . StaphylS. nepalensis 5-5, S. xylosus JCM 2418, S. hominis ICC_10-1_SCI_contig_1 and L. salicampi SF-20 might be potential candidates for controlling the BAs due to their high BA reduction ability as well as low BA production activity. In order to ascertain the BA reduction ability of the strains in the food matrix, we inoculated the strains into different fermented foods and determined the BA content in the samples after 7 days of continuous fermentation. All four strains can reduce the BAs in fish sauce, and S. nepalensis 5-5 and S. xylosus JCM 2418 especially showed the best BA reduction ability. In the shrimp paste, only S. nepalensis 5-5 and S. xylosus JCM 2418 can reduce the BAs, while the remaining strains increase the BA content. S. xylosus JCM 2418 has the highest reducing ability on HIS in Doujiang, while S. hominis ICC_10-1_SCI_contig_1 and L. salicampi SF-20 increased the content of HIS in Doujiang. S. nepalensis 5-5 had the best BA reduction ability in Sufu among all the strains . Therefore, it might be a key genus that determines the quality and safety of the final products. Tetragenococcus exhibits certain halotolerant characteristics and plays a major role in sauce flavor [Tetragenococcus halophilus MJ4 clearly repressed the formation of cadaverine during fermentation to improve the safety of fish sauce products [Tetragenococcus had a high BAs production ability, which had a great effect on the accumulation of BAs in sausage, shrimp paste, etc. [Staphylococcus, also played an important role in the quality and safety of fish sauce products, which is often used as a starter in fermented foods and can be used to control BAs during food fermentation [There are differences in the representative bacterial genera in the samples at different fermentation stages C. Lentibsh sauce . Psychroompounds . Howeverduce HIS . Pseudomduce BAs . Tetragee flavor . In addiproducts . Howeverte, etc. ,29. SomeLentibacillus and Psychrobacter, were negatively correlated with BAs, suggesting the BA accumulation might be inhibited by Lentibacillus and Psychrobacter during this period. As the microbial composition of the samples fermented for 6 months was similar to that of 9 months, BA accumulation was also low during the fermentation of fish sauce from 6 to 9 months. Pseudomonas, positively related to BAs, was a representative microorganism in fish sauce samples fermented for 12 months. During the fermentation period of 9–12 months, the content of BAs in fish sauce increased greatly, indicating that Pseudomonas might be promote the accumulation of BAs. Tetragenococcus was dominant during the whole fermentation process, and it was significantly positively correlated with BAs, indicating that Tetragenococcus might play a key role in the accumulation of BAs , putrescine (43.0%), tyramine (42.8%), and histamine (42.6%) content. Therefore, it is feasible to select suitable starters to reduce the accumulation of biogenic amines during the fermentation of fish sauce.To verify the results of the correlation analysis, we tested the BA production capacity of the isolated dominant strains . The BA ifferent . In addiifferent  demonstrifferent  used LacStaphylococcus strains, two Lentibacillus strains and two Tetragenococcus strains, and their BA reduction abilities were evaluated (Staphylococcus and Lentibacillus isolates showed high BA reduction ability. The results show that microbial-based solutions can be designed to reduce the BA content in fermented foods [Staphylococcus is often used as a starter to reduce BAs in fermented foods. For example, Muhammad et al. [Staphylococcus carnosus FS19 and could also reduce other amines during fermentation. Li et al.’s [Staphylococcus isolates including Staphylococcus pasteuri, Staphylococcus epidermidis, Staphylococcus carnosus, and Staphylococcus simulans could significantly reduce BAs and have the potential to control BAs in fermented meat products. Lentibacillus is a common genus of bacteria in fish sauce [S. nepalensis 5-5 and S. xylosus JCM 2418 were significantly reduced, indicating that the two strains could be utilized as potential candidates for controlling BAs in fermented foods.About 44.00% of the dominant strains in this study produce very little Bas; therefore, they may have BA reduction ability and potential as fish sauce starter cultures. Eight isolated strains were selected from the dominant species of fish sauce samples, including four valuated . Among ted foods . In prevd et al.  found thet al.’s  study shsh sauce . Thus, tTetragenococcus, Lentibacillus, Pseudomonas, Halomonas, Vagococcus and Staphylococcus by high-throughput sequencing. The correlation analysis between microorganisms and BAs indicated that Tetragenococcus, Halomonas and Pseudomonas were positively correlated with BAs, while Lentibacillus, Vagococcus and Staphylococcus were negatively correlated with BAs. By analyzing the BA production capacity of dominant isolates, the accumulation of BAs in fish sauce might be promoted by Tetragenococcus and Halomonas. Additionally, S. nepalensis 5-5 and S. xylosus JCM 2418 isolated from fish sauce were applied as starters to fish sauce and other fermented foods for reducing health risk. Our research assessed the BA reducing application of S. nepalensis 5-5 and S. xylosus JCM 2418 during fish sauce fermentation for the first time, and provided a theory to support the standardized and secure production of fish sauce.In summary, the bacterial community structure and BA profiles in fish sauce at different fermentation stages were comprehensively evaluated. The dominant bacteria of fish sauce were found to be


Частая сочетаемость сахарного диабета 2-го типа (СД2) и хронической обструктивной болезни легких (ХОБЛ) — социально значимая и далеко не изученная проблема. Однако ей посвящены лишь единичные работы. Для решения данной проблемы нами были проанализированы возможные патогенетические механизмы с позиции воздействия на гомеостаз глюкозы основных гормонов — инсулярных и контринсулярных. В настоящей работе внимание в этом плане больше сосредоточено на роли контринсулярных гормонов.Анализ проводился путем использования различных баз литературных данных, включая Index Medicus, Scopus, Pub Med, Embase, Кокрейна и другие, преимущественно за период 2000–2020 гг. Работы, посвященные непосредственно рассматриваемому аспекту, были опубликованы в основном в течение последних 5 лет.В результате анализа выявлено взаимоотягощающее влияние ХОБЛ и СД2 в случае сочетанного их протекания, в котором инициирующая роль принадлежит ХОБЛ. Также при этом выявлена значительная роль контринсулярных гормонов, во многом определяющая характер патогенеза СД2 при ХОБЛ. Кроме того, в статье обращается внимание на возможную роль генетических факторов, которые могут быть общими для ХОБЛ и СД2 и иметь немалое значение в коморбидности ХОБЛ и СД2. Полученные данные могут быть использованы как в диагностических, так и в терапевтических целях при коррекции нарушений углеводного обмена при ХОБЛ, что является уделом дальнейших исследований. Если рассматривать гормональную систему регуляции гомеостаза при хронической обструктивной болезни легких (ХОБЛ) как состоящую из двух групп гормонов — инсулярных и контринсулярных, то можно отметить, что в этом плане исследования посвящены главным образом проблеме состояния инсулярного аппарата поджелудочной железы [1–4]. В настоящей работе внимание будет акцентировано в основном на роли контринсулярных гормонов (КИГ) в гомеостазе глюкозы и в патогенезе сахарного диабета 2 типа (СД2) при ХОБЛ. Роль КИГ с позиции пульмонологии исследована фрагментарно и отражена лишь в единичных работах, а имеющиеся данные противоречивы. При этом предполагается, что они играют далеко не последнюю роль, если учесть то, что гиперпродукция КИГ, как это наблюдается при ряде эндокринопатий, способствует повышению сахара в крови и развитию сахарного диабета [5–9]. Выраженная гипергликемия, особенно в условиях нарушения так называемой «пластичности» β-клеток (способности их массы адаптироваться к потребностям организма в инсулине), неблагоприятно воздействует на инсулярный аппарат, еще больше подавляя выработку инсулина . Таким оДействие КИГ противоположно таковому инсулина. Их выработка является защитной реакцией на низкий уровень глюкозы в крови, что позволяет поддерживать его в нормальных пределах. Наряду с гормонами с эффектом явной контринсулярной направленности существуют гормоны, которые при определенных условиях обладают подобным эффектом, в частности андрогены, к которым относят тестостерон. КИГ всего несколько, и их основные биологические эффекты, наряду с упомянутыми андрогенами, представлены в При действии КИГ происходит активизация ферментов, способствующих снижению функциональной активности инсулина и его содержания, а также увеличению процессов инсулинорезистентности тканей и органов-мишеней. Избыточное образование КИГ обеспечивает торможение гликогенеза, активацию гликогенолиза, липолиза в жировых депо, а увеличение количества таких КИГ, как глюкокортикоиды и тироксин, вызывает активацию протеолиза в тканях и глюконеогенеза в печени .На экспериментальных моделях, а затем и клинически была показана значимость КИГ в развитии нарушений углеводного обмена, механизмы которых могут быть причастны и к СД2 . Все этиИнсулинорезистентность (ИР), развивающаяся в результате вышеуказанных факторов и являющаяся ведущим патогенетическим механизмом нарушений углеводного обмена при ХОБЛ, и неадекватная секреция инсулина могут усиливать друг друга. В результате компенсаторной гиперинсулинемии возрастают ИР и потребность в выработке инсулина, что ведет к развитию гипергликемии. Гипергликемия приводит к окислительному стрессу, вызванному аутоокислением глюкозы, и вызывает повреждения фосфолипидного слоя плазматических мембран бета-клеток и тканей-мишеней. Это способствует прогрессированию ИР, секреторные возможности инсулярного аппарата снижаются из-за апоптоза бета-клеток . Таким оБыло показано, что ХОБЛ является фактором риска СД2. Согласно современным представлениям, ХОБЛ является системным заболеванием, вовлекающим в патологический процесс многие органы и системы. В его основе лежат такие факторы, как хронический воспалительный процесс, не только касающийся респираторного тракта, но и имеющий системный характер, а также гипоксемия, курение, малоподвижный образ жизни и др. Однако они являются и причиной развития СД2. Именно эта общность в патогенезе указанных заболеваний и характер причинно-следственной связи и легли в основу нашей гипотезы о том, что ХОБЛ является фактором риска СД2. При этом данный фактор встречался с высокой достоверностью чаще у больных ХОБЛ р<0,001), чем в популяции, тогда как в когорте больных СД2 показатели распространенности ХОБЛ не превышали контрольных значений . На данн, чем в пЦелый ряд работ подтверждает гипотезу о наличии тесной взаимосвязи ХОБЛ и СД2 и их патогенетических механизмов. Связь между этими двумя болезнями сложна, многофакторна и не всегда понятна, но ее изучение и раскрытие могут оказать положительное влияние на подход к лечению этих высокозначимых социальных заболеваний. Понимание сути их частого совместного протекания важно для совершенствования и разработки новых методов диагностики и терапевтических подходов к этим заболеваниям . В частнСД2, по различным оценкам, поражает 2–37% пациентов с ХОБЛ. Компенсация СД2 также может коррелировать с качеством жизни и функцией внешнего дыхания (ФВД). Для изучения этой корреляции у больных, поступивших в стационар с обострением ХОБЛ, Mekov E.V. и соавт. (2016)  провели Для оценки распространенности сопутствующих заболеваний у пациентов был проведен метаанализ 11 исследований, включавших 47 695 183 пациента с ХОБЛ и 47 924  876 пациентов без ХОБЛ. Средний возраст пациентов с ХОБЛ составил 66,66±8,72 года, 55,4±11,9% пациентов составляли мужчины. Распространенность СД2 (отношение шансов (ОШ) 1,22; 95% ДИ 1,07–1,38; р=0,003) оказалась значительно выше у пациентов с ХОБЛ, чем в контрольной группе . ОцениваС целью изучения связи ХОБЛ с риском развития СД2 Rasmussen S.M. и соавт. (2018)  были проЛегочная гипертензия (ЛГ) является распространенным осложнением ХОБЛ. Недавние исследования показали, что СД2 является плохим прогностическим фактором у пациентов с ХОБЛ, однако связь между СД2 и ЛГ при хронических респираторных заболеваниях остается неясной. Takahashi T. и соавт. (2018)  попыталиКроме мнения, подтверждающего роль хронического воспаления, гипоксии и других факторов, присущих как для ХОБЛ, так и для СД2, выдвинуто предположение, что связь между СД2 и ХОБЛ в немалой степени может быть объяснена наличием общих генетических факторов. Это соотносится с информацией о том, что ХОБЛ — одна из главных причин заболеваемости и смертности в мире и связана с некоторыми системными заболеваниями, например, СД2. В 2015 г. Meteran H. и соавт. провели исследование, целью которого стало изучить связи между СД2 и ХОБЛ у близнецов во взрослом возрасте и определить, насколько сопутствующая патология между этими заболеваниями связана с общими факторами генетики или экологии . Были соОтраженный выше анализ свидетельствует о несомненном взаимоотягощающем влиянии ХОБЛ и СД2. При этом с позиции первичности, учитывая данные, полученные нами ранее, мы все же больше склоняемся к мнению о том, что имеет место не случайное сочетание протекания во времени СД2 и ХОБЛ, а коморбидность, инициатором, причинным фактором в которой выступает ХОБЛ. И это не противоречит пониманию, отраженному выше.Однако надо отметить, что хотя СД2 является распространенной сопутствующей патологией у пациентов с ХОБЛ, все еще остаются вопросы относительно связи между этими заболеваниями. Rogliani P. и соавт. (2014) ретроспективно оценили данные пациентов, страдающих ХОБЛ, в период между 2010 и 2012 гг. . ИсследуРоль КИГ в гомеостазе глюкозы и развитии гипергликемии информативно прослеживается на фоне синдрома гиперметаболизма при критических состояниях у лиц без диабета, когда имеет место повышение уровня КИГ 31–33]. Было показано, что в механизмы, лежащие в основе развития гипергликемии, входит выброс катехоламинов, кортикостероидов и медиаторов, участвующих в процессах воспаления. У таких больных гипергликемия может быть вызвана и ятрогенными причинами  . Было по. Таким оСреди КИГ определенную значимость представляют и гормоны щитовидной железы и коры надпочечников. Это необходимые и взаимосвязанные общеадаптационные элементы организма, чем и вызвана целесообразность их одновременного изучения. Существует не очень много данных о гормонах коры надпочечников в крови при ХОБЛ, и они весьма противоречивы.Кортизол и альдостерон — основные и наиболее изученные гормоны коры надпочечников. Результаты исследований, которые носят единичный характер, чаще свидетельствуют об их росте при ХОБЛ 35–38]. При этом в одной из работ при статистически недостоверном повышении уровня кортизола зафиксирована его прямая корреляция с интенсивностью кашля, лейкоцитозом и лейкоцитарным индексом интоксикации и обратная связь с ИМТ . При это. Что касОпределенный интерес с позиции инсулярного/контринсулярного действия могут представлять андрогены, возможные колебания исходного уровня которых в результате могут иметь некоторые гендерные отличия. Так, у мужчин дефицит андрогенов, в частности тестостерона, характеризуется проинсулярным действием, так как он предрасполагает к метаболическому синдрому и СД2. У женщин к нарушениям углеводного обмена могут приводить гиперандрогенные состояния, такие, например, как синдром поликистозных яичников. Они связаны с ИР, непереносимостью глюкозы и последующим развитием СД2 . То естьЗа последние годы установлено, что дефицит тестостерона, коррелируя с увеличением ИР, более высокими уровнями триглицеридов и наличием гипертонии, связан с различными компонентами метаболического синдрома. Этот синдром сопряжен с риском развития сердечно-сосудистых заболеваний, являющихся основной причиной летальности при СД2. Заместительная терапия тестостероном у пациентов с дефицитом тестостерона и СД2 и/или метаболическим синдромом показала снижение резистентности к инсулину, общего холестерина, холестерина липопротеинов низкой плотности и триглицеридов и улучшение гликемического контроля . СравнитИмеются сведения о снижении выработки другого андрогена — дегидроэпиандростерона сульфата (ДГЭАС) при ХОБЛ, вырабатываемого в основном корой надпочечников и лишь в 8–10% гонадами. Также отражается взаимосвязь его уровня в крови с клиническими особенностями заболевания, показателями обструкции дыхательных путей, гипоксемией и гиперкапнией, фазой обострения, ремиссией и тяжестью заболевания 47–50]. У больных ХОБЛ установлено понижение уровня ДГЭАС в крови и, наоборот, повышение уровня альдостерона и кортизола. Эти процессы связываются с обострениями и тяжестью заболевания. Также исследователи выяснили, что существует обратная связь содержания ДГЭАС с длительностью заболевания, стадией ХОБЛ, клинической картиной [. У больнтесты функции щитовидной железы у пациентов с ХОБЛ показали значительное увеличение средних значений FТ3 [Примечателен факт снижения ДГЭАС у больных ХОБЛ, выявленный в аспекте исследования биологического старения у них . Он являений FТ3 . По мереений FТ3 .Таким образом, неразрывная функциональная связь КИГ с инсулином, обеспечивающая гомеостаз глюкозы, и значительная патогенетическая связь ХОБЛ и нарушений углеводного обмена, в которой инициирующую роль играет ХОБЛ, что мы проиллюстрировали в упрощенной схеме , предполПри этом можно подчеркнуть, что изменение уровня КИГ влияет на одно из ключевых звеньев «порочного круга» в патогенезе данной коморбидности, в частности на оксидативный стресс, усугубляя его. Именно это звено во многом является узловым, сопровождая длительное системное воспаление при ХОБЛ, обусловливая развитие ИР и гипергликемии, на фоне которой повреждаются бета-клетки, и процесс, прогрессируя, способствует развитию СД2 или усугубляет течение уже имеющегося патологического процесса.Анализ литературы свидетельствует, что КИГ играют весьма заметную роль в развитии СД2 при ХОБЛ, воздействуя и усугубляя его ведущие патогенетические звенья, являющиеся во многом общими для этих социально значимых заболеваний. Однако, несмотря на потенциальную важность КИГ в патогенезе СД2 при ХОБЛ, эти проблема остается неизученной. Имеются лишь ограниченные и противоречивые данные об уровне гормонов коры надпочечников, которые пока не представляют возможности их практического применения. Аналогичная картина касается данных по исследованию гормонов щитовидной железы у данного контингента больных. И интерпретация факта снижения в крови больных ХОБЛ Т3 встречает затруднения как в аспекте их интерпретации, так и использования. Некоторое понимание и практический интерес представляют результаты исследования андрогенов при коморбидности ХОБЛ и СД2, указывающие на связь СД2 и изменения уровня тестостерона в этом случае, что открывает определенные диагностические и лечебные перспективы. Но это требует еще уточнения и соответствующих разработок. Поэтому проблема роли КИГ в патогенезе СД2 при ХОБЛ, оставаясь малоизученной, является большим полем для деятельности ее исследователей. Все это не только нацеливает на изучение патогенеза коморбидности ХОБЛ и СД2 и расширение знаний в этом плане, но и составляет перспективы для совершенствования диагностики и терапевтического воздействия в плане коррекции нарушений углеводного обмена при ХОБЛ.