A suitable health literacy assessment instrument for patients with chronic pain (HLCP) in China with good instrument's psychometric properties is required. A theoretical framework for the HLCP was developed by adopting the hierarchical model of health literacy proposed by Nutbeam. The reliability and validity of the HLCP were tested in a cross-sectional survey of 237 chronic pain patients from three pain clinics and wards of Grade-3A hospitals in Zhejiang Province, China. The discriminant degree method, correlation analysis method, factor analysis method , half reliability, and other methods were utilized to screen items for inclusion in the final version of HLCP, and the fitness of the model was subsequently evaluated by confirmatory factor analysis. Cronbach's alpha value and test-retest with two-week intervals were used to test the internal consistency and retest reliability of the HLCP. In the exploratory factor analysis, three domains, functional health literacy (10 items), interactive health literacy (14 items), and critical health literacy (7 items), comprising 31 items in total, were finally loaded; the model was determined to explain 70.9% of the total variance. HLCP's effective assessment of the health literacy level of patients with chronic pain and its acceptable reliability and validity were revealed through the results. Chronic pain was declared a disease by the International Association for the Study of Pain in 2000 . In manyThe concept of health literacy was first proposed by Simonds in 1974 ; since tWith growing interest in health literacy, and as good health literacy is considered an important prerequisite to improve treatment outcomes of chronic pain, effective measurement of health literacy has become particularly important. Although there are many instruments that measure health literacy (both for China-based patients and patients in other countries) in the contexts of various common chronic diseases  –19, healThe theoretical framework used by the present study's authors to conceptualize the HLCP was based on Nutbeam's 2008) framework, which defines health literacy as comprising three dimensions: functional health literacy, interactive health literacy, and critical health literacy [08 framewBehavioral change in humans can be divided into three interrelated processes: acquiring knowledge, generating belief, and forming behavior; this aligns with the Knowledge-Attitude-Behavior theory by Professor Mayo, which comprises knowledge, attitude, and behavior, and is associated with using health literacy to change one's health behaviors . Jordan'The items for the assessment instrument were developed by creating an item pool that was based on expert guidance, the definition of chronic-pain-related health literacy, the Nutbeam health literacy model, KAB theory (and other theories), and by referring to the “pain management program” published by the British Pain Society in 2010 and the “CDC Guideline for Prescribing Opioids for Chronic Pain-United States” published by the Centers for Disease Control and Prevention in 2016 , 24. FirA group of experts was established, comprising five physicians specializing in pain, one head nurse of a pain department, two chief physicians, and two nursing professors. The inclusion criteria for this group were as follows: working in the field of pain medicine and health management for over 10 years, familiarity with providing health education to and communicating with patients, and holding an intermediate or higher professional title. Review, discussion, and analysis of the preliminary items were performed by the expert group.The content validity of the framework was evaluated through expert consultations based on the Delphi method. Nineteen experts  were invited to participate in two-round mail/e-mail consultations (from August to October 2020). They were asked to consider whether the chosen items represented actual situations encountered by patients with chronic pain and whether the items clearly described such situations. Several items were deleted or merged to create a list of 41 initial items based on expert recommendations and repeated discussions regarding the items among research team members. Of the original item pool, 40 items were modified to avoid ambiguity, 10 items were deemed irrelevant and removed, three new items were added, and the order of the individual items was adjusted. HLCP items are scored using a five-point Likert scale , and the total is determined by summing the scores for each item. The higher the score, the higher the health literacy level of the respondent.To determine the appropriate level of difficulty of the items, as well as their clarity and accuracy, a pre-test was performed, in which 15 patients with chronic pain were selected and administered the prototype instrument in the pain inpatient ward of a Hangzhou Grade-A hospital. The results showed that all patients could complete the questionnaire satisfactorily and could understand the meaning of each item. The average time for questionnaire completion was 10 minutes. The 41 items in this questionnaire were used to create the initial HLCP.To test the HLCP, 250 participants were aimed to be recruited between November 2020 and January 2021. According to the sample estimation method proposed by Kendall, the sample size is determined as 5 to 10 times the item of “Initial HLCP for the Health Literacy of Patients with Chronic Pain,” with a sample loss rate of 5–10%. The approximate sample size for this survey is 205–410; 250 questionnaires were actually distributed, and a random-sampling method was used. The participants were recruited from the pain clinics and wards of three Grade-A hospitals in Hangzhou, Zhejiang Province, China.The inclusion criteria for the participants were patients with chronic pain, having a pain duration of over one month, being aged ≥18 years old, having normal thinking and language ability, having the ability to communicate orally and in writing, having clear consciousness, and having the ability to complete the scale. Participants with acute and serious illnesses, such as severe heart failure or advanced tumors, were excluded from the study. A total of 250 questionnaires were dispatched, along with an informed consent statement; the return of the questionnaire, which was completely voluntary and anonymous, was deemed to indicate consent. The questionnaire was in Chinese and translated into English by two professional researchers. The final sample size was 237 (response rate: 94.8%). The protocol of the present research was approved by the Ethics Committee of Hangzhou Normal University (20190090).The descriptive statistics were calculated (using frequencies and proportions) for the respondents' demographic data, which provided preliminary statistical information. Content validity was measured to determine whether the instrument content was capable of measuring the defined objective. Content validity refers to the consistency between the items in the assessment instrument and the content to be measured. To perform this, the opinion of five experts from the fields of pain, nursing management, and health management was sought. The experts were asked to evaluate each item in the instrument using a four-point Likert scale  and also to consider the scoring method and provide feedback. Based on these analyses, the item content validity index (I-CVI) and scale-content validity index (S-CVI) were measured. For the I-CVI and S-CVI, the criteria of item relevance, clarity, and simplicity were assessed, and for both the I-CVI and S-CVI, values >0.7 were considered acceptable.n = 237) and confirmatory factor analysis , respectively. EFA was used to assess the construct validity. All 31 items were analyzed using principal component analysis with varimax rotation, using a special value cut-off of >1. A factor loading value of ≥0.4 was regarded as indicating a significantly related item. The adequacy of the sample size was assessed using the Kaiser–Meyer–Olkin test (KMO). After these analyses, seven items were removed. The fitness of the model was examined using the following series of indices: chi-square/degrees of freedom , root mean square error of approximation (RMSEA < 0.08), comparative fit index (CFI > 0.90), and Tucker–Lewis index (TLI > 0.90).Structural validity refers to the degree of agreement between the structure of the scale being tested and the theoretical structure . The samα was used to assess the internal reliability of the scale. Based on suggestions made by previous researchers [α value of >0.7 was considered to be satisfactory. Then, to determine the external reliability, a retest was performed. The sample size for the test-retest was 1/10 of the original sample [P < 0.05 were considered acceptable.Reliability refers to the consistency and stability of the results produced by the instrument. Data for the total sample were used to examine the internal reliability  and external reliability  of the scale. Cronbach's earchers , Cronbacl sample . Thus, oAmos V.23.0 software and SPSS V.23.0 software were used for CFA and the aforementioned analyses, respectively.A total of 237 participants included 91 males and 146 females; the male-to-female ratio was 1 : 1.60. The mean age was 45.9 (±15.3) years. Regarding ethnicity, the sample was mainly Han, which accounted for 99.2%; ethnic minorities accounted for 0.8%. Most participants were married (87.3%) followed by unmarried (6.3%), divorced (5.5%), and widowed (0.8%). Most participants resided in urban areas (55.3%) followed by rural areas (13.1%) and villages (31.7%). Regarding occupation, freelancer and professional or technical personnel were the most common occupations, accounting for 33.8% and 18.6%, respectively. The education level was mainly high school or vocational school, accounting for 43.9%. Regarding monthly income, 5,000–9,990 yuan and more than 10,000 yuan were most common, accounting for 33.3% and 41.4%, respectively. Medical expenses were met by most participants through medical insurance, (81.4%); self-funded and public expenses accounted for 9.7% and 8.9%, respectively .The I-CVI of the HLCP was 0.75–1.00, and the S-CVI was 0.95. This indicated that the content validity of the HLCP was confirmed by the expert panel.P < 0.001); this indicated that the factor structure could be used for factor analysis. In EFA, using principal component analysis with varimax rotation, three domains with factor loadings of >50% were clearly distinguished , RMSEA, GFI, NFI, INI, CFI, etc., as statistical indicators. It is generally recommended that an RMSEA value of <0.08  and NFI, TLI, INI, and CFI values of >0.9 indicate good model fit [The present study aimed to develop and assess the psychometric properties of the HLCP, which is designed to measure the health literacy of patients with chronic pain in China. The validity of the questionnaire was assessed using a factor analysis, which identified three domains. The contexts of these three domains, including functional health literacy, interactive health literacy, and critical health literacy, were consistent with the theoretical foundation and structure used to develop the health literacy scale. These three domains explained 70.9% of the cumulative variance observed in the results. The EFA performed in this study returned a KMO value of >0.8 and a cumulative variance contribution rate of ≥40%, and the factor loading of each item was >0.4. The common factors extracted from the scale were consistent with the theoretical framework, and the contents of the items within the three common factors were consistent with the theoretical basis and the health literacy framework for patients with chronic pain. The CFA was performed using chi-square statistics . Additionally, the key elements of interactive health literacy emphasized in the definition of interactive health literacy include the ability to communicate, solve problems, and make decisions to treat diseases. The patient's belief in their ability to improve their chronic pain and willingness to do so are measured in items 11–14, 20, and 21.Regarding critical health literacy, the definition of this type of health literacy is reflected in item 28, as patients' application of critical thinking to analyze chronic pain information was examined through it. Critical thinking must be used by patients to analyze information concerning chronic pain in the contexts of their actual situations; this is reflected in items 25–30.First, the common characteristics of patients with chronic pain and the actual situations of such patients are considered in the HLCP. Patients with chronic pain who have low health literacy are more likely to have inaccurate knowledge regarding medication, and the risks associated with such a lack of information are often underestimated. For example, while the abuse of analgesics is prominent in the US , 45, theCompared with existing instruments for assessing health literacy among patients with chronic disease, the characteristics of chronic pain are better reflected in the HLCP. Moreover, the health literacy level of patients with chronic pain is accurately, scientifically, and comprehensively assessed through it. Therefore, the HLCP is considered more appropriate for use among patients in China compared with the existing health literacy scales for chronic patients, including HLSC and universal health literacy instruments. Data obtained through the HLCP, which accounts for the multiple dimensions of health literacy , can provide insights for future research on health literacy.Several suggestions can be made based on the findings of this study. First, there is a growing interest in exploring the factors influencing the health literacy of patients with chronic pain. However, to date, existing research and instrument development in this regard have been insufficient. Thus, future studies should draw attention to the above aspect. Second, little evidence exists regarding the influence of health literacy on chronic pain outcomes. The relationship between pain outcomes and health literacy should be explored in future studies. Third, after using the HLCP to measure the health literacy  of patients with chronic pain in China, the health literacy of such patients can be improved through interventions implemented at the individual, family, hospital, community, and government level. Health outcomes, prognoses, and quality of life could be improved, and the goal of good national health could be achieved.In conclusion, considering the high validity and reliability of the 31-item HLCP, as well as its advantages, such as the relatively low number of questions, its ease of implementation, and its ability to assess health literacy among patients with various kinds of chronic pain, the HLCP appears to be an appropriate instrument for assessing the health literacy of patients with chronic pain in China and has wide application value.This study has some limitations. First, as a result of restrictions regarding time and funding, all samples recruited were from Zhejiang Province; this may have generated selection bias. Second, some of the health information used in the HLCP is context-specific. To administer the HLCP in other regions of China, some items needed to be reexamined to ensure that they are suitable for the contexts in question. Third, although factors common to a variety of chronic pain diseases are focused on in the HLCP, it might not be suitable for certain kinds of chronic pain that have unique characteristics. Although the instrument developed and validated in this study offers a sound basis, further studies with larger sample sizes are required. In-depth exploration of patients with chronic pain is needed to continuously verify the reliability and validity of the evaluation instrument.


The accessory spleen has no anatomical or vascular relationship with the normal spleen, The tissue structure and physiological function of the accessory spleen are the same as those of the normal spleen, which usually locate in the splenic hilum and the tail of the pancreas. The aims of this manuscript are to present a rare case of the gastric accessory spleen and a review of the literature.A 19-year-old male patient was sent to the emergency department with stomach bleeding after drinking alcohol. The computed tomographic scan showed a 1.2 cm × 1.7 cm mass at the lesser curvature of the gastric fundus. Gastrointestinal endoscopy displayed a submucosal elevated lesion on the gastric fundus, and gastrectomy was performed. Postoperative pathological examination proved an accessory spleen in the stomach. The postoperative course was uneventful, and the patient was discharged on the 6th day after the surgery.The accessory spleen at the fundus of stomach is extremely rare, especially in this case, which is accompanied by acute gastric bleeding, and it is difficult to diagnosis before operation. Many literatures reported that it was misdiagnosis as tumor, so it is necessary to diagnose accessory spleen correctly. The spleen is derived from mesenchymal cells of the dorsal mesentery,and appears approximately at the sixth week of embryologic life , 2. The In November 2020, a 19-year-old man was sent to the emergency department for stomach bleeding after drinking alcohol. There was no hematemesis, melena, hematuria, hematochezia, dizziness and headache. Physical examination showed that there was no obvious gastrointestinal type and peristalsis wave, no abdominal tenderness and rebound pain. The patient was hemodynamic stability . therefore, laboratory tests, gastroscopy and Computed tomography (CT) scan were performed. Gastroscopy showed a submucosal elevated lesion in the gastric fundus (Fig. To perform the review of the literature, relevant articles in English were extensively searched from the PubMed, Web of Science database. The period of research was between 1921 and 2021. The date of the last search was February 27, 2021. The keywords used for the search were“stomach”, “stomachs”, “gastric”, “accessory spleen”, “splenculus” “splenulus”. These words were used individually “OR” with the Boolean operator “AND”. A total of 87 articles were analyzed from 1921 to 2021. The flow chart of the literature screening process is set out in Fig. According to the literature, accessory spleen are most commonly found in the splenic hilum and the tail of the pancreas and are rare in the stomach. The 12 reported cases of gastric accessory spleen including 5 females and 7 males, with a female to male ratio of 0.71 to 1. the age distribution of the patients was mainly between 30 and 70 years old, and these patients predominantly suffered from abdominal discomfort, with lesions mostly located in the gastric fundus. Most accessory spleens usually appears as a well-bundary ovoid mass, 1–3 cm in diameter, masses larger than 4 cm are very rare.In this case report, we reported a case of a 19-year-old man who developed a nodule in the gastric fundus. Due to the lesion is closely related to the fundus of stomach, clinicians were highly suspected that it was a gastric fundus stromal tumor. As mentioned in the literature, gastric stromal tumor is the most common mesenchymal tumors of the digestive tract , 6, The An accessory spleen is defined as ectopic splenic tissue that due to the failure of cell fusion during embryonic development while migrating from the midline to the left upper quadrant , 8. An aAt present, there are many clinical cases of accessory spleen misdiagnosed as tumor . This leFinally, if the accessory spleen is small and the patient has not any symptoms, there is no need for surgery. Surgical treatment should be performed if showing symptoms due to greater compression or torsion. All of the patients reported with gastric accessory spleen underwent surgery. In recent years, laparoscopic space-occupying lesions in the stomach have been primarily considered over open surgery because laparoscopic surgery is less invasive, has fewer complications and a lower mortality rate than open surgery.The position of accessory spleen may be different and gastric accessory spleen is a rare entity that arises as a result of a birth defect or an acquired condition. Preoperative diagnosis of accessory spleen is still difficult due to a lack of specificity in imaging studies which is similar to the imaging findings of some tumors in the stomach, Especially in an emergency, as our case, the accessory spleen may be removed by mistake. Although gastric accessory spleen is uncommon, it should be considered as one of the differential diagnoses of gastric diseases. While postoperative histopathologic examination is still the gold standard, fine nuclear medicine imaging and enhanced CT scan may be useful in the diagnosis of accessory spleen.


Myasthenia gravis (MG) is an autoimmune disease that is associated with the production of autoantibodies. The symptoms of MG are mainly mediated by pathogenic antibodies directed against nicotinic acetylcholine receptors, resulting in a decrease in the number of acetylcholine receptors molecules on the postsynaptic membrane of the neuromuscular junction endplate, leading to clinical symptoms of muscle fatigue and weakness. At present, traditional Chinese medicine (TCM) treatment of MG has a better effect by tonifying spleen and replenishing qi. The purpose of this study was to systematically evaluate the efficacy and safety of TCM therapy for tonifying spleen and replenishing qi in the treatment of myasthenia gravis.We searched the following databases from their establishment until December 2021: PubMed, Cochrane Library, EMBASE, Web of Science, Springer, CNKI, Wanfang, China Biomedical Database, China Science and Technology Journal Database, Chinese Knowledge Infrastructure, China Clinical Trial Registry, and Baidu Scholars. The literature search language was limited to Chinese and English, and publication time and status were not limited. Randomized controlled trials (RCTs) were included. Two researchers independently searched and screened the articles, assessed their quality, and used the RevMan 5.4.1 software to perform a meta-analysis of the included literature.This study compared the main outcome indicators: efficacy rate, recurrence rate, quality of life, and quantitative myasthenia gravis (QMG). Secondary outcome indicators were the clinical absolute score, TCM syndrome score, serum acetylcholine receptor antibody level, and electromyogram low-frequency repetitive nerve stimulation.This study aimed to evaluate whether the TCM method of tonifying spleen and replenishing qi is effective in the treatment of MG and to provide evidence-based data.The protocol of the systematic review did not require ethical approval because it did not involve human subjects. This article will be published in peer-reviewed journals and will be presented at conferences. Modern medical treatments for MG include cholinesterase inhibitors, adrenal cortex hormones, immunosuppressive agents, plasma exchange, and thymectomy. Cholinesterase inhibitors can improve symptoms, have a short onset time, and are only effective drugs for symptom control. Hormonal drugs are commonly used in the clinical practice. Although immunosuppressants have certain effects, they also have many side effects and are prone to relapse after drug discontinuation. Owing to the complicated etiology of MG, the long course of the disease, and its tendency to recur, it has caused a huge economic and psychological burden on patients, families, and society. Currently, there are no specific medications that can completely cure this disease. In recent years, Chinese medicine has achieved good clinical efficacy in the treatment of myasthenia gravis.Myasthenia gravis (MG) is an autoimmune disease mediated by acetylcholine receptor antibody (AChR-Ab), which is dependent on cellular immunity and complements the transmission of neuromuscular junctions. Therefore, TCM treatment of MG is mostly used to invigorate spleen and qi, and has achieved good clinical results. However, the efficacy and safety of MG treatment have not yet been systematically evaluated. This study aimed to systematically and comprehensively retrieve published systematic reviews and meta-analyses of the randomized controlled trial (RCT) literature provided by Chinese medicine for the treatment of myasthenia gravis using the method of tonifying spleen and replenishing qi, and clarifying the direction of clinical treatment.Traditional Chinese medicine (TCM) classifies MG into the Weizheng category. TCM believes that spleen qi nourishes the muscles of the whole body, and weak spleen qi causes weakness of the limbs, weakness of the eyelids, and fatigue. Deng Tietao, a master of TCM, believes that the pathogenesis of this disease is deficiency of the spleen and stomach, and the key to the disease is the sinking of qi deficiency.22.1 This program has been registered on the INPLASY website (registration number INPLASY2021120053). We strictly followed the preferred reporting items of the systematic review and meta-analysis protocols to complete the systematic review.The study was conducted following the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analysis Protocol (PRISMA-P).2.22.2.1We will include Chinese and English literature of RCTs reporting the safety and efficacy of tonifying spleen and replenishing qi in the treatment of myasthenia gravis. Non-RCTs, retrospective research literature, conference abstracts, case reports, repeated publications, and literature without data information were excluded.2.2.2All patients should be clearly diagnosed with MG according to internationally recognized diagnostic criteria. The patients were not limited by age, sex, occupation, education, country, ethnicity, or source. Patients with severe cardiovascular diseases, mental illnesses, or an inability to cooperate with treatment were excluded.2.2.3The control group was routinely administered Western medicine treatment, including cholinesterase inhibitors, glucocorticoids, immunosuppressants, alone or in combination, or a placebo.Based on western medicine treatment in the control group, the intervention group was treated with the method of tonifying spleen and replenishing qi , and the dosage form, dosage, and treatment course of the method of tonifying spleen and replenishing qi were not restricted.2.32.3.1We compared the efficacy rate , recurrence rate, quality of life , and QMG scores as the main outcome indicators.2.3.2We used the clinical absolute score , TCM syndrome score scale, level of serum AchR-Ab, and results of EMG low-frequency repetitive nerve electrical stimulation as secondary outcome indicators.2.4We searched the following databases: PubMed, Cochrane Library, EMBASE, Web of Science, Springer, China Knowledge Network (CNKI), Wanfang, China Biomedical Database, China Science and Technology Journal Database, China Knowledge Infrastructure, China Clinical Trial Registry, and Baidu Scholars. All RCTs on the Chinese medicine method of tonifying spleen and replenishing qi to treat MG were collected. We only searched for articles published in the self-built database until December 2021 in Chinese and English, and did not include unpublished articles. The search terms were as follows: myasthenia gravis, myasthenia, weizheng, tonifying spleen and replenishing qi, tonifying spleen qi, spleen, qi, TCM, Chinese herbal medicine, herbal medicine, Chinese patent medicine, RCTs, controlled clinical trials, and RCTs. Table 2.52.5.1  initially screened the articles based on the above inclusion criteria, imported them into EndNote V. 9.0, grouped them, and checked for duplication. The selected documents were then eliminated according to their title and abstract, and the documents were screened. Finally, the third research member (CTY) checks all the documents and makes a final decision based on the standards. All the screening processes were performed independently. If two research members disagree, a third research member will make the decision. We also recorded the excluded documents and explained the reasons for their exclusion. The research screening process is represented by a PRISMA flowchart Fig. .2.5.2After completing the literature search, two research members (XP and ZYB) extracted key information from the included literature into an Excel table. The following information was extracted: first author of the literature, year of publication, sex, age, disease course, and sample size of the subject; intervention measures for the intervention and control groups; effective rate, recurrence rate, quality of life score, QMG score, clinical absolute score before and after treatment, TCM syndrome score, serum AchR-Ab concentration, and repetitive nerve stimulation results. Two research members will extract data independently, and if there is a disagreement, they will be discussed, and a third research member (CTY) will decide. When information required for research in the literature was missing, the author was contacted to request the corresponding data.2.6 The following seven criteria will be assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of the result evaluator, incomplete result data, selective reports, and other deviations. The evaluation of low deviation risk, unclear deviation risk, and high deviation risk was given item by item. If the evaluation results of the two research members disagree, the final evaluation result is decided by a third research member (ZDM).The methodological quality of RCTs will be assessed independently by two research members (XP and LJ) using the Cochrane risk assessment tool to assess the risk of bias.2.7P < .05. Two research members (XP and JL) performed data extraction, entry, and calculation, and a third research member (ZDM) was responsible for the data verification. We used the mean deviation or standard mean deviation with a 95% confidence interval as the effect measure for the continuous data. Dichotomous results were analyzed using hazard ratios and 95% confidence intervals. I2 statistics were used to detect clinical heterogeneity. Heterogeneity will be assessed using the chi-square test and Higgins I2 test. If there was no significant heterogeneity , a fixed-effects model was used; if P < .10, I2 > 50%, a random-effects model was used for the meta-analysis.We used RevMan V.5.4.1 statistical software to conduct a meta-analysis of the literature, and it was considered statistically significant when 2.8I2 test >50%), sensitivity analysis was performed to obtain stable research results.If the results showed high heterogeneity (2.9If the research data are sufficient, subgroup analysis will be carried out from the following aspects: MG classification, treatment time, and type of Western medicine, to explain the heterogeneity between the studies.2.10We analyzed the quality of publication bias using RevMan 5.4.1 software in inverted funnel plots and performed Egger's test when more than 10 trials were included in the meta-analysis.2.11 The risk of publication, heterogeneity, indirectness, imprecision, and publication bias was assessed, and the results were divided into four levels: high, moderate, low, and very low.We will use the Grading of Recommendations Assessment, Development, and Evaluation to assess confidence in cumulative evidence.2.12In this study, no individual data from participants were involved and ethics approval was not required. This systematic review has been published in a peer-reviewed journal.3,13 The clinical manifestation of MG is skeletal muscle weakness caused by antibodies, with symptoms ranging from simple ocular symptoms to severe weakness of the limbs, bulbar, and respiratory muscles. Western medical treatment of MG mostly uses anticholinesterase drugs to improve symptoms; however, this drug is only a symptom-controlling drug with a short onset time. Although hormonal drugs and immunosuppressants commonly used clinically have certain effects, MG is still difficult to cure, with large side effects; some adverse reactions will occur, and relapse can easily occur after discontinuing the drug. Long-term clinical practice has proven that TCM can regulate immune function, effectively relieve clinical symptoms, reduce the recurrence of illness, and alleviate the toxicity and side effects of some Western medicines. In recent years, many studies on the treatment of MG with TCM have been published, especially on the treatment of patients with spleen and qi deficiencies by tonifying spleen and replenishing qi. The theory of TCM believes that spleen is the foundation of the acquired nature and is located in the middle Jiao. It produces and transmits qi, spleen governs movement and transformation, and the limbs and muscles. It is a source for qi and blood biochemistry. Insufficient lifting and lowering, insufficient qi and blood metaplasia, loss of muscle nutrition resulting in muscle weakness, and no use of limbs. It is necessary to conduct a systematic review to establish convincing evidence for evaluating the effectiveness and safety of TCM therapies for MG. Therefore, we will adopt a more rigorous systematic evaluation method to provide evidence-based data for the treatment of MG with the method of tonifying spleen and replenishing qi in TCM, and provide new ideas and methods for the treatment and research of MG.MG is an autoimmune disease with an annual incidence of 8 to 10 cases per million and a prevalence of 150 to 250 cases per million. The overall analysis of the age of disease found that the prevalence of MG in women was higher than that in men, with a ratio of approximately 3:2.Conceptualization: Li Jiang, Jian Wang.Data curation: Peng Xu, Yibin Zhang.Formal analysis: Peng Xu, Jing Lu.Funding acquisition: Peng Xu, Dongmei Zhang.Investigation: Jing Lu, Yibin Zhang.Methodology: Li Jiang, Tianying Chang.Project administration: Li Jiang, Dongmei Zhang.Resources: Jing Lu, Tianying Chang.Software: Li Jiang, Jing Lu.Supervision: Jian Wang.Validation: Dongmei Zhang, Tianying Chang.Visualization: Peng Xu, Yibin Zhang.Writing – original draft: Li Jiang, Peng Xu.Writing – review & editing: Li Jiang, Dongmei Zhang, Jian Wang.


Limited health literacy negatively impacts understanding of medication-related information. We describe an innovative methodology designed to optimize user understanding of patient medication labeling through the systematic application of evidence-based health literacy principles, using the Patient Package Insert (PPI) for bezlotoxumab  as an example.C. diff, caregivers, and general population members, with a pre-defined target sample of 25% with limited health literacy identified through two health literacy assessment tools: the Single Item Literacy Screener and the NVS.We used a mixed-model, iterative approach consisting of three phases: (1) content development; (2) focus group testing; and (3) comprehension testing. Content development was based on evidence-based health literacy principles and conducted through a collaborative partnership between industry and academia professionals. The PPI was then tested in four focus groups, two in Atlanta and two in Chicago, with an emphasis on collecting feedback from respondents with limited health literacy, evaluated using the Newest Vital Sign (NVS) health literacy assessment tool. Subsequent comprehension testing included patients with n = 34) provided generally favorable feedback, with insights revolving around organization and usability; language and comprehension; and volume of information. Comprehension testing of the revised PPI resulted in average comprehension scores of 96% for the overall population (n = 59), 90% for individuals presenting with limited health literacy (n = 14), and 97% for those with adequate health literacy (n = 45). This PPI development approach was similarly effective for subsequent products across diverse therapeutic areas, with comprehension scores ≥ 86% for all participants (n = 1197).Content development of the bezlotoxumab PPI occurred in May 2015. In June 2015, focus group respondents (This methodology represents a significant advancement for the development of understandable patient medication labeling, especially for people with limited health literacy.The online version contains supplementary material available at 10.1007/s43441-021-00325-5. The United States Department of Health and Human Services defines health literacy as “the ability to obtain, process, and understand health information to make appropriate health decisions” . It is eTo support safe and effective drug use, many countries have regulatory requirements governing medication labeling to ensure that the information is clear and accessible for patients, including those with limited health literacy –12. In tGiven the volume and complexity of prescription drug information, it is critical to ensure that all patients understand the information about their medications, which, in turn, may be expected to reduce medication errors, increase adherence, and promote patient health and safety. Over recent years, the FDA has sought guidance and participation from academia, patient advocacy groups, and the pharmaceutical industry to innovate and develop new strategies to improve patient understanding of drug information. The field of health literacy research has been a valuable resource for identifying ways to help people access and understand written medication materials , 21. TheClostridium difficile (C. diff) infection, which can damage one’s colon and cause stomach pain and severe diarrhea, was selected as an example to fully illustrate the health literacy development process. To inform the reproducibility of results using this methodology, comprehension testing scores of PPIs for multiple medications across diverse therapeutic areas are summarized.In the present report, the PPI for bezlotoxumab , a medication to treat A three-step, mixed-model, collaborative, iterative, health literacy PPI development methodology was used: 1) content development; 2) focus group testing; and (3) comprehension testing  . At the Once completed, the PPI draft was circulated by the medical writer through an open-access cross-functional review process, which included representatives from the following departments of the pharmaceutical manufacturer : Product Labeling, Clinical Development, Regulatory Affairs, Global Clinical Safety and Risk Management, Clinical Research, Marketing, Market Research, Legal, and Health Literacy. The PPI was revised by the medical writer in accordance with the comments from each stakeholder.Following content approval consensus, the PPI draft was submitted by the medical writer for critical review by health literacy experts from academia  who applied evidence-based health literacy best practices based on vast experience working with people across a range of health literacy levels . FurtherC. diff) to ensure that they had no specific prior knowledge of the disease. The population was heavily skewed towards having limited health literacy, which was evaluated using the Newest Vital Sign (NVS) assessment tool, a previously validated measure of health literacy with high sensitivity for detecting people with limited health literacy [Independent focus group testing was conducted by the academic partners and health literacy experts from Emory (K.L.J.) and Northwestern (M.S.W.) Universities. Representatives of the pharmaceutical company neither observed nor participated in the focus groups. Four focus groups were conducted, two in Atlanta and two in Chicago. In Atlanta, a convenience sample of patients was recruited from the outpatient primary care clinics of Atlanta’s inner-city indigent hospital, where patients have been shown to have limited health literacy skills . Patientliteracy . The focA facilitator’s topic guide  was developed to consistently assess participants’ overall comprehension of the PPI and collect feedback about the layout and design across sites. The focus group participants discussed the strengths and weaknesses of the bezlotoxumab PPI and provided suggestions for improvement. Specifically, participants were asked about why this medicine would be prescribed for a patient; how this medicine is different from antibiotics; what are the side effects of the medicine; and if they had any suggestions for improvements in content, logical structure, and level of detail.The focus group discussion results were reviewed, and the final recommendations formed the basis for further refinement of the PPI using the same academia–industry iterative process described for Phase 1. The resulting version of the PPI was forwarded to Phase 3 of the process: comprehension testing.C. diff infection (n = 24), caregivers who were primarily responsible or actively involved in the treatment decisions of patients diagnosed with C. diff (n = 12), and general population members who did not have C. diff, but had similar demographics  to patient populations with the highest incidence of C. diff infection (n = 24). General population participants were included to ensure that even people without prior knowledge of the disease state could understand the information presented in the bezlotoxumab PPI. As C. diff is more prevalent in older people, we ensured that most patients and general population participants were aged 65 and older.The interview flow for comprehension testing is illustrated in Table Research participants were recruited from the Schlesinger national database  either by telephone or online channels and supplemented with participants from literacy centers and senior centers to derive a diverse study sample, representative of broad age groups and health literacy levels. Based on feedback from external health literacy experts and assessment of the feasibility to recruit, a goal of at least 25% of the population with limited health literacy in the total sample was pre-specified. Health literacy levels were assessed during an initial screening process using the validated Single Item Literacy Screener (SILS): “How confident are you filling out medical forms by yourself?” . Prior rC. diff infection; (2) the common side effects associated with taking bezlotoxumab; (3) what patients should tell their doctor before starting bezlotoxumab; (4) how bezlotoxumab is administered; and (5) how long the administration process takes. Comprehension testing entailed a mix of in-depth, qualitative 45- to 60-min interviews conducted either in-person or by phone/Web . Both open-book  and closed-book  approaches to comprehension testing were used. The participant’s comprehension score was calculated as the percentage of correct answers on the test, with a goal score of at least 80% comprehension across all consumer segments, prospectively established based on a U.S. Elementary School-level grading system, in which 80% accuracy is equivalent to a “B” grade [The comprehension test was developed by the marketing research firm (Sommer Consulting) and was composed of multiple choice and true-or-false questions based specifically on the bezlotoxumab PPI. The comprehension test assessed the following topics: (1) what bezlotoxumab is used for and how it is used in addition to an antibiotic to treat B” grade . In addiA summary of the comprehension testing results from participants across health literacy levels was subsequently submitted to the FDA along with the final PPI for informational and approval purposes. Although not a regulatory requirement, the manufacturer believed this would be helpful insight for the FDA to consider during approval of the patient labeling.Following initial content development based on established health literacy principles, the bezlotoxumab PPI draft was provided by the drug manufacturer to health literacy experts at Emory University (K.L.J.) and Northwestern University (M.S.W.) for content review in May 2015. The guiding criteria used for the further refinement of the draft PPI were derived from the Institute of Medicine discussion on health literacy principles, which includes such factors as content, organization, layout, and graphics .C. diff as directed by the physician  organization and usability; (2) language and comprehension; and (3) volume of information . The results consistently demonstrate that this approach optimizes comprehension of PPIs across participant health literacy levels, with average comprehension testing scores ≥ 86% across all products and population segments studied  and representative  samples, with a pre-specified goal to include ~ 25% of participants with limited health literacy. The segment with limited health literacy is identified through validated health literacy screening methodology, using two separate screening tools: the SILS and the NVS. Compared with traditional readability formulae based solely on word length or syllable count, these health literacy assessment tools consider other measures, including structure, content, coherence, and design factors.For a variety of reasons, including fear or embarrassment of literacy abilities , lack ofFor comprehension testing of the PPI, the in-person interview format is effective for respondents with limited health literacy who may be hesitant to participate in research due to an inability to complete a questionnaire or who do not have access to technology. It also allows members of the PPI development team, including representatives from Product Labeling who would not have traditionally participated in comprehension testing, to observe interviews, identify visual cues, and assess respondents’ level of understanding of the materials. The phone/Web interview format allows for a broad, diverse geographic dispersion and reach.The use of both open-book and closed-book approaches to comprehension testing is consistent with health literacy and cognitive factors research recommendations, indicating that the task under evaluation should most accurately mimic what would be expected of a person during actual use. Allowing consumers to review and re-review content in the open-book approach is representative of real-world experience, since the PPI and other forms of drug information are external aids to which patients may refer as needed. The purpose of the closed-book approach is to determine recall and ensure understanding of key information; particularly, important side effects and when to contact a health care provider.The current process has been applied to subsequent development and testing of multiple PPIs. Our approach has been similarly effective for drugs across many diverse therapeutic areas, as evidenced by high comprehension scores among participants with both adequate and limited health literacy. Additionally, this methodology has been successfully used to develop other types of patient labeling, specifically Medication Guides and Instructions for Use. The reproducibility of results suggests that this approach is an optimal model for the development of patient labeling.To our knowledge, our process is the first mixed methods, health literacy approach to PPI development based on a collaborative partnership between industry professionals and health literacy experts from academia. Key strengths of this approach are the inclusion of multiple perspectives, particularly those of the patient/consumer, and incorporation of evidence-based health literacy principles and best practices throughout the entire process. Comprehension testing of the PPI is supported by a sample that is robust and representative of the patient population across health literacy levels. Indeed, the inclusion of 25% of participants with limited health literacy identified by two validated assessment instruments is a key strength. Finally, the reproducibility of results across multiple products in different therapeutic areas permits further confidence in the validity of this approach.The present research also has some limitations. The focus group results are based on a small sample of participants from large, urban US cities and may not be generalizable to different sociodemographic populations or countries. However, the comprehension testing phase recruits from a nationwide sample of urban, suburban, and rural areas across the country to ensure a mix of respondents. Further, only English-speaking (or English as their second or later language) participants were enrolled, as the PPI was written in English. Future research should consider a broader audience, including those from other regions and who do not speak English, especially considering that low English proficiency correlates with poor comprehension of health information. In addition, because there are many different health literacy assessment tools, classification of participants by health literacy level may vary between instruments. To help address this concern, two validated health literacy assessment tools, the SILS and the NVS, were used simultaneously to classify participants by health literacy level.The present health literacy approach represents a significant advancement in the development of prescription drug PPI. The success of this approach is demonstrated by high comprehension across all consumer segments, including people with limited health literacy.In practice, this approach to PPI development empowers patients to better manage their own health by facilitating an improved understanding of their prescribed medications. This approach is expected to culminate in greater medication adherence, fewer adverse drug reactions, and improved health outcomes.Additional research is needed to examine how the implementation of these best practices will improve patient knowledge and compliant use of prescription medications. This methodology may be expanded to other types of consumer health research and adopted by health care organizations and regulatory agencies to support the development of patient drug information that is widely understood across diverse populations and health literacy levels. The adoption of health literacy as a key advocacy initiative is needed to improve the understanding of medication information for all patients.Supplementary file1 (PDF 253 kb)Below is the link to the electronic supplementary material.


Gp.Mur is a clinically relevant antigen of the MNS blood group system that is highly prevalent in several Asian populations. Its corresponding antibody, anti-Gp.Mur, has been implicated in hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. Currently, identifying and confirming anti-Gp.Mur antibody presence in sera via agglutination of a panel of red blood cells (RBCs) is inefficient and difficult to quantify. Using a baculovirus expression system to express Gp.Mur antigen on insect cell surfaces, we have developed a quantitative cell-based system to confirm the presence of anti-Gp.Mur antibody in human serum. We obtained 10 serum samples preidentified as having anti-Gp.Mur antibody and another 4 samples containing noncorresponding antibodies from hospital patients. Insect cells displaying Gp.Mur antigen successfully adsorbed anti-Gp.Mur antibody in the sera and inhibited the RBC agglutination mediated by this antibody. By varying the concentration of Gp.Mur-displaying cells, we could grade levels of RBC agglutination by anti-Gp.Mur antibody. Densitometric analysis further enabled quantitative determinations of hemagglutination inhibition by Gp.Mur-displaying cells. We believe that this cell-based hemagglutination inhibition system greatly improves or supplements existing technology and is a convenient means for accurately identifying and quantifying anti-Gp.Mur antibody. Gp.Mup system ,4. In Sop system ,6,7,8,9.p system ,11. An ap system . Furtherp system . Given ip system . Anti-Gpp system ,8. Anti-p system ,15 and hp system . BecauseScreening and identification of antibodies of concern, such as the anti-Gp.Mur antibody, require the use of a panel of reagent RBCs that has been phenotyped for the most relevant antigens . Given tAutographa californica multiple nucleopolyhedrovirus (AcMNPV) has been widely used to produce eukaryotic recombinant proteins, such as human acid sphingomyelinase and human interferon-γ, with antiviral activity [p10 or polh) result in high expression of the target foreign proteins [Of the many expression systems available, the baculovirus–insect cell expression system may represent an ideal heterologous system for generating antigen-displaying cells applicable to cell-based hemagglutination inhibition assays. Baculoviruses are insect viruses, and the species activity ,25. AcMNactivity ,27,28. Bactivity . This suactivity ,31,32,33proteins ,35,36. Iproteins .In this study, we established an insect-cell-based hemagglutination inhibition assay for Gp.Mur antigen . This sySpodoptera frugiperda IPLB-Sf21 (Sf21) cells were cultured at 26 °C in TC100 insect medium  with 10% fetal bovine serum (FBS). Trichoplusia ni BTI-TN-5B1-4 (Hi5) cells were cultured at 26 °C in ESF 921 serum-free insect cell culture medium  without adding FBS. Recombinant baculovirus was generated using FlashBAC™ baculovirus genome  and propagated in Sf21 cells.TriEx promoter from pTriEx™-3 vector . A td-tomato reporter gene driven by an internal ribosome entry site (IRES) from Rhopalosiphum padi virus (RhPV-IRES) [® HD cloning kit  according to the manufacturer’s manual. The Gp.Mur construct was cotransfected with FlashBAC™ baculovirus genome in SF21 cells to generate a recombinant baculovirus expressing Gp.Mur antigen.The transfer vector  was consPV-IRES)  was inseThe recombinant Gp.Mur construct was expressed in Hi5 cells by infecting cells with the recombinant baculovirus expressing Gp.Mur antigen using a multiplicity of infection of 1 (MOI = 1). After incubation at 26 °C at different time points, the cells were detached, and the culture medium was removed by low-speed centrifugation. Dulbecco’s phosphate-buffered saline (DPBS) was added to remove the remaining culture medium and to wash the cells. The harvested cells were lysed using RIPA lysis and extraction buffer , and the cell lysates were then separated on a 10% sodium dodecyl sulfate–polyacrylamide gel . Proteins on gels were transferred to a polyvinylidene fluoride (PVDF) membrane and Western blotted using mouse anti-His antibody . As negative control, cells infected with wild-type baculovirus harboring the reporter gene alone (WT-td) was used simultaneously in the assays. As a loading control, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression was determined using rabbit anti-GAPDH .4) were seeded onto a 96-well plate  and infected with recombinant baculovirus expressing Gp.Mur antigen using MOI = 1. At 3 days post infection (dpi), the cells were fixed with 4% paraformaldehyde and blocked with 3% bovine serum albumin (BSA) in DPBS for 1 h. The cells were then incubated for 2 h with mouse anti-His antibody  at 25 °C. After three washes with DPBS with 0.1% Tween® 20  (DPBST), HRP-conjugated goat anti-mouse IgG secondary antibody was added (1:5000) and incubated for 1 h. The enzymatic reaction with 3,3′,5,5′-tetramethylbenzidine (TMB) substrate was stopped by adding 2N H2SO4 after 5 min of color development. The optical density (OD) of the Gp.Mur antigen expressed in insect cells was compared to that of WT-td-infected cells and uninfected cells (CO) to quantify surface expression of Gp.Mur antigen .Hi5 cells . The tests were performed separately on the immediate spin (IS) phase (at room temperature) and the antihuman globulin (AHG) phase (at 37 °C) [Human serum samples preidentified as having anti-Gp.Mur antibody by means of the polybrene method  were obtt 37 °C) .All experimental procedures were approved by the Ethics Committees of Linkou Changung Memorial Hospital (IRB No. 201800282B0), Taiwan, and performed in line with the Declaration of Helsinki II principles. Written informed consent was obtained from all participants prior to enrollment in the study.6 cells/mL  were pipetted into separate microtubes containing 100 μL of human serum preidentified as harboring anti-Gp.Mur antibody  imager to conduct densitometric scans of the agglutinates. The density of the agglutinates as reflected in the scans was quantified using ImageQuant TL 8.2 software  and expressed as signal intensity. The intensity of the agglutinates of the serum samples adsorbed by Gp.Mur-displaying insect cells was compared with that of the WT-td and expressed as % inhibition. To determine the specificity of hemagglutination inhibition, serum samples containing antibodies for other blood groups were used in the assay.To perform the hemagglutination inhibition assay, varying amounts of insect cell suspension resulting in different cell concentrations  wild-type-td , bacterial (T7), and baculovirus (p10) promoters. We fused a honeybee melittin signal peptide to the N-terminal of the Gp.Mur construct to enable extracellular secretion of the recombinant proteins. We assumed the recombinant protein would be anchored on the plasma membrane of the insect cell membrane via the transmembrane domain of Gp.Mur antigen fused with the 6C. A td-tomato fluorescence gene was inserted downstream of the Gp.Mur construct, which was driven by an IRES sequence. The td-tomato fluorescence signal therefore reflected successful baculovirus infection of cells and successful expression of Gp.Mur recombinant protein. After successful cotransfection of the Gp.Mur construct with the baculovirus genome, the resulting recombinant baculovirus harboring the construct was named v6H-Gp.Mur-6C.To display Gp.Mur antigen on insect cell surfaces, we generated a construct that encodes the Gp.Mur extracellular domain and its transmembrane domain fused with the AcMNPV 6C . Most of the serum samples presented a strong hemagglutination reaction at the IS phase (grades ranging from 3+ to 4+), except for sample J (grade 2+) . Sample Because RBCs host multiple antigens, a positive hemagglutination result means that the serum sample contains antibody or antibodies to at least one of the many antigens on the surface of the RBCs. Suspected antibody identity must be confirmed by further phenotyping a patient for the absence of corresponding RBC antigens or by reacting the serum with another batch of reagent RBCs that host the corresponding antigens. However, if a suspected antibody is adsorbed using a specifically expressed antigen and then subjected to an RBC hemagglutination assay, that would directly confirm antibody identity. Here, we expressed Gp.Mur antigen on the surface of insect cells, acting as the adsorbing material, to confirm the presence of anti-Gp.Mur antibody in serum samples. Varying concentrations of insect cells were added to serum samples and then indicator RBCs containing the target antigen were added . Resulti5) resulting in almost complete inhibition of hemagglutination  to 4+ (a single solid agglutinate) . This apTM Typhoon 5 Imager for densitometric scanning of the agglutinates. The scans were quantified using ImageQuant TL 8.2 software  to assess their relationship. We observed moderate positive correlations  between the two grading approaches, indicating that they were comparable. We compared the means of % inhibition generated according to the two grading approaches by means of paired Student t-test and the results were not significant (p > 0.05).These assays demonstrated that RBC hemagglutination was inhibited when anti-Gp.Mur antibody in the sera was adsorbed by insect cells expressing Gp.Mur antigen. At a cell concentration of 1.0 × 10ectively . To compb, anti-E, anti-D, and anti-S. The S antigen is highly homologous to the Gp.Mur antigen, so cross-reactivity with it may compromise test results if both anti-S and anti-Gp.Mur antibodies are present in a serum sample. We subjected these sera to the same procedures for antibody adsorption, grading, and quantification as conducted on sera preidentified as having anti-Gp.Mur antibody. Hemagglutination inhibition assays showed no observable or quantitative differences in levels of inhibition between WT-td-infected cells and v6H-Gp.Mur-6C-infected cells   .In this study, we report a practical use of insect cell surface antigenic display for hemagglutination inhibition assay. We have demonstrated that insect cells displaying Gp.Mur antigen on their surfaces can substantially inhibit anti-Gp.Mur antibody in serum samples from patients preidentified as having that antibody. Moreover, as a significant advantage over the conventionally adopted tube method, we could quantitatively assess levels of hemagglutination inhibition by means of densitometry using our insect-cell-based system. Thus, our method can replace or supplement the conventional confirmatory method that involves using several RBC reagents.We expressed Gp.Mur antigen on both Hi5 insect cells via recombinant baculovirus. We generated v6H-Gp.Mur-6C, which displayed a high level of surface expression of the antigen, demonstrating that the baculovirus 6C provides anchorage of the protein on insect cells. Baculovirus expression vector systems (BEVS) are superior to other expression systems such as yeast and bacteria as they exhibit better capacity for retaining post-translational modifications, protein oligomerization, and membrane protein expression . BecauseAlthough post-translational modifications (PTM) in insect cells differ slightly from mammalian cells, such as the inability of insect cells to produce end products containing terminal galactose and sialic acid , thousanThe conventional method of RBC antibody identification makes use of a panel of phenotyped human RBCs. Because RBCs contain multiple antigens, a positive agglutination reaction means that antibodies exist in the sera against one or several antigens on the RBCs. As an indirect means to identify the antibody in a serum sample, a panel of human RBCs is typically used so that antigens from the RBCs that do not show an agglutination reaction with the serum can be ruled out. However, this method is ineffective in cases of autoantibodies, antibodies against high-frequency antigens, and antibodies that display a dosage effect. Given the limitations of this conventional identification system, a binary “yes or no” system has been proposed , which cb, anti-E, anti-D, and anti-S), but the recombinant Gp.Mur antigen expressed in insect cells could not recognize those antibodies. Because S antigen shares conserved sequences with Gp.Mur antigen, the fact that our Gp.Mur antigen expressed in insect cells could not inhibit the hemagglutination activity of anti-S antibody strongly suggests that our recombinant Gp.Mur antigen is highly specific for anti-Gp.Mur antibody. Such specificity is highly important for identifying RBC antibodies as it informs which blood or blood products can be transfused into patients. Thus, the enhanced specificity of hemagglutination inhibition by recombinant RBC antigens could greatly aid in identifying the presence not only of the corresponding antibodies but also of antibodies of other specificities. Significantly, our recombinant Gp.Mur antigen expressed in insect cells is very stable, fully retaining its inhibitory characteristics even after storage at 4 °C for 30 days.Insect cell surface display of Gp.Mur antigen enabled specific recognition of the anti-Gp.Mur antibody in our patient serum samples. We also conducted hemagglutination inhibition assays on our recombinant baculovirus for other antibodies (anti-LeAnti-Gp.Mur antibody is one of the most commonly identified RBC antibodies in humans in Taiwan ,10,43, a


The institutionalization of evidence-informed health policy-making (EIHP) is complex and complicated. It is complex because it has many players and is complicated because its institutionalization will require many changes that will be challenging to make. Like many other issues, strengthening EIHP needs a road map, which should consider challenges and address them through effective, harmonized and contextualized strategies. This study aims to develop a road map for enhancing EIHP in Iran based on steps of planning.This study consisted of three phases: (1) identifying barriers to EIHP, (2) recognizing interventions and (3) measuring the use of evidence in Iran's health policy-making. A set of activities was established for conducting these, including foresight, systematic review and policy dialogue, to identify the current and potential barriers for the first phase. For the second phase, an evidence synthesis was performed through a scoping review, by searching the websites of benchmark institutions which had good examples of EIHP practices in order to extract and identify interventions, and through eight policy dialogues and two broad opinion polls to contextualize the list of interventions. Simultaneously, two qualitative-quantitative studies were conducted to design and use a tool for assessing EIHP in the third phase.We identified 97 barriers to EIHP and categorized them into three groups, including 35 barriers on the “generation of evidence” (push side), 41 on the “use of evidence” (pull side) and 21 on the “interaction between these two” (exchange side). The list of 41 interventions identified through evidence synthesis and eight policy dialogues was reduced to 32 interventions after two expert opinion polling rounds. These interventions were classified into four main strategies for strengthening (1) the education and training system (6 interventions), (2) the incentives programmes (7 interventions), (3) the structure of policy support organizations (4 interventions) and (4) the enabling processes to support EIHP (15 interventions).The policy options developed in the study provide a comprehensive framework to chart a path for strengthening the country’s EIHP considering both global practices and the context of Iran. It is recommended that operational plans be prepared for road map interventions, and the necessary resources provided for their implementation. The implementation of the road map will require attention to the principles of good governance, with a focus on transparency and accountability.Video abstractThe online version contains supplementary material available at 10.1186/s12961-021-00803-0. World leaders assembled at the United Nations on 23 September 2019 to move together to build a healthier world for all by recommitting to achieving universal health coverage (UHC) by 2030, as the core driver of the Sustainable Development Goals (SDGs) .Many efforts have been made at the national and global levels to link research evidence to policy-making –10. HoweAs a result of these efforts, the use of evidence was considered in developing, implementing and evaluating health policies. However, it is not well institutionalized  because The main barriers must be identified to establish a road map for improving EIHP. After that, practical and appropriate policy options should be chosen based on global experiences and the specific country context to address identified barriers. Moreover, to ensure progress in achieving EIHP, continuous assessment is advised to monitor the status of EIHP in the country and the impact of proposed interventions.Despite numerous studies in this field in Iran, their simple compilation did not lead to a specific approach to improving the status quo with respect to EIHP. A holistic approach is desperately needed as a basis for an action plan to enhance EIHP. Hence, a project called SASHA, consisting of three phases, was conducted to develop a road map for strengthening EIHP. Protocols and details published for each phase , 29 or tAn evidence-informed deliberative process  was emplThis phase was conducted through (1) foresight, (2) systematic review and (3) a policy dialogue. The foresight and systematic review were done to identify and summarize the emerging and current barriers to EIHP in Iran. Then, stakeholder analysis and a policy dialogue were conducted to finalize the barriers to EIHP and root causes. This part of the work was published in a separate article with the full details . In the During foresight, external trends that may affect the future of the health system were extracted through relevant documents. These trends were classified using the STEEP  model . Two focTo summarize the factors enabling or hindering the use of evidence in health policy at the macro level in Iran, a search was conducted in PubMed, Scopus, Embase, Health Systems Evidence, and Iranian databases including Magiran, Madlib, Irandoc and the Scientific Information Database . A searcThe stakeholders were then identified through a brainstorming session with the entire research team. The stakeholders were categorized based on their role in three KT activities. A policy dialogue was held with 16 stakeholders to get their views regarding barriers and facilitators to EIHP, previously identified through foresight and systematic review. Ten participants worked in push-side organizations, five in pull-side organizations, one in policy support organizations, and four in both push and pull organizations. This session helped inform the stakeholders about the project and finalize the main barriers to supporting EIHP in Iran.This phase was conducted through (1) scoping review, (2) searching the websites of benchmark institutions, (3) eight policy dialogues and (4) two rounds of opinion polls.An evidence synthesis was carried out through a scoping review and searching the institutes' websites for good examples of EIHP practices  to identify interventions to address each of the main barriers (eight) found in phase 1. Details of the search method can be found in one of the published articles on identifying interventions . In summAn overarching review of Iran's documents and the selected institutions' websites was also conducted to extract and compare interventions for supporting EIHP in Iran with those of other countries. The institutions are presented in Additional file Next, eight policy dialogues were held to contextualize the findings. The participants discussed the feasibility of interventions in Iran, key implementation considerations and lessons learned from similar interventions in Iran. The participants of policy dialogue were selected based on respondent-driven sampling. We chose them from different backgrounds and expertise. More details about these policy dialogues are presented in Additional file Two rounds of Delphi were used to obtain a consensus on the interventions. The experts participating in the process included all who were in previous policy dialogues. A brief about the whole project and the list of interventions were distributed to these 68 experts. They were asked to reflect on whether they agreed or disagreed with each intervention. Interventions were revised given the feedback of 14 experts and were sent to the same experts. The feedback of 17 experts was received during the second round. At least 75% response agreement with each intervention was considered the acceptable level for consensus. Disagreements were discussed in the core research team, and a decision was made to accept or reject based on their justifications. The list of pre-final interventions was sent to relevant individuals and institutions  across the country through official communication by the MOHME. These individuals were asked to indicate whether they agreed or disagreed with interventions within a set period of time (1 month). The final list of interventions was developed given the feedback received from 67 individuals and institutions. We finally organized a FGD with nine experts to develop the road map for strengthening EIHP in Iran. We categorized the interventions into strategies. Then, we drafted the main elements of the road map given the strategies and interventions, including the vision, the policy options and interventions, and the main entity responsible for each of them.A tool was designed and validated given the policy cycle's main stages, including problem identification, agenda-setting, policy development, implementation and evaluation to assess EIHP status. The SUPPORT approach was used to define the questions to examine the extent of the use of evidence . After sWe identified 97 barriers to EIHP and categorized them into three groups, including 35 barriers on the push side, 41 barriers on the pull side and 21 barriers on the exchange side. In addition to the details of barriers published in a separate paper , Table 1Table The final list was classified into four strategies: strengthening the education and training system (6 interventions), the incentive programmes (7 interventions) and the structure of policy support organizations (4 interventions), and enabling processes to support EIHP (15 interventions).By using the tools designed in this study, the status of the use of evidence in health policy-making in Iran was examined in two parts: (i) programme development , and (ii) after the implementation of the programme Table .Table 3T(i) Use of evidence during programme development: When developing policies, during the stage of identifying and putting the problems on the agenda, the policy-maker's experience has a leading role, prioritization is weak, and the function of civil society and the nongovernmental sector is minimal. In order to choose the appropriate solution to deal with health problems, one must first identify the causes of the problem and the causes of its persistence. Only about one third of the programmes examined the causes of the problem before selecting the solutions. WHO’s direct recommendations were the basis of half of the policies. In general, systematic review and the use of secondary data to identify solutions were forsaken. Also, before implementing the solution and revisions based on the pilot study, economic evaluations were done in a small number of programmes. Contextualization was not considered in 30% of programmes. The development of a monitoring and evaluation plan was neglected at the time of policy development.(ii) Use of evidence after implementing programmes: It was found that some programmes, although they did not make extensive use of evidence in their development phase, have taken steps to improve the programme after its national scale-up. As shown in Table We developed a national road map for strengthening EIHP by providing interventions to address the barriers to institutionalizing EIHP in Iran. We also sought to assess the current status of the use of evidence in health policy-making.The assessment of EIHP showed that the use of evidence in each stage of the policy cycle is not optimal. The root causes of the problems are not examined systematically; problem clarification, which is the first step for selecting appropriate solutions, is overlooked. When choosing and implementing solutions, the most crucial steps, including using policy-makers and stakeholders' views and experiences, synthesis of evidence, economic evaluations and pilot study, are not adequately considered. The policy-makers and managers do not take advantage of using evidence during the implementation and evaluation of interventions. The findings also showed that the WHO recommendations play a significant role in selecting and implementing solutions. Because of the substantial power of policy-makers and managers in shaping policies, criteria for choosing them, professional development and improving their competencies in evidence-informed decision-making must be considered priority actions.Even though phase 3 of the study was carried out simultaneously with the other two phases, it was impossible to use its results to identify the barriers. Still, in addition to our intention to obtain data on the current status of EIHP, this can be triangulated with the barriers identified in phase 1. The results of phase 3 showed that the EIHP is not well used in the policy-making and implementation process, and phase 1 showed that this is due to the lack of necessary skills among policy-makers and researchers. Researchers can be promoted based only on the number of articles published, and making health system changes is not adequately valued in their promotion criteria. Policy-makers are not encouraged to use evidence, either by considering the support of evidence as a criterion in accepting a programme or by including the use of evidence in their performance assessment.The relation between phases 1 and 2 of the study is also well established. The weaknesses of researchers' and policy makers' abilities and skills identified as barriers in phase 1 are covered in the first strategy and subsequent interventions in phase 2  for implementation.Additional file 1. The list of selected institutions have been reviewed.Additional file 2. Details of policy dialogues have been conducted to contextualize the intervention.


True evidence-informed decision-making in public health relies on incorporating evidence from a number of sources in addition to traditional scientific evidence. Lack of access to these types of data as well as ease of use and interpretability of scientific evidence contribute to limited uptake of evidence-informed decision-making in practice. An electronic evidence system that includes multiple sources of evidence and potentially novel computational processing approaches or artificial intelligence holds promise as a solution to overcoming barriers to evidence-informed decision-making in public health.This study aims to understand the needs and preferences for an electronic evidence system among public health professionals in Canada.An invitation to participate in an anonymous web-based survey was distributed via listservs of 2 Canadian public health organizations in February 2019. Eligible participants were English- or French-speaking individuals currently working in public health. The survey contained both multiple-choice and open-ended questions about the needs and preferences relevant to an electronic evidence system. Quantitative responses were analyzed to explore differences by public health role. Inductive and deductive analysis methods were used to code and interpret the qualitative data. Ethics review was not required by the host institution.Respondents (N=371) were heterogeneous, spanning organizations, positions, and areas of practice within public health. Nearly all  respondents indicated that an electronic evidence system would support their work. Respondents had high preferences for local contextual data, research and intervention evidence, and information about human and financial resources. Qualitative analyses identified several concerns, needs, and suggestions for the development of such a system. Concerns ranged from the personal use of such a system to the ability of their organization to use such a system. Recognized needs spanned the different sources of evidence, including local context, research and intervention evidence, and resources and tools. Additional suggestions were identified to improve system usability.Canadian public health professionals have positive perceptions toward an electronic evidence system that would bring together evidence from the local context, scientific research, and resources. Elements were also identified to increase the usability of an electronic evidence system. In the time of growing funding restraints for public health in Canada and across the world, public health professionals and organizations must function efficiently to meet the expanding public health needs. Changes to the funding structure of public health have been underway across Canada for several years . In the In addition to the impacts of restructuring and decreasing funding, the public health sector is challenged to function effectively with the exponential increase in the amount of scientific evidence generated and the local contextual data available, as seen in response to the COVID-19 pandemic. The amount of information available now exceeds the capacity of public health professionals to comprehensively assess, consider, and use in program planning decisions. Given these challenges, there is a need to understand how public health professionals and organizations can meet increasing demands for evidence-informed decision-making with fewer resources .A 2016 scoping review identified 4 factors that were associated with improved efficiency in public health systems: (1) increased financial resources, (2) increased staffing per capita, 3) jurisdictions serving a population of 50,000 to 500,000 people, and (4) evidence-based organizational and administrative features  jurisdic. Specifiinformed rather than based allows for nuances of the decision-making process that are not solely based in research evidence, such as considerations of the political climate and expertise of public health professionals . Th. Th11]. The goal of precision public health is similar to that of evidence-informed decision-making—to put forth effective public health interventions that improve population health . PrecisiThe available evidence systems are limited by the type of evidence they provide, requiring large time and expertise input by professionals to gather and analyze data from multiple platforms ,31-39. CA web-based cross-sectional survey was used to assess the preferences of public health professionals across Canada with respect to an electronic evidence system.Eligible participants were individuals currently working in any field in public health organizations in Canada. The web-based survey was available for completion in either English or French. Individuals who identified as students studying public health without any indication of work experience were excluded. Participants were recruited over a 2-week period in February 2019 through the NCCMT’s mailing list  and the Canadian Public Health Association’s bulletin listserv . Ethics review was not required by the host institution, as this evaluation aimed to inform about the needs for and future development of an electronic evidence system.The survey was developed by members of the research team with expertise in public health, AI, and informatics. The survey underwent multiple rounds of consultation between study investigators. Once agreement was reached, the questionnaire was translated by a certified French translator. The final questions were mainly multiple-choice questions, with 1 Likert scale question and 3 open-ended questions.Upon initiation of the questionnaire, via LimeSurvey (LimeSurvey GmbH), respondents were asked to consider the following hypothetical scenario:Imagine an electronic system that combines data about your local population with relevant research evidence about the effectiveness of health interventions. The data in this system would include measures of determinants of health, morbidity, and demographics, and could also be compared to similar measures for other geographic regions / populations. The research evidence could include information on the effectiveness of the interventions in different settings/populations and the resources required for implementing those interventions.Participants were asked to complete an 18-item questionnaire comprising questions on respondents’ characteristics, preference and need for an electronic evidence system, and barriers and facilitators to use . All resP=.05), we used a 1-way analysis of variance across the 3 independent groups. When the assumption of homogeneity of variance was not met, the Games-Howell post hoc test was used and the differences among the 3 groups were presented. For categorical data, the Pearson chi-square test was used with comparison across columns. When the cell sizes were less than 5, the Fisher exact test was used to compare the groups.Quantitative analysis was completed using SPSS . Descriptive statistics were calculated as means and SDs or percentages, where appropriate. Quantitative responses were categorized post hoc into three types of evidence from the evidence-informed decision-making model: community health issues and local context, research evidence, and public health resources . Given tother multiple-choice questions open text, data were imported into NVivo . The analysis began with an initial scan of the responses and a discussion of possible themes. Two authors (BD and SENS) independently reviewed the responses using an inductive line-by-line approach and then discussed themes emerging from data and refined the coding scheme  need a way to analyze context where an intervention is used. For example, if previously similar interventions had been tried in an area or subpopulation there may already be a delivery system or key partnerships in place, and there may also be a learning effect from previous work that is beneficial to achieving results with a “new” intervention.To support the need for contextual and implementation data, respondents also specifically mentioned the need for qualitative and mixed-methods research and needs assessments conducted within other communities or organizations.evaluation or implementation frameworks. There were also requests for tools to support practice, such as the Applicability and Transferability Tool [Related to resources and tools for practice, a need for theories, methods, or frameworks to support adaption or to implement a program in their community was identified. Some respondents mentioned specific frameworks, such as the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, whereas others had general suggestions for ity Tool , which sIn addition to the specific needs for an electronic system, a number of potential concerns or barriers emerged. Concerns were related to either the electronic system itself or the ability to adopt a system within public health organizations. Concerns about keeping a system up to date stemmed from the understanding that evidence is created at rapid rates and new data are constantly being collected. For such a system to be useful, data would need to be current. Sustainability of the system beyond its initial creation was seen as a critical element for successful implementation, with some participants citing concerns if the system were to be funded by a research grant. An understanding of plans for long-term upkeep and sustainability may be a requirement for individual users or organizations to invest time in learning how to use the system.The potential for duplication of existing resources was another concern related to such a system, with respondents citing specific databases or systems that already exist, and how existing databases and systems would complement or conflict with any new system. One respondent captured this sentiment, stating that:...these systems are difficult to set up AND keep up to date. In addition, other similar systems (except for intervention data) already exist and this may add to the confusion for users  Why do we observe differences between two systems for same indicator? Etc.Related to the ability of individuals and organizations to adopt and implement the system, major themes about usability and costs emerged. The cost of the proposed system was seen as a key potential barrier, with questions about who would pay for it arising frequently. Second, the ability of a system to work with existing information technology infrastructure, such as outdated or restrictive computer systems and limited or slow internet connectivity, was raised as a concern. Beyond the initial barriers of cost and access, an organization’s ability to adopt the use of a system in their regular workflow was reported to be dependent on the ability of individual staff to use the system adequately, which requires not only buy-in by the individual employee but also senior-level management. Finally, concerns about data privacy and maintenance of confidentiality were also expressed.A number of suggestions for success emerged from the qualitative data. The most frequently mentioned requirement to facilitate use of the system were transparency of methodology used, including the criteria to select evidence for inclusion, the methods used to evaluate and synthesize evidence, and the overall quality of the evidence included. One respondent stated that they “...would need a very detailed ‘methods’ section of this system to be able to be confident in it.” Sufficient staff training was also suggested to support the use of the proposed system.Finally, respondents requested specific functions or system formatting elements, such as the ability to make graphs, print or export data, and retrieve contact information of data sharers on the system.The purpose of this study is to understand the preferences of Canadian public health professionals for an electronic evidence system. The results indicate that there is a perceived need for an electronic evidence system; however, certain considerations related to the type of information included and how it would be presented must be addressed for such a system to be adopted and used effectively for public health decision-making.Preferences for all 3 types of evidence  were generally high. This aligns with previous research that public health professions value different sources of evidence . An impoThe need for information to examine and address the determinants of health and health equity came through strongly in this study. This is not surprising given the previous literature that suggests that equity information is commonly lacking in scientific publications. A 2016 scoping review of population health interventions found that most studies included minimal contextual information on the target population and intervention setting . This coA key concern that emerged from the qualitative data was avoiding duplication of existing resources, some of which were already in use within their organization. For example, in Canada, the Canadian Best Practice Portal captures intervention evidence on effective health promotion and chronic disease prevention, but it is no longer updated ; OpenDatBarriers to the use of an electronic evidence system identified in this survey are similar to those found in a previous systematic review on barriers to public health data sharing . In the In our survey, motivational, political, and ethical barriers were not raised; however, the survey did not specifically seek feedback on these factors. Although motivational barriers, which limit data sharing at an individual or organizational level, were not explicitly mentioned, some respondents suggested possible ways to overcome a component of this barrier, disagreements in data use . RespondAn additional barrier identified in the qualitative responses was the need for ongoing training of staff to use the system. Although AI has the potential to compile, process, synthesize, and analyze patterns at rapid rates and to improve efficacy in the use of evidence, blind reliance on its outputs runs the risk of misrepresenting variables or groups of people as it is dependent on data collection methods and evidence inputs ,46,48. EThere are some limitations to this study, which should be considered when interpreting the findings. First, we did not collect any individual demographic data or years of experience working in public health, limiting the extent to which we can characterize the types of individuals who took part in this survey. In allowing participants to select all that apply for organization type, role, area of public health, and practice discipline, our analysis was limited in its ability to compare differences in preferences across each of these categories. Although the survey was disseminated through two large Canadian-based listservs to recruit public health professionals, there was no qualifying question to confirm that the preferences that emerged were solely of public health professionals in Canada. Second, respondents in the survey ranged across roles, areas, and disciplines, and their results may not be generalizable across all Canadian public health professionals, as respondents who participated may have prior awareness of, or an interest in, electronic evidence systems or evidence-informed decision-making. Finally, the survey questions for a hypothetical electronic evidence system without considerations of feasibility may have skewed responses positively, where respondents more favorably indicated the need for all items listed .Public health professionals and organizations face many hurdles, including changes in structure, lack of funding and time, and exponential increases in new evidence. However, there is broad agreement that the hypothetical electronic evidence system proposed would make informed decisions more accessible. On the basis of our findings, public health professionals see the value in an electronic evidence system that combines local contextual evidence, research and intervention studies, and public health resources and tools. Our findings also highlight a number of elements that should be considered to ensure usability and facilitate trust in such an electronic evidence system. These elements include quality appraisals, interpretations of evidence, and transparent methods and funding models. Such an electronic evidence system may support professionals in evidence-informed decision-making, thereby enabling the Canadian public health system to be more effective in an environment with limited investment.