key: cord-254494-wbfgrez1
authors: Shi, Chunhong; Zhu, Haili; Liu, Jun; Zhou, Jian; Tang, Weihong
title: Barriers to Self-Management of Type 2 Diabetes During COVID-19 Medical Isolation: A Qualitative Study
date: 2020-10-14
journal: Diabetes Metab Syndr Obes
DOI: 10.2147/dmso.s268481
sha: 
doc_id: 254494
cord_uid: wbfgrez1

PURPOSE: Diabetes self-management behaviors are necessary to obtain optimum glycemic control, reduce the risk of complications, and improve health outcomes. The COVID-19 pandemic imposes an additional struggle for self-management by diabetes patients. Although previous studies have reported socio-demographic, behavioral, psychological, and cultural barriers to diabetes self-management, little is known about perceived barriers to diabetes self-management among patients during isolation following their recovery from COVID-19. The purpose of this study was to explore perceived barriers among type 2 diabetes patients during isolation following their recovery from COVID-19. PATIENTS AND METHODS: A qualitative, exploratory, and descriptive research design was utilized. Semi-structured telephonic interviews were conducted with 12 patients with diabetes who had been discharged from one COVID-19 designated hospital and underwent isolation in the designated facilities in Wuhan City, Hubei Province, China. Data were analyzed using Colaizzi’s seven steps. RESULTS: Barriers to diabetes self-management identified by patients with diabetes during isolation were categorized into five major themes: inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support. CONCLUSION: Perceived barriers to diabetes self-management described by diabetes patients indicated a lack of environmental resources and support strategies to meet their needs. Efforts to remove barriers are important in assisting patients with diabetes to improve their quality of life and health outcomes.

Coronavirus disease 2019 (COVID- 19) , which was declared a Public Health Emergency of International Concern by the World Health Organization (WHO) on 30 January 2020, has posed a severe threat to global public health. 1,2 Diabetes mellitus (DM) is a common chronic disease in China with a prevalence of 10.4%. 3 Although people of all ages are generally susceptible to COVID-19, patients with diabetes are at higher risk for COVID-19 due to the multiple concomitant chronic diseases and immunosuppression. 4, 5 According to the currently published literature, the prevalence of DM among COVID-19 patients and critically ill COVID-19 patients were 7.4-20.0% [6] [7] [8] [9] and 17%, 10 respectively. The Chinese Center for Disease Control and Prevention (China CDC) has stipulated that COVID-19 patients discharged from hospitals are subject to a 14-day period of isolation and medical observation. 11 As of midnight on August 19, 2020 , the total number of confirmed COVID-19 cases had reached 84,895 in China. 12 These facts indicated that a large number of COVID-19 patients with diabetes underwent isolation after being discharged from hospitals.

Patients with diabetes recovering from COVID-19, who experienced the chronic hyperglycemic state and persistent inflammatory states, are at higher risk of COVID-19 reinfection and the occurrence and progression of DM complications. 13 There is a compelling need for this vulnerable population to reduce this risk through good blood sugar control during their isolation. However, ideal blood sugar levels cannot be maintained solely by anti-diabetic medications; 14 good self-management behaviors play a crucial role in DM treatment-especially for those with type 2 diabetes mellitus (T2DM). 15 Self-management refers to long-term, and effective decisions and behaviors, to maintain patients' well-being, which involves medical, behavioral, and emotional management. 16 Positive and effective self-management not only alleviates the progression of DM on physiological indicators but also improves the patients' quality of life. 17 Scholars from Stanford University pioneered the application of the concept and methods of self-management in a community-based diabetes self-management program. 18 These early studies have opened new channels for the prevention, control, and treatment of DM and substantially improved the quality of life of patients with diabetes. 19 Promoting effective diabetes self-management has long been a challenging issue for the health systems, healthcare providers, community workers, and patients with diabetes. 20 Although the data regarding diabetes management for T2DM patients recovering from COVID-19 during isolation remain scarce, notably, previous studies have reported that among Chinese T2DM patients, only 22.76%-40.09% have achieved optimal glycemic control (hemoglobin A1c level<7.0%, 53 mmol/mol) 21-23 and 9.20%-16.43% have manifested good self-management behaviors. 21, 24 This raises the issue of how to identify factors that hinder diabetes selfmanagement and to address these potential barriers. Studies in developed countries such as the United States, Canada, the United Kingdom, and Singapore have found that common barriers to self-management include poor communication between patients and healthcare providers, limited accessibility to healthcare facilities, lack of family support, inadequate disease knowledge and limited disease treatment methods, lack of motivation for change, physical and cognitive disorders, limited access to diabetes education, and financial barriers. [25] [26] [27] [28] [29] [30] [31] [32] Evidently, factors that hinder diabetes self-management are complex and multifaceted. However, the barriers to diabetes self-management for patients with diabetes recovering from COVID-19 during their isolation are not precisely known.

To date, a considerable amount of literature on glycemic treatment and control in COVID-19 patients with preexisting DM has been published. 33, 34 Most studies, however, focused on hospital and physician practice, while few studies investigated or mentioned self-management among patients with diabetes during their isolation following recovery from COVID-19. A qualitative study is an ideal design for an in-depth understanding of the feelings and experiences of patients with diabetes. Such studies are of great significance to elucidate the perceived barriers to diabetes self-management among isolated patients. This study addressed a gap in this field by interviewing patients with diabetes subjected to medical isolation after recovering from COVID-19 to gain a deeper understanding of the barriers to diabetes self-management, and provide new perspectives and approaches for the design of interventions and formulation of policies.

This study adopted a descriptive qualitative methodology to collect data through telephonic interviews, which provided a rich and thick description of the participants' perceptions of barriers to diabetes self-management. A phenomenological approach was used to achieve an indepth understanding of the factors hindering diabetes selfmanagement from the patient's perspective. 35 

Participants were recruited through purposive sampling based on the following inclusion criteria: (1) T2DM patients with a disease duration of greater than 1 year, (2) COVID-19 patients with diabetes after being discharged from the hospital, (3) had stayed at designated isolation sites for at least 7 days, (4) spoke and understood Chinese (Mandarin), and (5) agreed to participate in the study. Patients with type 1 DM or younger than 18 years old were excluded. The primary researchers of this study, who were nurses at a designated COVID-19 hospital in Wuhan City, Hubei Province, China, contacted patients who met the inclusion criteria through the contact information listed on their medical records. The sample size was determined by data saturation-when no new information was obtained during the last two interviews. 36 Variations in age, education level, and duration of diabetes were considered to ensure diversity in the perception of barriers to self-management. We followed the consolidated criteria for reporting qualitative research to report the findings of this study. 37 

Semi-structured, in-depth telephonic interviews were conducted from February 20 to March 4, 2020, at a convenient time after dinner (approximately 19:00-20:00 Beijing Time) in a quiet and comfortable environment. Before each telephonic interview, the primary researchers explained the objectives and methods of the study to the participants, promised to perform confidentiality measures, and obtained verbal informed consent from all participants. All interviews were recorded using a cellphone and a recording pen (Newsmy V29, 16 GB internal memory) with the consent of the participants. An interview guide (Table 1 ) was used to conduct the interviews, which consisted of a series of open-ended questions regarding the various aspects of self-management. The interview guide was tested using pre-interviews with two patients of diabetes not included in the actual study, which resulted in corrections of the language and content. During the formal interviews, the interviewees were encouraged to express their thoughts and perceptions thoroughly and probing questions, such as, "Can you please elaborate on this?" were included to increase the depth of the discussion. The nonverbal information (eg, tone of voice, pause) and the important statements stressed by the patients were documented during the interview. Each interview lasted between 15 and 30 minutes.

Each audio recording was transcribed by a co-author within 24 hours of the interview and reviewed by another author who interviewed the patients to ensure accuracy of the transcript. The interviews, raw transcripts, and data analysis were conducted in Mandarin Chinese. Data analysis was conducted by two co-authors using Colaizzi's seven-step method 38 to extract themes and sub-themes. The detailed steps were as follows: (1) reading and re-reading raw data transcribed from the audio recordings; (2) marking and extracting significant statements pertaining to the investigated phenomena; (3) coding recurrent important viewpoints; (4) summarizing all coded viewpoints; (5) elaborating and articulating the meanings of the viewpoints; (6) integrating, categorizing, and refining similar viewpoints into themes; and (7) returning the formulated themes to the interviewees for validation. All authors agreed with the data analysis results.

To ensure the rigor of the study, the four criteria of dependability, credibility, transferability, and confirmability were 

In this study, 12 participants were interviewed. Table 2 shows the demographic information of the participants.

Barriers to diabetes self-management were categorized into five themes: inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support, as indicated in Table 3 .

Respondents in the study were found to have poor knowledge, inadequate self-care behavior and low-level beliefs regarding diabetes self-management. The theme "inadequate knowledge and behavioral beliefs" emerged from all discussions that contained three sub-themes, namely, limited diabetes knowledge, confusion about taking medications, and low adherence to self-monitoring of blood glucose.

Most participants (n=11) alluded to the fact that inadequate diabetes knowledge challenged their management of blood glucose. They often asked for help from those around them (eg, daughter or father). They had limited knowledge regarding diet management and physical exercise. Some of them even believed that refraining from sweets and carbohydrate-rich foods or insisting on physical exercise alone could achieve good glycemic control. One female patient stated, "My knowledge regarding diabetes has been gained from my daughter, who is a nurse. She told me which foods I can or cannot eat." (P6) Another male participant stated, "My dad also has diabetes. He controls this disease through exercise and obtains good outcomes, so I control my blood glucose by exercising." (P2)

A similar view was expressed by another patient, "I know a little about diabetes. I pay little attention to it in daily life and just engage in exercise to control my glucose." (P9)

All participants voiced their concerns about medication treatment. More than half of the patients were unfamiliar with the use of hypoglycemic agents. They were confused about taking medications, with most uncertainty involving the names, usage and side effects of the medications, which prevented participants from effectively managing their disease.

A female patient expressed unfamiliarity with the usage of hypoglycemic agents: I am worried whether I take too much acarbose. I take two tablets with each meal, and I do not know if it is too much . . . The doctor told me to alternate between metformin and acarbose, which made me confused. (P7)

A male patient stated, The hypoglycemic medicines prescribed by the doctor when I was discharged from hospital were different from what I used at home; maybe the effects are the same. I do not know whether these medicines are better or worse than the previous ones, I cannot judge them. (P4) Low Adherence to Self-Monitoring of Blood Glucose Among all patients, only one brought test strips and needles to the isolation site. They paid little attention to blood 

Most of the isolation facilities were converted from hotels or high school premises at short notice in response to the demand during the COVID-19 pandemic period. The shortage of resources at these facilities was another issue discussed by all patients. This theme consisted of four subthemes: limited space for exercise, unavailability of blood glucose monitoring, absence of a diabetic diet, and undersupply of hypoglycemic medications.

At the isolation sites, the participants were largely confined to their rooms because of social distancing policies. All participants described that they exercised daily but could only do so in their rooms or corridors.

As a male patient's transcripts showed, 

Regular blood glucose monitoring is essential for glycemic control in diabetes. Among all interviewees, only one had performed daily blood glucose monitoring; the remaining participants mentioned that they had not monitored their blood glucose at the isolation sites due to the unavailability of blood glucose monitoring.

An elderly female patient stated, 

All participants were concerned with diet, which is a crucial tool for managing T2DM. 40, 41 In particular, 5 participants clearly expressed that the diet provided at the isolation sites was unsuitable for patients with diabetes.

As stated by Participant 12, "Many food items at the isolation site contain sugar . . . I have no choice but to avoid food items with sugar . . . There is no diabetic diet." (P12)

Another female patient further added, 

Approximately half of the participants faced issues regarding the shortage of hypoglycemic medications, or medication changes, due to the non-supply of medications at the isolation sites. One participant mentioned, Another female patient stated, "The medicines prescribed by the hospital are not enough, I don't know if they can last till the end of the isolation period" (P8).

The participants described that they experienced hyperglycemia, physical discomfort, and insomnia during the mandatory isolation after contracting COVID-19, which discouraged them from self-managing the diabetes and reduced their motivation to self-manage their diabetes. Suffering from health problems is an important obstacle to adherence to self-management behavior.

Two thirds of the participants stated that their blood glucose levels increased and became difficult to control after contracting COVID-19. The unsteady blood glucose made them feel frustrated and impeded their self-efficacy in their journey of diabetes management.

As described by one participant, The elevation of blood glucose after contracting COVID-19 was also mentioned by another female patient. "After getting COVID-19 . . . My blood glucose was above 20 [mmol/L]. It has never been so high over the last 20-odd years." She continued, "Blood glucose is difficult to control; I can hardly manage it well." (P12)

Of note was that half of interviewees still experienced physical discomfort after COVID-19 treatment and hospital discharge such as tiredness, shortness of breath, aches and pains, or a headache. These physical symptoms prompted them to focus on COVID-19 recovery and treatment while ignoring the self-care of diabetes. Another patient also experienced physical discomfort. 

Nearly half of the participants experienced insomnia at the isolation facilities as they were unaccustomed to their isolation environments, subjected to activity constraints, and engaged in fewer social activities. Insomnia led to their fatigue, poor concentration, and tension during the day and disrupted their diabetes management routine.

The following examples demonstrated this experience. 

High contagious infectivity, potential fatality of COVID-19, loneliness in the isolated room, and difficulties in maintaining blood glucose levels elicited negative emotions in the participants. Three quarters of patients with diabetes expressed unpleasant or unhappy emotions toward COVID-19 and the isolation environment. Such emotions can cloud their judgments and reduce rationality in decision-making on self-management behaviors. Negative emotions as a barrier to self-management, emerging from the transcripts, included three sub-themes: stigma, dissatisfaction, and anxiety.

Participants may have perceived stigma for suffering from COVID-19. They feared discrimination from others and avoided full disclosure about their disease to both peers and healthcare workers, thereby influencing the way they view the disease and approach their self-management. A female patient expressed, 

The isolated patients faced various inconveniences at the isolation sites. Some of them complained about the lack of supplies (especially medications) and expressed dissatisfaction with the living conditions and diets provided at the sites. Dissatisfaction affected their activation of diabetes self-care and discouraged their behaviors toward diabetes self-management. One participant complained, "The isolation site offers nothing just serves for isolation . . . There's no fruit, no medicine . . . There are too many difficulties for us to manage diabetes." (P8)

A male participant expressed his dissatisfaction toward the isolation site, This place isn't as good as the hospital, the room is really tiny . . . the (medical) service here (isolation site) isn't so professional compared with the hospital . . . I just try to control my blood sugar by eating less food. (P9)

Patients with diabetes often felt stressed and worried about the medication, diabetes supplies, and blood sugar levels. A third of the patients expressed that they were somewhat worried or anxious. This emotional distress often brings about negative consequences for diabetes and further affects their self-management behaviors indirectly.

A participant stated, 

Most patients with diabetes who underwent forced isolation perceived a lack of guidance and support. These patients described their experiences as a struggle to trudge along a difficult path of diabetes self-management, as they were unable to seek help from anyone under the constraints of social isolation. Lack of support as a theme was expressed by most respondents, which had two subthemes: lack of professional guidance, and lack of family support.

Most healthcare providers at isolation facilities had been temporarily extracted from various healthcare departments, who might have had little diabetes knowledge and only took responsibility for COVID-19 prevention and education. The participants expressed the view that they felt helpless with regard to managing their diabetes without professional guidance. For instance, a participant stated, "Every morning, [healthcare providers] only ask if we feel comfortable and measure our body temperature . . . blood glucose is not monitored at the isolation site." (P7)

Another patient complained that "The doctors here show little concern for us . . . the healthcare providers differ from those at the hospital in terms of professional levels." (P6)

The COVID-19 isolation policy prohibits face-to-face visits from family members, which greatly affects the patient's access to family support. In addition, COVID-19 is characterized by familial aggregation, which also reduced the sources and types of family support provided to the participants.

As stated by a divorced female participant, During the isolation period, I have made no phone calls to my family and friends . . . my family members are also staying at the isolation sites, so it is too inconvenient . . .

Another participant expressed that she could not get actual assistance from her family members as they could only express their concern over the phone, "The concern from my family is of no use . . . sometimes they can't even send things to me because non-staff entering the isolation site is forbidden." (P12) 

This exploratory and descriptive qualitative study reported the barriers to self-management of T2DM patients who had recovered from COVID-19 during medical isolation. Five major themes were identified: inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support. Self-management is essential for prognosis and glycemic control in patients with T2DM. Understanding the barriers to self-management will help patients make changes and better manage their diabetes.

Our results showed that limited knowledge regarding DM is a major barrier to diabetes self-management. Participants tended to gain diabetes knowledge from the experiences of people around them. The common assumption was that low educational levels (average below high school) and old age (mean age: 59.75 ±7.93 years) limited their abilities to acquire medical information and seek better healthcare resources. Similarly, studies conducted in Ethiopia 42 and Iraq 43 have indicated that a lack of appropriate information/knowledge hinders self-management among patients with diabetes. A study by Ji et al showed that diabetes knowledge is positively correlated with overall self-management behavior. 23 Specifically, the higher the level of knowledge on diabetes, the better the self-management behavior of patients with diabetes. 44 Additionally, most patients also expressed their confusion about taking medication. Low education and lack of diabetes knowledge might provide a possible explanation for this. Previous studies have indicated that difficulties and frustrations in taking medications prevented diabetes patients from effectively self-managing. 45 In addition, low adherence to self-monitoring of blood glucose posed another barrier to diabetes self-management, which was consistent with the findings of Tewahido et al 42 and Mikhael et al. 43 This is more commonly associated with the patients' economic position, fear of needles, the erroneous belief that blood glucose will remain normal with timely medicating, physical activity, and dietary modifications. A study by Ji et al 21 also demonstrated that blood glucose monitoring was the lowest priority of patients with diabetes when compared to medications, diet, and physical activity. The results of this study emphasized the importance of improving self-management knowledge and behavioral beliefs in patients with diabetes. Efforts directed toward practical and person-centered diabetes selfmanagement education and support programs are necessary to improve patients' knowledge and behavioral beliefs and self-management levels.

A shortage of resources was frequently identified as the key factor that inhibited diabetes self-management in this study. Issues such as limited space at the isolation sites, unavailability of blood glucose monitoring resources, absence of a diabetic diet, and undersupply of hypoglycemic medications, were repeatedly mentioned by the participants. For instance, some participants expressed that the standardized diet at the isolation sites led to the inability to perform self-management in accordance with their specified nutrition plans. This finding was consistent with previous findings that residing in a community with limited healthy foods and the absence of safe exercise environments may be an important barrier to diabetes self-care and glycemic control. 46, 47 For all participants in this study, the provision of resources needed for diabetes selfmanagement by the isolation facilities was a significant issue. However, as was widely recognized, the locations used for isolation of COVID-19 patients had a unified layout and lacked the facilities conducive to diabetes selfmanagement. This finding suggests that creating a favorable environment for self-management of chronic diseases at the isolation sites, such as the provision of a diabetic diet and blood glucose monitoring as part of a daily health management program, is extremely important for the improvement of the quality of life and health of patients.

Suffering caused by the disease was a great barrier that emerged from the transcripts. This is consistent with the findings of Hu et al, 45 in which patients' physical suffering kept them from properly managing their disease. Moreover, the results of the present study provided additional evidence that COVID-19 may result in elevated blood glucose levels, which was congruent with the findings reported by Ilias et al 48 and Brufsky. 49 Persistently high blood glucose may cause frustration in patients, thereby affecting their passion towards self-management. Five participants in this study stated that they suffered from severe insomnia. In keeping with our findings, Xue et al 50 also reported significant sleep problems (eg, difficulty falling asleep, early awakenings) in the forced isolation population. In addition, poor sleep quality has been found to be significantly associated with decreased adherence to dietary, lower self-care adherence, and poorer diabetes control. 51 Given disease related suffering, it is imperative for healthcare and COVID-19 isolation organizations to develop and implement strategies to deliver continuous care for discharged COVID-19 patients, especially those with diabetes.

Negative emotions were discussed as a psychological barrier to self-management. Half of the participants felt stigmatized, which was mainly manifested as societal rejection; one-third complained about poor service at the isolation sites, and one-third expressed anxiety. Although the public health response to COVID-19 has been essential in preventing and containing the epidemic, it may also have aggravated the stigmatization of patients. 52, 53 Forced isolation and the associated measures have disrupted the social lives of patients with diabetes, resulting in them feeling fearful and trapped. Armitage et al 54 reported that social isolation exposes older adults to greater risks of negative emotions such as depression and anxiety. An online study conducted in Italy reported that longer isolation times, combined with smaller physical spaces, led to a deterioration in mental health. 55 Moreover, psychological distress affected the medication adherence and self-management of patients with diabetes. 31 Kato et al 56 found that the nonadherence behaviors of patients with diabetes may be a response to the internalization of stigma. Self-stigma is a negative independent factor that affects the self-care behavior of patients with T2DM. 57 Our results confirmed these findings and suggested that greater emphasis should be placed on the mental health of this vulnerable population, and healthcare and COVID-19 isolation organizations should adopt multifaceted strategies to eliminate potential drivers of negative emotions in isolated patients.

This study revealed that the lack of professional guidance from healthcare providers (eg, self-care measures, maintenance of target blood glucose, monitoring of complications) is a common barrier to diabetes selfmanagement. Healthcare providers play a unique role in delivering person-centered diabetes self-management education, supporting interventions, and assisting patients to undertake protective self-care behaviors. 58 Other qualitative studies have reported similar findings whereby patients with limited resources were particularly challenged when seeking medical services or obtaining care and support. 59, 60 Apart from the scarcity of guidance from healthcare providers, the participants also identified the lack of family support as another barrier to diabetes selfmanagement. During the isolation period, it is difficult for diabetes patients to obtain knowledge, care, and material support from their family members, although this support was essential for promoting lifestyle changes and improving self-management behavior in patients with diabetes. 23 Such a result matches the findings of previous studies, which considered family members, friends, and peers of patients with diabetes as primary promoters of selfmanagement. 30, 59, 61 Similarly, quantitative studies have also indicated that a higher level of social support is associated with better adherence to recommended selfmanagement behaviors. [62] [63] [64] In conclusion, there was insufficient support to encourage diabetic selfmanagement of the isolated patients. Such problems may be resolved by establishing electronic blood glucose records and a remote consultation system to provide practicable diabetes self-management education and support, and by enhancing telephonic and internet-based family support.

This study had several limitations. First, we obtained data from a small geographical area (Wuhan City) and a small, convenient sample (12 patients with diabetes), which might limit the generalizability of the findings. Second, our analysis was based on interview data. Therefore, it was impossible to explore the differences between the demographic characteristics (such as gender and education level) of the barriers to diabetes selfmanagement. Third, this study explored barriers to diabetes self-management from the patients' perspectives, without considering the experience of healthcare providers and family members. Fourth, qualitative studies have inherent limitations, such as the tendency for subjectivity during data analysis. Future research should collect data from larger samples or adopt a multicenter approach to obtain a broader view of barriers to diabetes self-management.

Our findings provide insight into barriers to diabetes selfmanagement among T2DM patients during isolation following recovery from COVID-19. We found that inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support were barriers to self-management among patients with diabetes. Understanding these barriers is beneficial for the formulation of targeted strategies, such as creating favorable isolation environments, strengthening medical and social support, and implementing patient-centered diabetes care, to promote successful self-management. At present, as many countries around the world are still in the critical period of pandemic prevention and control, greater concern should be paid to patients with diabetes during isolation. In addition, open dialogue among patients, healthcare providers, family members, and policy makers can be established to better support patients' diabetes journey and improve health outcomes. 

This study was approved by the Ethics Committee of Hunan Academy of Traditional Chinese Medicine Affiliated Hospital (Approval No.202003-09). We explained the objective, process, and methods of the study to the participants and obtained verbal informed consent prior to each telephonic interview. Participants were assigned anonymous identification numbers (P1, P2, etc), and personally identifiable information was deleted from the transcripts to protect patient privacy. The interview data were kept strictly confidential, and all audio recordings and transcripts were stored in a passwordprotected computer. Interviewees were free to withdraw from the study at any time without any reason.

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Original research, review, case reports, hypothesis formation, expert opinion and commentaries are all considered for publication. The manuscript management system is completely online and includes a very quick and fair peer-review system

We would like to express our gratitude to the Hunan Academy of Traditional Chinese Medicine Affiliated Hospital for the approval and support of this study and all participating patients for providing valuable information regarding barriers to the self-management of DM. Furthermore, we wish to express our gratitude to the Hunan Academy of Traditional Chinese Medicine for providing financial and material support. Finally, we thank our advisors Dr. Chunyan Li and Dr. Yinhua Zhang for their contribution of valuable insights in the process of this study. 

The authors report no conflicts of interest in this work.
