Based on dynamic changes of indicators during controlled ovarian hyperstimulation and of clinical outcomes of suboptimal ovarian response with different protocols, this study aimed to summarize the clinical characteristics of SOR and provide clinical recommendations.in vitro fertilization-embryo transfer were collected from a single medical center from January 2017 to January 2019. Basic clinical indexes, including age, BMI, antral-follicle count, infertility time, basic follicle-stimulating hormone, luteinizing hormone, LH/FSH ratio, estradiol, progesterone, testosterone, androstenedione, prolactin, anti-Mullerian hormone, and thyroid stimulating hormone levels, were analyzed using T-test. Dynamic indexes during COH, including amount and days of gonadotropin, sex hormone levels, and number of large/medium/small follicles at specified time periods, were analyzed using T-test and joint diagnosis analysis with ROC curves. Indexes of laboratory and clinical indicators were analyzed using the chi-square test.Data of 125 patients with SOR and 125 controls who had undergone appropriate protocols for 2, respectively. A combined diagnosis of the two indexes showed higher sensitivity (90%) and specificity (59%). In the GnRH-ant group, ROC curve analysis showed an LH level, an LH/FSH ratio on COH day 2, and BMI yielded cutoff values of 2.47 IU/L, 0.57, and 23.95 kg/m2, respectively. Combining the two indexes with BMI, both showed increased sensitivity (77%) and specificity (72% and 74%). The estradiol level and progesterone level during the late follicular stage in SOR patients were significantly lower than those in control patients for both protocol groups. At each monitoring time, delayed follicular development was observed. The live-birth rate in fresh cycles of the ultra-long/long group and the live-birth rate in cumulative cycles of the antagonist group in the SOR group were lower than those in the control group.For the SOR group, BMI, duration time, and dosage of gonadotropin used for SOR were significantly higher. In the ultra-long/long group, ROC curve analysis showed that the LH/FSH ratio and BMI yielded cutoff values of 0.61 and 21.35 kg/mSOR had adverse effects on clinical outcome. We provide some threshold values of basic LH/FSH ratio, BMI, COH day 2 LH, counts of follicles, and levels of estradiol/progesterone to be taken as reference to assist the early recognition of SOR. During the IVF process, most patients undergo normal reactions, which have not been clearly defined. According to experts, indicators, including age, ovarian reserve function, and past history of COH (low or high reaction), could be used to comprehensively evaluate ovarian reactions. Women with pure oviduct factors and/or male infertility belong to the population with normal ovarian reactions. Specific indicators predicting ovarian normal reaction (In controlled ovulation hyperstimulation (COH) during reaction  include In addition to the normal response, a considerable proportion of patients showed high and low ovarian responses, accounting for approximately 20% and 10%, respectively Figure 1Currently, several studies have been conducted on SOR, but its mechanism of occurrence and related factors remain elusive. Additionally, its effect on COH and pregnancy outcomes is inconclusive. SOR may have a negative effect on the outcome of ovulation induction and pregnancy . Since SA retrospective analysis was performed on clinical data from 125 patients with SOR  who underwent IVF-ET at Peking University Third Hospital from January 2017 to January 2019. According to the COH ovarian stimulation protocol, they were divided into ultra-long and long protocol group (71 cases) and antagonist protocol group (54 cases). Due to the limited sample size and similarity between the mechanisms of the ultra-long protocol and long protocol, both groups were combined into a single group for the analysis. The control group consisted of 125 patients with normal ovarian response who had undergone IVF-ET during the same period as the SOR group, with a similar number of patients in the corresponding protocol group in the SOR group. Due to attrition resulting from patients who canceled the cycle, some medical records were incomplete. Therefore, canceled cycles were not analyzed in this study. An overview of the patient recruitment process is shown in Generally, evaluation of ovarian function is based on age, weight, AFC, serum level of AMH, and basal serum level of hormones, followed by the development of COH protocols. Commonly used drugs during standardized long or ultra-long protocols include GnRH-agonist (GnRH-a) and Gn, while those during antagonist protocol are Gn and GnRH-antagonist (GnRH-ant). GnRH-a mainly used in our center include Diphereline  or Enantone , and Gn used in our center include 1) recombinant FSH: Gonal-F , Puregon , and Urofollitropin ; 2) menotropins for injection  and Menopur ; and 3) recombinant LH: Luveris (Merck Serono S.A). Antagonists used in our center include cetrorelix acetate  and Ganirek .Recombinant HCG (Merck Serono SA Aubonne Branch) was injected to retrieve oocytes. COH protocols refer to expert consensus on assisted reproduction ovulation induction drug treatment . The treThe dose and type of Gn were adjusted based on the patient’s age and follicular development. The patient’s level of serum LH, E2, and P and diameter of the follicles were monitored. When the patient’s dominant follicles’ diameter reached ≥18 mm, 250 μg of HCG  or Ovidrel  was injected intramuscularly. Thirty-six hours later, the oocytes were retrieved under vaginal ultrasound guidance. IVF or intracytoplasmic sperm injection (ICSI) fertilization was chosen based on the condition of the semen.The embryos transferred were clinically transferable embryos, and the embryo transfer program included the cleavage embryo transfer and blastocyst transfer. The Reproductive Medical Center of Peking University Third Hospital assessed the morphology of cleavage embryos based on the number of blastomeres for uniformity in size and fragmentation of the blastomeres. The embryos could be used with at least four cells and cell fragments below 30%. The blastocyst-stage embryo scoring used the blastocyst grading system proposed by Gardner et al. . AccordiOur center routinely performed fresh embryo transfer on day 3 post-fertilization. In the presence of factors that were not suitable for fresh embryo transfer, such as high risk of ovarian hyperstimulation syndrome (OHSS), endometrial factors, uterine effusion, progesterone elevation, and personal factors, the transfer would be cancelled, and remaining embryos or blastocysts would be vitrified and frozen, and thawed embryo transfer (FET) would be performed at an optimal time.Luteal phase support would be provided routinely after embryo transfer, involving oral, vaginal, or intramuscular progesterone. A blood test was performed after 14–16 days of transplantation. Serum HCG >5 mIU/ml was defined as a positive result  kit from Beckman Coulter, Brea, CA, USA). Biochemical pregnancy referred to the pregnancy in which the blood HCG was positive, but the gestational sac echo was not detected by ultrasound. When serum HCG levels were elevated, transvaginal ultrasound was performed about 4–5 weeks after embryo transfer, and the pregnancy sac was found in or outside the uterine cavity, clinical pregnancy was diagnosed. In the absence of pregnancy, corpus luteum support was stopped. If intrauterine pregnancy was confirmed, luteal support was continued until 9–10 weeks of pregnancy.Age, age of spouse, body mass index (BMI), AFC, years of infertility, basic FSH, basic LH, basic E2, basic pituitary prolactin , basic testosterone (T), basic androstenedione (AND), basic thyroid stimulating hormone (TSH) levels, levels of AMH, LH, FSH, E2, and P on 2nd day of COH, and vaginal ultrasound were used to detect the number of ovarian antral follicles. Follicle sizes were defined as follows: minimum follicle, diameter ≤10 mm; small follicle, 10 mm < diameter ≤15 mm; medium follicle, 15 mm < diameter of follicle ≤18 mm; large follicle, diameter >18 mm. Hormone levels were measured by electrochemiluminescence , and the operation was performed according to the manufacturer’s instructions.Gn using days; Gn using dose; COH 2nd-day FSH, LH, P, and E2 levels; changes in follicle number and diameter; LH, P, and E2 levels on COH 6th–8th, 9th–11th, 12th–14th, and 15th–17th days, and others; P/number of large follicles ; and P/E2 ratio on HCG day were the indicators of ovulation induction.These indicators included number of oocytes obtained, 2PN oocytes, fertilization number, cleavage number, high-quality embryo number, and corresponding 2PN rate, fertilization rate, cleavage rate, and high-quality embryo rate.They included biochemical pregnancy rate, clinical pregnancy rate, live birth rate, abortion rate, and term birth rate. As the data of patients whose cycles were cancelled due to SOR in our center were lost to follow-up due to the patients’ personal reasons, the statistics of SOR incidence and cycle cancellation rates were not accurate. Therefore, these two indicators were not calculated.All statistical analyses were performed using SPSS 24.0 (IBM SPSS Statistics CRZ1AML for Windows). Measurement data were expressed as mean ± standard deviation, and enumeration data were expressed as rates (%). Measurement data were tested for normality (P > 0.05). The data were normally distributed; therefore, t-test was used. The enumeration data were assessed using the chi-square test. The ROC survival curve was used to calculate the cutoff value, and the unconditional binary regression model was used for multivariate analysis. P < 0.05 indicated that the difference was statistically significant.Among patients enrolled, the baseline data of patients in the ultra-long and long protocol group were compared separately, and no statistical difference was observed (P > 0.05) Table 1.In the ultra-long and long protocol group, the SOR group had a longer response time to downregulation and longer Gn application time than the control group, and their total dose of Gn using was more than that of the control group. The basic LH/FSH ratio of the SOR group was 0.63 ± 0.37, significantly lower than the value of 0.84 ± 0.65 in the control group (P < 0.05)  with significance (P < 0.05). The number of small follicles in the SOR group on days 15–17 of COH was 7.03 ± 4.21, significantly higher than that of the control group, which was 4.75 ± 1.73 (P < 0.05), whereas the number of small follicles on days 9–11 of COH in the SOR group, the number of medium follicles on days 12–14 of COH in the SOR group, and the number of large follicles on days 15–17 of COH in the SOR group were lower than those in the control group (P < 0.05) indicators with statistical differences between the SOR group and control group in each protocol group.In the univariate analysis, the data with statistical differences in the early follicular phase and the median follicular phase were analyzed using the ROC curve according to the COH time sequence. Additionally, the threshold of SOR occurrence and the corresponding sensitivity and specificity of each index were calculated. The results are shown in In the antagonist protocol group, the SOR group had a longer downregulation time and ovulation induction time than the control group, and the total amount of Gn used was more than that of the control group. The level of serum LH of the SOR group on day 2 of COH was 3.28 ± 2.22 IU/l, significantly lower than 4.79 ± 3.57 IU/l in the control group (P < 0.05). Conversely, the LH level on HCG day in the SOR group was 3.10 ± 2.50 IU/l, higher than 1.91 ± 1.16 IU/l in the control group Figure 6In the univariate analysis, the data with statistical differences in the early and median follicular phases were analyzed using the ROC curve, according to the COH time sequence separately. The threshold of SOR occurrence and the corresponding sensitivity and specificity were calculated. The results are shown in Among the three COH protocol groups, compared with the control group, the SOR group had no statistical difference (P > 0.05) in the number of oocytes obtained, fertilized oocytes, 2PN oocytes, cleavage, and high-quality embryos and the rate of 2PN and high-quality embryos Table 4.The cumulative live-birth rate of the SOR group (40.54%) in the antagonist protocol group was lower than that of the control group (79.36%); the difference was statistically significant (P < 0.05). Compared with the control group, the biochemical pregnancy rate, clinical pregnancy rate, live-birth rate, miscarriage rate, and full-term birth rate of the SOR group were not different from those of the control group (P > 0.05) . A small section of the population could be more sensitive to downregulation, exhibiting excessive pituitary suppression and insufficient LH levels , 15. UsuOur results indicated that during the process of COH, the levels of E2 and P in each protocol group of the SOR group were lower than those of the control group. The relatively lower E2 is mainly manifested in the early follicular phase, whereas the lower serum P is mainly manifested in the late follicular phase. This reason of lower E2 lies in that, in the early follicular phase, LH can stimulate the theca cells (TCs) to synthesize androgens, which are substrates for estrogen synthesis, and estrogen plays an important role in follicular growth and development. When the downregulation is too deep and the level of serum LH is too low, androgen synthesis will be insufficient, leading to a poor increase in serum E2 level and follicular development stagnation.With regard to lower serum P, of note, it mainly happened at the late follicular phase in our study. Progesterone in the early follicular phase is mainly secreted by the adrenal glands, whereas progesterone in the late follicular phase is mainly derived from the ovaries, and this steroidal conversion by the adrenal gland is regulated by the ovaries . GCs expPrevious studies have shown that a high PFI , 19 and In the ultra-long/long protocol group, the minimum follicle number in the SOR group on COH days 6–8 was more than that in the control group, and this difference persisted until COH days 12–14, whereas the number of relatively larger follicles was lower than that in the control group, which is shown by the fact that in the cross section of each monitoring time, the retardation of follicular development persists and gradually accumulates.Notably, the number of large follicles in the SOR group in the late follicular phase was lower than that in the control group in both protocol groups, but statistical difference only showed in the ultra-long/long protocol group. It might be caused by our limitation to a single center and small sample size but more likely due to the pituitary downregulation treatment in the ultra-long/long protocol, because correction of the excessively deep pituitary inhibition state through the adjustment of Gn in the later stage is more difficult in this group, resulting in the difficulty for the final number of mature follicles to reach the normal level, whereas for patients in the antagonist protocol group, Gn is activated without pre-pituitary downregulation.There is no significant difference in laboratory outcomes between SOR patients and control patients in both protocol groups, possibly due to the prolonged use of Gn because clinicians in our reproductive center identified SOR in the early stage of the COH process and added r-LH/HMG or prolonged the time frame of treatment to revert SOR to a normal response. Early identification and remedial measures are essential to transforming SOR to a normal response to obtain good clinical outcomes.Lower fresh-cycle live-birth rates of the SOR group were recorded in the ultra-long/long protocol group (P <0.05), and lower cumulative-cycle live-birth rates of the SOR group were recorded in the antagonist protocol group (P <0.05), indicating that the occurrence of SOR has an adverse effect on pregnancy outcome, although no significant difference of laboratory outcomes between SOR patients and control group. Because of technical limitation, we can only asses the outcome of COH referring to the number of oocytes retrieved and the morphology of oocytes and embryos, but not the quality of the oocytes in in essence . On the Recognizing that SOR in time is important clinically, in most cases sensitivity has greater clinical significance than specificity; clinicians should at least detect patients at higher risk first and distinguish real SOR patients. A comprehensive evaluation of these indicators can improve the detection sensitivity of SOR.2, the patient is more likely to have SOR, and clinicians need to have a high index of suspicion to deal with such cases in time. In the follow-up period of follicular monitoring, when the minimum follicle number on COH days 9–11 >10.5, number of small follicles on COH days 9–11 <3.5, minimum follicle number on COH days 12–14 >5.5, or number of medium follicles <2.5, and serum P <1.52 nmol/l, the patient may have already experienced SOR at this time, and the clinician should be able to manage. COH days 12–14 belong to the middle follicular phase; therefore, if not treated in time, SOR may not be rescued.Based on our results, for patients who adopt the ultra-long/long protocol, when the basic LH/FSH ratio <0.61 and the BMI >21.35 kg/m2, or the LH/FSH ratio on COH day 2 <0.57 and BMI >21.35 kg/m2, SOR may possibly occur, and clinicians should have a high index of suspicion to detect and manage the patient early. In the follow-up follicle monitoring period, COH days 9–11, serum E2 <3,372.0 pmol/l, serum P < 1.62 nmol/l, minimum follicle number >8.5, minimum follicle number on COH days 12–14 >5, or number of large follicles <2.5 indicates that the patient has already experienced SOR at this time and needs to be treated in time; otherwise, SOR may not be rescued.For patients undergoing the antagonist protocol, when LH on COH day 2 <2.47 IU/l and BMI >21.35 kg/mDue to the limitation of sample size, this study did not separately calculate the indicators of the ultra-long protocol and long protocol. Therefore, the results are limited in clinical application, but they serve as reference and foundation for future studies with larger sample sizes.Based on our study, some points should be emphasized. In treating patients with SOR, first, an experienced doctor should comprehensively and accurately assess the patient’s general condition to the greatest extent. Previous history of SOR or even a poor COH outcome and all possible related risk factors of SOR should be brought to the forefront, including general condition such as BMI, previous IVF records, ovarian reserve, uterine condition, and basal serum hormone condition, to assess the function of the hypothalamic–pituitary–ovarian (HPO) axis. Patients with obesity should be recommended to lose weight .Next, during the COH process, clinicians should carefully observe the patient’s follicular growth, serum E2 level, and COH time to identify abnormal growth conditions. Here based on our analysis, some threshold values of some clinical indexes including BMI and levels of serum sex hormones are provided to be taken as reference for the early recognition of SOR.In our reproductive center, Gn dosage was calculated according to the estimated ovarian function based on clinical routines and adjusted during the COH process according to the experience of clinicians. In most cases, the application of FSH should be sufficient, and even if insufficient, the monitoring doctors make adjustments to supplement the FSH dosage when patients first return to the hospital on days 4–6 following FSH severing; therefore, the majority of patients have good outcomes. However, SOR still occurs, indicating the complexity of SOR. We could preliminarily divide the possible causes of SOR into the following categories: 1) too deep pituitary function suppression by GnRH-a; 2) different sensitivity to Gn in the patient population, some of which might be explained by FSH receptor and/or LH receptor gene polymorphism  20); 3); 3)20); Currently, receptor polymorphism inspection is not able to be widely used in clinic because it is time-consuming and money-consuming for most patients; of course, for patients with unexplained refractory SOR, FSH/LH receptor gene polymorphism inspection should be suggested to patients. Half-dose long-acting injection of GnRH-a or even 1/4~1/3 dosage can be considered to prevent excessive suppression of the pituitary gland for some patients with a history of SOR . Informed consent was waived because this was a data analysis with no personally identified information. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YY performed the literature search, collected and analyzed the data, and wrote the manuscript; RQ, XM, and SQ helped screening the medical records and collecting the data; XN and LC helped analyzing the data; RY, YW, RL, and JQ critically reviewed and revised the manuscript. All authors read and approved the final submission.This work was supported by National Natural Science Foundation of China [81873833], National Natural Science Foundation of China [81550022], and Key Clinical Research Project of Peking University Third Hospital (BYSY2018016).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The extraction of retinol serum was performed and analyzed using the high-performance liquid chromatography method (HPLC). The retinol level was calculated in mmol/L, and levels below 0.7 μmol/L (20 µg/dL) were considered to be a vitamin A deficiency. Our findings suggest that the participants with mild and critical COVID-19 had lower retinol levels compared to the healthy controls (p = 0.03). In addition, milder cases of COVID-19 were associated with increased symptoms and prolonged symptoms after 90 days since the beginning of infection. However, the survival analysis showed no association with higher cases of death among participants with vitamin A deficiency (p = 0.509). More studies are needed to understand how nutritional status, including vitamin A levels, can influence prognosis and is a risk factor for the development of long COVID syndrome.The new coronavirus infection represents a serious threat to global health and economies. In this sense, it is paramount to know the nutritional factors that may be related to the prognosis of the disease. Evidence shows that vitamin A may play an important preventive and therapeutic role in supporting respiratory infections as in COVID-19. The aim of our study was to evaluate the association of vitamin A (retinol) status with the prognosis of the disease. A case–control study from a cohort study was conducted in Brazil between May and October 2020. The study population was chosen by convenience, consisting of participants diagnosed with COVID-19. Recruitment was carried out using different approaches, including through dissemination on social media and in four hospitals in the city of Natal/RN, Brazil, recruiting participants from the COVID-19 ward and hospitalized participants who tested positive for the disease. The participants were allocated into two groups according to severity, with a group of mild ( A new coronavirus was reported by researchers in Wuhan City, Hubei Province in China. On 30 January 2020, the World Health Organization declared the SARS-CoV-2 epidemic a health emergency of international concern . It subsAlthough vaccination has been effective in significantly reducing the development of severe cases of the disease, it does not prevent infection. In addition, the need for booster doses is still being investigated. Part of the population has been shown to be resistant to immunizations, and the specific antiviral medication is controversial. In addition, the emergence of new variants threatens global health and economies .Moreover, management of the patient after discharge is still a challenge, since many patients persist with symptoms 4 weeks after the onset of the disease, being characterized in the literature as “post-COVID syndrome” or “long COVID”. The most common symptoms include anosmia, fatigue, chest pain, hair loss, difficulty concentrating, and sexual dysfunction . The etiThe role of nutritional status and diet are widely discussed in the literature given their importance in controlling and treating infections. In the context of COVID-19, nutrients have been associated with decreased cytokine storm due to their anti-inflammatory capacity . EvidencThe biological role of retinoids is widely discussed, including the maintenance of vision and health, epithelial and mucosal regulation, bone metabolism, and antioxidant properties . VitaminVitamin A has been shown to be a potential therapeutic target for COVID-19 through mechanisms including the inhibition of inflammatory responses and biological processes associated with reactive oxygen species, possibly binding to fatty acids in the spike protein in SARS-CoV-2, inhibiting its entry into the cell and signaling gene expression, which induces the neutralization of signals associated with COVID-19 ,16,17,18Thus, this study characterized a population of mild and critical patients with COVID-19 and their retinol levels compared to a control population. Our objective was to evaluate the association of vitamin A (retinol) status with disease prognosis and discuss possible explanations for the associations found.2) < 94%, the arterial partial oxygen pressure to the fraction of inspired oxygen (PaO2/FiO2) ratio < 300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%, and/or respiratory failure, septic shock, and/or multiple organ dysfunction [This case–control study was conducted between May/2020 and October/2020. The study population was chosen by convenience and composed of adults and older adults (from 18 years of age) of both sexes, diagnosed with COVID-19 through polymerase chain reaction (PCR) or serology performed by immunofluorescence. Recruitment was carried out using different approaches: the first was through dissemination on social media , local media , and in 4 hospitals in the city of Natal/RN, Brazil, recruiting participants from the COVID-19 ward and hospitalized participants who tested positive for the disease. Participants were grouped by disease severity according to the National Institutes of Health 2022) criteria: mild when presenting any of the signs and symptoms of COVID-19, but who did not have shortness of breath, dyspnea, or abnormal chest imaging; critical cases were considered as those with oxygen saturation levels  from self-reported values by the study participants or from the electronic medical records of the hospitals. The control group came from the database of a previous study by our research group , consistg) after thawing to separate the whole blood and the serum. Finally, aliquots containing 500 μL of serum were stored at −80 °C until the biochemical analysis. The retinol serum extraction was performed according to a method adapted from Ortega et al. (1998) [Peripheral blood samples were collected by trained professionals in a home environment or made available by selected hospitals. The samples were allocated in tubes for serology with separator gel and then taken for centrifugation (at room temperature) for 5 min (500× . (1998) , and ana. (1998) .n absolute. We used the Kruskal–Wallis test followed by a post-hoc test to evaluate the differences among the continuous variables. The chi-squared independence test was used to detect associations among the groups of categorical variables. Survival was assessed using Kaplan–Meier survival curves. Differences among the groups were considered statistically significant when the p-value was less than 0.05.The collected data were transferred to the Research Electronic Data Capture  input tool and analyzed by the Statistical Package for the Social Sciences (IBM SPSS Statistics version 26). The Kolmogorov–Smirnov test was used to determine the normality of the variables. The continuous variables were represented by the median (interquartile range—IQR) and the categorical variables by the percentage and As shown in p = 0.241) or sex (p = 0.973) among the groups, showing homogeneity among the participants regarding these variables. No significant differences were found in relation to body mass index (p < 0.001). Similarly, higher ALT, AST, and creatinine values were observed in critical participants, which were significantly different than in the other groups.A higher median age of 67  years was observed in critical participants, which was significantly higher than in the other groups studied (p < 0.001) in the numbers of comorbidities in the participants between the groups. Participants with 1 to 2 comorbidities were more frequent among mild cases, totaling 55.7% (49). Among the critical cases, the highest frequency of participants in this group presented 2 to 3 comorbidities, totaling 41.5% (44).As shown in p < 0.001) between the groups.However, the mild participants had more symptoms associated with COVID-19 compared to the critical participants. While the critical participants had mostly 1 to 4 symptoms, representing 67.9% (72) of this group, there was a greater variation in the reported symptoms among the mild cases, since 26.4% (23) had 1 to 4 symptoms, 34.5% (30) had from 5 to 8, and 31.0% (27) had more than 9. There was a significant difference (p < 0.001) compared to the mild patients, with a median of 24  days versus 10  days.In addition, participants with critical COVID-19 had a longer duration of illness (p = 0.036) between the mild participants and the controls (p = 0.036). In addition, deficiency prevalence was also found in higher frequency among the mild cases compared to the control group (p = 0.001), with 38.60% (34) of participants in this condition.Higher retinol levels were observed in the control group, with a median of 1.85  mmol/L, compared to the participants with COVID-19, in which median values of 1.20  mmol/L were found among the mild cases and 1.58  mmol/L among the critical cases, as shown in p = 0.01), both groups showed high CRP values (>0.3 mg/dL) according to the reference.The median CRP values were 2.70 mg/dL  among the mild participants and 14.05  mg/dL among the critical participants, as shown in p = 0.509) were found in the Kaplan–Meier survival analysis between deaths (outcome) and participants’ retinol status (factor) in the time between the date of diagnosis and contact 90 days later , immunosuppression, and diabetes ,27,28,29Although the mild participants had a lower number of comorbidities compared to the critical cases, a higher frequency of reported symptoms was observed among these participants. Differences in the distribution of initial symptoms between severe cases and mild cases were evaluated in a meta-analysis , includiHowever, with advancing age, the ability to report the presence of symptoms, and the alteration of perceptions such as the senses  are diminished by genetic and environmental causes that alter the anatomy and physiology of the systems involved, compromising their ability to feel and report these variations ,32,33. IThe mild participants were more likely to have persistent symptoms after 90 days from the onset of the disease. The emergence of “long COVID”, a term currently adopted to describe a diverse set of persistent symptoms in participants with COVID-19, is suggested after a minimum of 4 weeks since the onset of infection . FindingAlthough the mechanisms surrounding COVID-19 are not fully understood, in previous epidemics of SARS, H1N1, and Ebola, for example, cases of participants who had symptoms even after the disease have also been reported . The preWhen compared to the control group, the highest age group was also found among the critical participants. In addition, increased creatinine, AST, and ALT levels were observed in the critical participants, differing significantly from the groups compared. The literature explains a significant association between high creatinine, ALT, and AST levels and the severity of COVID-19. The identification of these clinical laboratory predictors is important for risk stratification and to evaluate disease progression ,39. The participants were also evaluated for their nutritional status of vitamin A (retinol), where the median ROH values were lower among the mild participants, who also presented a higher deficiency frequency for this micronutrient. Experimental studies have shown that retinoic acid-inducible gene-I (RIG-I) rapidly consumes a large amount of the body’s retinoid reserve for viral identification mechanisms during SARS-CoV-2 infection, leading to decreased plasma retinol levels during infection. These findings also suggest that the serum values of these micronutrients may be reduced during COVID-19 ,16.However, overexpression of the SARS-CoV-2 N protein suppresses the activation of retinoic acid-inducing gene type I (RIG-I), preventing interaction between the tripartite protein 25 (TRIM25) and RIG-I and interaction with the DExD/H domain, which prevents activation of this inflammatory pathway. These results demonstrate that a high viral load, as is the case for critical participants, can attenuate activating this receptor, and therefore, maintain plasma vitamin A levels, since they are not being used for the activation of these receptors ,17,18. Studies have shown a range from 0.18 to 1.68 μmol/L of retinol in patients with COVID-19, for which the blood levels were lower in the patients than the controls, similar to our findings ,42,43,44In this case, the retinol values in the participants with COVID-19 may be reduced as a result of a decrease in their carrier, and not necessarily because they have decreased baseline values. C-reactive protein (CRP) is a protein synthesized by the liver, and its levels increase in response to inflammation. At the same time, the production of a number of other proteins is reduced, as is the case with retinol-binding protein (RBP). Thus, the decrease in hepatic RBP synthesis may reflect a lower secretion of retinol from hepatic stores, even in situations of adequate hepatic reserves .As limitations of this study, we can highlight the difference in the collection times between the evaluated groups, since the mild participants had their samples collected after isolation, and the critical participants at the time of hospitalization. Another point is the lack of previous information on these participants that could demonstrate the real influence of the infection on the parameters evaluated, as well as the size of our cohort, especially the control group. However, the sample size was sufficient to carry out the statistical analyses presented and create comparative groups. In addition, it was possible to identify that the participants with COVID-19 had significantly different changes according to severity, and also compared to the control group. Additional studies are important to investigate how nutritional status, including vitamin A, may be influencing the persistence of symptoms after COVID-19.Our findings show that the COVID-19 participants had lower retinol levels compared to the controls. The critical participants had a higher median age and worse prognosis, such as longer disease time, need for hospitalization, death, and a greater number of comorbidities. In addition, milder cases of COVID-19 were associated with increased symptoms and prolonged symptoms 90 days after the beginning of infection. However, the survival analysis showed no association between higher cases of death among the participants with vitamin A deficiency. More studies are needed to understand how nutritional status, including vitamin A levels, can influence long COVID syndrome.


Introduction: Type 2 diabetes (T2D) is a multifactorial complex chronic disease with a high prevalence worldwide, and Type 2 diabetes patients with different comorbidities often present multiple phenotypes in the clinic. Thus, there is a pressing need to improve understanding of the complexity of the clinical Type 2 diabetes population to help identify more accurate disease subtypes for personalized treatment.Methods: Here, utilizing the traditional Chinese medicine (TCM) clinical electronic medical records (EMRs) of 2137 Type 2 diabetes inpatients, we followed a heterogeneous medical record network (HEMnet) framework to construct heterogeneous medical record networks by integrating the clinical features from the electronic medical records, molecular interaction networks and domain knowledge.Results: Of the 2137 Type 2 diabetes patients, 1347 were male (63.03%), and 790 were female (36.97%). Using the HEMnet method, we obtained eight non-overlapping patient subgroups. For example, in H3, Poria, Astragali Radix, Glycyrrhizae Radix et Rhizoma, Cinnamomi Ramulus, and Liriopes Radix were identified as significant botanical drugs. Cardiovascular diseases (CVDs) were found to be significant comorbidities. Furthermore, enrichment analysis showed that there were six overlapping pathways and eight overlapping Gene Ontology terms among the herbs, comorbidities, and Type 2 diabetes in H3.Discussion: Our results demonstrate that identification of the Type 2 diabetes subgroup based on the HEMnet method can provide important guidance for the clinical use of herbal prescriptions and that this method can be used for other complex diseases. Type 2 diabetes (T2D) is the most common type of diabetes and accounts for approximately 90% of all diabetes cases worldwide; T2D is a complex, serious and multifactorial chronic disease that has become an increasingly prevalent health issue and imposes a tremendous economic burden worldwide . People Precision medicine has been recognized as a new medical approach for refining the disease taxonomy and improving the healthcare capability . RecentlIn this study, we collected large-scale real-world TCM clinical data on T2D and used an established heterogeneous medical record network (HEMnet)  method tThe data of 2137 inpatients diagnosed with T2D were collected from the EMR database of the Second Affiliated Hospital of Shandong University of TCM from 2016 to 2021, which included all inpatient information obtained during hospitalization, such as demographic information, symptoms, laboratory or physical tests, diagnoses and treatment. Because most data were in free text that cannot be used directly for analysis, we used a clinical information extraction tool  to efficIn this study, several external data sources were used to support this research. The efficacy of botanical drugs was extracted from ChP 2020, and human protein‒protein interactions (PPIs) were obtained from the STRING database . The phe1) PPI. This network was based on HumanNet, an external network of protein-encoding genes . The nod2) Phenotype–genotype associations. This network was obtained from SymMap. The nodes were phenotype or genotype, and the undirected edges were the association of the phenotype and genotype.3) Co-occurrence of clinical entities from the EMR. We directly added the clinical cooccurrence edges of botanical drugs from each medical record. The missing data was one of the main challenges of electronic medical records (EMR) analysis, especially the lack of symptom information. Botanical drugs can represent symptom precision to address missing symptom information in EMR. We repeated this for all clinical features in each patient’s medical record.Missing data and semantic mismatch were the two main challenges of EMR analysis. Therefore, we used HEMnet to address the challenges of EMR analysis by leveraging information from several external sources to supplement clinical data . In our Then, HEMnet uses an embedding method, ProSNet , to infeThe K-means clustering  was usedRR = (Cij/Ci)/((Cj-Cij)/(N-Ci)), where Ci is the number of patients in subgroup i, Cj is the number of patients with a clinical feature j, Cij represents the number of patients in subgroup i and with a clinical feature j and N is the total number of patients in the study. A p-value <0.05, which was obtained from the chi-square test, and an RR > 1 indicated that a clinical feature was truly significant.The chi-square test and relative risk (RR)  were useThe GO and KEGG pathway enrichment analysis are useful to trackle the DNA-related and protein-related problems. And they offers considerable power for discovering the biological functions of genes and proteins . The GenAs shown in the table below , of the Then, we analysed the distribution of the top five clinical features including symptom phenotypes, syndrome diagnoses, botanical drugs, and comorbidities .With the method introduced in the Materials and Methods, we utilized three distinct categories of edges to create the HEMnet, which contained 5,846 nodes and 125,426 connected edges. There were 3,000 symptom nodes and 2,846 gene nodes. Furthermore, there were 16,641 PPI edges, 8,749 phenotype–genotype edges, and 100,036 symptom edges.Then, the embedding method ProSNet was used to generate low-dimensional vector representations of nodes in the HEMnet. A similarity matrix was constructed according to the similarity between every two embedding vector features, which was calculated by cosine similarity, and used to fill in missing features of the original patient characteristics to form the patient phenotypes. Finally, using the K-means clustering algorithm, eight non-overlapping patient subgroups were obtained. The t-SNE algorithm was used to visualize the clustering results . The nump < 0.05, see Materials and methods) were used to screen the significant clinical features.We then selected the top 10 clinical features in these modules according to their frequency in each subgroup. Then, the RR and chi-square test . Then, we obtained the pathways and GO terms for the botanical drugs, comorbidities and T2D in H3 and H6 by the DAVID program . Finally, we screened out pathways and GO terms with 3 and H6 . In H3, In recent years, the continual growth of EMR databases has facilitated clinical research, paved the way for data mining applications, and supported population health. However, missing data is the biggest barrier to using EMRs . In our Analysing disease comorbidities with EMR data has become popular in real-world clinical settings for chronic disease conditions such as T2D and chronic liver diseases . In thisper se contributes to high blood pressure are still somewhat uncertain  Hypertension. Although the mechanisms by which defective insulin action ncertain . But prencertain . Astragancertain . So the Our study has several potential limitations. Our sample included only 2137 hospitalized patients, resulting in an insufficient number of patients with some subtypes of T2D for identification of additional significant TCM phenotypes. In future studies, more patients should be included to ensure the abundance of the results. Another limitation is that Western medicine and laboratory tests were not included in our study. Therefore, the resulting disease subtypes would incorporate little information on these features. In addition, some patients were not given herbal prescriptions. This might affect the results of data mining. Finally, we used EMRs from only one hospital, and the resulting patient subgroups that were identified may not be representative. And further experiments should be performed to verify the results of this paper .Our results demonstrate that Cardiovascular disease (CVD) and Qi-Yin deficiency syndrome were significant comorbidity and TCM syndrome of T2D in subgroup H3, respectively. Regarding treatment, Poria, Astragali radix, Glycyrrhizae radix et rhizoma, Cinnamomi ramulus, and Ophiopogonis radix were the significant botanical drugs in subgroup H3. In subgroup H6, cerebral infarction and its sequelae, Qi deficiency and blood stasis syndrome were significant comorbidities and TCM syndrome, respectively. Regarding treatment, Chuanxiong rhizoma, Gastrodiae rhizoma, and Baked ziziphi spinosae semen were the significant botanical drugs. So identification of the T2D subgroup based on the HEMnet method can provide important guidance for the clinical use of herbal prescriptions and that this method can be used for other complex diseases.


Porphyromonas gingivalis in C57BL6/J mice. We generated 24 metatranscriptomic libraries from individual mouse oral swabs, representing health and disease. On average, 76% ± 11.7% reads in each sample belonged to the murine host genome and the remainder to the microbes. We found 3,468  murine host transcripts differentially expressed between health and disease, of which 76% were overexpressed in periodontitis. Predictably, there were prominent alterations to genes and pathways linked with the host immune compartment in disease—the CD40 signaling pathway being the top enriched biological process in this data set. However, in addition, we observed significant alterations to other biological processes in disease, particularly cellular/metabolic processes and biological regulation. The number of differentially expressed microbial genes particularly indicated shifts in carbon metabolism pathways in disease with potential consequences for metabolic end-product formation. Together, these metatranscriptome data reveal marked changes between the gene expression patterns in both the murine host and microbiota, which may represent signatures of health and disease, providing the basis for future functional studies of prokaryotic and eukaryotic cellular responses in periodontal disease. In addition, the noninvasive protocol developed in this study will enable further longitudinal and interventionist studies of host–microbe gene expression networks.Periodontal disease is accompanied by alterations to cellular profiles and biological activities of both the subgingival microbiome and host tissues. Although significant progress has been made in describing the molecular basis of the homeostatic balance of host–commensal microbe interactions in health compared to the destructive imbalance in disease, particularly with respect to immune and inflammatory systems, few studies have attempted a comprehensive analysis in diverse host models. Here, we describe the development and application of a metatranscriptomic approach to analysis of host–microbe gene transcription in a murine periodontal disease model, based on oral gavage infection using  Periodontal disease is characterized by a deregulated immune and inflammatory response and shift in the microbial population structure of subgingival biofilms, eventually leading to irreversible tissue destruction and ultimately tooth loss . SeveralOur understanding of the role of the oral microbiome and etiology of periodontal disease has particularly improved with the use of laboratory mouse models—including wild-type specific pathogen-free (SPF), germ-free (GF) mice, as well as gene-knockout mice . We recePorphyromonas gingivalis oral gavage model has been used extensively in periodontal disease studies, particularly as it generates a chronic form of alveolar bone loss and inflammation, like that observed in human disease . It is recognized that saliva has the potential to act as a diagnostic fluid for oral diseases , althougAppendix.The materials and methods are described in the P. gingivalis oral gavage showed significant loss of alveolar bone levels  with a mean bone loss of 0.03 ± 0.01 mm over 8 wk (P = 0.0003)  reads selected for bacterial gene annotation represented 5% ± 1.6% of total microbial reads.P < 0.05, and effect size >0.5, a total of 3,468 transcripts were found to be differentially represented between health and disease in the host gene transcripts. The top 100 genes in each condition, based on fold change, are presented in Appendix Table 1. The full list of 3,468 transcripts is available at https://doi.org/10.6084/m9.figshare.20364114.With filters of a minimum mean fold change (FC) threshold of 2 (FC >2), P = 0.76).Of these, 836 (24%) transcripts were overrepresented in the control mice, of which 268 (32%) were absent in all the diseased mice samples. The remaining 2,632 transcripts (76%) exhibited overexpression in the diseased group, of which 811 transcripts (30%) were absent in all the control mice samples . CanonicAt the gene level, these differentially expressed transcripts represent 3,067 unique genes with similar distribution between health (24.9%) and disease (75.1%). Using the Panther Classification system, these genes were classified into 22 different classes of proteins .Appendix Table 2 for the reader. The extensive list of transcripts, which can serve as a useful reference data set, is available at https://doi.org/10.6084/m9.figshare.20364117.In addition to the differential expression between health and disease, the healthy mouse oral metatranscriptome in this study generated 108,807 transcripts, the top 500 of which, based on gene expression levels, have been listed in Appendix Table 3). The top 25 ontologies in each condition ranked according to combined score are presented in Appendix Fig. 2).The Panther Classification system was used to categorize the differentially expressed gene list into gene ontologies based on both biological processes and molecular functions. The mouse host genes were classified into 20 different biological processes, the most abundant of which were cellular process, metabolic process, biological regulation, localization, and response to stimulus . Among mCD86, ITGB1, RNF31, TNIP2, and PHB2). We then investigated other enriched immune-related pathways in disease to obtain a list of 18 functional gene ontologies associated with immune signaling and regulation, driven by 56 genes in the mouse host genome that were differentially represented in disease (Appendix Table 4). In contrast, 12 enriched immune-associated pathways linked with only 22 genes were overrepresented in health (Appendix Table 4).The top candidate in the list of enriched biological processes in the disease category  was the Appendix Fig. 3).We also generated a list of immune-related genes from the differentially expressed gene set using keywords such as chemokine, interleukin, B-cell, T-cell, neutrophil, TLRs, and fibroblasts to generate a list of 64 genes—44 of which (69%) were overrepresented in disease   . Some ofondition . A plot ondition .Appendix Table 5). Of these, 12 were overrepresented in the control samples and 17 in disease , although the difference was not statistically significant. The graph was replotted after excluding the extreme outlier sample (Pg12), and the separation between health and disease groups was more clearly observed .We demonstrate here a noninvasive protocol to obtain a global snapshot of the oral gene expression profile in murine models comprising both the host and the resident microbiota. Oral swabs are known to present challenges with nucleic acid yields , more soAppendix Table 2), which is to be expected given the sampling methodology, although differential analysis also demonstrated significant contributions from alternative host cell sources.In addition to the health and disease comparison, the gene expression atlas of the mouse oral transcripts generated from healthy SPF mice can serve as a reference database for future studies using murine models. The most abundant transcripts were largely of epithelial origin, including, for example, oral keratins .Among the 29 differentially expressed bacterial genes, patterns of functional relevance were observed wherein number of the genes overrepresented in disease involved metabolic enzymes and transport activities—also observed in the gene ontology network analysis . KEGG K, with onThe overexpression of bacterial metabolism genes could be an indicator of the pathogenic role of bacterial products such as short-chain fatty acids (SCFAs) in both homeostasis and driving periodontal disease. Consistent with this hypothesis, a saliva metabonomic analysis comparing health and periodontitis, reported by P. gingivalis has a well-characterized heme acquisition mechanism via hemagglutinins and gingipains, key virulence factors in the pathogenicity of the organism , the main candidates in health were housekeeping activities related to repair and maintenance, while biggest networks in disease were linked with metabolic and enzymatic processes. This may reflect an increased rate of metabolism and rapid growth of microbes triggered in periodontal disease, potentially reflecting the emergence of GCF as a major source of microbial nutrition in disease as opposed to saliva-based nutrition in health.Among molecular functions of the gene ontology network analysis in health, the overrepresentation of sialidase activities and oligosaccharide/polysaccharide metabolism potentially reflects the breakdown/utilization of salivary glycoproteins as the primary source of oral bacterial nutrition in health. In disease, a large network related to metal binding functions is observed—a trait observed among Gram-positive and Gram-negative pathogens as part of the infection process of disease . Notablyorganism . Among tVeillonella in expressing putative virulence factors in periodontal disease  the optimization of a low-yield RNA extraction and sequencing protocol, 2) the first use of a targeted murine microbiome reference database, and 3) generation of a murine oral host gene expression resource for the first time. Thus, this data set and methodology should offer potential for further in vitro and in vivo studies to investigate the pathogenesis of periodontal disease as well as mechanisms of host immunity in health and disease.S. Joseph, M. Carda-Diéguez, contributed to conception and design, data acquisition, analysis and interpretation drafted and critically revised the manuscript; J. Aduse-Opoku, contributed to conception and data design, drafted and critically revised the manuscript; A. Alsam, contributed to data acquisition and data analysis, critically revised the manuscript; A. Mira, contributed to conception and design, data interpretation, critically revised the manuscript; M.A. Curtis, contributed to conception and design, data interpretation, drafted and critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of the work.Click here for additional data file.Supplemental material, sj-docx-1-jdr-10.1177_00220345221149675 for The Murine Oral Metatranscriptome Reveals Microbial and Host Signatures of Periodontal Disease by S. Joseph, M. Carda-Diéguez, J. Aduse-Opoku, A. Alsam, A. Mira and M.A. Curtis in Journal of Dental Research


AGR2 is a secreted protein widely existing in breast. In precancerous lesions, primary tumors and metastatic tumors, the expression of AGR2 is increased, which has aroused our interest. This review introduces the gene and protein structure of AGR2. Its endoplasmic reticulum retention sequence, protein disulfide isomerase active site and multiple protein binding sequences endow AGR2 with diverse functions inside and outside breast cancer cells. This review also enumerates the role of AGR2 in the progress and prognosis of breast cancer, and emphasizes that AGR2 can be a promising biomarker and a target for immunotherapy of breast cancer, providing new ideas for early diagnosis and treatment of breast cancer. In 1998, Devon A.Thomson and Ronald J.Weigel of Stanford University in the United States used suppression subtractive hybridization (SSH) to screen the homologous gene with Xenopus anterior gradient-2 (XAG-2) from the cDNA library of estrogen receptor positive breast cancer cell line MCF7, named hAG-2, or anterior gradient-2 (AGR2)  is important for the correct structure and function of most protein complexes . ProteinFletcher et al.  found twThe most well characterized AGR2 binding protein is the AAA+ superfamily protein Reptin . AGR2 inAGR2 protein can specifically bind to a specific peptide motif (TTIYY), thus driving the interaction with other proteins . This moIn addition, under normal conditions, AGR2 has been shown to interact with subtype of uracil DNA glycosylase protein (UNG1), which plays a key role in base excision and repair of mitochondria . Guo et AGR2 can participate in a variety of biological effects through protein-protein interactions. Meanwhile, AGR2 activity can also be regulated in a variety of ways. In breast cancer, AGR2 co exists with estrogen receptor and is induced by estrogen  decipherIn conclusion, AGR2 has a unique primary protein structure, including secretory signal, endoplasmic reticulum retention sequence, as well as protein disulfide isomerase active site and a variety of protein binding sequences, which endows AGR2 with diverse roles in breast cancer cells. Intracellular AGR2 can promote the growth and survival of cancer cells, while extracellular AGR2 can be defined as a microenvironment regulator that makes cancer cells more aggressive . Intracein vivo (in vitro (in vivo. The injection of AGR2 transfected rat mammary gland cells (Rama 37) into the mammary fat pad of homologous rats could induce a high incidence of lung metastasis, but the incidence of primary tumors in the rat model did not increase, which indicated that the expression of AGR2 may be related to metastasis. However, they did not analyze the correlation with patient survival. In addition, in a group of 225 ER positive breast cancer patients treated with tamoxifen, the survival rate of patients with AGR2 positive in breast cancer cells was lower than that of patients with AGR2 negative (AGR2 was found by comparing the protein differences between ER positive and negative breast cancer cells . AGR2 onin vivo  and in vn vitro  confirmen vitro  used tisn vitro  subsequenegative . In contnegative  studied negative  performenegative  analyzednegative  knocked negative  comparednegative  also useWhen considering molecular stratification, Lacambra et al.  retrospeSo far, AGR2 participates in various tumor processes, such as differentiation, proliferation, migration, invasion and metastasis , and plaAGR2, as a promising biomarker, has aroused great interest because of its increased expression pattern in precancerous lesions, primary tumors and metastatic tumors, which is used to detect the most common cancers . As a seThe incidence of ER positive breast cancer is the highest, accounting for about 75% of all cases of breast cancer . ER posiWith the gradual deepening of research, the key regulation of AGR2 in cancer is gradually clear. It can be used as a cytoplasmic protein or through secretory form, mediate inflammatory response and external stimuli, regulate endoplasmic reticulum stress, affect the activity of p53, so as to regulate the survival, adhesion and metastasis of tumor cells, enhance the malignant transformation of tumor and promote the resistance of cancer cells to drugs. Therefore, AGR2 is an important target for cancer treatment.in vitro (The first antibody developed against AGR2 is a mouse monoclonal antibody, called 18A4, which has been proved to inhibit the growth of breast cancer cells n vitro . Subsequn vitro . The AGRn vitro . Recentln vitro , 102. A n vitro  based onn vitro  found thn vitro  divided n vitro . If AGR2n vitro  designedn vitro  focused n vitro . Therefon vitro , leadingn vitro . The devn vitro . Zhang en vitro  designedIn the past few years, AGR2 protein has aroused great interest in oncology. Its various carcinogenic properties and pathological effects mainly depend on the specificity of its cellular or extracellular localization. Intracellular AGR2 is a catalyst for the protein balance of endoplasmic reticulum to meet the secretory needs of cancer cells, while extracellular AGR2 is involved in the pro cancer signal transduction of epithelial tumorigenesis, ECM remodeling, inflammatory response and angiogenesis. In addition, this secreted AGR2 can be found in the body fluid of cancer patients, and the expression level can be distinguished from normal patients, which indicates that AGR2 can be used as a marker for diagnosis, prognosis and drug resistance. Diagnostic tools such as microfluidic detection devices or biosensors can be developed to detect AGR2 specifically and sensitively. Combining AGR2 with other tumor markers can improve the sensitivity of breast cancer diagnosis, which is one of the hot spots that clinicians need to pay attention to in the future. So far, therapeutic strategies targeting AGR2 have shown promising results. For example, by constructing the bispecific antibodies of AGR2 antibody and immune checkpoint proteins, it can play its role in tumor tissue with maximum target concentration, which is a clinical transformation direction to improve the efficacy and reduce side effects. However, we also need to study the changes of key genes in AGR2 related signaling pathways, and better understand the upstream and downstream molecular mechanisms of AGR2. The in-depth understanding of the mechanism of AGR2 is of great significance for the study of the mechanism of tumor occurrence and development, as well as the early diagnosis, treatment and prognosis of AGR2 as a molecular target in clinic.KZ: investigation, data curation, visualization, methodology, and writing-original draft. YL: investigation, visualization, writing-original draft, and funding acquisition. XK: methodology, writing-original draft, and writing-review and editing. CL: writing-original draft, and funding acquisition. HY: writing-original draft, and funding acquisition. NW: data curation and writing-original draft. ZW: conceptualization, supervision, validation, and project administration. HC: validation, supervision, and writing-review and editing. LX: conceptualization, resources, supervision, and funding acquisition. All authors contributed to the article and approved the submitted version.


Adsorption has become the most popular and effective separation technique that is used across the water and wastewater treatment industries. However, the present research direction is focused on the development of various solid waste-based adsorbents as an alternative to costly commercial activated carbon adsorbents, which make the adsorptive separation process more effective, and on popularising the sustainable options for the remediation of pollutants. Therefore, there are a large number of reported results available on the application of raw or treated agricultural biomass-based alternatives as effective adsorbents for aqueous-phase heavy metal ion removal in batch adsorption studies. The goal of this review article was to provide a comprehensive compilation of scattered literature information and an up-to-date overview of the development of the current state of knowledge, based on various batch adsorption research papers that utilised a wide range of raw, modified, and treated agricultural solid waste biomass-based adsorbents for the adsorptive removal of aqueous-phase heavy metal ions. Metal ion pollution and its source, toxicity effects, and treatment technologies, mainly via adsorption, have been reviewed here in detail. Emphasis has been placed on the removal of heavy metal ions using a wide range of agricultural by-product-based adsorbents under various physicochemical process conditions. Information available in the literature on various important influential physicochemical process parameters, such as the metal concentration, agricultural solid waste adsorbent dose, solution pH, and solution temperature, and importantly, the adsorbent characteristics of metal ion removal, have been reviewed and critically analysed here. Finally, from the literature reviewed, future perspectives and conclusions were presented, and a few future research directions have been proposed. As per the United Nations World Water Development Report in 2020 , around g2+ ions ,4,5. Amoon (WHO) .2+, Pb2+, Hg2+ Cr3+, Cu2+, Mn2+, Fe3+, and Zn2+ are significantly toxic and pose risks to both humans and the environment [The major sources of heavy metal ion pollution comprise discharge from various untreated industrial effluents from refineries, coal-fired power plants, mining industries, alumina refineries, metallurgical industries, heavy chemicals, chloro-alkali industries, battery industries, dyes and pigments, fertilisers, metal smelters, paints and ceramics, tanneries, textiles, etc. ,7. The mironment ,9. Thereironment . Heavy mironment ,12. Therironment . DetaileA number of conventional technologies, such as chemical precipitation, oxidation, advanced oxidation, coagulation/flocculation, electrocoagulation, photo catalysis, membrane processes, reverse osmosis (RO), filtration, adsorption, solvent extraction, electroplating, ion exchange, activated sludge, and aerobic and anaerobic treatment, have been used to remove these potential pollutants from water and wastewater with varying levels of success ,18,19,20Adsorption may be defined as the transfer of one or more solute molecules from the bulk fluid phase to the solid adsorbent surface and getting retained there. The solid that adsorbs a solute component is called the adsorbent, and the solute component that is adsorbed is termed the adsorbate. When the adsorption arises as a result of weak Van der Waals or short-range forces, it is called physical adsorption. In contrast, in the case of chemical adsorption, a chemical covalent or ionic bond formation takes place between the adsorbate and the adsorbent via electronic transfer, which is irreversible in nature . There aTo predict the rate of adsorption and to identify the mechanisms underlying adsorption and the adsorbent’s capacity, it is vital to understand the various reported adsorption kinetic models and isotherm model equations ,29. In tAdsorption isotherm studies are crucial for understanding the mechanisms of adsorption and for finding the maximum adsorption capacity of the adsorbent. Several adsorption isotherm models have been reported in the literature, such as the Langmuir, Freundlich, Redlich–Peterson, Tempkin, and Toth isotherm models. Of these isotherm models, the Freundlich 1906  and LangThe adsorption process depends on the nature and the types of the adsorbent and adsorbate characteristics. The adsorbate characteristics, such as molecular weight, structure, size, charge, and solution concentration, and the adsorbent characteristics, such as particle size, surface area, surface charge, and surface functional groups are all responsible for effective adsorption ,38. AparModified agricultural solid waste has been widely used as an effective adsorbent in the removal of various contaminations from wastewater, and this has ben attributed to their surface properties improvements. Raw biomass can be modified using acids, such as hydrochloric, phosphoric, sulfuric, nitric, citric acids etc., or alkaline solutions, such as sodium hydroxide, potassium hydroxide, zinc chloride, calcium chloride, ammonia etc., or cross-linked with other materials . ChemicaIn recent times, these agricultural by-products have raised environmental awareness about their safe disposal, and therefore any kind of their utilisation is considered as a win-win situation for effective solid waste management as well. Hence, this review article will provide a comprehensive compilation of all the up-to-date developments of the current state of knowledge on various batch adsorption results using a wide range of raw and modified agricultural solid waste adsorbents in the removal of heavy metal ions from water and wastewater. The significance of this review is not only the compilation and up-to-date developments of the current state of knowledge, but also the critical analysis of the recent research articles that have been published in the directions of agricultural solid waste and modified agricultural solid waste adsorbents. In this review, we have also reported and compiled the various batch heavy metal ion adsorption results under various physicochemical process parameters. Therefore, the structure of this review article began with a general introduction section comprising heavy metal ion water pollution and their sources, toxicity, and treatment methods. Emphasis has been given to agricultural by-product-based adsorbents for the removal of aqueous phase heavy metal ions through adsorption under various process conditions. Finally, the knowledge gap between the future perspectives and the future directions have been presented.Laurus nobilis is an effective adsorbent in the removal of Cd2+, Cu2+, Pb2+, and Zn2+ toxic metal ions from its aqueous solution and strong functions of temperature and solution pH with the adsorption capacity as the pH increases. A theoretical maximum Cr6+ adsorption capacity of 70.49 mg/g for data palm empty fruit bunch biomass was obtained at an optimum solution pH of 2 and a temperature of 30 °C [2+ metal ions and their reported maximum adsorbent capacities were found to be 21 mg/g and 18.4 mg/g, respectively [2+ and Cr6+ were also effectively removed from water using the peanut shell residue adsorbent [3+, Cu2+, and Pb2+ ions with an adsorption capacity of 7.7 mg/g, 10.2 mg/g, and 29.1 mg/g, respectively [Artocarpus odoratissimus leaves [Colocation esculenta leaves [The current research has primarily been driven towards using lignocelluloses, and carbonaceous, agricultural, and forest-based adsorbents for water decontamination, including metal decontamination using an adsorption alternative to the costly CAC. These materials are available locally in large quantities and are almost priceless, with a minimum pre-treatment cost for improvements in terms of their effectiveness, efficiency, and environmental friendliness, and are an alternative adsorbent to the costly CAC. Further, agricultural solid waste adsorbent materials require minimal pre-treatment operations, such as washing, drying, grinding, or minor chemical treatments . The adsof 30 °C . Rice brectively . Similardsorbent ,47. The ectively . Afroze ectively  reviewedectively  reviewedectively , durian ectively , banana ectively , raw pomectively , watermeectively , and cocectively , along ws leaves , and Cola leaves . All thea leaves . There aa leaves ; Saukat a leaves ; Ogunlala leaves ; Afroze a leaves  on aqueopzc), bulk density, and the presence of surface functional groups [The effectiveness and adsorbent capacity depend on the adsorbent’s size, shape, and morphological and chemical structure, including surface characteristics such as the surface area, pore volume, point of zero charge . At lower concentration ranges, the available adsorbent sites are occupied by adsorbate molecules and hence increase the adsorption capacity [2+ metal ions by the sorghum hull adsorbent was found to have decreased from 50.98% to 12.8% for the metal ion concentration range of 10–50 mg/L, respectively [2+, 96.12% to 65.42% for Pb2+, and from 94.36% to 66.83% for Zn2+, respectively [2+, Zn2+, Ni2+, and Cu2+ metal ions was increased with the metal ion concentrations of 2–100 mg/L, respectively [2+ adsorption studies by the chemically-treated tomato waste where the percentage of metal ion removal decreased with the increase in the initial metal ion concentration, and the adsorbed amount of metal (eq) per gram of adsorbent increased with the initial metal ion concentration. Similarly, Kilic et al. [2+ and Co2+, eq (mg/g), by almond shell biochar with the Ni2+ and Co2+ metal ion concentration ranges of 50–150 ppm and 100–200 ppm, respectively, under various temperatures, which are presented in eq (mg/g)) was increased with the increased temperature, which is also shown in 2+ increased from 5.63 to 107.26 mg per gram, respectively, with the increase in the metal ion concentration [To understand the adsorbate load and their optimum load concentration, a wide range of initial adsorbate metal ion concentrations has been examined across various reported batch adsorption studies ,104. Gencapacity . Sometimcapacity . Generalcapacity ,69,104. ectively . With thectively ,109. Simectively  that theectively . Yargic ectively  reportedc et al.  presenteGenerally, the percentage removal of aqueous phase pollutants by initial adsorption increases with the contact time, and then slowly reaches a steady-state saturation level. It may present in the form of either a two-stage or multistage adsorption process ,14,49,63eq (mg/g) decreases with the increase in the adsorbent dose, whereas the percentage removal of metal ions increases along with the increase in the adsorbent dose [2+ and Co2+ metal ions by the almond shell biochar increased from 10% to 38%, and from 25% to 50%, with the increase in the adsorbent doses from 1 to 10 g/L, respectively. In contrast, Ni2+ and Co2+ adsorbent’s capacities, eq (mg/g), were decreased from 10 mg/g to 3 mg/g, and from 24 mg/g to 7 mg/g, respectively, for which their results are presented in For the successful design, development, and scale-up of a continuous adsorption column, the knowledge of the adsorption capacity of the adsorbent is essential. The effect of an adsorbent dose on heavy metal adsorption in a solution indicates its adsorption capacity, which also depends on the available active sites on the adsorbent’s surface for adsorption ,97. In gent dose . A high ent dose . Howeverent dose ,114. Mucent dose , who rep2+ adsorption by modified eucalyptus sheathiana bark biomass, and it was found that their adsorbent capacity, eq (mg/g), decreased from 72.52 mg g−1 to 17.57 mg g−1 with the increase in the adsorbent doses from 0.01 g to 0.03 g, respectively [2+, Co2+, Cr2+, Cu2+, Mn2+, Ni2+, Pb2+, and Zn2+) adsorption, and critically analysed their comparative results at high, medium, and low adsorbent doses. When the amount of adsorbent mass in a fixed-volume solution is below the optimum value, the removal of metal ions is also low due to the lower number of available active sites for adsorption [Afroze et al.  also repectively . There aectively . Imran-Sectively  reviewedsorption . Table 3pzc), and hence the surface charge. The point of zero charge (pzc) or the isoelectric point (iep) is defined as a particular pH where the surface charge becomes zero, i.e., where the extent of the adsorption of the positively charged species equals that of the negatively charged species. The point of zero charge (pHpz) of various raw, treated, or modified agricultural biomass-based adsorbents was determined by many investigators to obtain a better understanding of the adsorptive removal mechanism [pzc, the adsorbent surface becomes positively charged and hence less metal cation adsorption takes place due to electrostatic repulsion between the positive cations and the positive surface-binding sites. Whereas, at pH > pHpzc, the surface becomes negatively charged and favours metal cation adsorption. However, at a higher basic pH, metal complex formation occurs resulting in precipitative separation instead of adsorptive metal ion separation [3)2 in solution predominately exists as Pb2+ ions. Meanwhile, with an increasing solution pH, for example at pH = 8, Pb (OH)+ formation occurs, and at pH = 11, it will precipitate as Pb (OH)2 [pzc due to the presence of the functional groups, such as the OH−, and COO− groups, while anionic adsorbate adsorption is favoured at pH < pHpzc due to the presence of H+ ions [2+, Ni2+, and Cr2O72− ions with the avocado peel adsorbent. They found that the percentage removal of the cationic Pb2+ and Ni2+ adsorption was increased with the increase in the solution pH, whereas the adsorption of anionic Cr2O72− was decreased with the same increasing solution pH. Abbar et al. [2+, Ni2+, and Zn2+ adsorption by the flax fibre tows (FFTs) adsorbent in the solution pH range from 1.6 to 8.5, respectively, for all metal ions. To investigate the effects of the solution pH on metal ion precipitation, Abbar et al. [2+ and Cu2+ ions occurred in the solution pH range of 4–6, whereas for Zn2+ metal ions, the maximum values were observed at the solution pH of 7, respectively. At a higher pH, lead, copper, and zinc metal ions precipitate as hydroxides and reduce the rate of adsorption and hence reduce their removal capacity as well [2+ and Co2+ adsorption, eq (mg/g), by the almond shell biochar was increased from solution pH 2 to 6, and then decreased with the increasing solution pH, as shown in zpc, and the surface becomes more negatively charged due to the presence of the stretching hydroxyl (–OH) and carboxyl (–COOH) functional groups [2+ adsorption using the pinecone biochar adsorbent. At a low solution, the pH tends to decrease the adsorption capacity of the cations onto the adsorbent due to the presence of hydronium (H3O+) ions competing with the cationic metal ions for the available adsorption sites [The variation of solution pH plays a major role in changing the adsorbent surface charges, degree of ionisation, and metal speciation in solution, and hence causes changes to the adsorption capacity during the adsorption process ,123. Theechanism ,127,128.paration . For exaPb (OH)2 ,129. The H+ ions ,130. An  H+ ions  mentione H+ ions ,131 repor et al.  presenter et al.  presente as well . Similar as well  reportedon sites . HoweverG0), enthalpy (ΔH0), and entropy (ΔS0), for the heavy metal ion adsorption by the agricultural solid waste-based adsorbents, which can be determined by the following two equations [eq is the amount of metal ion adsorbed per unit mass adsorbent (mg/g), eC is the equilibrium concentration (mg/L), T is the temperature in K, and R is the universal gas constant (8.314 J/molK).Temperature plays an important role in the adsorption of metal ions associated with the thermodynamics of the adsorption process. Temperature was found to be another significant physiochemical process parameter that influences the adsorption/biosorption mechanism and hence the equilibrium adsorbent capacity ,42,132. quations :ΔG0=ΔH0−2+ > Pb2+ > Cu2+ > Cr6+ > Co2+ > Zn2+ > Ni2+ > Cd2+ and in the order of Pb2+ > Cd2+ > Zn2+ at the medium level, respectively. Meanwhile, for the high level of temperature, the order was Cd2+ > Pb2+ > Cr2+ > Cu2+. Temperature is an important indicator of the exothermic or endothermic nature of the adsorption reaction process [Shaukat et al.  recently process . The sol process . An incr process . However process .2+ on the cashew nut shell was decreased from 80.13% to 74.32% with the rise in temperature from 30 °C to 60 °C, respectively. Many studies have also reported that metal ion uptake by some adsorbents is reduced with an increasing temperature [The temperature effect on the agricultural adsorbent’s capacity depends on the surface functional groups . They reperature ,142.To overcome the high costs of commercial activated carbon (CAC) and to overcome the other operational issues that have been associated with the use of CAC as the adsorbent, raw and modified agricultural biomass residue-based adsorbents have gained a significant level of attention as an alternative, carbon-containing, easily accessible, and cost-effective adsorbent in the removal of aqueous phase heavy metal ions with a high degree of binding capacity. From the extensive literature review on adsorption-based wastewater treatment technology, the following points presented are the challenges and future directions that need to be addressed so that adsorption-based technology may be more effective and popularize this technology for the future remediation of water pollution.Overall economy: the overall economically feasible operation of an adsorption-based treatment plant depends on many factors. Various costs associated with the operating costs, fixed costs, including the installation cost, adsorbent pre-treatment/preparation costs, and cost of adsorbent regeneration are all especially important for determining the feasibility of the full process. Among them, the adsorbent cost alone, including its procession, is above 60% of the total operating cost. Therefore, the adsorbent material selection is crucial for the adsorptive separation process. Various non-conventional solid waste-based adsorbents may be an alternative, cost-effective solution to this process.Industrial scale problems and lab-based experiments: due to the introduction of various environmental protection laws and regulations, industries have imposed the discharge of waste into the environment. However, industries sometimes discharge harmful chemical waste at a higher than prescribed limit. Therefore, the industry always looks into some low-cost technology like adsorption, and many industries have already adopted this technology. However, the effectiveness of this adsorption-based technology is mainly judged using the laboratory-based batch adsorption results with limited continuous experimental results. Therefore, more continuous adsorption operation results, if possible, along with the pilot-scale results are required before commercial implementation.Batch and continuous column analysis: based on the literature review over the last two decades, it has been found that more than 80% of adsorption-based studies are of the batch scale. The challenge of adsorption-based studies lies here. These batch studies are confined to various kinetics, isotherm, and thermodynamic analysis with a very small lab scale. The batch-scale study results cannot be adopted directly for industrial use without continuous operation. Several recent studies have come up with some lab or bench-scale continuous studies of adsorption in a packed bed, fluidised bed, and semi-fluidised system to help in the scale up of this process. More research is required in the field of continuous adsorption systems and scale-up processes.Adsorption modelling: For large-scale operation and process design adsorption modelling, the procedure for the accurate estimation of various kinetic parameters, isotherm models, and the thermodynamic parameters for the multicomponent system are essential.Adsorbent regeneration and reuse: it has been mentioned previously in that the 60% cost of an adsorption-based system depends on the cost of the adsorbent. Therefore, in the age of sustainable development, adsorbent regeneration must be given significant priority. To reduce waste production, secondary pollution, and operating costs, and to make the overall technology more cost-effective for further reuse, regeneration of the loaded adsorbents is an essential process. Moreover, the capture adsorbate must be recovered as they may be valuable products or to aid in minimising secondary pollution. Hence, an eco-friendly and low-cost alternative regeneration method must be developed to reduce waste production and cost, as well as maximise the cycle number to use for a greater number of times under industrial operations.Process optimisation: in adsorption-based studies, process optimisation is required under controlled conditions and for further applications in real-field situations. In most cases, the actual process effluents are multicomponent and compete with the adsorbates. The multicomponent systems always reduce the ideal adsorption capacity, meaning therefore that the modelling and optimisation of these multicomponent systems will be quite complex.Water pollution due to heavy metal ion contamination resulting from various sources, including untreated industrial effluent discharge and agricultural activities, is of global concern and to find out an efficient but sustainable and cost-effective remediation solution to these important global problems imposes a challenging task on scientists, researchers, and practising engineers. Among the various conventional remediation techniques, adsorption-based separation technology is considered to be one of the most effective approaches widely used in treating heavy metal contaminated water and wastewater due to its simple operation, design simplicity, high separation efficiency, efficiency at lower pollutant concentrations, high selectivity at the molecular level, low energy consumption, ability to separate multiple pollutant components, and minimize secondary pollution. This review article presented a compilation of various scattered literature data along with the up-to-date development batch metal cation adsorption results using a wide range of non-conventional and cost-effective agricultural solid waste-based adsorbents under various process conditions. It is clear from the present literature survey in that non-conventional raw or modified agricultural solid waste-based adsorbents are emerging as effective, but low-cost adsorbents for heavy metal ions present decontamination problems. The utilisation of this large amount of agricultural solid waste-based effective adsorbents in the water and wastewater treatment industries is a sustainable and cost-effective pollution control option alternative to the costly CAC adsorbents. The literature has also revealed that in some cases, the modification of the adsorbent increased the removal efficiency of adsorption. The effective metal removal efficiency from the aqueous phase mainly depends on the adsorbent’s characteristics and various physicochemical process parameters. Therefore, this review article was compiled to critically analyse the large batch adsorption results on heavy metal ion adsorption by the wide ranges of agricultural solid waste-based adsorbents, specifically the adsorbent’s characteristics, and under various influential process parameters, such as the initial adsorbate metal ion concentration, the initial solution pH, the adsorbent doses, and the temperature, respectively.


This study aimed to investigate the cost-effectiveness of stent retriever (SR) versus best medical management (BMM) in patients with basilar artery occlusion (BAO) in China.We used a two-step approach to compare the cost-effectiveness of SR plus BMM with that of BMM alone over 20 years. A decision tree was initially constructed for the first 3 months, followed by a Markov model for the subsequent period. Collected data on clinical aspects were extracted from the BAOCHE investigation, while costs-related information was sourced from previously published research. The key metric for evaluating the primary outcome was the incremental cost-effectiveness ratio (ICER), achieved $/QALY. The threshold for identifying SR as highly cost-effective was set at an ICER below $12,551/QALY, SR was deemed cost-effective if the ICER ranged from $12,551 to $37,654 per QALY. Uncertainty was addressed using scenario, one-way sensitivity, and probabilistic sensitivity analyses (PSA).For Chinese patients with BAO, the 20-year cost per patient was $8678 with BMM alone and $21,988 for SR plus BMM. Effectiveness was 1.45 QALY for BMM alone, and 2.77 QALY for SR plus BMM. The ICER of SR + BMM versus BMM alone was $10,050 per QALY. The scenario and one-way sensitivity analyses revealed that in certain situations the ICER could exceed $12,551 per QALY, but remain below $37,654 per QALY. Results from the PSA suggested that SR was likely to be cost-effective for Chinese patients with BAO, with a probability exceeding 98% when considering a willingness-to-pay (WTP) threshold of $12,551 per QALY.Our study indicates that SR is an intervention option that is highly likely to be cost-effective for Chinese patients with BAO, with a probability of over 98% under the current WTP threshold of $12,551 per QALY. Stroke is a leading cause of death and disability worldwide, with more than 3.94 million new stroke cases, 28.76 million prevalent stroke patients and 2.19 million stroke-related deaths in 2019 in China –7.Mechanical thrombectomy (MT) using stent retrievers (SR) is now primary approach for managing acute stroke resulting from large-vessel occlusion in the anterior circulation . EconomiCurrently, the cost of SR is significantly higher than that of BMM . A studyThis study adhered to the reporting guidelines outlined in the 2022 Statement of the Consolidated Health Economic Evaluation Reporting Standards .This study focused on Chinese patients with BAO who experienced stroke symptoms within a time window of 6–24 h after symptom onset. In total, 217 patients were included in the BAOCHE study . The meaThis was a modeling study, and ethical approval from the institutional review board was not applicable for this type of study.The comparators in this study were SR plus BMM and BMM alone. All patients included in the study were admitted to acute stroke units or neurological intensive care units (NICU) and received treatment in accordance with the current Chinese guidelines for acute ischemic stroke management , which wWe devised an integrated decision tree and Markov model to assess the cost-effectiveness of SR alongside BMM in comparison to BMM alone, from the viewpoint of the Chinese healthcare system. Within the decision tree framework, patients meeting the eligibility criteria for BAO were randomly assigned to either SR plus BMM or BMM alone. The observation period extended to 90 days . Following this, patients were transitioned into the Markov model, commencing from the state defined in the decision tree and progressing through subsequent cycles until reaching the endpoint of mortality. The simulation period encompassed 20 years, with each cycle lasting 3 months. In the BAOCHE study, the average age of the participants was 64 years, and the Markov model comprised 79 cycles (corresponding to 19.75 years). Notably, the simulation period was extended beyond the life expectancy of 78 years reported for China in 2021 . The ratThere were three transition states of “non-disabling stroke,” “disabling stroke,” “Recurrent stroke,” and an absorbed state of “Dead.” Patients had the potential to transition from one state to another or remain in the same state throughout the course of the study, but the process would conclude should the patient transition into the absorbed state.The current investigation was undertaken from the viewpoint of the healthcare system in China, with particular emphasis on assessing direct medical costs. It is important to note that our analysis did not include direct nonmedical or indirect costs in the evaluation. The expenses within the decision tree and Markov model were combined to compute the overall cost, while the total effectiveness was determined using an analogous approach. The conversion of all costs to USD was based on the exchange rate of 6.4515 Chinese Yuan (CNY) to 1 USD . FollowiSeveral assumptions were made to simulate cost and effectiveness in Chinese patients with BAO. First, the transition probability of clinical events for stroke caused by BAO in patients with the same mRS score was assumed to be equivalent to that for stroke caused by anterior circulation occlusion. This assumption is based on a cohort study that investigated long-term mortality after BAO. This study demonstrated that the long-term mortality rate in patients with BAO who survived the first 3 months corresponded to the large-artery stroke subtype of the anterior circulation. Secondly, it was assumed that “recurrent stroke” originating from "non-disabling stroke" has the potential to transition to "non-disabling stroke," "disabling stroke," or "dead." Conversely, recurrent strokes originating from "disabling stroke" can only transition to "disabling stroke" or "dead" and cannot lead to a more favorable outcome of "non-disabling stroke.” This assumption was based on the advice of neurologists. Third, the long-term outcomes were assumed to depend solely on the mRS scores at 3 months, regardless of whether SR was performed. Previous studies have adopted such assumptions ,23,24.The effectiveness of SR plus BMM versus BMM alone in Chinese patients with BAO was obtained from the BAOCHE study. In the BAOCHE study, the proportion of “non-disabling stroke (mRS 0–2),” “disabling stroke (mRS 3–5),” and “dead (mRS 6)” at 90 days was 0.391, 0.300, and 0.309, respectively, in the SR plus BMM group, and the corresponding proportion was 0.140, 0.439, 0.421, respectively, in the BMM group .Due to the lack of accessible transition probability of patients diagnosed with BAO, we utilized transition probability data for stroke caused by anterior circulation occlusion in our Markov model. Although these probabilities were not directly derived from patients with BAO, they were suitable approximations for our analysis (10). In our Markov model, the 3-month transition probability remained consistent throughout the first three cycles and continued to be uniform for cycles beyond 1 year. However, it is important to note that the transition probabilities differed between the first three cycles and subsequent cycles, highlighting the distinction between these two periods. The transition probability was converted from the incidence rate with the formula of “3-month transition probability” = 1- exp (- “3-month incidence rate”) .In the BAOCHE study, the Solitaire device, a self-expanding stent that is retrievable and detachable, was employed for SR. The total cost of SR using the Solitaire device was $10,608 in 2019, and it would be inflated to $11,695 in 2021, considering the discount rate ,27. The The cost of BMM for stroke treatment was extracted from the China National Stroke Registry ,13, whicThe most significant factor influencing quality of life, the primary indicator of utility, was whether the stroke was disabling or non-disabling. Utility values for different stroke types were derived from a randomized controlled trial (RCT) conducted in China, yielding 0.76 for non-disabling stroke, 0.21 for disabling stroke, and 0.42 for recurrent stroke ,29 Tabl. QualityThere was a controversy surrounding the decision to discount utility ; in our The outcome was the incremental cost-effectiveness ratio (ICER), which measured the additional cost per quality-adjusted life year (QALY). The willingness-to-pay (WTP) threshold for high cost-effectiveness was set at one per capita GDP, while the threshold for cost-effectiveness was set at three times per capita GDP. If the In previous studies, both the cost of MT and health utility had the most significant impact on the ICER ,13,26, iTo assess the robustness of the findings, we conducted sensitivity analysis to account for result uncertainty. In the one-way sensitivity analysis, variations in input parameters caused fluctuations in the ICER, while we set the WTP threshold to evaluate result certainty. In the probabilistic sensitivity analysis (PSA), Monte Carlo simulation randomly sampled input parameters to model healthcare interventions, generating numerous simulations and forming a distribution of cost-effectiveness ratios . Input pWithin the BAOCHE study, the occurrences of symptomatic intracranial hemorrhage (sICH) were recorded at 6% in the SR group and 1% in the BMM group . The treFor Chinese patients with BAO, the total cost per patient over a 20-year period was $8678 if they received BMM alone. However, if they received SR plus BMM, the cost would increase to $21,988. The corresponding effectiveness outcomes were 1.45 QALY for BMM and 2.77 QALY for SR plus BMM. The ICER for SR plus BMM compared to BMM alone amounted to $10,050 per QALY, falling below the per capita GDP threshold of $12,551. If life quality was not taken into consideration, the corresponding effectiveness was 3.27 LY and 4.69 LY; thus, an ICER of $9385/LY was obtained .In the scenario analysis considering undiscounted utility, the ICER was lower than the per capita GDP. Furthermore, when the cost of SR increased to 150% of the current price, the ICER was calculated as $14,466/QALY. Although slightly higher than the per capita GDP, it remained lower than threefold the per capita GDP benchmark. In the other scenarios analyzed, the ICER remained consistently lower than the per capita GDP .PSA demonstrated that, at a WTP threshold of $12,551 per QALY, SR demonstrated remarkable cost-effectiveness, with a probability surpassing 98%. . The cosTo the best of our knowledge, this is the first study to investigate the cost-effectiveness of SR in Chinese patients with BAO. Our findings indicate that SR is highly cost-effective in this patient population. From an economic standpoint, this study supports the use of SR in Chinese patients with BAO.Currently, four RCTs have investigated the efficacy of MT or endovascular treatment (EVT) in patients with BAO ,15,30,31In our study, we employed data from the BAOCHE trial as our base-case analysis rather than conducting a meta-analysis of the aforementioned four RCTs ,15,30,31Previous studies have consistently demonstrated the efficacy of using a SR in MT for anterior circulation occlusion ,34. FurtBAO is associated with poor functional prognosis even when BMM is administered ,36. AlthFor several reasons, SR is highly cost-effective in Chinese patients. First, SR provides great benefits to patients with BAO. It could be observed that the effectiveness was 1.45 QALY in the BMM group but 2.77 in the SR group, which was mainly due to the reduction of mortality and disabling stroke in the SR group. Second, the cost of SR was lower in China than in other regions at $9427 in 2013 China and $13,803 in 2014 UK. Third, the mean age of Chinese patients with BAO was not very high, at 66 years in the ATTENTION study and 64 years in the BAOCHE study; the remaining life expectancy was over 10 years if a patient with BAO survived the stroke event. Currently, the average life expectancy in China exceeds 78 years, and a patient with BAO might benefit greatly from SR.Based on the utilization of clinical data obtained exclusively from Chinese patients with BAO and cost data derived from domestic sources, our study results are robust. However, this study had some limitations. First, the conclusion of the present study was drawn from a mathematical model, and a real-world study might provide stronger clinical evidence . Second,In conclusion, our study indicates that for Chinese patients with BAO, SR stands as a cost-effective intervention option, surpassing a 98% probability of cost-effectiveness at the current WTP threshold of $12,551 per QALY. Moreover, as MT technology advances, the cost of SR is likely to decrease, while the acceptability of this treatment may rise. These findings offer crucial insights for clinical decision-makers and healthcare policy developers. Nonetheless, it is imperative to acknowledge the need for real-world studies to validate our conclusions, ensuring their applicability and robustness in practical clinical settings.S1 Table(DOC)Click here for additional data file.S1 File(DOC)Click here for additional data file.S1 Fig(DOC)Click here for additional data file.S2 FigForest plot of results of meta-analysis.(DOC)Click here for additional data file.