Discontinuation was noted in 6.2% of patients. An increase in antimicrobial sensitivity was seen in 15.3% (n = 55) and 16.3% (n = 36) in the aminoglycoside and aminoglycoside/polymyxin groups, respectively. Conclusions: Current evidence supports the use of intravesical aminoglycoside instillation as an efficacious and safe treatment for refractory UTIs. Nevertheless, data is limited, and larger volume studies with longer follow-up periods are required.Background: Antibiotic resistance in urinary pathogens is increasingly common, leading to rising cases of complicated urinary tract infections. Conventional antimicrobial treatment may be insufficient in these cases and broad-spectrum systemic antibiotics contribute to the problem. Intravesical aminoglycoside instillation is an alternative treatment option that delivers localized and high-dose treatment to the source of infection. This study summarizes the existing evidence for the efficacy and safety of this treatment. Methods: A systematic search was conducted of worldwide literature according to PRISMA methodology and Cochrane standards for systematic review. Studies were included if they reported outcome data for the prevention and reduction in urinary tract infections, eradication of antimicrobial-resistant organisms, or change in sensitivities allowing conventional oral antimicrobial treatment after the administration of intravesical aminoglycoside with or without polymyxin therapy. Results: The search identified 826 articles, of which, 19 were included in the final data analysis and narrative synthesis. A successful outcome was identified in 80.7% ( The increasing incidence of multi-drug resistant organisms is one of the greatest challenges facing modern medicine. Urinary tract infections are one of the most common reasons for conventional antibiotic prescribing and resistance amongst urinary bacteria is an increasingly significant issue. The availability of effective alternative treatment strategies is therefore imperative, particularly in cases of complicated, refractory, and recurrent infection. One option is intravesical antimicrobial instillations. Existing literature indicates that this could be useful in the treatment and prophylaxis of UTIs, but its true role has yet to be fully established ,2. This Studies for inclusion in this review were selected according to the following criteria.Studies reporting on the administration of intravesical aminoglycosides for the treatment and prevention of refractory UTIs.Articles written in the English language.All age groups, including pediatric studies.Studies with a minimal sample size of three patients.Exclusion criteria:Non-human studies, review articles, editorials, guidelines, and case reports.Studies with a non-UTI treatment indication.Studies reporting on non-aminoglycoside intravesical instillations.Inclusion criteria:A systematic review was conducted according to the Cochrane and preferred reporting items for systematic reviews and meta-analyses (PRISMA) standards . An elecBoolean operators  were used alongside keywords including ‘aminoglycosides’, ‘gentamicin’, ‘neomycin’, ‘nebramycin’, ‘intravesical’, ‘instillation’, ‘irrigation’, ‘recurrent’, ‘UTI’, and ‘urinary tract infection’. The literature search included English articles from inception to May 2022. Eligible studies identified by the search were screened by title and abstract and then by the full text to identify eligible studies.Data extraction was conducted independently by two authors (A.O. and A.P.) and discrepancies were resolved by mutual consensus. A decision was made to include articles investigating aminoglycosides in conjunction with polymyxin to allow for comparison against the efficacy of aminoglycosides alone. The measure of a successful outcome differed between the studies. Therefore, to aid comparison, this review defined a successful outcome as the prevention of UTI, a ≥50% reduction in the rate of UTI, eradication of antimicrobial-resistant organisms, or the change in sensitivities allowing for the oral antimicrobial treatment of UTI. Articles were reviewed for data on method of delivery, follow-up, change in antimicrobial sensitivity, discontinuation of treatment, and antibiotic dose and regime.An initial search identified 826 articles; 32 were selected from an analysis of the title and abstract for full-text review. In total, 3 were excluded as they were case reports with fewer than 3 participants, 2 were systematic reviews, 7 were irrelevant, and 1 was an animal study. After an analysis of the full text, 19 were included in our final review ; 12 aminA total of 584 patients were included in the systematic review. The mean age was 35 years. The gender demographics of participants were not included in two studies, and of those listed, 222 were male and 162 were female. In summary, 10 studies assessed the efficacy of gentamicin, 3 studies treated gentamicin-resistant patients with amikacin, tobramycin, or garamycin, and 2 studies assessed netilmicin and neomycin. Seven studies assessing the use of an intravesical aminoglycoside in combination with polymyxin were included for comparison. All the studies were observational, apart from two randomized control trials comprising 52 participants ,20.The indication for the use of IVA was a mixture of treatment and prophylaxis of refractory UTIs. Underlying pathology included intermittent self-catheterization/long-term catheterization, recurrent UTIs, prostate carcinoma, benign prostate hyperplasia, and urinary diversion. The most common underlying pathology identified was neurogenic bladder (listed in 74% of papers).n = 289) of the patients in the papers assessing the use of aminoglycoside alone. A total of 79.5% (n = 163) of successful outcomes were measured in the papers evaluating treatment with an aminoglycoside in combination with polymyxin  ,20,21,22n = 55) and 16.3% (n = 36) in the aminoglycoside and aminoglycoside/polymyxin groups, respectively  of patients; 10.4% (n = 61) in the aminoglycoside group and 3.6% (n = 21) in the aminoglycoside/polymyxin group.Amongst these patients, oral antibiotics were used rather than intravenous antibiotics, which reduced UTI-related hospital admissions. New antimicrobial resistance was reported in 14.0% (n = 27) of patients. Renal impairment was reported in three patients. However, this was attributed to a known background of chronic renal insufficiency [One case of an elevated serum level of gentamicin was noted by Marei et al. . No consficiency . Stalenhficiency . Once agLocalized, high-concentration IVA treatment aims to effectively eradicate multi-resistant organisms and limit growing antimicrobial resistance through the avoidance of broad-spectrum intravenous antibiotics . This sup = 0.025) [Whilst the studies differ in duration of follow-up, findings consistently suggest that IVA has a role in the management of UTIs in the short term. Over a six-month period of review, Chernyak et al. found a statistically significant reduction in the incidence of UTIs from 2.5 to 1.5 per 6 months (= 0.025) . The stu= 0.025) . Assessi= 0.025) . The relComplications such as ototoxicity and nephrotoxicity are well established with the use of high-dose aminoglycosides . IntraveThe low discontinuation rate of 6.2% and the high proportion of patients self-administering IVA suggests that patients were agreeable to this method of drug administration. Reducing the burden of staff required to administer the medication increases patient accessibility for IVA. Low complication rates (4.6%) and good patient compliance with the treatment suggest that IVA treatment is not only efficacious but a well-tolerated method of treatment for patients.n = 55) and 16.3% (n = 36) in the aminoglycoside and aminoglycoside/polymyxin groups, respectively), this was a promising finding in the endeavor to reduce antimicrobial resistance. Increased antimicrobial susceptibility broadens the range of treatments available to these patients. This could avoid hospital admission, reduce the incidence of complications associated with hospital admission, and improve quality of life [p = 0.065) [n = 82) of patients; 10.4% (n = 61) in the aminoglycoside group and 3.6% (n = 21) in the aminoglycoside/ polymyxin group. It was not possible to identify a trend between IVA and antimicrobial sensitivity based on our findings. Further studies should assess the long-term impact of IVA on antimicrobial resistance both in the treatment and the prophylaxis of UTIs.An improvement in antimicrobial sensitivity was observed from data collected from 10 papers. Although this was only a small percentage (15.3% (= 0.065) . OverallMost of the data included were retrospective and therefore vulnerable to bias and unable to be generalized across various healthcare settings. Most of the papers in the aminoglycoside group assessed the efficacy of gentamicin. However, the aminoglycoside used varied between studies and even within studies in some cases due to resistance. The reliability of the findings is therefore limited by inconsistent outcome measures between papers. For example, only 10 of the included papers included data on antimicrobial sensitivity, and only 8 papers reported on the serum level of aminoglycoside. Due to these data insufficiencies, definitive conclusions cannot be drawn. Additionally, although the majority of patients had a neurogenic bladder as the underlying pathology, there was great variation in the inclusion criterion between papers.The review is limited by the heterogeneity of the studies and variation in sample sizes. Variability in study design was noted in the definition of recurrent/refractory UTI, the measure of successful outcomes, the categorization of groups into treatment versus prophylactic IVA, and the duration of follow-up. As a result of these key design differences, it was not possible to accurately evaluate the merits or failures of IVA treatment amongst these patients .The short follow-up in some studies prevents the true assessment of success in these patients. Five of thirteen papers are characterized by a short follow-up duration. Haldorson et al., Wan et al., Praba et al., and Cox and Waites et al. describe a follow-up that goes from a minimum of 4 days to a maximum of 8 weeks . Given that the definition of recurrent UTIs is ≥2 infections in six months or ≥3 infections in one year, UTI resolution should be defined with a longer follow-up after the treatment. However, in view of limited patient numbers and poor patient compliance to long-term follow-up, these papers were also included.Future studies with a more robust methodology and longer follow-ups are required to draw meaningful conclusions. This would allow for a more accurate assessment of treatment efficacy with a view to aid clinical guidelines. It was noted the patient demographics were often not disclosed or sparsely documented in the included papers. This could be explored further to evaluate the optimum demographic characteristics of patients that would benefit from IVA and evaluate the impact of patient co-morbidity.This study observed that IVA is an efficacious method of managing the treatment and prophylaxis of refractory UTIs in the short term. The intravesical method of administration allows for higher concentrations of aminoglycoside to be given in a localized approach with no systemic absorption of aminoglycoside or associated side effects. Patients were able to self-administer the treatment and the low discontinuation rates suggest that it is a well-tolerated treatment option. Further research with larger sample sizes, longer follow-up periods, and analysis of trends in antimicrobial susceptibility will better assess the efficacy of IVA for the treatment and prophylaxis of UTIs.


Endoscopic submucosal dissection has become the primary option of treatment for early gastric cancer. However, lymph node metastasis may lead to poor prognosis. We analyzed factors related to lymph node metastasis in EGC patients, and we developed a construction prediction model with machine learning using data from a retrospective series.Two independent cohorts’ series were evaluated including 305 patients with EGC from China as cohort I and 35 patients from Spain as cohort II. Five classifiers obtained from machine learning were selected to establish a robust prediction model for lymph node metastasis in EGC.The clinical variables such as invasion depth, histologic type, ulceration, tumor location, tumor size, Lauren classification, and age were selected to establish the five prediction models: linear support vector classifier (Linear SVC), logistic regression model, extreme gradient boosting model (XGBoost), light gradient boosting machine model (LightGBM), and Gaussian process classification model. Interestingly, all prediction models of cohort I showed accuracy between 70 and 81%. Furthermore, the prediction models of the cohort II exhibited accuracy between 48 and 82%. The areas under curve (AUC) of the five models between cohort I and cohort II were between 0.736 and 0.830.Our results support that the machine learning method could be used to predict lymph node metastasis in early gastric cancer and perhaps provide another evaluation method to choose the suited treatment for patients. Gastric cancer is one of the most common and deadly cancers in the world . AccordiEarly gastric cancer (EGC) is defined as a stomach lesion confined to the mucosa and/or submucosa, regardless of its area or lymph node metastatic (LNM) status . Due to The previous studies confirmed that several risks such as tumor size, invasion depth, ulceration, histological types, and lymph vascular invasion were related with LNM in EGC –16. EvenArtificial intelligence (AI) is an advanced technology that has been used in many fields such as in industry, agriculture, navigation, driverless car, and healthcare –23. AI iCurrently, ML has been used to the wide area of medicine; the potential ability of ML can improve the efficiency and accuracy of clinical work, such as analyzing millions of clinical data to create prognostic, screening, and diagnostic models –29. ML hThis was a multicenter, retrospective analysis. The cohort I was obtained from the Sixth Affiliated Hospital of Sun Yat-Sen University , which was used to construct the prediction models, and the cohort II as the external validation date was from the University Hospital Virgen del Rocio , which was performed to verify the ability of models. The present study was approved by the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-Sen University and the University Hospital Virgen del Rocio; the approval number is E2021197.The authors retrieved EGC patients who only received additional gastrectomy from the electronic medical record system of the Sixth Affiliated Hospital of Sun Yat-Sen University . All patients were recruited from January 2012 to March 2021. After screening, a total of 373 records were found, and 68 patients met any of the exclusion criteria; then, 305 cases with pathologically confirmation of T1a/T1b stage were included in the study and underwent additional gastrectomy with systemic lymphadenectomy (D2) Figure 1The medical records for blood analysis, gastroscopy, and pathological reports for each patient were reviewed for the analysis. From the blood analyses data were gathered tumor markers such as CEA, CA199, CA125, CA153, and AFP. Gastroscopy data were collected from the report, which included the location of the tumor. The pathological results provided information about invasion depth (T1a/T1b), histologic type, Lauren classification, tumor size, and ulceration. The clinical characteristics of the patients, including sex, age, body mass index (BMI), and personal pathological history were also collected.p-value greater than 0.05 in Shapiro–Wilk test and Levine’s test) and the Mann–Whitney test. The chi-square test or Fisher’s exact test was also used for tumor markers after categorization into binary variables using the following cutoff points set as normal range  . The statistical analyses were performed using SPSS® version 26 (IBM SPSS Statistics for Macintosh) and R Studio .For ML approach, all features included in the model were determined by the Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC), and the Least Absolute Shrinkage and Selection Operator (LASSO), which were widely used for finding the best features for models , 47. AccAll selected categorical features were transformed into dummy variables. Then, all features were used to construct the ML models to predict LNM. All models used fivefold cross-validation on both cohort I and cohort II. All models were evaluated by the receiver operating characteristic curve (AUC) and optimized by the grid search; the Bayesian method was used to improve the ability of model. For LRC and Linear SVC models, the importance of features was calculated by their weight coefficients. For XGBoost and LightGBM, the importance of features was also plotted. All models were constructed and analyzed by Python (version 3.9.4). All files used for model construction have been placed in the supplement.All ML models were verified by external validation data and accuracy; AUC, Brier score, F1 score sensibility, specificity, and 95% ICs were estimated using the bootstrap method. Other bioinformatic approaches such as confusion matrices, ROC curves, and calibration curves were used in the present analysis. The groups that exhibited a high-risk were established by predictive probability, and their relative odds ratios were calculated.t = 2.64, P = 0.009). After categorization, this variable was divided into five groups based on the risk of cancer associated to age from National Cancer Institute of US  . The biomarkers such as CEA  and CA125  met the variable filter criteria, but their binary form  were not statistically significant . Other categorized variables such as invasion depth , histologic type  and LAUREN classification  were statistically significant, and the presence of ulcer presented a high trend toward significance . Nevertheless, tumor size  and tumor location  exhibited no association with LNM.The primary cohort (cohort I) included a total of 305 patients, of whom 69 patients (22.6%) had LNM according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system . The cla0 years) . The chip-values in univariable analysis were less than 0.15 , extreme gradient boosting classifier (XGBoost), LRC, and linear support vector machine classifier (Linear SVC) are shown in The confusion matrices for the five classifiers in the cohort I and cohort II with the percentage of their true label are displayed in vs. 0.803, 95% CI 0.799–0.808). However, compared with the different values of AUC between the cohort I and cohort II for all models, the XGBoost (0.781 vs. 0.804) and the Gaussian process classification (0.816 vs. 0.803) had tiny difference in both sides. It meant that these two models had the almost same ability for the prediction in cohort I and cohort II . LRC demonstrated the negative gradient comparing the high and medium risk (4.5 vs. 4.8), and LightGBM showed the negative gradient in medium and low risk (0.89 vs 1).Subsequently, the predicted probability was categorized as low, medium, and high risk. With the development of minimally invasive endoscopic technology, ESD is the gold standard to treat the EGC , 50, 60,According to the feature selection, we found that the risk factors related to LNM such as age; the presence of ulceration, tumor size, and depth of invasion; the histologic tumor type; the tumor location; and Lauren classification were common in each model  Figure 2Another point in this study was the use of ML for the prediction of LNM. Here, we found that the Linear SVC and Light gradient boosting classifier (LightGBM) were the best models to detect the actual positive cases, although the rest three models presented excellent abilities to detect the actual negative cases Figure 4It is undeniable that this study also has certain limitations. First, the model was constructed using a retrospective cohort; therefore, a prospective data set could be appropriate to improve the ability of the prediction model; perhaps we can find more risks that could be related to LNM. In addition, all preoperative examination results were obtained from reports; therefore, information bias was unavoidable. This study has been performed with a limited sample size, especially cohort II. However, results differed slightly between the cohort I and cohort II, which implies not only a different origin (China and Spain) but also a different ethnicity. In future work, we will make a prospective trial that includes more variables, such as biomarkers, and supplement with more predictive models to improve the prediction ability.In conclusion, we established five commonly used ML models to predict LNM in EGC; according to our results, machine learning can be used to detect high-risk LNM in EGC, especially the Gaussian Process Classification had the best comprehensive predictive ability. This could be applied to indicate that additional lymphadenectomy is necessary after the endoscopic resection in EGC. From another point of view, machine learning could provide a new solution to find the related factors in clinical research for prediction of LNM in EGC.The original contributions presented in the study are included in the article/Study concept and design: TY, JM-U, JL, and SM-C; Acquisition of data: TY, IA, and XJ; Build Models’ code: CL; Analysis and interpretation: TY, WL, YX, XJ, and YZ; Study supervision: SM-C and ZY. All authors contributed to the article and approved the submitted version.This work was supported by grants from the International Postdoctoral Exchange Fellowship Program 2020 by Human Resources and Social Security Department of Guang Dong Province support; Guangdong Provincial Department of Science and Technology 2021 Guangdong International, Hong Kong, Macao and Taiwan High-end Talent Exchange Overseas Famous Teacher Project ; the National Key Clinical Discipline, the National Natural Science Foundation of China , the Science and Technology Program of Guangzhou , and the Natural Science Foundation of Guangdong Province, China .This study was supported by Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, and the Unit of Innovation in Minimally Invasive Surgery, Department of General and Digestive Surgery, University Hospital “Virgen del Rocio”, Sevilla, Spain.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.


Due to significant heterogeneity , the random-effects model was followed. The stratified meta-analysis showed that the selenium levels were lower in the cases compared with the normal controls in the third trimester ; p ≤ 0.01). The same trend was observed in the studies published before the year 2014 ; p ≤0.01) and those published in or after 2014 ; p = 0.05). None of the investigated covariates in the meta-regression analysis  were significantly associated with the selenium SMD. The current evidence indicates that selenium levels are lower among women with GDM in comparison to those without GDM; however, after the correction of the reporting bias, the result was no longer significant. Further studies with more prospective designs are needed to confirm this evidence and explain the function of selenium in GDM throughout pregnancy.Several studies have investigated the association between selenium levels and gestational diabetes mellitus (GDM); however, their results are not conclusive. This systematic review and meta-analysis aimed to update and draw conclusions regarding the evidence from published studies that investigated selenium levels in relation to GDM. PubMed, Google Scholar, Cochrane Library and ScienceDirect were searched for studies related to selenium and GDM, published from the inception of each database through to July 2022. The meta-analysis was conducted by measuring the standardized mean difference (SMD) between the selenium levels of women with GDM and those pregnant without GDM (control group). Stratified meta-analysis, meta-regression analysis and reporting bias were applied. The “meta” package in the open-access software R was used to analyze all of the data. A total of 12 studies, including 940 pregnant women with GDM and 1749 controls met this study’s inclusion criteria. The selenium levels were significantly lower in women with GDM compared with the control group : ;  Gestational diabetes mellitus (GDM) is a common endocrine problem during pregnancy, with a prevalence of 15% of all pregnancies worldwide . GDM is The definite cause of GDM has not yet been fully explored. However, many risk factors that may contribute to the susceptibility to GDM, such as maternal obesity, past history of GDM and family history of DM ,6,7,8, hSelenium is an important trace element necessary for optimal several physiological processes . SeleniuSeveral studies reported an association between selenium deficiency and T2DM ,18,19. ATwo previous systematic reviews and meta-analyses published in 2015 and 2016 reported significantly lower levels of selenium among cases with GDM compared with normal controls ,28. HoweThe protocol for this systematic review and meta-analysis was listed in an international database of prospectively registered systematic reviews in health and social care (PROSPERO), with the registration number CRD42021239431 .The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were strictly followed . An elecP (population): pregnancy OR pregnant women OR gestation;I (intervention): selenium OR selenate OR Se;C (comparison): euglycemic OR normal pregnancy OR healthy pregnancy;O (outcome): gestational diabetes OR gestational diabetes mellitus OR gestational hyperglycemia OR GDM;S (study type): case–control OR cross-sectional OR cohort.Two investigators (SZH and IA) independently screened and carefully chose eligible studies for this meta-analysis after perusal, reading and assessment. Any disagreement was resolved by a discussion with the referee investigator (HZH). The search was aided by LitSuggest , an autoThe articles were included if the studies (1) investigated the association between selenium levels and GDM; (2) employed case–control, cohort or cross-sectional designs; (3) reported mean (standard deviation (SD)), median (interquartile) or median (range) values of the selenium levels in the case and the control groups and provided a measurement unit; (4) described the methods used to measure the selenium levels and measured the selenium levels in blood, plasma or serum and (5) were written in the English language.Systematic review articles, case reports, commentaries, editorials, clinical trials, abstracts and duplicate publications were excluded. The studies that reported selenium levels from hair samples and those written in languages other than English were also excluded.The primary outcome of this study is the investigation of the association between selenium levels and the development of GDM in comparison to healthy normoglycemic pregnant women. According to Carpenter and Coustan , GDM is Two investigators (IA and SZH) assessed the quality of the included studies by using the Newcastle–Ottawa Scale (NOS) for the case–control and cohort studies; the modified version of the NOS was used to assess the cross-sectional studies . Three mThe Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument was used to extract the data from each eligible study . Brieflymeta package [2I. Cochrane Q with p < 0.010 and 2I > 50% indicated evidence of inter-study heterogeneity [The open-source statistical software R 4.0.3  was used to measure the standardized mean differences (SMDs) in selenium levels between the case and control groups by applying the function “metacont” in the  package . The eff package . The hetogeneity .p-value < 0.05 was considered statistically significant in this study.Due to the high inter-study heterogeneity, the random-effects model was followed in this meta-analysis. Sensitivity analysis was applied to recognize any study that significantly changed the selenium SMD upon exclusion. A graphical funnel plot and a quantitative Egger’s test were used to investigate reporting bias. Any evidence of reporting bias was further examined by means of the trim-and-fill method in order to correct the asymmetry in the funnel plot. Stratification meta-analysis was conducted by grouping the studies according to the trimester in which the blood samples were collected for selenium measurement  and the study’s year of publication (before 2014 and in or after 2014), as we noticed that studies published after 2014 had smaller selenium SMDs than those published before 2014. Meta-regression analysis was performed to assess the relations between the selenium SMD and the following factors: study quality score, publication year, study continent, selenium measurement trimester, selenium quantification methods, regional economic ranking and study sample size. A The preliminary search in the databases retrieved a total of 224 articles. Out of this total, 56 were excluded as duplicates and 85 were irrelevant. The two investigators screened the titles and the abstracts of the remaining 83 articles. After screening, 21 were removed as they were animal studies, and 2 more were removed because they not written in English. Out of the 60 articles that were retrieved, 48 were found to be irrelevant, and 7 were primarily about children. Finally, 12 studies were included for meta-analysis, as shown in In this systematic review and meta-analysis, the included 12 studies comprised a total of 940 GDM cases and 1749 controls ,38,43,44Of the 12 studies, 8 were case–control ,38,43,44Six studies were published before 2014 ,23,24,26p = 0.0007 . Accordingly, the random-effects model was followed.The overall pooled estimate of the standardized mean difference of selenium levels was SMD = −0.66; 95% CI, ; = 0.0007 . The meaSensitivity analysis revealed that none of the included studies significantly changed the SMD of selenium upon deletion, as shown in p ≤ 0.01); see p ≤ 0.01) was higher than in the studies published in or after 2014 ; p = 0.05); see Stratified meta-analysis based on the trimester of selenium quantification, revealed that the heterogeneity level increased with the trimester. Likewise, the SMD of selenium levels increased along with the trimester, and was the highest during the third trimester ; second trimester: SMD = −0.54 ; third trimester: SMD = −1.85 ; In the meta-regression analysis, none of the investigated factors—geographic location, trimester of selenium quantification, World Bank economic ranking, methods of selenium quantification, study design, study quality score, publication year and study sample size—showed any evidence of a relation with the overall estimate .t = −2.34; p = 0.032). Therefore, the trim-and-fill method was applied, which corrected the plot asymmetry by adding four studies. The newly corrected pooled measures for the 16 studies were SMD = −0.15; 95% CI: ; p = 0.473  meta-analysis . This reIn a previous meta-analysis , it was Despite the subgroup analysis, the level of heterogeneity did not decrease significantly. Therefore, sensitivity analysis was performed in an attempt to identify the study or studies that could significantly change the overall effect and had heterogeneity. However, none of the investigated studies was found to significantly change the overall effect. This study found evidence of reporting bias, and four studies were estimated to be possibly missed in this meta-analysis. The supposed four missed studies influenced the overall effect and shifted it from a significant to an insignificant level. Although in their meta-analysis Kong et al. observed an asymmetrical distribution of studies in the funnel plot, no evidence of reporting bias was found, which was also the case in the meta-analysis by Askari et al. ,28. The Although this study updates the current literature, it has some limitations that must be acknowledged when interpreting the findings. First, reporting bias was corrected by adding four studies. However, other types of bias, such as selection bias, could not be avoided. Second, although cohort studies were included, which could explain the causality, the conclusions of these studies were neither uniform nor clear enough to formulate a conclusion about causality. Third, BMI and participant age were not reported in all the included studies. Consequently, a more in-depth analysis regarding these two important covariates could not be conducted. Fourth, the included studies reported varying levels of selenium while providing minimal or no details about validation or quality control for the method of determination. Fifth, the diagnostic criteria for GDM were neither uniform nor reported in all of the studies. This could alter the diagnostic threshold for glucose levels, and hence the diagnoses.This updated systematic review and meta-analysis indicates that selenium is lower among women with GDM in comparison to pregnant women with no GDM, who comprised the control group. However, the difference was not statistically significant after the correction of the reporting bias by means of the trim-and-fill method. There is a need for further research that includes more well-designed cohort studies, as well as the measurement of selenium levels throughout the trimesters, to more clearly explain the kinetics of selenium in GDM.


P < 0.0001), DLQI (P < 0.0001), NRS (P < 0.0001). The total expenditure for Dupilumab, in the observed period, amounted to € 589.748,66 for 1358 doses, and a positive correlation was shown between annual expenditure and delta percentage of variation pre- and posttreatment for the clinical parameters evaluated.Health care spending in Italy is high and continues to increase; assessing the long-term health and economic outcomes of new therapies is essential. Atopic dermatitis (AD) is a chronic, pruritic, immune-mediated inflammatory dermatosis, a clinical condition that significantly affects patients' quality of life at a high cost and requires continuous care. This retrospective study aimed to assess the direct cost and adverse drug reactions (ADRs) of Dupilumab and patients' clinical outcomes. All AD patients treated with Dupilumab at the Sassari University Hospital, Italy, between January 2019 and December 2021 were included. Eczema Area Severity Index, Dermatology Life Quality Index, and Itch Numeric Rating Scale scores were measured. ADRs and drug expenses were analyzed. A statistically significant posttreatment improvement was observed for all the indices measured: EASI ( This binding to IL-4α inhibits signaling of the Th2 cytokines IL-4 and IL-13 that contribute to the pathogenesis of AD [Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease with a complex pathogenesis involving genetic susceptibility, immunological dysfunction, the epidermal barrier, and environmental factors. AD is one of the most studied dermatological diseases in recent years, especially with the recent progress with the use of biological therapies, of which the first approved drug for moderate-to-severe AD is Dupilumab. Dupilumab  is a fully human monoclonal antibody that targets the interleukin (IL)-4 receptor-All 57 AD patients  treated with Dupilumab at the Dermatology Clinic, Azienda Ospedaliera Universitaria, Sassari, Italy, between January 2019 and December 2021 were included in this retrospective study. During the observation period, all the patients had at least 4 months of treatment with Dupilumab up to 3 years, in order to assess the clinical outcome. Our unit has a catchment population of approximately 335,000 living in an area of 4300 square kilometers (Sassari province). Ethical approval was waived by the local Ethics Committee of the Azienda Ospedaliero-Universitaria di Sassari given the retrospective nature of the survey, which was conducted in complete agreement with the principles of the Declaration of Helsinki. Each participant received detailed information and provided informed consent. Patients received subcutaneous Dupilumab 300 mg with an initial loading dose of 600 mg at time zero, followed by 300 mg after two weeks, continuing with 300 mg every other week. One pediatric patient was administered with the 200 mg dose on a similar schedule. At each visit and throughout the study period, the dermatologist performed a subjective clinical assessment of AD using the Eczema Area Severity Index (EASI). Each patient, through an Itch Numeric Rating Scale (NRS), compiled a diary that recorded the overall severity of the skin condition, the severity of itching, and sleep disturbances. A questionnaire was placed at each clinical control to evaluate the Dermatology Life Quality Index (DLQI).Data regarding the treatment and regimen were extracted from the dermatology clinic records, web-based monitoring records by the Italian Medicines Agency , and data flows included in the New Health Information System (Nuovo Sistema Informativo Sanitario-NSIS). Data on safety were evaluated as the number and severity of suspected adverse reactions to drugs  observed during the analysis of medical records. The costs of human monoclonal antibodies under analysis were extracted by the IT system of the Sardinian Region, adopted by all healthcare facilities in Sardinia.p value <0.05 was considered statistically significant. STATA software , version 17, was adopted for all statistical analyses.Demographic and clinical variables were collected in an electronic database. Qualitative data were summarised with absolute and relative frequencies (percentages), whereas quantitative data were described with medians and interquartile ranges (IQRs) based on the nonparametric distribution of the variables. The Wilcoxon signed-rank test was used to compare pre- and posttreatment clinical outcomes. Spearman's correlation was calculated to assess the relationship between the percentage variation in clinical indices before and after treatment and the annual expenditure for Dupilumab. A two-tailed The number of patients with moderate-to-severe AD treated with Dupilumab was 57. The total treatment cost during the analyzed period amounted to € 589.748,66 for 1358 doses. 798 doses for males and 564 for females corresponding, respectively, to 343.774,45 euros and 345.974,19 €. In 2019, the total expenditure related to Dupilumab treatment amounted to 24.710,37 € for 54 doses; 34 doses for males and 20 doses for females corresponding, respectively, to 15.558,38 € and 9.151,99 €. In 2020 the total expenditure amounted to 258.976,2 € for 566 doses; 310 doses for males; and 256 doses for females corresponding, respectively, to 141.841,73 € and 117.134,45 €. In 2021, the total expenditure amounted to 306.062,09 € for 738 doses: 450 doses for males and 288 for females corresponding, respectively, to 186.374,34 € and 119.687,75 € . The areP < 0.0001). The median DLQI reduced from 10 at baseline to 3 at the end of the treatment, with a Delta DLQI percentage of 80.0 (P < 0.0001). The median NRS reduced from 10 at baseline to 2 at the end of the treatment with a Delta NRS percentage of 80.0 (P < 0.0001). These results required a median annual cost for patient of 9073 €. It is difficult to estimate the real annual cost for patient under systemic or topical treatment as the following variables need to be taken into consideration. In recent years, patients with moderate-to-severe AD, due to the clinical manifestations, were frequently hospitalized for long periods to undergo systemic treatments, often intravenously. Patient management, therefore, involved long periods of hospitalization. To date, this type of hospitalization is no longer performed, and the management of patients treated with monoclonal antibodies takes place through outpatient check-ups resulting in considerable savings for the SSN. Additional costs include screening, monitoring, and prescription of standard systemic treatments such as corticosteroids, cyclosporine, and azathioprine. Dupilumab treatment also reduces the use of antihistaminic intake and supportive topical treatment and emollients. As evidenced by our analysis, the initiation of therapy with monoclonal antibodies has significantly decreased the use of other treatments with benefit for the patient and the SSN. The significant improvement due to Dupilumab treatment compared with the other standard treatment reasonably reduces morbidity with related costs [Most physicians are involved in the care of patients with AD, a disease which, depending on the severity of the clinical form, can significantly influence the quality of life of the affected individuals. Itching often disrupts sleep, leading to daytime drowsiness and irritability, which can lead to psychological stress and impaired performance at school and work. Most patients with atopic dermatitis use bland moisturizers and emollients for treatment, along with meticulous and often difficult or lengthy skin care routines –7. The m of 80.0  and a st of 80.0 , with a ed costs . Among ted costs . FurtherThe favorable benefit-risk-cost profile in this study supports the long-term role of Dupilumab treatment for patients with moderate-to-severe AD. Although the Dupilumab treatment direct cost might appear higher than standard treatments, when taking in consideration the overall expenditure sustained by the SSN and patients, the improvement of the quality of life, the reduced use of standard topical and systemic treatments, the reduction of screening and monitoring patients, and the reduction of morbidity, it is reasonable to state that the overall cost-effectiveness might be advantageous for Dupilumab. The introduction of novel therapies has a cost that health systems will have to foresee in the coming years, considering the overall clinical benefits and the reduction in the number of hospitalizations, especially in a pandemic era.


I2 = 21.4%; p = 0.282), DCR , PD , and QOL  and higher proportions of CD3+ T , CD4+ T , and the CD4+/CD8+ T ratio . The number of adverse events (AEs) was significantly lower in the TCM + chemotherapy group. The active components and targets of 19 high-frequency Chinese medicines obtained from the meta-analysis were screened and explored in network pharmacology analysis. Also, a regulatory network of active components and targets, a core network and key genes, a diagram of protein interaction, network topology analysis, and gene body GO function and KEGG pathway enrichment analysis were performed. A total of 120 active components were identified. NPM1 and HSPA8 are the most critical target proteins in the core network of protein interaction. HSP90AA1 is the most important target protein in the TCM group. KEGG enrichment analysis showed that it was highly significant in the lipid and atherosclerotic pathways. Therefore, moderate evidence revealed that TCM plus chemotherapy has obvious advantages over chemotherapy alone in terms of tumor responses, QOL, peripheral blood lymphocyte levels, and fewer AEs in the treatment of GC. The potential important targets and core genes were displayed.This meta-analysis plus network pharmacology aimed to investigate whether traditional Chinese medicine (TCM) combined with chemotherapy is associated with more beneficial efficacy data in the treatment of gynecological cancer (GC). A total of 11 randomized controlled trials (RCTs) consisting of 863 GC patients were included. Results showed a better ORR (RR: 1.42, 95% CI: 1.18–1.71; www.crd.york.ac.uk/PROSPERO/, identifier CRD42021252500. More than 8.6 million global women are diagnosed with cancer per year, with approximately 1.3 million cases of gynecological cancer (GC) . DespiteThe main treatment methods for gynecological tumors include surgery, chemotherapy, radiotherapy, or a combination of them. Chemotherapy is an important part of the treatment of gynecological tumors, but it will inevitably induce adverse effects such as deterioration, myelosuppression, and reduction. Take ovarian cancer (OC), for example. OC is the most common malignant tumor in gynecology, and the current standard treatment plan of which is postcytoreductive surgery combined with “paclitaxel + carboplatin” therapy. Also, emerging treatments such as poly(ADP-ribose) polymerase (PARP) inhibitor  and neoaIn China, traditional Chinese medicine (TCM) has gained more and more attention for malignant tumors because of its beneficial effects, such as low toxicity and enhanced efficiency , 8. FurtTherefore, we aimed to drive this meta-analysis to investigate the efficacy and safety of combination therapy by using TCM plus chemotherapy compared with chemotherapy alone, in which way we can spot suitable prescriptions to improve patients’ survival rates. High-frequency Chinese herbs will be extracted from those beneficial prescriptions. Whereas, there are still large gaps in our understanding of TCM, such as what are the essential effective components in TCM, what are the key potential targets, and whether interplays exist between these herbal components. As a result, we performed network pharmacology analysis to explore the potential pharmacological mechanisms and targets of TCM in the treatment of GC.This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The protocol for this review was registered with PROSPERO (CRD42021252500).Three investigators independently searched several databases: PubMed, EMBASE, Cochrane, Chinese biological medicine (CBM), China Wanfang database, China National Knowledge Infrastructure databases (CNKI), Chinese Clinical Trial Registry (ChiCTR), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to September 26, 2021. Moreover, we also obtained the data sources from the abstracts and presentations recorded at some annual meetings, symposiums, or congresses such as ASCO, ESMO, ESGO, and so on, to ensure the relevant minutes were not overlooked. The complete search strategy was introduced in the Studies were included if they met the following criteria: if the people enrolled were GC patients ; if the subjects included had no contraindication to chemotherapy and no other systemic disease and were expected to live longer than 3 months; if TCM was in combination with chemotherapy for GC in the intervention group; if patients were treated with no TCM, or placebo, or conventional chemotherapy alone in the control group; if tumor response rate, QOL, AEs, serum tumor marker, and peripheral blood lymphocyte levels were reported (at least one of these outcomes); and if they were randomized controlled trials (RCTs).We excluded studies if they had not met our baseline requirements; if they employed the methods of acupuncture, massage, and other TCM treatment; if they did not offer the outcomes we needed; and if they were case reports, case series, observational studies, or other types of articles.+ T, CD4+ T, CD8+ T, and CD4+/CD8+ T ratio. Serum tumor markers were evaluated by CEA, AFP, and other common tumor markers.Three independent investigators finished this part following the requirements of PRISMA according to the above inclusion and exclusion criteria. All disagreements about selection were discussed and resolved by all investigators. The data extraction included the author, year, country, research type, number of cases, age of patients, and the indicators for demonstrating outcomes. Tumor response was the primary outcome, including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The CR rates combined with PR rates were equal to the ORR; the CR, PR, and SD rates were equal to the DCR. Quality of life (QOL) and the incidence of AEs were also the main outcomes. Immune function , KPS score, and serum tumor marker were the secondary outcomes. Peripheral blood lymphocytes were evaluated by the levels of CD3Three researchers independently carry out the literature quality evaluation by applying the Cochrane evaluation handbook of RCTs (5.1.0), which includes the following characteristics covering randomization sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personal (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. We used the Review Manager 5.3 software risk assessment tool to finish this part, and we decided through discussion or consultation with a third party when opinions were inconsistent.RevMan  and STATA  were utilized to perform statistical analyses including pooling the data and producing the forest plots.p-value less than 0.05 to be statistically significant. The I² test was also used to assess the between-study heterogeneity. If the heterogeneity test is p ≥ 0.1 and I2 ≤ 50%, it indicates that studies are homogenous between studies, and the fixed-effects model is used for combined analysis. Otherwise, we used a random‐effects model to pool effect size. I² regarded an estimated value applied to three fixed knots at 25%, 50%, and 75% as an indicator of mild, moderate, and high heterogeneity. Sensitivity analysis was also performed for examining the robustness of included trials to different aspects from methodological bias. In addition to this, publication bias was also estimated by an inverted funnel plot.The combination of relative ratio (RR) and mean difference (MD) with a 95% confidence interval (CI) was used to assess outcomes and considered a https://www.ncbi.nlm.nih.gov/), we selected the database GEO datasets. GMS mainly includes vulvar neoplasms (VN), vaginal cancer (VC), uterine cervix cancer (UCC), endometrial carcinoma (EC), OC, and fallopian tube carcinoma (FTC).VC and FTC were too few to have reliable disease samples in the GEOncbi database. Targets of VN, EC, and OC were mainly obtained, while the reliable disease samples of VC and FTC were too few to acquire. We searched for “vulvar neoplasm,” “uterine neoplasms,” and “ovarian neoplasms,” respectively. On the left, only series and expression profiling by an array of human tags are retained to narrow the screening range and obtain the corresponding samples of three tumor diseases  was used for obtaining the effective components of each TCM. The medicinal DL ≥0.18 condition played an important role in screening the effective components of TCM. Related targets were entered, and the corresponding targets of the selected active ingredients were derived. Perl has been used as an important tool for gene standardization, converting full names to genetic symbols.Section 2.7. The intersection of the two was taken, and a Venn diagram was drawn.A variety of active ingredients and corresponding targets of TCM were retrieved from the TCMSP database. Perl was used to form the “component-target” database of the active ingredients and GC disease targets in https://string-db.org/), the species was limited to humans, and a score of >0.9 was set to construct the protein interaction network diagram of the TCM group-GC. The data were then saved as TSV files, and the information of Node1, Node2, and combined score are imported into Cytoscape V3.7.2. Finally, the proximity centrality and intermediary centrality of each node are calculated by using the CytoNCA function package and a reference degree value. Finally, the core gene targets with the highest significance in topology analysis were selected.The intersected genes were imported into the STRING database  and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis should be performed for the intersection genes of TCM group-GC using the R language. First, the culsterProfiler package is imported, and the enrichGO function is used to import the human gene database through org.Hs.eg. and db function packages according to the intersection gene ID obtained previously. Under the conditions of “pvalueCutoff=0.05” and “qvalueCutoff=0.05,” the ID is converted into gene names and output to BP, CC, and MF groups for the GO enrichment analysis. Finally, the enrichPLOT and GGploT2 function packages are used to draw visual diagrams. Secondly, the KEGG enrichment analysis is carried out using the enrichKEGG function, and then the pathway—gene files and node files obtained by Perl are imported into CytoscapeV3.7.2 to build a KEGG network. Based on the above enrichment analysis results, we can predict the action mechanism of GC treated by various TCM.As shown in The main characteristics of the 11 included studies are shown in All of the 11 studies referred to randomization. Only 2 trials , 21 usedI2 = 21.4%; p = 0.000)   , and a meta-analysis was conducted through a random-effects model. The pooled results show that the quality of life of the combination therapy group is significantly better than that of the chemotherapy alone group  , CD4+ T , and CD4+/CD8+ T ratio  of the combination therapy group were significantly higher than those in the chemotherapy-alone group. While the level of CD8+ T cells of the combination therapy group didn’t show an obvious increase    Figure 8Sensitivity analysis eliminates each included study one by one and performs a summary analysis on the remaining studies to assess whether a single included study has an excessive impact on the results of the entire meta-analysis. The result of the sensitivity analysis is shown in The funnel plot is shown in To discern the commonality of the TCM formulae for combined chemotherapy in the included studies, we analyzed the occurrence frequency and compatibility of the compounds in those Chinese herbal prescriptions.We analyzed the characteristics of the 10 different TCM prescriptions mentioned in the included trials. Ordered according to their frequency of use, the TCM whose counts were more than three are listed in In addition, 4 of these studies (40%) used a combination of Dangshen/Renshen, Gancao, Baizhu, and Fuling, which is the most representative prescription for nourishing qi and is known as Sijunzi decoction. Based on these findings, it can be inferred that in the treatment of GC by TCM + chemotherapy, using basic qi tonic TCM to invigorate qi and strengthen the spleen can be an effective method, which was also found in some experiments. A new effective prescription was composed of these 19 herbs for subsequent network pharmacology analysis.Through the above meta-analysis, 19 kinds of TCM  have good effects on GC treatment. Due to the large number of Chinese medicines, we took Counts4 as the screening standard, and took the first 9 Chinese medicines as the TCM group.Using the TCMSP database, the TCM group was entered into the database, and the obtained ingredients were screened according to oral bioavailability (OB) of ≥30% and drug like (DL) of ≥0.18. Through searching the TCMSP database, there is no effective ingredient in Shengdi that meets ADME standards. Therefore, the remaining 8 TCM in the TCM group are used to screen the effective ingredients. Finally, there were 6 active components in Fuling, 88 active components in Gancao, 4 active components in Baizhu, 2 active components in Danggui, 16 active components in Huangqi, 8 active components in Baishao, 3 active components in Mudanpi, and 12 active components in Dangshen. After weight removal, there were 120 active components in the TCM group.Section 2.7. The genes with a high correlation with GC in |log FC|>1 adj.p-val<0.05 were screened by the method in Section 2.7. A total of 626 high correlation targets in VN, 3,884 high correlation targets in EC, and 5,665 high correlation targets in OC were obtained. As there were few highly correlated targets in VN, we expanded the screening conditions and screened |log FC|>0.5 p-val<0.05 as a highly correlated gene of VN. A total of 2,144 highly correlated targets in VN were obtained. After deleting the overlapping targets in the three groups of data, 8,949 high correlation targets of GC disease were obtained.The GEO database difference analysis was performed on the whole gene matrix of VN, EC, and OC obtained in In total, 120 active components were retrieved from the TCMSP database, and 225 directly corresponding targets were obtained after weight removal. A total of 8,949 highly correlated targets of GC disease were retrieved from the GEO and GeneCards databases, including 139 drug-disease common targets. After standardizing the gene, the full name of the gene is transformed into the gene symbol. Finally, Cytospace3.7.2 software was used to construct the regulation network of the TCM group  network was then required. The data in According to the results of topological parameter analysis, genes NPM1 and HSPA8 were the most critical genes in GC. Through the PPI core network, HSP90AA1, HSPA5, CDK2, and ESR1 were found to be the core genes directly associated with the effective components of the TCM group, among which HSP90AA1 ranked the highest.An enrichment analysis was carried out for 139 intersection genes of the screened TCM group and GC disease targets, and the analysis results of biological process (BP), cell composition (CC), and molecular function (MF) involved in this core target could be obtained in From the analysis of Whether the Chinese traditional medicine group—the intersection of GC disease gene KEGG enrichment analysis, gets the core targets in lipid and atherosclerosis, Kaposi’s sarcoma-associated herpesvirus infections, hepatitis B, diabetes complications of AGE-RAGE signaling pathways, fluid shear stress and atherosclerosis, and the human cytomegalovirus pathway is salient. It indicates that the components in the TCM group may achieve the purpose of curing diseases by acting on the above signal pathways  or progression-free survival (PFS); they only illustrated the curative effects of factors including tumor responses, QOL, peripheral blood lymphocyte levels, and AEs in treating GC. Thus, more newly offered evidence needs to be stated to confirm whether TCM plus chemotherapy could prolong the long-term survival rates of GC patients. Among those trials, lacking the data on the applications of injection-based, pill, and external administration of TCM, the included formulas were all oral administration. Also, almost all TCM were used after the chemotherapy cycle ended. The utilization of TCM before or during the chemotherapy cycle still needs more data to support. More studies to determine the best dosage form and use time of TCM are needed in the future.Myelosuppression, hepatic and renal dysfunction, and gastrointestinal reactions were common chemotherapy-related side effects , 31, whiWe also perform network pharmacology to explore the specific effect of the TCM group on the GC treatment process. According to the results of the PPI and KEGG parts, the TCM group plus three core genes mentioned above and the relevant signaling pathway obtained by GO and KEGG enrichment analysis have more to do with the occurrence and development of malignant tumors. Current studies demonstrate that the level of NPM1 is associated with the promotion of endometrial cancer by circWHSC1 . In addiNPM1 is a protein widely expressed in the nucleoli, which can travel between the nucleus and cytoplasm, participate in the assembly and transportation of ribosomal proteins, regulate centrosome replication, and regulate the expression of tumor suppressor ARF. Mutations in NPM1 push the protein to transfer from the nucleus to the cytoplasm, causing acute myeloid leukemia. However, Fan et al.  showed tMoreover, HSPA8 is a component of the HSP70 family expressing homologous proteins and is crucial to many cellular processes. In particular, its regulatory role in autophagy is decisive . FunctioFurthermore, the HSP90AA1 gene is a core gene directly associated with GC. Functioning as a homologous dimer, the protein it encodes is an inducible molecular chaperone. The encoded proteins contribute to the correct folding of specific target proteins through the cochaperone-regulated ATPase activity. There is evidence  that HSPThe strengths of our study include our wide-ranging online searches of literature in both English and Chinese databases. We applied broad criteria for pooling studies. We conducted a meta-regression analysis to determine if specific preparation yielded differing effects over the broad group, and in several cases they did.in vivo and in vitro. So we still need to take these compelling results with caution and this study should be carefully disseminated for clinical application. Our findings need to be further confirmed via more RCTs conducted in a rigorous manner.Some limitations may affect the drawn conclusion. First, there was a lack of large, multicenter, standardized RCTs, and the sample sizes of our included studies were mostly small or of moderate size. More RCTs with larger sample sizes are required to confirm these outcomes. Second, TCM’s individualized treatment and self-formulated prescription for inconsistent treatment with Chinese medicine may have led to heterogeneity in the meta-analysis, and none of them were able to provide definitive options for clinical treatment. Moreover, randomization methods, allocation concealment, and blinding are not clearly described in those included trials, which may result in inherent bias and exaggeration of the efficacy of the treatment group. In addition, our study induced a certain degree of heterogeneity due to the different classifications of tumors, pathologic stage of the tumor, the application of adjuvant therapy, and duration of treatment among included trials. Furthermore, almost all studies were conducted in China, which may lead to unavoidable regional bias. All these limitations may have resulted in insufficient evaluations of the outcome indicators. There are also some shortcomings in network pharmacology analysis. Due to the incomplete research on drug components and targets, the relevant data in the disease database are incomplete, leading to certain limitations and defects in the statistical results of network pharmacology in this paper. Also, the method of screening components of TCM by DL and OB values did not take the active ingredients into full consideration, which may affect the results. Furthermore, network pharmacology studies ignored the influence of component content of TCM on experimental results, and subsequent studies should focus on the relationship between content and curative effect. Moreover, network pharmacology is based on computer simulation analysis and molecular network data, whose statistical and predictive results need to be confirmed by specific experiments All in all, we hope the findings of this analysis will provide a shred of helpful evidence for clinicians to formulate the best treatment strategy for patients with GC and also provide scientific clues for researchers in this field. Moreover, the methodological ideas of this paper are shown in In summary, our study indicates that TCM plus chemotherapy is highly effective and safe in the treatment of people with GC. TCM plus chemotherapy has the characteristics of multiple pathways, multiple components, and multiple targets in the treatment of GC and diseases. Our study will provide valuable evidence for further evaluation of TCM. Moreover, some limitations increased the risk of bias, which, to some extent, affects the credibility of the satisfactory result. Thus, to confirm these finding, more rigorous randomized controlled trials are needed.The original contributions presented in the study are included in the article/LZ, LS and JY contributed to the design and conception of the study. JY and NR carried out the collection and processing of data. LQ and GY finished the figure diagramming. ZZ and LY performed the data analysis and interpretation. NR and LY wrote the manuscript. LZ, LS and JY revised the manuscript, then LZ gave the final approval of manuscript.This study was financially subsidized by the Project funded by Plan Project of Zhejiang Province Medical and Health Science and Technology ; China Postdoctoral Science Foundation ; Young Elite Scientists Sponsorship Program by CAST ; Research Project of Zhejiang Chinese Medical University ; The Construction Fund of Medical Key Disciplines of Hangzhou (OO20200385); Research Project of Zhejiang Chinese Medical University .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.


Asthma and stroke share many risk factors. Previous meta-analysis has indicated that asthma is associated with an increased risk of stroke. However, this study were limited by the small number of articles included and the lack of subgroup analyses of different stroke types and different populations. This meta-analysis aimed to synthesize evidence systematically to investigate the impact of asthma on stroke.via PubMed), Web of Science and EMBASE databases and manually identified eligible studies  that analyzed the association between asthma and stroke. We conducted quality assessment to evaluate the risk of bias of studies and sensitivity analyses to test the robustness of results.We searched Medline : 1.34, 95% confidence interval (CI): 1.21–1.47]. Moreover, asthma significantly increased the risk of ischemic stroke  without increasing the risk of hemorrhagic stroke . Asthma increased the risk of stroke in both men  and women  with no significant difference between the sexes. We also found that patients with inactive asthma, child-onset asthma, or no smoking history did not have an increased risk of stroke.These results supported the finding that asthma could significantly increase the risk of stroke, but this impact was not consistent in different populations.https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=290745, identifier: CRD42021290745. Asthma is a common chronic inflammatory disease. Globally, it is estimated that 334 million people have asthma, including children and adults . The incPatients with asthma have reduced lung function and a high risk of comorbidities. Essentially, asthma is due to chronic airway inflammation, and the main features are airway hyper-reactivity and reversible airway limitation. However, chronic asthmatic inflammation is not limited to the airway, but affects the whole body , 4. ConsStroke is responsible for over 5.5 million deaths annually, and it is estimated that 166 million healthy-life years are lost due to stroke . The queConsidering the growing incidence of asthma and the high disability rate and mortality associated with stroke, there is an urgent need to determine how asthma affects the risk of stroke. Moreover, knowledge about the degree of stroke risk induced by asthma in different populations will assist in developing population-wide interventions. In addition, this knowledge could inform the clinical management of patients with asthma that have high stroke risk.A previous meta-analysis of 5 cohort studies noted that asthma was associated with an increased risk of stroke . HoweverThis meta-analysis was conducted according the MOOSE  and PRISMA  checklist , to ensuWe searched electronic databases up to December 25, 2021 . The detailed search terms are provided in We included observational cohort studies with both prospective and retrospective designs. The inclusion criteria were: both asthma and control groups had to be included; the total number of subjects had to be >1,000, to reduce bias; outcome measures had to include an analysis of the association between asthma and stroke; and the data had to include hazard ratios (HRs), relative risks (RRs), odds ratios (ORs), or the number of stroke events in the asthma and control groups.The titles and abstracts of eligible studies were analyzed independently by two independent investigators (Z-FL and Z-YA). Disagreements were settled by discussing with a third author (Z-HL) to reach a consensus. Then, the reviewers independently assessed the full text of all studies for inclusion, based on the criteria related to population selection, study design, and outcome. The investigators also attempted to contact the corresponding author for information on missing data.The risk of study bias and quality were assessed with the Newcastle-Ottawa Scale (NOS) for cohort studies. NOS scores below 6 indicated low quality, NOS scores of 6 or 7 indicated medium quality, and NOS scores above 7 indicated high quality. Two authors (S-CH and M-DH) independently completed the quality assessments. In cases of disagreement, a third investigator .I2 statistic was used to evaluate the heterogeneity of the included studies. To address the variability of each outcome of interest, an I2 > 50% was defined as significant heterogeneity . When adjusted estimates were unavailable, we included unadjusted estimates and the number of events to calculate stroke incidence in the asthma and control groups. The ogeneity , and we We conducted subgroup analyses investigating the risk of stroke of people with asthma in different stroke types (including ischemic stroke and hemorrhagic stroke) and different populations including asthma status, smoking status, gender and age of asthma onset. We also conducted sensitivity analyses to test the robustness of results.Our searches identified 254 articles. After applying the inclusion and exclusion criteria, we included 18 observational studies , 14–30 . Among tAmong 18 the observational studies included, 10 were cross-sectional studies –30. Of tWe collected baseline patient characteristics from each study . The comp < 0.00001; I2: 89%, p < 0.00001). Most of the subsets (22 of 26) showed an increased risk of stroke in patients with asthma, but the heterogeneity was pronounced. Moreover, the risk of stroke was significantly increased with asthma, in both the cohort studies  and the cross-sectional studies , and no difference was found between analysis results of cohort studies and cross-sectional studies (p = 0.07 for between-group difference)  .p < 0.00001; I2: 93%, p < 0.00001). In contrast, the probability of hemorrhagic stroke did not increase significantly in patients with asthma   .p < 0.0001; I2: 24%, p = 0.22) and women  with asthma, compared to individuals without asthma (p = 0.07 for between-group differences).Next, we examined the risk of stroke in different populations. The risk of stroke was significantly increased in both men . Conversely, we found that, among patients with a smoking history, those with asthma had an elevated risk of stroke, compared to those without asthma , and non-smokers (those that had never smoked). The reference subgroups were individuals with the same smoking status, but without asthma. We found that, among patients that did not have history of smoking, those with asthma did not have an elevated risk of stroke, compared to those without asthma , but not in patients with inactive asthma  (p = 0.008 for the between-group difference).Next, we compared patients with active asthma to patients with inactive asthma. Active asthma was defined as either a negative response to the question, “Do you still have asthma?” , 21, or  = 0.34) . Thus, ap = 0.001; I2: 0%, p = 0.81)  .We performed sensitivity analyses to test the robustness of the main outcomes –5. By omThe publication bias was evaluated with a funnel plot. The funnel plot was visually symmetrical overall .p = 0.008). These results were consistent with previous studies, which showed that asthma, particularly active asthma, significantly increased the risk of stroke (This study assessed the effects of asthma on stroke by including previous studies comprehensively, particularly those with data for different populations. Our results showed that patients with asthma had a 34% higher risk of stroke than those without asthma. Furthermore, active asthma significantly increased the risk of stroke compared to inactive asthma (RR: 1.48 vs. RR: 0.95, f stroke .The chronic inflammatory state of asthma accelerates the process of atherosclerosis, which can lead to the development of stroke . Asthma Previous studies have suggested that asthma caused similar increases in the risks of ischemic and hemorrhagic stroke. In contrast, the present study showed that asthma mainly increased the risk of ischemic stroke and had less effect on the risk of hemorrhagic stroke. Our findings were supported by the association between asthma and atherosclerosis. Indeed, atherosclerosis directly drives thrombosis, which leads to ischemic stroke, and it is much less related to hemorrhagic stroke. In contrast, the main risk factors for hemorrhagic stroke are trauma and congenital vascular developmental malformations, which are more weakly associated with asthma.The greatest strength of this study was that it included the largest sample size of any study to date that aimed to analyze the relationship between asthma and stroke. Moreover, we characterized the effect of smoking status on this association with a sufficiently sized subgroup analysis.However, this study also had some limitations. First, unfortunately, we could not obtain sufficient data on patient asthma treatments to analyze their effects on stroke risk. Previous studies have shown that asthma treatment medications, like β receptor-agonists and glucocorticoids, could influence stroke outcomes –39. MoreIn conclusion, this meta-analysis provided evidence to support the notion that asthma is an important risk factor for stroke. This information is important for the development of strategies for preventing and treating asthma and stroke. In the future, well-designed, large, multicenter cohort studies should be conducted with a particular focus on a quantitative assessment of the effects of asthma on patients during stroke treatment.The original contributions presented in the study are included in the article/Z-FL: analysis of data, interpretation results, drafting, and editing the article. Z-HF, Z-YA, S-CH, M-DH, and W-XZ: design of study, solution of problem, and reviewing the article. S-CH and M-DH: extraction of data and assessment of articles quality. All authors contributed to the article and approved this version of article.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.


As a result of the COVID-19 outbreak and the enforced quarantine, universities in Malaysia were required to switch to an online class format. The resulting changes in the environmental factors of students may have had an impact on their psychological health and academic performance. This study aimed to determine the effects of environmental factors and the psychological health of students and examine their structural relationship with academic performance. A cross-sectional design with an online self-reported questionnaire was adopted, and the study was conducted among 207 undergraduate medical students at the Health Campus of Universiti Sains Malaysia. The environmental factors were measured using the lighting–noise–temperature scale and technology scale, while psychological health was assessed using the short version of the General Health Questionnaire and academic performance was determined based on Grade Point Average. Descriptive statistics and structural equation modeling were used for analysis of the data. No significant relationship was found between environmental factors and academic performance, or between environmental factors and psychological health. Nonetheless, the hypothesized structural model provided scientific evidence of an inverse relationship between psychological health and academic performance. These findings could be helpful for academics, health policymakers, and health educators in terms of understanding and promoting psychological wellbeing among university students, as well as improving their academic performance. The global disruption caused by COVID-19 poses a massive challenge to global health and continues to affect people as well as students worldwide. Borders and all academic institutions were closed, and economic activities came to a standstill due to the implementation of the Movement Control Order (MCO) in Malaysia on 18 March 2020, to keep the spread of COVID-19 and associated mortality under control [Medical students were one of the most severely affected groups, as their lessons at hospital and other health care centers where they learn essential clinical skills had been suspended until further notice. They were also required to adapt quickly to the online learning format, which required much adjustment and was unlike their face-to-face and patient-based learning format in the health care setting. These unfavorable circumstances probably led to an increase in stress levels among medical students, especially those who experienced coping and adjustment difficulties. All these factors may have contributed to depression, anxiety, and stress among medical students.Mahdy (2020) demonstrated that the lockdown imposed as a result of the COVID-19 pandemic had varying degrees of impact on most students’ academic performance , as theyp = 0.023) [During the COVID-19 pandemic, psychological health problems, especially depression, anxiety, and stress, have become common among students, especially medical students . In stud= 0.023) . Rising = 0.023) . The tro= 0.023) . The switch to the online learning mode has led to severe anxiety among medical students, who have also reported inadequate internet access, which is required for online learning . HappineHowever, no studies in Malaysia so far have focused on the relationship between psychological health and environmental factors (LNT and technology) and how they affect academic performance. Therefore, this research aimed to study the relationship between environmental factors (LNT and technology), psychological health, and academic performance among medical students at the Health Campus of USM during the COVID-19 period in Malaysia. It is important to examine the factors that influence students’ academic performance during the pandemic period, as this can provide insight into how the Malaysian university and government can improve the online learning environment in Malaysia. The hypothesized relationship between environmental factors, psychological health, and academic performance is depicted in A cross-sectional study was conducted on 207 undergraduate medical students from the School of Medical Sciences, USM. Second- and third-year undergraduate medical students in academic year 2021–2022 who participated in online learning during the second semester of academic year 2020–2021 were included. Re-sit students and students with a history of underlying psychological issues were excluded. The study was approved by the Human Ethics Committee of USM  and the academic office of the university. This ethical approval allowed the researcher to conduct the research on the target population. Implied consent was obtained from each of the participants after they had received the link to the Google form of the questionnaire. The information provided about the research included the purpose of the study, study procedures, potential risks of participation, and benefits of participation in the study. All participants voluntarily participated in this research study. The researcher guaranteed that the data collected were kept confidential and only used for research purposes. After the survey was completed, the participants were thanked for their involvement in the research study.With regard to the classification of household income, there are three classes of household income in Malaysia: B40, M40, and T20. B40 represents the bottom 40% of the average Malaysian household income and corresponds to less than RM4850 per month. M40 represents the middle 40% and corresponds to RM4851–RM10970 per month. T20 represents the top 20% of Malaysian household income and corresponds to RM10971 per month. In this study, 42% of participants were classified under M40, that is, they had a family income of RM4851 to RM10970. The sample size was calculated based on the method of Kline (2011) . He suggData were collected using an online self-administered questionnaire. The link to the Google Form of the questionnaire was sent to the class leader of each year through WhatsApp and email. They shared the online survey link with other students. Participants completed the online survey in 20–30 min. They were informed that it was compulsory to answer all the questions. The GPA reported by the students in the survey was verified with the results provided by the academic office.This questionnaire consists of three parts: (i) 9-item proforma form (about sociodemographic profiles and GPA for the second semester of the academic year 2020/2021 examination), (ii) 15-item questionnaire on environmental factors (LNT and technology questionnaires) and (iii) 12-item psychological health questionnaire (GHQ-12).The LNT scale was developed by Realyvásquez-Vargas et al. (2020)  and consp-value < 0.001). The CR for lighting, noise, and temperature was 0.82, 0.81, and 0.84, respectively. The AVE for lighting, noise, and temperature was 0.61, 0.59, and 0.63, respectively.The present study shows that the measurement model had a good fit based on recommended fit indices without modification indices. The results of robust fit indices were as follows: CFI = 0.99, TLI = 0.98, SRMR = 0.03, and RMSEA = 0.03. The factor loadings ranged from 0.74 to 0.82 , which measures the effects of indoor lighting on students’ academic performance during online classes. The second domain is noise (three items), which measures the effects of noise pollution on students’ academic performance during online classes. The third domain is temperature (three items), which measures the effects of thermal comfort on students’ academic performance during online classes.The technology scale was developed by Abou Naaj et al. (2012)  and consp-value < 0.001). The CR for technology was 0.84, and the AVE for technology was 0.51. The present study showed that the model had a good fit based on the values of all indices, except for the upper 90% CI of robust RMSEA, which was 0.16. These were the values for the remaining robust fit indices: CFI = 0.99, TLI = 0.97, SRMR = 0.02, and RMSEA = 0.06. The factor loadings ranged from 0.62 to 0.79  to 3 . It consists of 12 items that describe mood states, with six of them positively phrased  and six of them negatively phrased  . AccordiIBM SPSS Statistics version 27.0  and the Lavaan package of R Studio were used for data analysis. Descriptive statistics of the numerical variables are presented as mean and standard deviation (SD), while categorical variables are presented as frequency and percentage. Further, inferential statistics were analyzed with SEM, which was used to examine the structural relationship between environmental factors, psychological health, and academic performance. Due to the violation of normality, the maximum likelihood estimator (MLR) was used in the analysis. The items in the measurement model for psychological health were parceled into one domain , while the measurement models LNT and Technology were maintained.Fit indices were used to evaluate the model’s fitness. RMSEA < 0.08, SRMR < 0.08, TLI > 0.95, and CFI > 0.95 ,34. SignThe items in the measurement model for psychological health were parceled into one domain, named psychological health, and were treated as observed items. The descriptive statistics of the constructs are shown in Nine items in The six items presented in The twelve items presented in β = −0.21, p = 0.004).The environmental factors (LNT and technology), psychological health, and academic performance were imputed into the proposed structural model using the estimator MLR, in order to examine their relationship. A virtual learning environment (VLE) is a set of teaching and learning tools designed to enhance a student’s learning experience by including computers and the internet in the learning process. The principal components of a VLE package include curriculum mapping (breaking curriculum into sections that can be assigned and assessed), student tracking, online support for both teacher and student, electronic communication , and internet links to outside curriculum resources. In general, VLE users are assigned either a teacher ID or a student ID. The teacher sees what a student sees, but the teacher has additional user rights to create or modify curriculum content and track student performance. There are a number of commercial VLE software packages available, including Blackboard, WebCT, Lotus LearningSpace, and COSE.In view of the COVID-19 pandemic and the MCO imposed by the government, a blended learning substitution model was adopted. With this model, students learn through online classes as well as traditional face-to-face lessons. Online class learning is composed of asynchronous and synchronous methods. Asynchronous methods include online teaching and learning strategies that do not involve real-time interaction, for example, recorded videos/lectures and self-guided learning materials. The Elearn@USM platform is the university’s official e-learning platform used for asynchronous online teaching and learning. Both lecturer and student can access this learning platform. Synchronous online teaching and learning methods involve online teaching and learning in real time. Lecturers use online meeting platforms, such as Webex, Microsoft Team, Zoom, Google Meet, and others, to conduct teaching sessions with students. The students can interact or ask questions, and lecturers can respond in real time.The COVID-19 pandemic and lockdown had varying degrees of effects on most students . Some stIn the current study, the overall mean (SD) scores for the lighting and noise scales were 12.78 (2.13) and 10.19 (2.76), respectively. A study by Realyvásquez-Vargas et al. (2020) on Mexican students which used the same scales reported that the overall mean score of lighting and noise were 11.88 and 9.95, respectively . These rThe overall mean score (SD) for the technology scale was 23.88 (3.47). Compared to study by Selvanathan et al. (2020), which was also conducted among students in Malaysia’s universities and used the same scale, the overall mean score for the technology scale was 3.66 and the overall mean score was 20.22 . AlthougIn the current study, the mean score (SD) for psychological health was 4.16 (3.92). A score of more than 4 indicates that the participant has psychological problems. Therefore, the mean score implies that most undergraduate medical students at USM have psychological problems. This result was somewhat similar to that for medical students from Suez Canal University, Egypt, who had a mean (SD) score of 4.7 (3.1). However, the score in the present cohort was higher than that reported in previous studies on undergraduate students (3.12 (3.32)) from the faculties of medicine, dentistry, and health sciences on the Health Campus of USM .s  =  −0.171, n  =  397, p  <  0.001) [The interrelationship between environmental factors, psychological health, and academic performance were examined with SEM. The structural framework was built on a conceptual framework based on previous theoretical and empirical studies. The findings of the structural model analysis revealed that only one of the nine hypothesized relationships was significant. That is, in this study, psychological health scores were found to have an inverse relationship with academic performance (indicated by GPA). The findings showed that students with higher scores for psychological health were likely to have lower GPAs. This supports the findings of previous studies which showed that higher scores for psychological health were associated with lower GPAs ,15,37,38Further, Bas (2021) demonstrated a positive relationship between mental health and academic performance , and ChaIn the present study, environmental factors (LNT and technology) did not have a significant relationship with academic performance. This is because most of medical students had good score in academic performance. The students learned through Elearn@USM platform as an asynchronous online learning. Asynchronous learning includes recorded videos/lectures, self-guided learning materials, etc. If the students had any problems regarding their subjects, they can look back at the recorded videos, uploaded by their lecturers. However, this contradicts the findings of previous studies ,44,45,46In Mexico, a study was conducted by Realyvásquez-Vargas et al. (2020) to explore whether environmental factors (LNT) affected students’ academic performance during COVID-19 . They foThe present findings indicated that environmental factors (LNT and technology) do not have a significant relationship with psychological health, but these findings are also contrary to those of previous studies ,28,29,30To the best of the researcher’s knowledge, this is the first study to use SEM to examine the relationship between environmental factors (LNT and technology), psychological health, and academic performance among Malaysian students. SEM was used to investigate the multiple interrelationships between variables in the hypothesized structural model. As a result, the type 1 error for the study is assumed to be below. In addition, the questionnaires used were valid and reliable, and the GPA was verified by the academic office. However, there are a few limitations that need to be addressed. The data were collected only from a single college and university, and this may have led to a ceiling effect as most students were exposed to the same environmental factors. In addition, it limits the generalizability of the results to other university students. Due to time constraints, data re-collection to anticipate the problem arising from the ceiling effect was not conducted. The convenience sampling method was applied, instead of random sampling, because of the online format of the questionnaires, the large sample size needed for this study, and the time constraint. As online self-administered questionnaires were used for data collection, there is a possibility of bias arising from insincere or dishonest responses. Furthermore, the study had a cross-sectional design. As a result, the exposure and the outcome were evaluated concurrently, and this made it impossible to distinguish between the cause-and-effect factors. Thus, it was not possible to determine the direction of effect due to a lack of evidence to establish a temporal association between the exposure and the outcome. For example, psychological health scores were found to be significantly and negatively associated with GPA. However, the data do not shed light on whether psychological health problems lead to low GPA, or vice versa. Moreover, the researcher did not include internet speed issue as a technology-related item. It is recommended that this factor be included as a technology-related item in future studies on this topic.The present study demonstrated an inverse relationship between psychological health scores and academic performance. In contrast, environmental factors were not found to be associated with psychological health or academic performance. Therefore, the environmental factors light, noise, temperature, and technology were not found to have a direct or indirect effect on academic performance.