Supplementary Material for: Lenvatinib Combined With PD-1 Inhibitor Camrelizumab in The Treatment of Primary Liver Cancer Caused Hemorrhagic Exfoliative Gastritis

Introduction：Patients with advanced primary liver cancer often lose the opportunity for surgery when they are found, and the treatment options are limited. Lenvatinib, as a multi-target tyrosine kinase inhibitor, has been used as the first-line treatment for advanced liver cancer. Immune checkpoint inhibitors, such as programmed cell death protein 1 inhibitors, have been successfully used in advanced or metastatic liver cancer. Case presentation：We report a case of combined lenvatinib and the programmed cell death protein 1 inhibitor camrelizumab in the treatment of primary liver cancer, in which the rare complication of full-thickness gastric mucosa exfoliation occurred. To the best of our knowledge, this is the first report of the side effect of haemorrhagic exfoliative gastritis with the combination of lenvatinib and camrelizumab.Conclusion：haemorrhagic exfoliative gastritis is an extremely rare clinical complication. Lenvatinib inhibits vascular proliferation and could causes gastrointestinal perforation, which is considered to be the main factor, but whether camrelizumab plays a role in it or only causes gastrointestinal reactions leading to nausea and vomiting, resulting in gastric mucosal exfoliation bleeding remains to be further explored

Supplementary Material for: Transarterial Chemoembolization Combined with Lenvatinib for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Introduction: The treatment of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) and lenvatinib individually has shown favorable outcomes, but there is currently no meta-analysis based on randomized controlled trials (RCTs) to investigate the efficacy and safety of this combined treatment for HCC. The aim of this study is to identify the efficacy and safety of TACE plus lenvatinib for the treatment of HCC. Methods: A systematic search of MEDLINE (via PubMed), the Cochrane Library, EMBASE, and the Web of Science was conducted on July 31, 2023. RCTs evaluating the efficacy and safety of TACE in combination with lenvatinib for the treatment of HCC were included. The risk of bias in the included studies was assessed using the Risk of Bias 2 tool. Outcome measures such as objective response rate (ORR), CR (complete remission), progression-free survival (PFS), overall survival (OS), and safety parameters were extracted from the included studies. Binary outcomes were analyzed using odds ratio (OR), risk ratio (RR), or hazard ratio (HR), while continuous variables were analyzed using mean difference (MD) or standardized MD (SMD) in Rstudio. The quality of the evidence was graded using the GRADE approach. Heterogeneity was considered significant when the I-squared was 50% or less. Results: Five RCTs involving 638 patients were included. The meta-analysis revealed that patients in the TACE plus lenvatinib group had a significantly higher mean ORR compared to the control group (OR: 3.65, 95% CI: 2.50–5.32, fixed effects model; OR: 3.58, 95% CI: 2.45–5.24, random effects model, I2 = 0, moderate quality). Specifically, 40.9% of patients in the TACE plus lenvatinib group achieved a PR, which was significantly higher than the control group (OR: 3.51, 95% CI: 2.41–5.13, fixed effects model; OR: 3.46, 95% CI: 2.36–5.07, random effects model, I2 = 0, moderate quality). The HR for OS was 0.47 (95% CI: 0.35–0.62, fixed effects model and random effects model, I2 = 0, moderate quality). The meta-analysis revealed that the TACE plus lenvatinib group had a significantly higher total adverse effects rate than the control group (OR: 1.86, 95% CI: 1.01–3.43, fixed effects model; OR: 1.85, 95% CI: 1.00–3.43, random effects model, I2 = 0, moderate quality). Conclusion: Our study suggests that the combination of TACE and lenvatinib in the treatment of HCC has shown promising results, with extended OS and improved ORR

Supplementary Material for: Association of Performance on Multiple Cognitive Domains with Sarcopenia Among Middle-aged and Older Adults

Introduction: The relationship between cognitive function and subsequent sarcopenia remains unclear. Therefore, this study aimed to examine the associations of performance on multiple cognitive domains with sarcopenia in the middle-aged and older adults. Methods: This longitudinal analysis (wave 2011-2013) included 2934 participants from the CHARLS study. Sarcopenia was defined by the Asian Sarcopenia Working Group 2019 criteria. Cognitive function was measured by the Chinese version of the Mini-Mental State Examination (MMSE). Three interpretable techniques, namely SHapley Additive exPlanations (SHAP) and two built-in methods (coefficients of logistic regression and Gini importance of random forest), were used to assess the relationship between MMSE, its components (orientation, attention, episodic memory, and visuospatial ability) and sarcopenia. In addition, the association of MMSE score and its components with sarcopenia was further validated using stepwise regression. Results: All interpretable methods showed that MMSE score was important predictors for sarcopenia, especially for SHAP (MMSE score ranked top one). For its components, episodic memory, visuospatial ability, and attention showed high predictive value compared with orientation. Stepwise regression analyses showed that MMSE score and its components of episodic memory and visuospatial ability were correlated with sarcopenia, with their odds ratios of 0.93 (95% CI: 0.91-0.96, p<0.001), 0.87 (95% CI: 0.82-0.93, p<0.001), and 1.32 (95% CI: 1.05-1.65, p=0.016), respectively. Conclusions: Better cognitive function especially episodic memory and visuospatial ability was negatively associated with incident sarcopenia among community middle-aged and older adults

Supplementary Material for: Transarterial Chemoembolization Combined with Lenvatinib for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Introduction: The treatment of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) and lenvatinib individually has shown favorable outcomes, but there is currently no meta-analysis based on randomized controlled trials (RCTs) to investigate the efficacy and safety of this combined treatment for HCC. The aim of this study is to identify the efficacy and safety of TACE plus lenvatinib for the treatment of HCC. Methods: A systematic search of MEDLINE (via PubMed), the Cochrane Library, EMBASE, and the Web of Science was conducted on July 31, 2023. RCTs evaluating the efficacy and safety of TACE in combination with lenvatinib for the treatment of HCC were included. The risk of bias in the included studies was assessed using the Risk of Bias 2 tool. Outcome measures such as objective response rate (ORR), CR (complete remission), progression-free survival (PFS), overall survival (OS), and safety parameters were extracted from the included studies. Binary outcomes were analyzed using odds ratio (OR), risk ratio (RR), or hazard ratio (HR), while continuous variables were analyzed using mean difference (MD) or standardized MD (SMD) in Rstudio. The quality of the evidence was graded using the GRADE approach. Heterogeneity was considered significant when the I-squared was 50% or less. Results: Five RCTs involving 638 patients were included. The meta-analysis revealed that patients in the TACE plus lenvatinib group had a significantly higher mean ORR compared to the control group (OR: 3.65, 95% CI: 2.50–5.32, fixed effects model; OR: 3.58, 95% CI: 2.45–5.24, random effects model, I2 = 0, moderate quality). Specifically, 40.9% of patients in the TACE plus lenvatinib group achieved a PR, which was significantly higher than the control group (OR: 3.51, 95% CI: 2.41–5.13, fixed effects model; OR: 3.46, 95% CI: 2.36–5.07, random effects model, I2 = 0, moderate quality). The HR for OS was 0.47 (95% CI: 0.35–0.62, fixed effects model and random effects model, I2 = 0, moderate quality). The meta-analysis revealed that the TACE plus lenvatinib group had a significantly higher total adverse effects rate than the control group (OR: 1.86, 95% CI: 1.01–3.43, fixed effects model; OR: 1.85, 95% CI: 1.00–3.43, random effects model, I2 = 0, moderate quality). Conclusion: Our study suggests that the combination of TACE and lenvatinib in the treatment of HCC has shown promising results, with extended OS and improved ORR

Supplementary Material for: Transarterial Chemoembolization Combined with Lenvatinib for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Introduction: The treatment of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) and lenvatinib individually has shown favorable outcomes, but there is currently no meta-analysis based on randomized controlled trials (RCTs) to investigate the efficacy and safety of this combined treatment for HCC. The aim of this study is to identify the efficacy and safety of TACE plus lenvatinib for the treatment of HCC. Methods: A systematic search of MEDLINE (via PubMed), the Cochrane Library, EMBASE, and the Web of Science was conducted on July 31, 2023. RCTs evaluating the efficacy and safety of TACE in combination with lenvatinib for the treatment of HCC were included. The risk of bias in the included studies was assessed using the Risk of Bias 2 tool. Outcome measures such as objective response rate (ORR), CR (complete remission), progression-free survival (PFS), overall survival (OS), and safety parameters were extracted from the included studies. Binary outcomes were analyzed using odds ratio (OR), risk ratio (RR), or hazard ratio (HR), while continuous variables were analyzed using mean difference (MD) or standardized MD (SMD) in Rstudio. The quality of the evidence was graded using the GRADE approach. Heterogeneity was considered significant when the I-squared was 50% or less. Results: Five RCTs involving 638 patients were included. The meta-analysis revealed that patients in the TACE plus lenvatinib group had a significantly higher mean ORR compared to the control group (OR: 3.65, 95% CI: 2.50–5.32, fixed effects model; OR: 3.58, 95% CI: 2.45–5.24, random effects model, I2 = 0, moderate quality). Specifically, 40.9% of patients in the TACE plus lenvatinib group achieved a PR, which was significantly higher than the control group (OR: 3.51, 95% CI: 2.41–5.13, fixed effects model; OR: 3.46, 95% CI: 2.36–5.07, random effects model, I2 = 0, moderate quality). The HR for OS was 0.47 (95% CI: 0.35–0.62, fixed effects model and random effects model, I2 = 0, moderate quality). The meta-analysis revealed that the TACE plus lenvatinib group had a significantly higher total adverse effects rate than the control group (OR: 1.86, 95% CI: 1.01–3.43, fixed effects model; OR: 1.85, 95% CI: 1.00–3.43, random effects model, I2 = 0, moderate quality). Conclusion: Our study suggests that the combination of TACE and lenvatinib in the treatment of HCC has shown promising results, with extended OS and improved ORR

Supplementary Material for: Interaction between serum cotinine, magnesium intake with childhood asthma: a cross-sectional study

Introduction: Serum cotinine and magnesium intake are often associated with childhood asthma. This study evaluated the interaction between serum cotinine, magnesium intake with childhood asthma. Methods: This cross-sectional study included 14,159 subjects from National Health and Nutrition Examination Survey 2005-2018. Serum cotinine levels were classified according to the lower quartile: ≤0.2089 ng/mL as low-level and >0.2089 ng/mL as high-level. Magnesium intake were categorized as high (>98 mg/1000kcal) or low level (≤98 mg/1000kcal) based on the upper quartile. Adopted the weighted logistic regression analyses to analyze the association between cotinine, magnesium intake and childhood asthma. Additionally, the combined effect of cotinine and magnesium intake on childhood asthma risk was examined. The stratified analyses based on gender, body mass index and family history of asthma to further examine the relationship between cotinine, magnesium intake and childhood asthma. Results: The prevalence of asthma was approximately 17.56%. Compared to low-level cotinine, high-level cotinine was associated with asthma [odds ratio (OR) = 1.25, 95% confidence interval (CI): 1.04-1.50]. Low-level magnesium intake was related to asthma compared with high-level magnesium intake (OR=1.21, 95%CI: 1.04-1.40). Using interaction analysis, we also found that the combined effect of cotinine and magnesium intake was associated with childhood asthma risk, and the interaction between high-level cotinine and low-level magnesium intake was associated with the highest risk of childhood asthma (OR=1.35, 95%CI: 1.04-1.74). Additionally, this interaction was also found in male, overweight/non-overweight and those with family history of asthma. Conclusion: There was an interaction between serum cotinine and magnesium intake on childhood asthma. The results suggested that implementing smoking bans in certain settings (e.g., communities, schools) and promoting the consumption of magnesium-rich foods may be effective strategies for preventing childhood asthma

Supplementary Material for: Iridoids with Genipin Stem Nucleus Inhibit Lipopolysaccharide-Induced Inflammation and Oxidative Stress by Blocking the NF-κB Pathway in Polycystic Ovary Syndrome

<b><i>Background/Aims:</i></b> Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, and it is usually characterized by chronic inflammation, oxidative stress, and altered microRNA expression. The aim of this study is to investigate how the effects of iridoids with genipin stem nucleus inhibit PCOS complications. The interactions between iridoids were investigated, as well. <b><i>Methods:</i></b> The chronic inflammation cell model was induced using lipopolysaccharide (LPS) in the RAW 264.7 and KGN cell lines. Levels of mRNA and protein expression were quantified using real time-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. The target of the iridoids was identified using the drug affinity responsive target stability (DARTS) method. The ability to scavenge free radicals was evaluated using the DPPH radical scavenging method and the ultra oxygen anion (O₂^-) radical scavenging method. <b><i>Results:</i></b> The cells recovered from the inflammatory conditions and showed significantly decreased levels of interleukins after treatment with iridoids. The iridoids were demonstrated to target NF-κB, inhibit the phosphorylation and degradation of IκB, inhibit the nuclear entry of NF-κB, and inhibit the expression of inflammatory factors. Though only genipin showed an efficient ability to scavenge O₂^-, the iridoids, IκB inhibitor (BAY 11-7085), and NF-κB inhibitor (PDTC) could inhibit LPS-induced oxidative stress on the cells, indicating that the iridoids exert their anti-oxidant effects via the NF-κB pathway. The expression levels of microRNAs (miRNAs) were also altered by LPS, but the iridoids could scarcely rescue the abnormal condition. <b><i>Conclusion:</i></b> Chronic inflammation may be an important incentive for oxidative stress and abnormal microRNA expression in PCOS, and iridoids can protect patients from inflammatory damage by regulating the NF-κB pathway

Supplementary Material for: Early feeding for the prevention of neonatal hypoglycaemia: a systematic review and meta-analysis

Background: Poor feeding, among other factors, predisposes neonates to hypoglycaemia. Early feeding is widely recommended to prevent hypoglycaemia in those at risk, but the effectiveness of this is uncertain. This review aimed to summarise and analyse the evidence on the effectiveness of early feeding for prevention of neonatal hypoglycaemia. Methods: Four databases and three clinical trials registries were searched from inception to 24th May 2023. Published and unpublished randomised controlled trials (RCTs), quasi-RCTs, cluster randomised trials, non-randomised studies of interventions, and observational studies with comparison groups were considered for inclusion with no language or publication date restrictions. We included studies of neonates who were fed early (within 60 minutes of birth or study defined) versus delayed. Study quality was assessed using the Cochrane Risk of Bias 1 tool or Effective Public Health Practice Project Quality Assessment tool. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RevMan 5.4.1 or R were used to synthesise results in random-effects meta-analyses. This review was registered prospectively with PROSPERO (CRD42022378904). Results: A total of 175,392 participants were included across 19 studies, of which two were RCTs, 14 cohort studies, two cross-sectional studies, and one a case-control study. Most studies (13/19) were conducted in low- or lower-middle-income countries. Early feeding may be associated with reduced neonatal hypoglycaemia (four cohort studies, 744 infants, OR 0.19 (95% CI: 0.10 to 0.35), p<0.00001, I2 = 44%) and slightly reduced duration of initial hospital stay (one cohort study, 1,673 infants, MD -0.20 days (95% CI: -0.31 to -0.09), p=0.0003), but the evidence is very uncertain. One RCT found early feeding had little or no effect on the risk of neonatal mortality, but three cohort studies found early feeding may be associated with reduced risk (136,468 infants, OR 0.51 (95% CI: 0.37 to 0.72); low certainty evidence; p<0.0001; I2=54%). Conclusion: We found that early feeding may reduce the incidence of neonatal hypoglycaemia, but the evidence is very uncertain. Given its many other benefits, early feeding should continue to be recommended. This review was primarily funded by the Aotearoa Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health

Supplementary Material for: Contribution of IVIM to Conventional Dynamic Contrast-Enhanced and Diffusion-Weighted MRI in Differentiating Benign from Malignant Breast Masses

<p><b><i>Background:</i></b> The aim of this study was to determine whether the indicators obtained from intravoxel incoherent motion (IVIM) imaging can improve the characterization of benign and malignant breast masses compared with conventional dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted magnetic resonance imaging (DW-MRI). <b><i>Patients and Methods:</i></b> This study included 23 benign and 31 malignant breast masses of 48 patients. Main indicators were initial enhancement ratio (IER), time-signal intensity curve (TIC), apparent diffusion coefficient (ADC), tissue diffusivity (D), pseudodiffusivity (D*), and perfusion fraction (f). The discriminative abilities of the different models were compared by means of receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) analysis. <b><i>Results:</i></b> D had the highest AUC (0.980), sensitivity (93.55%), specificity (100%), and diagnostic accuracy (96.36%). Both D and TIC could provide the independent predicted features for malignant breast masses. The combination of D and TIC had an AUC of up to 0.990. <b><i>Conclusion:</i></b> D of IVIM can effectively complement existing conventional DCE-MRI and DW-MRI in differentiating malignant from benign breast masses. IVIM combined with DCE-MRI is a robust means of evaluating breast masses.</p

Supplementary Material for: Isotetrandrine Reduces Astrocyte Cytotoxicity in Neuromyelitis Optica by Blocking the Binding of NMO-IgG to Aquaporin 4

<b><i>Objective:</i></b> Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease that affects the optic nerves and spinal cord with no cure and no FDA-approved therapy. Research over the last decade revealed that the binding of NMO-IgG to the water channel protein astrocyte aquaporin 4 (AQP4) might be the primary cause of NMO pathogenesis. The purpose of this study was to identify potential blockers of NMO-IgG and AQP4 binding. <b><i>Methods:</i></b> We developed a two-step screening platform consisting of a reporter cell-based high-throughput screen assay and a cell viability-based assay. Purified NMO-IgG from NMO patient serum and transfected Chinese hamster lung fibroblast V79 cells stably expressing human M23-AQP4 were used for primary screening of 40,000 small molecule fractions from 500 traditional Chinese herbs. <b><i>Results:</i></b> Thirty-six positive fractions were identified, of which 3 active fractions (at 50 μg/ml) were found to be from the same Chinese traditional herb <i>Mahonia japonica </i>(Thunb.). A bioactivity-guided method based on a primary screening assay for blocking activity led to the isolation of an active single natural compound, isotetrandrine, from the 3 fractions. Our immunofluorescence staining results showed that isotetrandrine can block NMO-IgG binding to AQP4 without affecting the expression and function of AQP4. It can also inhibit NMO-IgG binding to astrocyte AQP4 in NMO patient sera and block NMO-IgG-dependent complement-mediated cytotoxicity with the IC₅₀ at ∼3 μM. <b><i>Conclusions:</i></b> The present study developed a cell-based high-throughput screen to identify small molecule inhibitors for NMO-IgG and AQP4 binding, and suggests a potential therapeutic value of isotetrandrine in NMO