Causal links between gut microbiomes, cytokines and risk of different subtypes of epilepsy: a Mendelian randomization study.

Objective: Recent research suggests a potential link between the gut microbiome (GM) and epilepsy. We undertook a Mendelian randomization (MR) study to determine the possible causal influence of GM on epilepsy and its various subtypes, and explore whether cytokines act as mediators. Methods: We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM, cytokines, and four epilepsy subtypes. Furthermore, we assessed whether cytokines mediate the relationship between GM and epilepsy. Significant GMs were further investigated using transcriptomic MR analysis with genes mapped from the FUMA GWAS. Sensitivity analyses and reverse MR were conducted for validation, and false discovery rate (FDR) correction was applied for multiple comparisons. Results: We pinpointed causal relationships between 30 GMs and various epilepsy subtypes. Notably, the Family Veillonellaceae (OR:1.03, 95%CI:1.02-1.05, p = 0.0003) consistently showed a strong positive association with child absence epilepsy, and this causal association endured even after FDR correction (p-FDR < 0.05). Seven cytokines were significantly associated with epilepsy and its subtypes. A mediating role for cytokines has not been demonstrated. Sensitivity tests validated the primary MR analysis outcomes. Additionally, no reverse causality was detected between significant GMs and epilepsy. Of the mapped genes of notable GMs, genes like BLK, FDFT1, DOK2, FAM167A, ZSCAN9, RNGTT, RBM47, DNAJC21, SUMF1, TCF20, GLO1, TMTC1, VAV2, and RNF14 exhibited a profound correlation with the risk factors of epilepsy subtypes. Conclusion: Our research validates the causal role of GMs and cytokines in various epilepsy subtypes, and there has been no evidence that cytokines play a mediating role between GM and epilepsy. This could provide fresh perspectives for the prevention and treatment of epilepsy.

Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury.

Previous studies have identified metabolites as biomarkers or potential therapeutic targets for traumatic brain injury (TBI). However, the causal association between them remains unknown. Therefore, we investigated the causal effect of serum metabolites and cerebrospinal fluid (CSF) metabolites on TBI susceptibility through Mendelian randomization (MR). Genetic variants related to metabolites and TBI were extracted from a corresponding genome-wide association study (GWAS). Causal effects were estimated through the inverse variance weighted approach, supplemented by a weighted median, weight mode, and the MR-Egger test. In addition, sensitivity analyses were further performed to evaluate the stability of the MR results, including the MR-Egger intercept, leave-one-out analysis, Cochrane's Q-test, and the MR-PRESSO global test. Metabolic pathway analysis was applied to uncover the underlying pathways of the significant metabolites in TBI. In blood metabolites, substances such as 4-acetaminophen sulfate and kynurenine showed positive links, whereas beta-hydroxyisovalerate and creatinine exhibited negative correlations. CSF metabolites such as N-formylanthranilic acid were positively related, while kynurenate showed negative associations. The metabolic pathway analysis highlighted the potential biological pathways involved in TBI. Of these 16 serum metabolites, 11 CSF metabolites and metabolic pathways may serve as useful circulating biomarkers in clinical screening and prevention, and may be candidate molecules for the exploration of mechanisms and drug targets.

Causal association between gut microbiomes and different types of aneurysms: a Mendelian randomization study.

Background: Previous studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear. Methods: A two-sample Mendelian randomization was conducted to investigate whether gut microbiomes have a causal effect on the risk of intracerebral aneurysm (IA), thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA), and aortic aneurysm (AA). Single nucleotide polymorphisms (SNPs) smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. We used inverse-variance weighted (IVW) test as the primary method for the evaluation of causal association. MR-Egger, weighted median, weighted mode, and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods were conducted for sensitive analysis. The p-value was adjusted by the false discovery rate (FDR) which adjust the results of multiple comparisons, a p < 0.05 and q < 0.1 was considered a significant causal association. Additionally, a p < 0.05 and q > 0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality. Results: The phylum Firmicutes (OR = 0.62; 95% CI, 0.48-0.81), class Lentisphaeria (OR = 0.75; 95% CI, 0.62-0.89), and order Victivallales (OR = 0.75; 95% CI, 0.62-0.89) have a causal protective effect on the risk of AAA. Additionally, class Verrucomicrobia, class Deltaproteobacteria, order Verrucomicrobiale, family Verrucomicrobiacea, genus Eubacterium rectale group, genus Akkermansia, and genus Clostridium innocuum group were negatively associated with the risk of different types of aneurysms, whereas class Negativicutes, order Selenomonadales, and genus Roseburia had positive causal association with different types of aneurysms (p < 0.05; q > 0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05). Conclusion: Our MR analysis confirmed the causal association of specific gut microbiomes with AAA, and these microbiomes were considered as protective factors. Our result may provide novel insights and theoretical basis for the prevention of aneurysms through regulation of gut microbiomes.

Dysregulation of LINC00324 promotes poor prognosis in patients with glioma.

BACKGROUND: LINC00324 is a long-stranded non-coding RNA, which is aberrantly expressed in various cancers and is associated with poor prognosis and clinical features. It involves multiple oncogenic molecular pathways affecting cell proliferation, migration, invasion, and apoptosis. However, the expression, function, and mechanism of LINC00324 in glioma have not been reported. MATERIAL AND METHODS: We assessed the expression of LINC00324 of LINC00324 in glioma patients based on data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to identify pathways involved in LINC00324-related glioma pathogenesis. RESULTS: Based on our findings, we observed differential expression of LINC00324 between tumor and normal tissues in glioma patients. Our analysis of overall survival (OS) and disease-specific survival (DSS) indicated that glioma patients with high LINC00324 expression had a poorer prognosis compared to those with low LINC00324 expression. By integrating clinical data and genetic signatures from TCGA patients, we developed a nomogram to predict OS and DSS in glioma patients. Gene set enrichment analysis (GSEA) revealed that several pathways, including JAK/STAT3 signaling, epithelial-mesenchymal transition, STAT5 signaling, NF-κB activation, and apoptosis, were differentially enriched in glioma samples with high LINC00324 expression. Furthermore, we observed significant correlations between LINC00324 expression, immune infiltration levels, and expression of immune checkpoint-related genes (HAVCR2: r = 0.627, P = 1.54e-77; CD40: r = 0.604, P = 1.36e-70; ITGB2: r = 0.612, P = 6.33e-7; CX3CL1: r = -0.307, P = 9.24e-17). These findings highlight the potential significance of LINC00324 in glioma progression and suggest avenues for further research and potential therapeutic targets. CONCLUSION: Indeed, our results confirm that the LINC00324 signature holds promise as a prognostic predictor in glioma patients. This finding opens up new possibilities for understanding the disease and may offer valuable insights for the development of targeted therapies.

Causal association of leisure sedentary behavior and cervical spondylosis, sciatica, intervertebral disk disorders, and low back pain: a Mendelian randomization study.

Background: Some studies suggest sedentary behavior is a risk factor for musculoskeletal disorders. This study aimed to investigate the potential causal association between leisure sedentary behavior (LSB) (including television (TV) viewing, computer use, and driving) and the incidence of sciatica, intervertebral disk degeneration (IVDD), low back pain (LBP), and cervical spondylosis (CS). Methods: We obtained the data of LSB, CS, IVDD, LBP, sciatica and proposed mediators from the gene-wide association studies (GWAS). The causal effects were examined by Inverse Variance Weighted (IVW) test, MR-Egger, weighted median, weighted mode and simple mode. And sensitivity analysis was performed using MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and MR-Egger intercept test. Multivariable MR (MVMR) was conducted to investigate the independent factor of other LSB; while two-step MR analysis was used to explore the potential mediators including Body mass index (BMI), smoking initiation, type 2 diabetes mellitus (T2DM), major depressive disorder (MDD), schizophrenia, bipolar disorder between the causal association of LSB and these diseases based on previous studies. Results: Genetically associated TV viewing was positively associated with the risk of CS (OR = 1.61, 95%CI = 1.25 to 2.07, p = 0.002), IVDD (OR = 2.10, 95%CI = 1.77 to 2.48, p = 3.79 × 10-18), LBP (OR = 1.84, 95%CI = 1.53 to 2.21, p = 1.04 × 10-10) and sciatica (OR = 1.82, 95% CI = 1.45 to 2.27, p = 1.42 × 10-7). While computer use was associated with a reduced risk of IVDD (OR = 0.66, 95%CI = 0.55 to 0.79, p = 8.06 × 10-6), LBP (OR = 0.49, 95%CI = 0.40 to 0.59, p = 2.68 × 10-13) and sciatica (OR = 0.58, 95%CI = 0.46 to 0.75, p = 1.98 × 10-5). Sensitivity analysis validated the robustness of MR outcomes. MVMR analysis showed that the causal effect of TV viewing on IVDD (OR = 1.59, 95%CI = 1.13 to 2.25, p = 0.008), LBP (OR = 2.15, 95%CI = 1.50 to 3.08, p = 3.38 × 10-5), and sciatica (OR = 1.61, 95%CI = 1.03 to 2.52, p = 0.037) was independent of other LSB. Furthermore, two-step MR analysis indicated that BMI, smoking initiation, T2DM may mediate the causal effect of TV viewing on these diseases. Conclusion: This study provides empirical evidence supporting a positive causal association between TV viewing and sciatica, IVDD and LBP, which were potentially mediated by BMI, smoking initiation and T2DM.

Efficacy and safety of the innovative monoclonal antibodies in adults with generalized myasthenia gravis: a Bayesian network analysis.

Background: A series of clinical trials support the effectiveness of monoclonal antibodies for generalized myasthenia gravis (MG) compared to the placebo, but the priority among drugs remains unclear. Therefore, we conduct a frequentist network meta-analysis (NMA) to compare the relative effects of different drugs for generalized MG. Methods: PubMed, Embase, Cochrane Library, and clinicaltrials.gov were systematically searched for eligible studies up to 1 June 2023. The primary outcome was efficacy (Myasthenia Gravis Activities of Daily Living [MG-ADL] score and Quantitative Myasthenia Gravis [QMG] score) and safety (adverse events [AEs]). Mean difference (MD) and risk ratio (RR) with their 95% credible intervals (95%CrIs) were used to show the effect size of continuous and categorical variables, respectively. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: Thirteen studies involving 1167 individuals were identified for NMA. For efficacy outcomes, belimumab, efgartigimod, mezagitamab 600mg, and nipocalimab 60mg/kg were inferior to rozanolixzumab 7mg/kg (MD ranged from 2 to 3.69) and rozanolixzumab 10mg/kg (MD ranged from 2.04 to 3.72) in MG-ADL score, and rozanolixzumab had the highest rank probability (83%) according to the subjective surface under the curve ranking area (SUCRA). For QMG score, batoclimab 340mg (MD ranged from 4.32 to 8.52) and batoclimab 680mg (MD ranged from 4.11 to 9.31) were more effective than placebo and other monoclonal antibodies except for rozanolixzumab, with the highest SUCRA value (93% and 97% respectively). For safety outcomes, belimumab achieved the highest SUCRA value (89.8%) with significant statistical difference compared to rozanolixzumab 7mg/kg (RR 0.08, 95%CrI 0.01 to 0.94) and rozanolixzumab 10mg/kg (RR 0.08, 95%CrI 0.01 to 0.86). Conclusion: While all monoclonal antibodies were superior to the placebo, rozanolixzumab and batoclimab might be the most effective for generalized MG. However, rozanolixzumab was associated with higher incidence of AEs. Given the limitations inherent in indirect comparisons, further head-to-head and extensive observational studies are necessary to confirm our findings. Systematic review registration: https://inplasy.com/?s=202370112, identifier 202370112.

Motor function improvement and acceptability of non-invasive brain stimulation in patients with Parkinson's disease: a Bayesian network analysis.

Background: Parkinson's disease (PD) is a neurodegenerative disorder defined by progressive motor and non-motor symptoms. Currently, the pro-cognitive effects of transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) are well-supported in previous literatures. However, controversy surrounding the optimal therapeutic target for motor symptom improvement remains. Objective: This network meta-analysis (NMA) was conducted to comprehensively evaluate the optimal strategy to use rTMS and tDCS to improve motor symptoms in PD. Methods: We searched PubMed, Embase, and Cochrane electronic databases for eligible randomized controlled studies (RCTs). The primary outcome was the changes of Unified Parkinson's Disease Rating Scale (UPDRS) part III score, the secondary outcomes were Time Up and Go Test (TUGT) time, and Freezing of Gait Questionnaire (FOGQ) score. The safety outcome was indicated by device-related adverse events (AEs). Result: We enrolled 28 studies that investigated various strategies, including high-frequency rTMS (HFrTMS), low-frequency rTMS (LFrTMS), anodal tDCS (AtDCS), AtDCS_ cathode tDCS (CtDCS), HFrTMS_LFrTMS, and Sham control groups. Both HFrTMS (short-term: mean difference (MD) -5.21, 95% credible interval (CrI) -9.26 to -1.23, long-term: MD -4.74, 95% CrI -6.45 to -3.05), and LFrTMS (long-term: MD -4.83, 95% CrI -6.42 to -3.26) were effective in improving UPDRS-III score compared with Sham stimulation. For TUGT time, HFrTMS (short-term: MD -2.04, 95% CrI -3.26 to -0.8, long-term: MD -2.66, 95% CrI -3.55 to -1.77), and AtDCS (short-term: MD -0.8, 95% CrI -1.26 to -0.34, long-term: MD -0.69, 95% CrI -1.31 to -0.08) produced a significant difference compared to Sham stimulation. However, no statistical difference was found in FOGQ score among the various groups. According to the surface under curve ranking area, HFrTMS ranked first in short-term UPDRS-III score (0.77), short-term (0.82), and long-term (0.84) TUGT time, and short-term FOGQ score (0.73). With respect to the safety outcomes, all strategies indicated few and self-limiting AEs. Conclusion: HFrTMS may be the optimal non-invasive brain stimulation (NIBS) intervention to improve motor function in patients with PD while NIBS has generally been well tolerated. However, further studies focusing on the clinical outcomes resulting from the different combined schedules of tDCS and rTMS are required. Systematic review registration: https://inplasy.com/inplasy-2023-4-0087/, identifier: 202340087.

Comparison of different surgical techniques for chronic subdural hematoma: a network meta-analysis.

Background: Chronic subdural hematoma (CSDH) is a neurosurgical condition with high prevalence. Many surgical approaches are recommended for treating CSDH, but there needs to be a consensus on the optimal technique. This network meta-analysis (NMA) compared the efficacy and safety of different surgical treatments for CSDH. Methods: Electronic databases, including PubMed, Embase, and the Cochrane Library, were searched for relevant studies up to February 2023. An NMA was performed to compare the outcomes of patients with CSDH treated by single-hole or double-hole craniotomy (SBHC and DBHC, respectively), twist-drill craniotomy (TDC), mini-craniotomy, and craniotomy. The NMA protocol was registered at INPLASY (registration no. 202320114). Results: The NMA included 38 studies with 7,337 patients. For efficacy outcomes, DBHC showed the highest surface under the cumulative ranking area (SUCRA) values for recurrence (96.3%) and reoperation (87.4%) rates. DBHC differed significantly from mini-craniotomy in recurrence rate (odds ratio [OR] = 0.58, 95% confidence interval [CI]: 0.35, 0.97) and from SBHC (OR = 0.48, 95% CI: 0.25, 0.91) and TDC (OR = 0.40, 95% CI: 0.20, 0.82) in reoperation rate. For operative time, TDC was superior to SBHC (mean difference [MD] = -2.32, 95% CI: -3.78 to -0.86), DBHC (MD = -3.61, 95% CI: -5.55, -1.67), and mini-craniotomy (MD = -3.39, 95% CI: -5.70, -1.08). Patients treated by TDC had a shorter hospital stay than those treated by SBHC (MD = -0.82, 95% CI: -1.51, -0.12). For safety outcomes, there were no significant differences between groups in mortality and complication rates; however, mini-craniotomy (79.8%) and TDC (78.1%) had the highest SUCRAs. Conclusion: DBHC may be the most effective surgical treatment for CSDH based on the low recurrence and reoperation rates, although all examined techniques were relatively safe. Systematic review registration: https://inplasy.com/inplasy-2023-2-0114/.

Early versus late tracheostomy in stroke-related patients: A systematic review and meta-analysis.

BACKGROUND: Tracheostomy is an operative intervention for patients who require ventilator assistance while in the intensive care unit (ICU). This study aimed to compare efficacy and safety between early tracheostomy (ET) and late tracheostomy (LT) in stroke patients. METHODS: Embase, PubMed, and the Cochrane Library were searched for available studies. Stroke-related patients were categorized into ET and LT groups using seven days as the cutoff timepoint. The primary efficacy outcome was mortality; secondary efficacy outcomes were modified Rankin Scores (mRS) obtained at follow up, as well as durations of hospital stay, ICU stay, and ventilator use. Safety outcomes were total complication and ventilator associated pneumonia (VAP) incidence. RESULTS: Nine studies with 3,789 patients were included in the current analysis. No statistical difference in mortality was observed. ET was associated with shorter hospital stay (MD -5.72, 95% CI -9.76 to -1.67), shorter ICU stay (MD -4.77, 95% CI -6.82 to -2.72), and shorter ventilator duration (MD -4.65, 95% CI -8.39 to -0.90); however, no statistically significant difference was found in follow-up mRS scores. Examination of safety measures found the ET group exhibited a lower rate of VAP compared with LT (OR 0.80, 95 % CI 0.68 to 0.93), while no statistical difference was found in total complications. CONCLUSION: Our meta-analysis concluded that ET was associated with shorter hospital stay, less time on a ventilator, and lower incidence of VAP. Future studies are warranted to investigate the functional outcomes and the occurrence of complications of ET in stroke patients.

Efficacy and tolerability of minocycline in depressive patients with or without treatment-resistant: a meta-analysis of randomized controlled trials.

Background: Minocycline, an antibiotic with anti-inflammatory, antioxidant, and neuroprotective properties, has been used for treating psychiatric disorders in research. This systematic review aimed to evaluate the efficacy and tolerability of minocycline in patients having depression with or without treatment-resistance. Methods: Electronic databases including Embase, PubMed, and the Cochrane library were searched for relevant studies published up to October 17, 2022. The primary efficacy outcome was the change in depression severity scores and the secondary efficacy outcomes included the changes in Clinical Global Impression (CGI) and Beck Depression Inventory (BDI) scores and the incidence of response and partial response. Safety outcomes were evaluated based on the incidence of classified adverse events and all-cause discontinuation. Results: Five studies with 374 patients were selected for analysis. The minocycline group demonstrated a significant reduction in depression severity scale (standardized mean difference [SMD]: -0.59, 95% confidence interval [CI]: -0.98 to -0.20, P = 0.003) and CGI (SMD: -0.28, 95% CI: -0.56 to -0.01, P = 0.042) scores; however, no statistical difference was found in terms of the BDI score, response, and partial response. No significant differences were found between the groups in terms of adverse events (other than dizziness) and discontinuation rates. Subgroup analysis showed that minocycline was also effective in reducing depression severity scores in treatment-resistant depression (SMD: -0.36, 95% CI: -0.64 to -0.09, P = 0.010). Subgroup analysis of Hamilton Depression Rating Scale (17-item) scores showed a statistical difference in response in patients with depression (relative risk: 2.51, 95% CI: 1.13 to 5.57, P = 0.024). Conclusions: Minocycline may improve depressive symptoms and augment response to treatment in patients with depression irrespective of treatment-resistance. However, clinical trials with large sample sizes are warranted for evaluating long-term outcomes with minocycline. Systematic review registration: https://inplasy.com/inplasy-2022-12-0051/.

Different monoclonal antibodies and immunosuppressants administration in patients with neuromyelitis optica spectrum disorder: a Bayesian network meta-analysis.

BACKGROUND: A variety of novel monoclonal antibodies and immunosuppressant have been proved effective in treating Neuromyelitis Optica Spectrum Disorder (NMOSD). This network meta-analysis compared and ranked the efficacy and tolerability of currently used monoclonal antibodies and immunosuppressive agents in NMOSD. METHODS: Electronic database including PubMed, Embase and Cochrane Library were searched for relevant studies evaluating monoclonal antibodies and immunosuppressants in patients with NMOSD. The primary outcome measures were annualized relapse rate (ARR), relapse rate, the Expanded Disability Status Scale (EDSS) score, and total adverse events (AEs). RESULTS: We identified 25 studies with 2919 patients in our meta-analysis. For the primary outcome, rituximab (RTX) (SUCRA: 0.02) ranked first in reduction ARR with a significant difference compared with azathioprine (AZA) (MD - 0.34, 95% CrI - 0.55 to - 0.12) and mycophenolate mofetil (MMF) (MD -0.38, 95% CrI - 0.63 to - 0.14). Tocilizumab (SUCRA: 0.05) ranked first in relapse rate, which was superior to satralizumab (lnOR - 25.4, 95% CrI - 74.4 to - 2.49) and inebilizumab (lnOR - 24.86, 95% CrI - 73.75 to - 1.93). MMF (SUCRA: 0.27) had the fewest AEs followed by RTX (SUCRA: 0.35), both of which showed a significant difference compared with AZA and corticosteroids (MMF vs AZA: lnOR - 1.58, 95% CrI - 2.48 to - 0.68; MMF vs corticosteroids: lnOR - 1.34, 95% CrI - 2.3 to - 0.37) (RTX vs AZA: lnOR - 1.34, 95% CrI - 0.37 to - 2.3; RTX vs corticosteroids: lnOR - 2.52, 95% CrI - 0.32 to - 4.86). In EDSS score, no statistical difference was found between different interventions. CONCLUSION: RTX and tocilizumab showed better efficacy than traditional immunosuppressants in reducing relapse. For safety, MMF and RTX had fewer AEs. However, studies with larger sample size on newly developed monoclonal antibodies are warranted in the future.

Research on Molecular Structure and Electronic Properties of Ln3+ (Ce3+, Tb3+, Pr3+)/Li+ and Eu2+ Co-Doped Sr2Si5N8 via DFT Calculation.

We use density functional theory (DFT) to study the molecular structure and electronic band structure of Sr2Si5N8:Eu2+ doped with trivalent lanthanides (Ln3+ = Ce3+, Tb3+, Pr3+). Li+ was used as a charge compensator for the charge imbalance caused by the partial replacement of Sr2+ by Ln3+. The doping of Ln lanthanide atom causes the structure of Sr2Si5N8 lattice to shrink due to the smaller atomic radius of Ln3+ and Li+ compared to Sr2+. The doped structure's formation energy indicates that the formation energy of Li+, which is used to compensate for the charge imbalance, is the lowest when the Sr2 site is doped. Thus, a suitable Li+ doping site for double-doped lanthanide ions can be provided. In Sr2Si5N8:Eu2+, the doped Ce3+ can occupy partly the site of Sr12+ ([SrN8]), while Eu2+ accounts for Sr12+ and Sr22+ ([SrN10]). When the Pr3+ ion is selected as the dopant in Sr2Si5N8:Eu2+, Pr3+ and Eu2+ would replace Sr22+ simultaneously. In this theoretical model, the replacement of Sr2+ by Tb3+ cannot exist reasonably. For the electronic structure, the energy level of Sr2Si5N8:Eu2+/Li+ doped with Ce3+ and Pr3+ appears at the bottom of the conduction band or in the forbidden band, which reduces the energy bandgap of Sr2Si5N8. We use DFT+U to adjust the lanthanide ion 4f energy level. The adjusted 4f-CBM of CeSr1LiSr1-Sr2Si5N8 is from 2.42 to 2.85 eV. The energy range of 4f-CBM in PrSr1LiSr1-Sr2Si5N8 is 2.75-2.99 eV and its peak is 2.90 eV; the addition of Ce3+ in EuSr1CeSr1LiSr1 made the 4f energy level of Eu2+ blue shift. The addition of Pr3+ in EuSr2PrSr2LiSr1 makes part of the Eu2+ 4f energy level blue shift. Eu2+ 4f energy level in EuSr2CeSr1LiSr1 is not in the forbidden band, so Eu2+ is not used as the emission center.