Gap-free chromosome-level genomes of male and female spotted longbarbel catfish Hemibagrus guttatus.

Hemibagrus guttatus, also named as spotted longbarbel catfish, is an economical fish in China. However, their gender cannot be easily distinguished from their appearance, which largely impedes their artificial breeding. Therefore, we provided two gap-free chromosome-level genomes of male and female spotted longbarbel catfish by combining wtdbg2, LR_Gapcloser and TGS-GapCloser assembly approaches with Hi-C data and accurate Pacbio HiFi long-reads. We assembled 30 chromosomes without any gap. Their genome sizes are approximately 749.1 Mb and 747.8 Mb of male and female individuals. The completeness results of BUSCO evaluation show about 94.2% and 95.0%, representing a high-level of completeness of both genomes. We also obtained 35,277 and 34,571 protein-coding gene sets from male and female individuals. Both available gap-free chromosome-level genomes of H. guttatus will provide excellent references for resequencing of male and female individuals to identify accurate markers for distinguishing gender of this fish.

Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway.

High-altitude pulmonary edema (HAPE) is a deadly form of altitude sickness, and there is no effective treatment for HAPE. Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cell isolated from dental pulp tissues and possess various functions, such as anti-inflammatory and anti-oxidative stress. DPSCs have been used to treat a variety of diseases, but there are no studies on treating HAPE. In this study, Sprague-Dawley rats were exposed to acute low-pressure hypoxia to establish the HAPE model, and SOD1-modified DPSCs (DPSCsHiSOD1) were administered through the tail vein. Pulmonary arterial pressure, lung water content (LWC), total lung protein content of bronchoalveolar lavage fluid (BALF) and lung homogenates, oxidative stress, and inflammatory indicators were detected to evaluate the effects of DPSCsHiSOD1 on HAPE. Rat type II alveolar epithelial cells (RLE-6TN) were used to investigate the effects and mechanism of DPSCsHiSOD1 on hypoxia injury. We found that DPSCs could treat HAPE, and the effect was better than that of dexamethasone treatment. SOD1 modification could enhance the function of DPSCs in improving the structure of lung tissue, decreasing pulmonary arterial pressure and LWC, and reducing the total lung protein content of BALF and lung homogenates, through anti-oxidative stress and anti-inflammatory effects. Furthermore, we found that DPSCsHiSOD1 could protect RLE-6TN from hypoxic injury by reducing the accumulation of reactive oxygen species (ROS) and activating the Nrf2/HO-1 pathway. Our findings confirm that SOD1 modification could enhance the anti-oxidative stress ability of DPSCs through the Nrf2/HO-1 signalling pathway. DPSCs, especially DPSCsHiSOD1, could be a potential treatment for HAPE. Schematic diagram of the antioxidant stress mechanism of DPSCs in the treatment of high-altitude pulmonary edema. DPSCs can alleviate oxidative stress by releasing superoxide dismutase 1, thereby reducing ROS production and activating the Nrf2/HO-1 signalling pathway to ameliorate lung cell injury in HAPE.

Investigation of the Single-Particle Scale Structure-Activity Relationship Providing New Insights for the Development of High-Performance Batteries.

As electric vehicles, portable electronic devices, and tools have increasingly high requirements for battery energy density and power density, constantly improving battery performance is a research focus. Accurate measurement of the structure-activity relationship of active materials is key to advancing the research of high-performance batteries. However, conventional performance tests of active materials are based on the electrochemical measurement of porous composite electrodes containing active materials, polymer binders, and conductive carbon additives, which cannot establish an accurate structure-activity relationship with the physical characterization of microregions. In this review, in order to promote the accurate measurement and understanding of the structure-activity relationship of materials, the electrochemical measurement and physical characterization of energy storage materials at single-particle scale are reviewed. The potential problems and possible improvement schemes of the single particle electrochemical measurement and physical characterization are proposed. Their potential applications in single particle electrochemical simulation and machine learning are prospected. This review aims to promote the further application of single particle electrochemical measurement and physical characterization in energy storage materials, hoping to achieve 3D unified evaluation of physical characterization, electrochemical measurement, and theoretical simulation at the single particle scale to provide new inspiration for the development of high-performance batteries.

Hemorrhage profile associated with immune checkpoint inhibitors: a systematic review and a real-world study based on the FAERS database.

OBJECTIVES: To investigate the risk of hemorrhage associated with Immune Checkpoint Inhibitors (ICIs) and characterize its clinical features. METHODS: We systematically reviewed randomized clinical trials (RCTs) of hemorrhage related to ICIs and calculated odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting ICIs-related hemorrhage cases from the FAERS database and assessing disproportionalities by reporting odds ratios (RORs) and information components (ICs). RESULTS: A total of 79 RCTs involving 45,100 patients were finally included in the systematic review, with four published RCTs (n = 1965) and 75 unpublished RCTs (n = 43135). The primary analysis showed no significant difference in ICIs compared to the control group (OR 1.18 [95% CI 1.00-1.38], p = 0.05). In subgroup analyses, anti-PD-L1 combined with anti-CTLA-4 increased the risk of hemorrhage (OR 1.95, p = 0.03), and anti-CTLA-4 increased the risk of hemorrhage in the gastrointestinal system (OR 2.23, p = 0.04). 3555 cases of hemorrhage from the FAERS database were included in the disproportionate analysis, and the result suggested that ICIs increased the risk of hemorrhage (IC025 = 0.23). CONCLUSION: Our study suggests that ICIs increase the risk of hemorrhage, and in particular, anti-CTLA-4 significantly increases the risk of hemorrhage in the gastrointestinal system.

Non-Equivalent Donor-Acceptor Type Polymers as Dopant-Free Hole-Transporting Materials for Perovskite Solar Cells.

Electron donor (D)-electron acceptor (A) type conjugated polymers present bright prospects as dopant-free hole-transporting materials (HTMs) for perovskite solar cells (PVSCs). Most of the reported D-A polymeric HTMs contain equivalent amounts of D and A units, while the appropriate excess proportion of D units could optimize the aggregation state of polymer chains and improve the hole transport properties of the polymers. Herein, a non-equivalent D-A copolymerization strategy was utilized to develop three indacenodithiophene-benzotriazole-based polymeric HTMs for PVSCs, named as F-10, F-15, and F-20, and the equivalent D-A polymer F-00 was studied in parallel. Effects of D : A ratio on the hole transport properties of these D-A type polymeric HTMs, including energy level, molecular stacking, hole mobility, and surface morphology, were investigated by theoretical simulation and test analysis. F-15 performed best due to the appropriate D : A ratio, endowing the PVSCs a champion power conversion efficiency of 20.37 % with high stability, which confirms the fine-tuning D : A ratio via non-equivalent D-A copolymerization strategy is very helpful to construct D-A type polymeric HTMs for high-performance PVSCs.

Flexible biopolymer-assisted 3D printed bioceramics scaffold with high shape adaptability.

Bioceramics are widely used in bone tissue engineering, yet the inherent high brittleness and low ductility of the ceramics lead to poor machinability, which restricts their clinical applications. Here, a flexible and processable 3D printed bioceramic scaffold with high ceramic content (66.7 %) and shape fidelity (volume shrinkage rate < 5 %) was developed by freeze-thaw cycles, which was assisted by polyvinyl alcohol (PVA) and silk fibroin (SF). The hydrogen bonding between PVA imparted printability to the ceramic ink and enabled the subsequent formation of flexible scaffolds, which can be twisted, bend and cut to match bone defects. After adding SF, the printability of the inks and hydrophilicity of the scaffolds were enhanced, owing to the interactions between PVA and SF. Further, combined with the formation of ß-sheet in SF, the scaffolds exhibited superior mechanical strength and excellent thermal stability, and can fully recover at 35 % compressive strain, which was breaking through the brittleness bottleneck of conventional ceramic scaffolds. Moreover, in vitro experiments showed excellent mineralization ability, osteogenic and angiogenic activities of the scaffolds, demonstrating its potential in bone regeneration. This initial study offers a promising personalized material for bone repair that can be used rapidly during surgery.

G-quadruplex formation within the promoter region of HSPB2 and its effect on transcription.

G-rich sequences in DNA and RNA tend to fold into stable secondary structures called G-quadruplexes. Except for the telomere region, G-quadruplex-forming sequences are widely present in gene promoters and have been implicated in transcriptional regulation. Single nucleotide polymorphisms (SNPs) can disrupt the G-quadruplex structure of a gene promoter. In this study, we confirmed the promoter of HSPB2, a cancer-related gene, tends to form an unusual DNA secondary structure. The dual luciferase assay revealed that the SNP rs2234704 in the HSPB2 promoter with a single G > A mutation increased the transcriptional activity of the HSPB2 promoter. Circular dichroism and native PAGE revealed that the G-rich strand of the DNA in this promoter preferred to form a parallel G-quadruplex, which could be destabilized by the SNP rs2234704 (G > A) mutation. Furthermore, we found that the SNP rs2234704 (G > A) greatly increased and influenced the overexpression of HSPB2 in breast cancer samples. These results suggest SNP rs2234704 (G > A) may play a role in the occurrence of breast cancer by destroying the G-quadruplex structure and promoting the expression of HSPB2.

Facial palsy induced by immune checkpoint blockade: A systematic analysis of clinical trials and a pharmacovigilance study of postmarketing data.

BACKGROUND: To estimate the risk of facial nerve palsy (FP) associated with immune checkpoint inhibitors (ICIs), and to describe its clinical features. METHODS: Data from randomized controlled trials (RCTs) and FDA Adverse Event Reporting System (FAERS) database were included. The primary outcome was the risk of FP events associated with ICIs. For data from RCTs, pooled analysis was performed by using risk ratios (RRs) with 95%CIs. In a separate retrospective pharmacovigilance study of FAERS, disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). RESULTS: A total of 21 RCTs (193,05 patients) were included, ICIs were associated with increased risk of FP (OR = 3.07, 95%CI:1.43-6.58). Results of subgroup analysis indicated that OR of ICI-related FP did not vary significantly by tumor type, ICIs treatment schedule, case of events, study design, median PFS and publication status. FAERS pharmacovigilance data identified 274 cases of FP related to ICIs therapy. ICIs were significantly associated with over-reporting frequencies of FP (ROR = 3.03, 95%CI:2.69-3.42; IC = 1.56, 95%CI:1.38-1.76). The median onset time of FP was 5.5 weeks, drug interruption was recorded in 78.0% of cases, with a positive dechallenge in 82.8 % of cases, and 71.7% of cases were recovered or recovering. CONCLUSIONS: These data suggest that ICIs were significantly associated with increased risk of FP in both trial settings and in clinical practice.

A high-throughput UHPLC-MS/MS method for the determination of eight anti-tumor drugs in plasma.

Rapidly developing UHPLC-MS/MS bioassays with high throughput and quality are challenging yet desired in routine clinics. METHODS & RESULTS: A high-throughput UHPLC-MS/MS bioassay has been built for simultaneously quantifying gefitinib, ruxolitinib, dasatinib, imatinib, ibrutinib, methotrexate, cyclophosphamide and paclitaxel. After the protein precipitation with methanol, samples were separated on an Acquity BEH C18 column following a gradient elution system with methanol and 2 mM ammonium acetate in water at 40 °C with a run time of 3 min (flow rate 0.4 mL/min). Mass quantification in the positive ion SRM mode was then performed with electrospray ionization. The method of specificity, linearity, accuracy, precision, matrix effects, recovery, stability, dilution integrity and carryover were all validated as per the guideline of the China Food and Drug Administration whose values met the admissible limits. Application of the bioassay to therapeutic drug monitoring revealed important variability in the studied anti-tumour drugs. CONCLUSION: This validated approach was shown to be reliable and effective in clinical management, being a valuable support in therapeutic drug monitoring and subsequent individualized dosing optimization.

Screening of antibiotics to obtain axenic cell cultures of a marine microalga Chrysotila roscoffensis.

Due to high growth rate, outstanding abiotic stress tolerance, and rich value-added substances, Chrysotila roscoffensis, belonging to the phylum of Haptophyta, can be considered as a versatile resource for industrial exploitation of bioactive compounds. However, the application potential of C. roscoffensis has drawn attention until just recently, and the understanding related to the biological properties of this species is still scarce. For example, the sensitivities of C. roscoffensis to antibiotics, which is essential for the verification of heterotrophic capacity and the establishment of efficient genetic manipulation system is still unavailable. Aiming to provide fundamental information for future exploitation, the sensitivities of C. roscoffensis to nine types of antibiotics were tested in this study. The results demonstrated that C. roscoffensis exhibited relatively high resistances to ampicillin, kanamycin, streptomycin, gentamicin, and geneticin, while was sensitive to bleomycin, hygromycin B, paromomycin, and chloramphenicol. Using the former five types of antibiotics, a bacteria removal strategy was established tentatively. Finally, the axenicity of treated C. roscoffensis was confirmed based on a multi-strategy method including solid plate, 16S rDNA amplification, and nuclear acid staining. This report can provide valuable information for the development of optimal selection markers, which are meaningful for more extensive transgenic studies in C. roscoffensis. Moreover, our study also paves the way for the establishment of heterotrophic/mixotrophic cultivation modes of C. roscoffensis.

Interstitial lung disease in patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi): analysis of results from clinical trials and the FDA Adverse Events Reporting System database.

OBJECTIVE: To evaluate the risk of interstitial lung disease associated with poly (ADP-ribose) polymerase inhibitors (PARPi) and characterize its clinical features. METHODS: We systematically reviewed phase III randomized clinical trials of interstitial lung disease related to PARPi and calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting cases of PARPi-related interstitial lung disease from the FDA Adverse Events Reporting System and assessing disproportionalities by reporting ORs and information components. RESULTS: A total of five randomized clinical trials involving 2980 patients were included. Although PARPi showed a tendency to increase the risk of interstitial lung disease compared with controls, this difference was not significant (Peto OR: 4.92; 95% CI: 0.92 to 26.35). A total of 170 cases of interstitial lung disease related to PARPi were included, with a median latency of 99 days. PARPi had a significantly increased reporting of interstitial lung disease (reporting OR: 2.86; 95% CI: 2.46 to 3.33; information component (IC): 1.49; 95% CI: 1.28 to 1.74). Our sensitivity analyses showed strong robustness of the disproportionalities between PARPi as a class, olaparib, and interstitial lung disease. Some 91.9% of patients experienced discontinuation, 51.6% achieved remission, and no deaths were reported. CONCLUSION: Our pharmacovigilance study suggested increased reporting of interstitial lung disease related to PARPi particularly olaparib.

Injectable chondroitin sulfate-grafted self-antioxidant hydrogels ameliorate nucleus pulposus degeneration against overactive inflammation.

Overactive inflammatory cascade accompanied by oxidative stress in the nucleus pulposus exacerbates intervertebral disc degeneration (IVDD). Hydrogels have been demonstrated to be promising in treating IVDD, yet they remain less efficacious in the case of anti-inflammation associated with antioxidation. In this study, we designed an injectable self-antioxidant hydrogel (HA/CS) with enhanced inflammation inhibitory performance for delivering chondroitin sulfate (CS) with well-documented anti-inflammatory property to treat IVDD. The hydrogel was rapidly formed via dynamic boronate ester bonding between furan/phenylboronic acid and furan/dopamine-modified hyaluronic acid (HA), and mechanically enhanced by Diels-Alder reaction-induced secondary crosslinking, partial dopamine groups of which contribute to grafting phenylboronic acid-modified CS (CS-PBA). This hydrogel exhibits favorable injectability, mechanical property, and pH-responsive delivery behavior. The dopamine moiety endows the hydrogel with efficient antioxidative property. By sustained delivery of CS, the HA/CS hydrogel is well competent to inhibit inflammatory cytokine expression and maintain anabolic/catabolic balance in an inflammation-simulated environment. Most importantly, the HA/CS hydrogel significantly ameliorates degeneration in a puncture-induced IVDD rat model. The self-antioxidant HA/CS hydrogel designed in this work may serve as a novel and promising therapeutic platform for IVDD.

Injectable and tissue adhesive EGCG-laden hyaluronic acid hydrogel depot for treating oxidative stress and inflammation.

Oxidative stress and inflammation are common pathological mechanisms for the progression of tissue degeneration. Epigallocatechin-3-gallate (EGCG) features antioxidant and anti-inflammatory properties, which is a promising drug for the treatment of tissue degeneration. Herein, we utilize the phenylborate ester reaction of EGCG and phenylboronic acid (PBA) to fabricate an injectable and tissue adhesive EGCG-laden hydrogel depot (EGCG HYPOT), which can achieve anti-inflammatory and antioxidative effects via smart delivery of EGCG. Specifically, the phenylborate ester bonds, formed by EGCG and PBA-modified methacrylated hyaluronic acid (HAMA-PBA), endow EGCG HYPOT injectability, shape adaptation and efficient load of EGCG. After photo-crosslinking, EGCG HYPOT exhibits good mechanical properties, tissue adhesion and sustained acid-responsive release of EGCG. EGCG HYPOT can scavenge oxygen and nitrogen free radicals. Meanwhile, EGCG HYPOT can scavenge intracellular reactive oxygen species (ROS) and suppress the expression of pro-inflammatory factors. EGCG HYPOT may provide a new idea for alleviation of inflammatory disturbance.

Thromboembolism profiles associated with cyclin-dependent kinase 4/6 inhibitors: a real-world pharmacovigilance study and a systematic review.

BACKGROUND: Thrombosis is the second leading cause of mortality in cancer patients. This study aimed to investigate the association between cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and thrombosis. RESEARCH DESIGN AND METHODS: A retrospective pharmacovigilance analysis based on real-world data combined with a systematic review was used to explore the thrombotic risk profiles of CDK4/6i. The study has been registered with Prospero (CRD42021284218). RESULT: In the pharmacovigilance analysis, CDK4/6i showed a higher rate of reported venous thromboembolism (VTE) (ROR = 2.78, 95% CI = 2.64-2.92), with the highest signal for trilaciclib (ROR = 27.55, 95% CI = 13.43-56.52) but only 9 cases, followed by abemaciclib (ROR = 3.73, 95% CI = 3.19-4.37). For arterial thromboembolism (ATE), only ribociclib increased the reporting rate (ROR = 2.14, 95% CI = 1.91-2.41). In the meta-analysis, palbociclib, abemaciclib, and trilaciclib all increased the risk of VTE (OR = 2.23, 3.17, and 3.90). In the subgroup analysis, only abemaciclib increased the risk of ATE (OR = 2.11, 95% CI = 1.12-3.99)    . CONCLUSIONS: CDK4/6i had different profiles of thromboembolism. Palbociclib, abemaciclib, or trilaciclib increased the risk of VTE. Ribociclib and abemaciclib showed a weak association with the risk of ATE.

SGLT-2 inhibitors and euglycemic diabetic ketoacidosis/diabetic ketoacidosis in FAERS: a pharmacovigilance assessment.

AIMS: To investigate the main feature and the association between euglycemic diabetic ketoacidosis (euDKA) /diabetic ketoacidosis (DKA) and sodium-dependent glucose transporters 2 inhibitors (SGLT-2i) from the FDA adverse event reporting system (FAERS). METHODS: Cases of SGLT-2i-associated with euDKA/DKA were extracted from the FAERS database and compared with the reports for other hypoglycemia agents (ATC10 class). Disproportionality analyses used the reporting odds ratio (ROR) and information components (IC). The lower limit of the IC 95% credibility interval for IC > 0 is considered a reported signal, with at least 3 cases. RESULTS: A total of 10,195 cases of euDKA (n = 1680) and DKA (n = 8515) associated with SGLT-2i were identified from the FAERS. The SGLT-2i was associated with higher reporting of euDKA and DKA compared to other hypoglycemia agents (ROR = 16.69 [95% CI 14.89-18.70], IC = 3.27 [95% CI 2.91-3.66] for euDKA; ROR = 16.44 [95% CI 15.72-17.20], IC = 3.19 [95% CI 3.05-3.34] for DKA). In available data, the median onset time of euDKA/DKA was 31 days, and canagliflozin had the longest onset time (96.5 days for euDKA and 75 days for DKA) compared with dapagliflozin and empagliflozin (p < 0.05). Male patients predominate in euDKA (51.9%), and female patients predominate in DKA (53.7%). Most patients discontinue the treatment (95.5% for euDKA, 93.9% for DKA), and approximately 49.0% (n = 3658) of patients had symptomatic remission after discontinuation of SGLT-2i, and 2.3% (n = 173) of patients had no remission. About 75.6% (n = 6126) of patients need hospitalization after euDKA/DKA. CONCLUSIONS: Post-marketing data showed that SGLT-2i was significantly associated with higher reporting of euDKA/DKA. Although euDKA/DKA is rare, clinicians should be aware of SGLT-2i-associated euDKA/DKA events.

Immune checkpoint inhibitors increase the risk of kidney transplant rejection: a real-world pharmacovigilance study.

BACKGROUND: Kidney transplant recipients with cancer are at higher risk of kidney transplant rejection (KTR), and the safety of immune checkpoint inhibitors (ICIs) is unclear. The present study investigates the relationship between ICIs and KTR using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: Case reports of KTR inducted by ICIs in FAERS from 1 January 2011, to 30 June 2021, were collected, and a disproportionate analysis was performed to assess the correlation between ICIs and KTR. RESULTS: A total of 99 cases of ICI-related KTR were reported in the FAERS database. Most of them were male patients (n = 63, 84.0%), and more than half of patients suffered from malignant melanoma (n = 46, 52.9%). The median onset time after the medication was 22 days, the withdrawal rates of ICIs were 78.0%, and the overall death rate was 29.3%. In general, there was a significant relevance between ICIs and KTR (ROR = 3.92[3.21-4.79] IC025 = 1.56), of which PD-1 was the most prominent (n = 81 ROR = 5.26[4.22-6.57] IC025 = 1.86). CONCLUSIONS: ICIs may increase the risk of KTR in organ transplant recipients with cancer.

Type 1 diabetes with immune checkpoint inhibitors: A systematic analysis of clinical trials and a pharmacovigilance study of postmarketing data.

BACKGROUND: To estimate the risk of type 1 diabetes associated with immune checkpoint inhibitor (ICI-T1DM), and to describe its clinical features. METHODS: ICI-T1DM events in randomized clinical trials (RCTs) available in electronic databases were systematically reviewed. The primary outcome was the summary risk of T1DM related to ICIs, a meta-analysis was conducted to obtain Peto odds ratios (ORs) with 95 % CIs. In pharmacovigilance study, ICI-T1DM cases were extracted from FAERs. Disproportionality analyses were performed by calculating reporting odds ratio (ROR) and information components (IC). RESULTS: A total of 29 RCTs (20,234 patients) were included, treatment with ICIs significantly increased the risk of all-grade ICI-T1DM (OR: 4.54, 95 % CI: 2.66-7.72), and high-grade (grade 3 or above) ICI-T1DM (OR: 4.26, 95 % CI: 2.12-8.58). No significant differences among subgroup analyses were observed: ICIs treatment schedule, tumor type, case of events (T1DM vs F-T1DM), study design (double blind vs open label) or median PFS (PFS favours ICIs vs PFS favours Control). A total of 978 case reports form FAERS was extracted, treatment with ICIs significantly increased the reporting of ICI-T1DM (n = 978; ROR = 38.45, 95 %CI:35.70-41.41; IC = 4.77, 95 %CI:4.43-5.14). In cases with available data, the median latency period was 10.4 weeks, drug interruption was recorded in 82.3 % of cases, with a positive dechallenge in 76 % of cases, and death was recorded as outcome in 3.6 % of reports. CONCLUSIONS: Both data from clinical trials and postmarketing suggested that ICIs was associated with increased risk of ICI-T1DM. As ICIs gain greater clinical use, practitioners must be aware of ICI-T1DM events.

Exploring the trend in religious diversity: Based on the geographical perspective.

The formation and development of religious diversity is a manifestation of the free expression of human thought, belief, and practice, as well as a historical premise and ideological condition for the gradual recognition and integration of modern religions into modern political values. This study examines the spatial characteristics of the development of the global religious diversity index (RDI) and the evolution trend through a geographical perspective by the LISA space-time transition and convergence test. The results show that: (1) At the temporal level, RDI showed a fast and then slow increase after WWII, with an increase of 61.11%. (2) At the spatial level, Latin America has seen the most significant increase in RDI, followed by Europe, North America and the Caribbean, while Asia has a slight decrease. (3) At the country level, most countries with the highest levels of RDI are located in North America and the Caribbean, Sub-Saharan Africa, and most of these countries have a history of being colonized. RDI was mainly influenced by factors such as the missionary effect in the colonial period, precipitation, GDP per capita, and genetic diversity. (4) The evolution of the spatial structure of global RDI has a certain path-dependent, but this trend is gradually weakening. In addition to countries' own development, RDI is also influenced by spillover effects from the neighboring countries. (5) There is a significant σ convergence and absolute ß convergence in the global RDI, and most of the continental units have club convergence, i.e., the internal differences in RDI levels at the global and regional levels are gradually narrowing, and there is a spillover effect of higher RDI levels to the surrounding lower regions, and this diffusion or influence allows the lower regions to catch up in the gap of RDI.

Ileus in patients treated with immune checkpoint inhibitors: A retrospective, pharmacovigilance study using Food and Drug Administration Adverse Event Reporting System database.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been widely used in cancer treatment; however, some case reports suggested that ICIs treatment might result in ileus. This study aims to comprehensively reveal the relationship between ileus and ICIs treatment in real-world cases from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: Reports from January 1, 2011 to December 31, 2020 were extracted from the FAERS. ICIs-related adverse events in patients were defined as related to use of anti-programmed cell death protein 1 antibodies (PD-1, nivolumab and pembrolizumab), anti-programmed cell death-ligand 1 inhibitors (PD-L1, atezolizumab, durvalumab, avelumab, and cemiplimab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab and tremelimumab). ICIs-related ileus cases were identified to characterize their clinical features. Reporting odds ratios (ROR) and information component (IC) were used to assess the relationship between ICIs and ileus. RESULTS: Among the 105 001 cases related to ICIs, 245 were reported with ICI-related ileus. The affected patients were mainly elderly (median age, 64.5 years) and male (58%, n = 143). The median onset for all cases was 36 (range 0-880) days, and no statistical difference was observed between monotherapy and combination therapy (PD-1 or PD-L1 plus CTLA-4) (p = 0.21). Most patients required drug withdrawal treatment (n = 113, 74%) and can achieve a recovered-resolved state (n = 72, 46%). All ICIs were significantly associated with ileus (ROR = 4.27, 95%Cl: 3.75-4.85; IC = 2.04, 95%Cl: 1.79-2.31). Ileus events were most commonly reported in PD-1 treatment (n = 164, ROR = 3.83, 95%Cl: 3.28-4.48; IC = 1.90, 95%Cl: 1.62-2.21). CONCLUSION: This pharmacovigilance database analysis suggested that ICIs are related to ileus. However, combination therapy may not speed up the onset of ileus.