High positive predictive value of CNVs detected by clinical exome sequencing in suspected genetic diseases.

BACKGROUND: Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent-offspring trios and proband only analysis. METHODS: We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. RESULTS: Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. CONCLUSION: CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.

Discovery of novel harmine derivatives as GSK-3ß/DYRK1A dual inhibitors for Alzheimer's disease treatment.

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.

Two cases of microvillus inclusion disease caused by MYO5B deficiency with prenatal abnormalities.

BACKGROUNDS: Microvillus inclusion disease (MVID) characterizes as intractable life-threatening watery diarrhea malnutrition after birth. MATERIALS & METHODS: Here we describe two patients with prenatal ultrasound findings of bowel dilation or increased amniotic fluid volume presented intractable diarrhea after birth. Exome sequencing and Intestinal biopsy were performed for the patients and their parents to reveal the underlying causes. The mutations were verified by Sanger sequencing and quantitative polymerase chain reaction. RESULTS: Exome sequencing revealed that both of the patients carrying MYO5B compound heterozygote mutations that were inherited from their parents. CONCLUSION: Here we describe two cases with MVID caused by MYO5B deficiency, which was the most common caused with prenatal ultrasound findings of bowel dilation and increased amniotic fluid volume. Due to the lack of effective curative therapies, early diagnosis even in prenatal of MVID can provide parents with better genetic counseling on the fetal prognosis.

The significance of trisomy 7 mosaicism in noninvasive prenatal screening.

BACKGROUND: This study was an evaluation of the role of noninvasive prenatal testing (NIPT) in the detection of trisomy 7 in prenatal diagnosis. METHOD: A total of 35 consecutive cases underwent screening for trisomies by cell-free DNA testing between April 2015 and November 2017 due to suspicious NIPT results; these cases represented 0.11% of patients (35/31,250) with similar frequencies of abnormal results among the laboratories performing the tests. NIPT was offered to further screen for common fetal chromosomal abnormalities. Karyotype analysis, chromosomal microarray analysis (CMA), and next-generation sequencing (NGS) were used to detect 20, 14, and 25 patients, respectively, who accepted confirmatory diagnostic testing. RESULTS: High-risk results by NIPT were recorded for trisomy 7 alone in 29 women: dual aneuploidy in 4 patients and multiple aneuploidy in 2 patients. Karyotype analysis of amniotic fluid cells was normal in all 20 pregnancies, suggesting a probability of confined placental mosaicism. Further CMA data were obtained in 14 of the cases mentioned above, and 2 fetuses were detected with positive results with copy number variation. The NGS results suggested that all these samples were placental chimerisms of chromosome 7, except for one sample that was found to be an additional chimerism of chromosome 2, which was also consistent with the NIPT result. CONCLUSION: Our results may be useful for the counseling of pregnant women in the detection of trisomy 7 by NIPT.

Factors affecting cell-free DNA fetal fraction: statistical analysis of 13,661 maternal plasmas for non-invasive prenatal screening.

BACKGROUND: The identification of cell-free fetal DNA (cffDNA) facilitated non-invasive prenatal screening (NIPS) through analysis of cffDNA in maternal plasma. However, challenges regarding its clinical implementation become apparent. Factors affecting fetal fraction should be clarified to guide its clinical application. RESULTS: A total of 13,661 pregnant subjects with singleton pregnancies who undertook NIPS were included in the study. Relationship of gestational age, maternal BMI, and maternal age with the cffDNA fetal fraction in maternal plasmas for NIPS was investigated. Compared with 13 weeks (12.74%) and 14-18 weeks group (12.73%), the fetal fraction in gestational ages of 19-23 weeks, 24-28 weeks, and more than 29 weeks groups significantly increased to 13.11%, 16.14%, and 21.17%, respectively (P < 0.01). Compared with fetal fraction of 14.54% in the maternal BMI group of < 18.5 kg/m2, the percentage of fetal fraction in the group of 18.5-24.9 kg/m2 (13.37%), 25-29.9 kg/m2 (12.20%), 30-34.9 kg/m2 (11.32%), and 35-39.9 kg/m2 (11.57%) decreased significantly (P < 0.01). Compared with the fetal fraction of 14.38% in the group of 18-24 years old, the fetal fraction in the maternal age group of 25-29 years old group (13.98%) (P < 0.05), 30-34 years old group (13.18%) (P < 0.01), 35-39 years old group (12.34%) (P < 0.01), and ≥ 40 years old (11.90%) group (P < 0.01) decreased significantly. CONCLUSIONS: The percentage of fetal fraction significantly increased with increase of gestational age. Decreased fetal fraction with increasing maternal BMI was found. Maternal age was also negatively related to the fetal fraction.

Noninvasive prenatal detection of hemoglobin Bart hydrops fetalis via maternal plasma dispensed with parental haplotyping using the semiconductor sequencing platform.

BACKGROUND: Thalassemia is one of the most common monogenetic diseases in the south of China and Southeast Asia. Hemoglobin Bart's hydrops fetalis syndrome was caused by a homozygous Southeast Asian deletion (-/-) in the HBA gene. Few studies have proved the potential of screen for Bart's hydrops fetalis using fetal cell-free DNA. However, the number of cases is still relatively small. Clinical trials of large samples would be needed. OBJECTIVE: In this study, we aimed to develop a noninvasive method of target-captured sequencing and genotyping by the Bayesian method using cell-free fetal DNA to identify the fetal genotype in pregnant women who are at risk of having hemoglobin Bart hydrops fetalis in a large-scale study. STUDY DESIGN: In total, 192,173 couples from 30 hospitals were enrolled in our study and 878 couples were recruited, among whom both the pregnant women and their husbands were detected to be carriers of Southeast Asian type (-/αα) of α-thalassemia. Prenatal diagnosis was performed by chorionic villus sampling, amniocentesis, or cordocentesis using gap-polymerase chain reaction considered as the golden standard. RESULTS: As a result, we found that the sensitivity and specificity of our noninvasive method were 98.81% and 94.72%, respectively, in the training set as well as 100% and 99.31%, respectively, in the testing set. Moreover, our method could identify all of 885 maternal samples with the Southeast Asian carrier and 36 trisomy samples with 100% of sensitivity in T13, T18, and T21 and 99.89% (1 of 917) and 99.88% (1 of 888) of specificity in T18 and T21, respectively. CONCLUSION: Our method opens the possibility of early screening for maternal genotyping of α-thalassemia, fetal aneuploidies in chromosomes 13/18/21, and hemoglobin Bart hydrops fetalis detection in 1 tube of maternal plasma.

Association between fetal fraction at the second trimester and subsequent spontaneous preterm birth.

OBJECTIVE: To evaluate the association between the fetal fraction of cell-free DNA at the second trimester and subsequent spontaneous preterm birth. METHODS: In this retrospective cohort study, data were collected from women with singleton pregnancies who underwent noninvasive prenatal testing at 14 to 25 weeks of gestation. The eligible patients were classified into three groups according to pregnancy outcome: birth at ≥37 weeks of gestation (term group), delivery at <34 weeks of gestation (early spontaneous preterm), and delivery at 34+0 to 36+6  weeks of gestation (late spontaneous preterm). Stepwise linear regression was performed to determine the maternal characteristics associated with the fetal fraction of cell-free DNA. Logistic regression was used to determine the relationship between the fetal fraction of cell-free DNA and pregnancy outcomes by adjusting for history of preterm birth. RESULTS: A total of 8129 singleton pregnancies met the recruitment criteria. Among them, 7790 (95.83%) were in the term group, 284 (3.49%) were in the late spontaneous preterm group, and 55 (0.68%) were in the early spontaneous preterm group. The fetal fraction of cell-free DNA was negatively correlated with body mass index, maternal age, nulliparity, and history of spontaneous preterm birth; positively correlated with gestational age; and not correlated with assisted reproduction or surface antigen of hepatitis B virus (HBsAg) positivity. After adjusting for history of preterm birth, a logistic regression analysis demonstrated no statistically significant associations between the fetal fraction of cell-free DNA and spontaneous preterm birth in any of the preterm groups (<34 weeks, 34+0 to 36+6  weeks, and <37 weeks). CONCLUSION: Our preliminary study found no relationship between the fetal fraction on NIPT at the second trimester and subsequent spontaneous preterm birth.

Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA.

Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.

XAF1 contributes to dengue virus-induced apoptosis in vascular endothelial cells.

The mechanism of vascular leakage in severe dengue infection remains unclear. Here, we used primary human umbilical vein endothelial cells (HUVECs) and the EA.hy926 cell line to study the molecular events that occur after dengue virus serotype 2 (DENV2) infection. DENV2-induced apoptosis was confirmed using nuclear staining, TUNEL assay, and electron microscopy. A genome-wide transcriptome analysis was performed using a microarray of DENV2-infected HUVECs. Notably, interferon-inducible genes were differentially expressed after DENV2 infection. Prominent among these genes was the X chromosome-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1; up-regulated 1.2-fold in the microarray analysis and ∼8-fold by qRT-PCR after DENV2 infection). XAF1 protein levels were up-regulated after DENV2 infection in both HUVECs and EA.hy926 cells. Evidence indicated interaction between XAF1 and XIAP during DENV2 infection based on their cellular localization, as observed by confocal microscopy and the coimmunoprecipitation of XIAP with an anti-XAF1 antibody. Next, recombinant EA.hy926 cell lines in which XAF1 was either knocked down or overexpressed were constructed. The expression levels of the apoptosis-related genes caspase 3, caspase 8, caspase 9, and poly-(ADP-ribose) polymerase (PARP) were down-regulated in the XAF1 knockdown (24-48 h postinfection) but were up-regulated in XAF1 overexpressing cells (36 h postinfection). This is the first study of the role of XAF1 in promoting apoptosis in vascular endothelial cells after DENV2 infection.

Coordinated regulation of autophagy and apoptosis determines endothelial cell fate during Dengue virus type 2 infection.

Dengue is the most prevalent mosquito-borne viral disease in tropical regions. Severe cases may progress to Dengue hemorrhagic fever, suggesting vascular endothelial dysfunction in disease pathogenesis. In our previous study, we found that Dengue virus type 2 (DENV2) induced apoptosis of vascular endothelial cells via FasL/Fas- and XIAP-associated factor 1 (XAF1)-dependent pathways. In this paper, we demonstrate that DENV2 can induce autophagy in primary human umbilical vein endothelial cells (HUVECs) and the human umbilical vein endothelial cell line EA.hy926. Inhibition of autophagy with 3-methyl adenine promoted apoptosis, while inhibition of apoptosis with Z-VAD-FMK facilitated autophagy in DENV2-infected HUVECs and EA.hy926 cells. Interferon-alpha-inducible protein 6 (IFI6), a putative apoptosis regulator, inhibited DENV2-induced autophagy in EA.hy926 cells, while XAF1, an inhibitor of anti-apoptotic XIAP, facilitated autophagy. Molecular regulators of apoptosis and autophagy interact at multiple levels to determine cell fate. Our data suggest that XAF1 and IFI6 are involved in regulating the balance between autophagy and apoptosis in DENV2-infected endothelial cells.

[Surgical resection versus radiofrequency ablation for primary hepatocellular carcinoma of 3-5 cm in diameter: a meta-analysis].

OBJECTIVE: To compare the therapeutic effects of surgical hepatic resection (HR) and radiofrequency ablation (RFA) in treatment of primary hepatocellular carcinoma of 3-5 cm in diameter. METHODS: The databases PubMed, CBMdisc, CNKI, WanFang Data and VIP databases were searched for controlled clinical trials on evaluating the efficacy between RFA and HR in treatment of primary hepatocellular carcinoma of 3-5 cm in diameter published from January 1990 to February 2014. Two reviewers independently screened the literature, extracted the data and assessed the methodological quality of the studies included. Then the meta-analysis was performed by using RevMan5.0 software. RESULTS: Eleven controlled clinical trials were included, including one randomized controlled trial and 10 non-randomized controlled trials. A total of 811 patients were involved: 404 patients were treated with RFA as the initial treatment and 407 patients with surgical resection. Meta-analysis showed that for a single lesion with diameter of 3-5 cm of primary hepatocellular carcinoma, the 3-， 5-year disease-free survival rates in HR group was significantly higher than those in RFA group (all P<0.05). There were no significant difference in the 1-， 3-， 5-year overall survival rates and 1-year disease-free survival rate between RFA group and HR group (P>0.05). For 1-2 nodules with diameters of 3-5 cm of primary hepatocellular carcinoma, the 3-， 5-year disease-free survival rates and 5-year overall survival rates in HR group was significantly higher than those in RFA group (all P<0.05). No significant difference in 1-， 3-year overall survival rates and 1-year disease-free survival rate was found between RFA group and HR group (P>0.05). For maximum nodule of 3-5 cm of multiple primary hepatocellular carcinoma, the 5-year overall survival rates in HR group was significantly higher than that in RFA group (all P<0.05). No significant difference in 1-， 5-year overall survival rates was noted between RFA group and HR group (P>0.05). CONCLUSION: For primary hepatocellular carcinoma of 3-5 cm in diameter, HR is better than RFA. For the limitation of quality and quantity of included studies, this conclusion needs to be confirmed by more high quality studies.

[Research progress on distal interlocking screws of cephalomedullary nails in intertrochanteric fractures].

Objective: To summarize the new research progress in distal interlocking screws of cephalomedullary nails for the treatment of intertrochanteric fractures. Methods: Relevant domestic and foreign literature was extensively reviewed to summarize the static/dynamic types of distal interlocking screw holes, biomechanical studies, clinical studies and application principles, effects on toggling in the cavity, and related complications of distal interlocking screws. Results: The mode of the distal interlocking screw holes can be divided into static and dynamic. Distal interlocking screws play the role of anti-rotation, maintaining femur length, resisting compression stress, increasing torque stiffness, resisting varus stress, etc. The number of the screws directly affects the toggling of the main nail in the cavity. At present, regardless of whether long or short nails are used, distal interlocking screws are routinely inserted in clinical practice. However, using distal interlocking screws can significantly increase the duration of anesthesia and operation, increase fluoroscopy exposure time, surgical blood loss, and incision length. There is a trend of trying not to use distal interlocking screws in recent years. No significant difference is found in some studies between the effectiveness of dynamic and static interlocking for AO/Orthopaedic Trauma Association (AO/OTA) 31-A1/2 fractures. At present, the selection of the number and mode of distal interlocking screws is still controversial. When inserting distal interlocking screws, orthopedists should endeavor to minimize the occurrence of complications concerning miss shot, vascular injuries, local stress stimulation, and peri-implant fractures. Conclusion: Distal interlocking screws are mainly used to prevent rotation. For stable fractures with intact lateral walls, long cephalomedullary nails can be used without distal interlocking screws. For any type of intertrochanteric fractures, distal interlocking screws are required when using short cephalomedullary nails for fixation. Different interlocking modes, the number of interlocking screws, and the application prospects of absorbable interlocking screws may be future research directions.

Valve-in-valve implantation to seal post-dilation-induced annular rupture in transcatheter aortic valve replacement.

An 85-year-old woman was admitted to our hospital with severe symptomatic aortic stenosis. Preoperative computed tomography and transesophageal echocardiography (TEE) revealed a type I bicuspid aortic valve.

How much of the superolateral femoral neck should be removed in intramedullary nail fixation for intertrochanteric fracture?

The objective of this study was to measure how much of the superolateral femoral neck should be removed to reduce the incidence of wedge effect. Simulating surgery: Computed Tomography images of 131 intertrochanteric fracture patients were included, three-dimensionally reconstructed, virtually reduced and implanted with Proximal Femoral Nail Antirotation blade-Ⅱ(PFNA-Ⅱ) nail. The antero-posterior length and media-lateral width of the intersection between superolateral femoral neck and PFNA-Ⅱ nail were measured. Retrospective study: The pre- and postoperative CT of 30 patients were collected. The average varus angle of the neck-shaft angle and the correlation between the angles and the difference in the actual and estimated width of the fragments removed were measured. Models of 108 patient were selected for analysis. The average antero-posterior length and media-lateral width were 14.46 mm (14.00-14.93 mm) and 9.33 mm (8.79-9.87 mm), respectively. The AO/OTA classification was not significantly associated with the outcome, but the gender was. In the retrospective study, the mean value of the varus angles was -4.58° (SE = 6.85°), and the difference of width was strongly positively correlated with the varus angle with a correlation coefficient of 0.698. Results obtained in this study can improve the understanding of this region and help surgeons to make appropriate preoperative planning to reduce the incidence of wedge effect. Retrospective study provided effective proof of the reliability of this study.

[Prdx1 regulates macrophage polarization by maintaining mitochondrial homeostasis].

In order to investigate the role of Prdx1 in macrophage polarization, mouse leukemia cells of monocyte macrophage (RAW264.7) were treated with lipopolysaccharides (LPS)+ interferon gamma (IFNγ) or IL-4 to induce type 1 macrophage (M1) and type 1 macrophage (M2) macrophages, respectively. The Prdx1 gene knockout cells (Prdx1-/-) were used for the study. Flow cytometry was conducted to detect M1/M2 macrophage markers, and ELISA kits were used to measure M1/M2 cytokine levels. Inducible nitric-oxide synthase (iNOS) activity, arginase-1 (Arg-1) activity, and oxidative damage were also assessed. The Seahorse XFe24 Extracellular Flux Analyzer was employed to measure extracellular acidification rate and oxygen consumption rate. The mitochondrial membrane potential was analyzed using the mitochondrial membrane potential dye (JC-1) fluorescent probe, and mitochondrial superoxide was detected through fluorescence staining. Additionally, the impact of adding a mitochondrial reactive oxygen species (ROS) scavenger on RAW264.7 macrophage polarization was examined. The results demonstrated an increase in ROS, hydrogen peroxide, and 8-hydroxy-2 deoxyguanosine (8-OHDG). Cytotoxicity and mitochondrial toxic effects, including mitochondrial superoxide accumulation, decreased adenosine-triphosphate (ATP) production, reduced mitochondrial membrane potential, and decreased mitochondrial DNA copy number, were observed. Furthermore, down-regulation of translocase of inner mitochondrial membrane 23 (TIM23) mitochondrial protein and mitochondrial stress protein heat shock protein 60 (HSP60) was noted. The extra cellular acidification rate (ECAR) in M1 macrophage polarization in RAW264.7 cells was increased, while oxygen consumption rate (OCR) in M2 macrophages was reduced. These findings indicate that Prdx1 knockout in RAW264.7 cells can inhibit M2 macrophage polarization but promote M1 macrophage polarization by impairing mitochondrial function and reducing oxidative phosphorylation.

Biomarker profiling to determine clinical impact of microRNAs in cognitive disorders.

Alzheimer's disease (AD) and post-stroke cognitive impairment (PSCI) are the leading causes of progressive dementia related to neurodegenerative and cerebrovascular injuries in elderly populations. Despite decades of research, patients with these conditions still lack minimally invasive, low-cost, and effective diagnostic and treatment methods. MicroRNAs (miRNAs) play a vital role in AD and PSCI pathology. As they are easily obtained from patients, miRNAs are promising candidates for the diagnosis and treatment of these two disorders. In this study, we performed complete sequencing analysis of miRNAs from 24 participants, split evenly into the PSCI, post-stroke non-cognitive impairment (PSNCI), AD, and normal control (NC) groups. To screen for differentially expressed miRNAs (DE-miRNAs) in patients, we predicted their target genes using bioinformatics analysis. Our analyses identified miRNAs that can distinguish between the investigated disorders; several of them were novel and never previously reported. Their target genes play key roles in multiple signaling pathways that have potential to be modified as a clinical treatment. In conclusion, our study demonstrates the potential of miRNAs and their key target genes in disease management. Further in-depth investigations with larger sample sizes will contribute to the development of precise treatments for AD and PSCI.

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib.

Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

Single-ion-conducted covalent organic framework serving as Li-ion pump in polyethylene oxide-based electrolyte for robust solid-state Li-S batteries.

Poly(ethylene oxide) (PEO)-based electrolytes are widely used for building solid-state lithium-sulfur (Li-S) batteries but suffer from poor lithium-ion (Li+) transportation kinetics. Here, a lithium-sulfonated covalent organic framework (TpPa-SO3Li) was synthesized and functionalized as a Li+ pump in a PEO-based solid-state electrolyte to fabricate robust Li-S batteries. The designed TpPa-SO3, Li with its porous skeleton and abundant lithium sulfonate groups not only provided iontransport channels but also enhanced the fast migration of Li+. The PEO composite electrolyte containing 5 %-TpPa-SO3Li exhibited a notable ionic conductivity of 6.28 × 10-4 S cm-1 and an impressive Li+ transference number of 0.78 at 60 °C. As a result, Li-Li symmetric batteries with the optimized PEO/TpPa-SO3Li composite electrolyte stably cycled for 300 h, with a minimal overpotential of only 100 mV at 0.5 mA cm-2. Moreover, the customized solid-state Li-S batteries based on PEO/TpPa-SO3Li were stable for 600 cycles at 60 oC with a high Coulombic efficiency of approximately 98 %. This study provides a promising strategy for introducing covalent-organic-framework (COF)-based Li+ pumps to build robust solid-state Li-S batteries.