Pathogenic microorganism DNA high-throughput genetic sequencing to diagnose peritoneal dialysis-associated peritonitis due to Mycobacterium tuberculosis infection.

Peritoneal dialysis-associated peritonitis is a serious complication of peritoneal dialysis, and the prevention and treatment of this condition are important for improving the long-term survival and quality of life of patients. However, peritoneal dialysis-associated peritonitis due to Mycobacterium tuberculosis infection is relatively rare and not easily diagnosed. Here, we present a case of peritoneal dialysis-associated peritonitis caused by Mycobacterium tuberculosis identified by pathogenic microbial DNA high-throughput genetic sequencing. This case demonstrates that pathogenic microbial DNA high-throughput genetic sequencing could be used to improve the detection rate of pathogenic microorganisms in patients with complex conditions, thereby allowing for earlier initiation of treatment.

The incidence, clinical features and risk factors for postoperative retropharyngeal hematoma and related dyspnea following anterior cervical discectomy and fusion: a single-center study of 10615 patients.

BACKGROUND CONTEXT: Postoperative retropharyngeal hematoma (PRH) and related dyspnea are rare but life-threatening complications following anterior cervical discectomy and fusion (ACDF) that require urgent recognition and treatment. However, current knowledge of PRH after ACDF is limited. Meanwhile, whether the morphological features of upper airway are the risk factors of PRH remains unknown. PURPOSE: The study aimed to investigate the incidence, clinical features, and risk factors, especially the morphological features of upper airway, of PRH and related dyspnea following ACDF. STUDY DESIGN: A nested case‒control study. PATIENT SAMPLE: Consecutive patients who underwent ACDF at a single institute from January 2010 to December 2021 were retrospectively reviewed. OUTCOME MEASURES: The outcome measures included the incidence, clinical features, intervention, outcome and risk factors for PRH and related dyspnea. METHODS: All patients with PRH were classified into the hematoma group. For each PRH subject, 3 control subjects without PRH were randomly selected as the control group. The clinical features, interventions and outcomes of patients were described. Potential risk factors were evaluated, including demographics, comorbidities, surgical characteristics, coagulation function, blood loss, preoperative blood pressure, and the morphological features of upper airway [prevertebral soft tissue thickness (PVT) and location of transverse arytenoid muscle (TAM) and epiglottis]. Univariate tests and multivariable logistic regression analysis were used to determine the risk factors for PRH. Subgroup analysis was also conducted for PRH patients with and without dyspnea. RESULTS: Among the 10615 patients who underwent ACDF, 18 (0.17%) developed PRH. The median time from the index surgery to PRH formation was 8.5 hours (25 and 75 percentile: 4 hours to 24 hours). All the PRH patients initially presented with wound swelling. Twelve (0.11%) patients presented dyspnea due to PRH, 2 of whom received urgent intubation and 1 of whom received emergent tracheotomy. All patients underwent hematoma evacuation, and most of them presented with completely relieved symptoms after evacuation, except for 1 patient who died from ischemic hypoxic encephalopathy. A level between the epiglottis and the TAM (LET) greater than 2, ossification of posterior longitudinal ligament (OPLL) and higher diastolic blood pressure (DBP) before surgery were found to be risk factors for PRH formation. Subgroup analysis revealed that a smaller prevertebral soft tissue thickness at C5 was associated with the development of dyspnea. CONCLUSION: This study is the largest study to date focusing on the PRH and related dyspnea after ACDF. Our study showed that the incidences of PRH and related dyspnea after ACDF were 0.17% and 0.11%, respectively. The predominant symptoms of PRH were wound swelling and acute dyspnea. Most PRH cases occurred in the acute postoperative period. We demonstrated the risk factors for PRH to be (1) OPLL, (2) LET≥2 and (3) higher DBP before surgery and advocate paying increased attention to upper airway morphological features for identifying the risk of PRH after ACDF. With urgent recognition and timely intervention, severe clinical outcomes could be avoided.

PAK2 promotes proliferation, migration, and invasion of lung squamous cell carcinoma through LIMK1/cofilin signaling pathway.

Although the p21-activated kinase 2 (PAK2) is an essential serine/threonine protein kinase, its role in lung squamous cell carcinoma (LUSC) progression has yet to be fully understood. We analyzed PAK2 mRNA levels and DNA copy numbers as well as protein levels by quantitative real-time PCR and immunohistochemical staining, respectively, in human LUSC tissues and adjacent normal tissues. Then, we used colony formation assays, cell counting kit-8 assays, matrigel invasion assays, wound healing assays and xenograft models in nude mice to investigate the functions of PAK2 in LUSC progression. We demonstrated that the mRNA levels, DNA copy numbers, and protein levels of PAK2 were up-regulated in human LUSC tissues than in adjacent normal tissues. In addition, a higher PAK2 expression was correlated with a poorer prognosis in LUSC patients. In the in vitro study, we found that PAK2 promoted cell growth, migration, invasion, EMT process, and cell morphology regulation in LUSC cells. Furthermore, PAK2 enhanced tumor cell proliferation, migration, and invasion by regulating actin dynamics through the LIMK1/cofilin signaling. Our findings implicated that the PAK2/LIMK1/cofilin signaling pathway is likely a potential clinical marker and therapeutic target for LUSC.

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy for treating previously treated advanced endometrial cancer in Sweden.

OBJECTIVE: Pembrolizumab plus lenvatinib was recently approved for the treatment of advanced or recurrent endometrial carcinoma in women with disease progression on or following prior treatment with a platinum­containing therapy in any setting, and who are not candidates for curative surgery or radiation (KEYNOTE-775/Study-309; NCT03517449). The objective was to assess the cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy from a Swedish healthcare perspective. MATERIALS AND METHODS: A lifetime partitioned-survival model with three health states (progression free, progressed disease, death) was constructed. Chemotherapy was represented by paclitaxel or doxorubicin. Overall survival, progression-free survival, time on treatment, and utility data were obtained from KEYNOTE-775 (database lock: March 1, 2022). Costs (in 2020 Swedish Krona [SEK]) included drug acquisition and administration, health state, end of life, adverse event management, subsequent treatment, and societal (scenario analysis). Outcomes were calculated as quality-adjusted life-years (QALY) and life-years. Model results were presented as incremental cost-effectiveness ratios for all-comers, patients with proficient mismatch repair tumors, and deficient mismatch repair tumors. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Pembrolizumab plus lenvatinib is a cost-effective treatment when compared with chemotherapy, with estimated deterministic and probabilistic incremental cost-effectiveness ratios of SEK 795,712 and 819,757 per QALY gained. Pembrolizumab plus lenvatinib was associated with a large incremental QALY and life-year gain per person versus chemotherapy over the model time horizon (1.49 and 1.76). LIMITATIONS: Time-to-event data were incomplete and semiparametric and parametric curves were utilized for lifetime extrapolation. Willingness-to-pay thresholds, costs, and utility weights vary by country, which would vary the treatment's cost effectiveness in different countries. CONCLUSIONS: This partitioned survival analysis suggests that pembrolizumab plus lenvatinib is cost effective compared with chemotherapy in Sweden for women with advanced or recurrent endometrial carcinoma following previous systemic therapy. Results were robust to mismatch repair status and to changes in parameters/assumptions.

Few-Shot Relation Extraction With Automatically Generated Prompts.

Relation extraction (RE) tends to struggle when the supervised training data is few and difficult to be collected. In this article, we elicit relational and factual knowledge from large pretrained language models (PLMs) for few-shot RE (FSRE) with prompting techniques. Concretely, we automatically generate a diverse set of natural language templates and modulate PLM's behavior through these prompts for FSRE. To mitigate the template bias which leads to unstableness of few-shot learning, we propose a simple yet effective template regularization network (TRN) to prevent deep networks from over-fitting uncertain templates and thus stabilize the FSRE models. TRN alleviates the template bias with three mechanisms: 1) an attention mechanism over mini-batch to weight each template; 2) a ranking regularization mechanism to regularize the attention weights and constrain the importance of uncertain templates; and 3) a template calibration module with two calibrating techniques to modify the uncertain templates in the lowest-ranked group. Experimental results on two benchmark datasets (i.e., FewRel and NYT) show that our model has robust superiority over strong competitors. For reproducibility, we will release our code and data upon the publication of this article.

Cost-effectiveness of pembrolizumab for previously treated MSI-H/dMMR solid tumours in the UK.

OBJECTIVES: Patients with previously treated microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) tumours have limited chemotherapeutic treatment options. Pembrolizumab received approval from the EMA in 2022 for the treatment of colorectal, endometrial, gastric, small intestine, and biliary MSI-H/dMMR tumour types. This approval was supported by data from the KEYNOTE-164 and KEYNOTE-158 clinical trials. This study evaluated the cost-effectiveness of pembrolizumab compared with standard of care (SoC) for previously treated MSI-H/dMMR solid tumours in line with the approved EMA label from a UK healthcare payer perspective. METHODS: A multi-tumour partitioned survival model was built consisting of pre-progression, progressed disease, and dead health states. Pembrolizumab survival outcomes were extrapolated using Bayesian hierarchical models (BHMs) fitted to pooled data from KEYNOTE-164 and KEYNOTE-158. Comparator outcomes were informed by published sources. Tumour sites were modelled independently and then combined, weighted by tumour site distribution. A SoC comparator was used to formulate the overall cost-effectiveness result with pembrolizumab as the intervention. SoC comprised a weighted average of the comparators by tumour site based on market share. Drug acquisition, administration, adverse events, monitoring, subsequent treatment, end-of-life costs, and testing costs were included. Sensitivity and scenario analyses were performed, including modelling pembrolizumab efficacy using standard parametric survival models. RESULTS: Pembrolizumab, at list price, was associated with £129,469 in total costs, 8.30 LYs, and 3.88 QALYs across the pooled tumour sites. SoC was associated with £28,222 in total costs, 1.14 LYs, and 0.72 QALYs across the pooled tumour sites. This yields an incremental cost-effectiveness ratio (ICER) of £32,085 per QALY. Results were robust to sensitivity and scenario analyses. CONCLUSIONS: This model demonstrates pembrolizumab provides a valuable new alternative therapy for UK patients with MSH-H/dMMR cancer at the cost of £32,085 per QALY, with confidential discounts anticipated to improve cost-effectiveness further.

Biomechanical and histomorphological analysis of the mandible in rats with chronic kidney disease.

The present study aimed to investigate the biomechanical and histomorphological features of mandibles in an adenine-induced chronic kidney disease-mineral and bone disorder (CKD-MBD) rat model of CKD. A total of 14 Sprague-Dawley rats were randomized into the following two groups: control group and CKD group. At the end of the sixth week, all rats were euthanized, and serum was collected for biochemical marker tests. Macroscopic bone growth and biomechanical parameters were measured in the right hemimandible, while the left hemimandible was used for bone histomorphometric analysis. Compared to the control group, the CKD group showed a significant increase in serum creatinine, blood urea nitrogen, and serum parathyroid hormone at the end of the sixth week. The biomechanical structural properties significantly decreased in the CKD group compared to the control group. Bone histomorphometric analysis indicated that the trabecular bone volume of rats in the CKD group was significantly lower than that of the control group. In the CKD groups, the bone formation parameters of the trabecular bone were significantly increased, while the bone mineralization apposition rates of both the trabecular bone and periosteal cortical bone were significantly increased. The rat CKD model showed deteriorated structural mechanics, low trabecular bone volume, high trabecular bone formation, increased trabecular bone mineralization apposition rate, and increased cortical bone mineralization apposition rate, which met the characteristics of osteitis fibrosa, indicating that this model is a useful tool for the study of mandible diseases in CKD patients.

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-ß peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear. Methods: Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS. Results: We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice. Conclusion: These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.

EGFR Inhibition Overcomes Resistance to FGFR4 Inhibition and Potentiates FGFR4 Inhibitor Therapy in Hepatocellular Carcinoma.

Aberrant activation of the FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of hepatocellular carcinoma (HCC). As such, FGFR4 inhibition has emerged as a novel therapeutic option for the treatment of HCC and has shown preliminary efficacy in recent clinical trials for patients exhibiting aberrant FGF19 expression. Resistance to kinase inhibitors is common in oncology, presenting a major challenge in the clinical treatment process. Hence, we investigated the potential mechanisms mediating and causing resistance to FGFR4 inhibition in HCC. Upon the successful establishment of a battery of cellular models developing resistance to FGFR4 inhibitors, we have identified the activation of EGFR, MAPK, and AKT signaling as the primary mechanisms mediating the acquired resistance. Combination of inhibitors against EGFR or its downstream components restored sensitivity to FGFR4 inhibitors. In parental HCC cell lines, EGF treatment also resulted in resistance to FGFR4 inhibitors. This resistance was effectively reverted by inhibitors of the EGFR signaling pathway, suggesting that EGFR activation is a potential cause of intrinsic resistance. We further confirmed the above findings in vivo in mouse xenograft tumor models. Genomic analysis of patient samples from The Cancer Genome Atlas confirmed that a segment of patients with HCC harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.

Risk Factors for Cerebrospinal Fluid Leakage After Extradural Spine Surgery: A Meta-Analysis and Systematic Review.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is 1 of the common complications of spine surgery and is largely caused by intraoperative or postoperative dural tears. Associations of different factors with postoperative CSF leakage have not been consistent. In this study we aimed to identify demographic, disease-related, and surgical risk factors for CSF leakage after extradural spine surgery in a systematic review and meta-anlysis. METHODS: The PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Wanfang data, Chinese Weipu Database, and SinoMed databases were searched from inception until October 24, 2022. Fixed-effects or random-effects models were used to calculate odds ratios and 95% confidence intervals. The quality of observational studies was evaluated using the Newcastle-Ottawa scale instrument. RESULTS: A total of 15 observational studies with 1,719,923 participants were included in this systematic review. All studies had a Newcastle-Ottawa scale score greater than or equal to 6. Age older than 70 years, smoking, ossification of the posterior longitudinal ligament, adhesion of spinal dura, spinal canal stenosis, cervical fracture, spondylolisthesis, revision surgery, and multiple surgical segments were all related to CSF leakage in the pooled analysis. Obesity and disease duration>1 year were not associated with the leakage of CSF. CONCLUSIONS: This study will provide a reference for the identification of patients at high risk of developing CSF leakage, which suggests clinicians to strengthen the observation of drainage fluid in high-risk groups.

Role of lncRNAs in the pathogenesis of sepsis and their clinical significance.

Sepsis is a fatal organ dysfunction caused by the host's uncontrolled response to infection, with high morbidity and mortality. Early diagnosis and intervention are the most effective methods to reduce the mortality due to sepsis. However, there is still a lack of definite biomarkers or intervention targets for the diagnosis, evaluation, prognosis, and treatment of sepsis. Long non-coding RNAs (lncRNAs) are a type of non-coding transcript with a length ranging from 200 to 100,000 nucleotides. LncRNAs mainly locate in the cytoplasm and nucleus and participate in various signaling pathways related to inflammatory reactions and organ dysfunction. Recent studies have reported that lncRNAs are involved in regulating the pathophysiological process of sepsis. Some classical lncRNAs have been confirmed as promising biomarkers to evaluate the severity and prognosis of sepsis. This review summarizes the mechanical studies on lncRNAs in sepsis-induced acute lung, kidney, myocardial, and liver injuries, analyzes the role of lncRNAs in the pathogenesis of sepsis, and explores the possibility of lncRNAs as potential biomarkers and intervention targets for sepsis-induced multiple organ dysfunction.

Cost-Effectiveness Analysis of Pembrolizumab as an Adjuvant Treatment of Resected Stage IIB or IIC Melanoma in the United States.

INTRODUCTION: Pembrolizumab was approved in the US as adjuvant treatment of patients with stage IIB or IIC melanoma post-complete resection, based on prolonged recurrence-free survival vs. placebo in the Phase 3 KEYNOTE-716 trial. This study aimed to evaluate the cost-effectiveness of pembrolizumab vs. observation as adjuvant treatment of stage IIB or IIC melanoma from a US health sector perspective. METHODS: A Markov cohort model was constructed to simulate patient transitions among recurrence-free, locoregional recurrence, distant metastasis, and death. Transition probabilities from recurrence-free and locoregional recurrence were estimated via multistate parametric modeling based on patient-level data from an interim analysis (data cutoff date: 04-Jan-2022). Transition probabilities from distant metastasis were based on KEYNOTE-006 data and network meta-analysis. Costs were estimated in 2022 US dollars. Utilities were based on applying US value set to EQ-5D-5L data collected in trial and literature. RESULTS: Compared to observation, pembrolizumab increased total costs by $80,423 and provided gains of 1.17 quality-adjusted life years (QALYs) and 1.24 life years (LYs) over lifetime, resulting in incremental cost-effectiveness ratios of $68,736/QALY and $65,059/LY. The higher upfront costs of adjuvant treatment were largely offset by reductions in costs of subsequent treatment, downstream disease management, and terminal care, reflecting the lower risk of recurrence with pembrolizumab. Results were robust in one-way sensitivity and scenario analyses. At a $150,000/QALY threshold, pembrolizumab was cost-effective vs. observation in 73.9% of probabilistic simulations that considered parameter uncertainty. CONCLUSION: As an adjuvant treatment of stage IIB or IIC melanoma, pembrolizumab was estimated to reduce recurrence, extend patients' life and QALYs, and be cost-effective versus observation at a US willingness-to-pay threshold.

Cost-Effectiveness Analysis of Pembrolizumab as an Adjuvant Treatment of Renal Cell Carcinoma Post-nephrectomy in the United States.

INTRODUCTION: Pembrolizumab was recently approved as an adjuvant treatment of renal cell carcinoma (RCC), based on prolonged disease-free survival compared to placebo in the phase III KEYNOTE-564 trial. The objective of this study was to evaluate the cost-effectiveness of pembrolizumab as monotherapy in the adjuvant treatment of RCC post-nephrectomy, from a US health sector perspective. PATIENTS AND METHODS: A Markov model with 4 health states (disease-free, locoregional recurrence, distant metastases, and death) was developed to compare the cost and effectiveness of pembrolizumab versus routine surveillance or sunitinib. Transition probabilities were estimated using patient-level KEYNOTE-564 data (cutoff: June 14, 2021), a retrospective study, and published literature. Costs of adjuvant and subsequent treatments, adverse events, disease management, and terminal care were estimated in 2022 US$. Utilities were based on EQ-5D-5L data collected in KEYNOTE-564. Outcomes included costs, life-years (LYs), and quality-adjusted LYs (QALYs). Robustness was assessed through one-way and probabilistic sensitivity analyses. RESULTS: Total cost per patient was $549,353 for pembrolizumab, $505,094 for routine surveillance, and $602,065 for sunitinib. Over a lifetime, pembrolizumab provided gains of 0.96 QALYs (1.00 LYs) compared to routine surveillance, yielding an incremental cost-effectiveness ratio of $46,327/QALY. Pembrolizumab dominated sunitinib with 0.89 QALYs (0.91 LYs) gained while saving costs. At a $150,000/QALY threshold, pembrolizumab was cost-effective versus both routine surveillance and sunitinib in 84.2% of probabilistic simulations. CONCLUSION: Pembrolizumab is projected to be cost-effective as an adjuvant RCC treatment versus routine surveillance or sunitinib based on a typical willingness-to-pay threshold.

Learning to Generate Tips from Song Reviews.

Reviews of songs play an important role in online music service platforms. Prior research shows that users can make quicker and more informed decisions when presented with meaningful song reviews. However, reviews of songs are generally long in length and most of them are non-informative for users. It is difficult for users to efficiently grasp meaningful messages for making decisions. To solve this problem, one practical strategy is to provide tips, i.e., short, concise, empathetic, and self-contained descriptions about songs. Tips are produced from song reviews and should express non-trivial insights about the songs. To the best of our knowledge, no prior studies have explored the tip generation task in music domain. In this paper, we create a dataset named MTips for the task and propose a learning-to-generate framework named GenTMS for automatically generating tips from song reviews. The dataset involves 8,003 Chinese tips/non-tips from 128 songs which are distributed in five different song genres. Experimental results show that GenTMS achieves top-10 precision at 85.56%, outperforming the baseline models by at least 3.34%. Besides, to simulate the practical usage of our proposed framework, we also experiment with previously-unseen songs, during which GenTMS also achieves the best performance with top-10 precision at 78.89% on average. The results demonstrate the effectiveness of the proposed framework in tip generation of the music domain.

[Clinical features and genetic analysis of a child with acute form of Tyrosinemia type I due to a novel variant of FAH gene].

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child with acute form of tyrosinemia type I (TYRSN1). METHODS: A child with TYRSN1 who presented at the Gansu Provincial Maternal and Child Health Care Hospital in October 2020 was selected as the subject. The child was subjected to tandem mass spectrometry (MS-MS) and urine gas chromatography-mass spectrometry (GC-MS) for the detection of inherited metabolic disorders, in addition with whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: The child's clinical features included abdominal distension, hepatomegaly, anemia and tendency of bleeding. By mass spectrometry analysis, her serum and urine tyrosine and succinylacetone levels have both exceeded the normal ranges. WES and Sanger sequencing revealed that she has harbored c.1062+5G>A and c.943T>C (p.Cys315Arg) compound heterozygous variants of the FAH gene, which were inherited from her father and mother, respectively. Among these, the c.943T>C was unreported previously. CONCLUSION: Considering her clinical phenotype and result of genetic testing, the child was diagnosed with TYRSN1 (acute type). The compound heterozygous variants of the FAH gene probably underlay the disease in this child. Above finding has further expanded the spectrum of FAH gene variants, and provided a basis for accurate treatment, genetic counseling and prenatal diagnosis for her family.

Whole-exome sequencing identified a homozygous novel RAG1 mutation in a child with omenn syndrome.

INTRODUCTION AND OBJECTIVES: Omenn syndrome (OS) is a very rare type of severe combined immunodeficiencies manifested with erythroderma, eosinophilia, hepatosplenomegaly, lymph-adenopathy, and elevated level of serum IgE. OS is inherited with an autosomal recessive mode of inheritance. Germline mutations in the human RAG1 gene cause OS. MATERIALS AND METHODS: In this study, we investigated a 2-month-old boy with cough, mild anaemia, pneumonia, immunodeficiency, repeated infection, feeding difficulties, hepatomegaly, growth retardation, and heart failure. Parents of the proband were phenotypically normal. RESULTS: Karyotype analysis and chromosomal microarray analysis found no chromosomal structural abnormalities (46, XY) and no pathogenic copy number variations (CNVs) in the proband. Whole-exome sequencing identified a novel homozygous single nucleotide deletion (c.2662delC) in exon 2 of the RAG1 gene in the proband. Sanger sequencing confirmed that both the proband parents were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters and one elder brother of the proband and in the 100 ethnically matched normal healthy individuals. This novel homozygous deletion (c.2662delC) leads to the frameshift, which finally results in the formation of the truncated protein (p.Leu888Phefs*3) V(D)J recombination-activating protein 1 with 890 amino acids compared with the wildtype V(D)J recombination-activating protein 1 of 1043 amino acids. Hence, it is a loss-of-function variant. CONCLUSIONS: Our present study expands the mutational spectrum of the RAG1 gene associated with OS. We also strongly suggested the importance of whole-exome sequencing for the genetic screening of patients with OS.

YAP signaling is involved in WDR1-regulated proliferation and migration of non-small-cell lung cancer cells.

As a major co-factor of F-actin depolymerization, WD-repeat domain 1 (WDR1) affects the cellular microenvironment by cytoskeleton remodeling, thereby influencing cell molecular behavior. Our previous study showed that WDR1 activates YAP (Yes-associated protein) signaling in non-small-cell lung cancer (NSCLC) cells, but the mechanism remains unclear. We discovered that knockdown WDR1 in NSCLC cells decreased the expression of YAP and the nucleus-to-cytoplasm ratio. Disruption of cortical stress by drugs significantly inhibited YAP nuclear trafficking and enhanced YAP phosphorylation. In WDR1-knockdown NSCLC cells, inhibition of Hippo pathway reduced the nuclear exclusion of YAP and phosphorylated YAP. Our data suggest that WDR1-mediated cortical stress might be involved in regulating YAP signaling, thereby affecting the proliferation and migration of NSCLC cells.

Serum Cystatin C Level Monitoring for Intervention Opportunity of CBP in Children with Severe Sepsis.

Objective: The aim of this study is to investigate the instruction value of the serum cystatin C (Cys C) level monitoring for intervention opportunity of continuous blood purification technology (CBP) in children with severe sepsis. Methods: 67 children with severe sepsis in the pediatric intensive care unit (PICU) with CBP treatment were retrospectively selected from May 2016 to April 2020. According to the time intervals between the time point of serum Cys C level began to increase (>15 mg/L) and the time point of CBP began, all children were divided into group A (<24 h, 29 cases), group B (24-48 h, 22 cases), and group C (>48 h, 16 cases). The children's general characteristics, vital signs, biochemical parameters, acute physiology and chronic health evaluation (APACHE II), and sequential organ failure assessment (SOFA) scores were evaluated. The influence factors of prognosis of children with severe sepsis were analyzed by multivariate regression analysis. Results: The intervals between the time point of PICU hospitalization and the time point of CBP began and the times of CBP in group A were significantly more than those in group B and C (P < 0.05). There was no statistically significant duration of CBP among three groups (P > 0.05). After follow-up of 28 d, there was no significant difference on the occurrence of coagulation disorders and hypovolemic shock induced by CBP among three groups (P > 0.05). However, the mortality of children in group A was lower than that in group C (P < 0.05). Children in group A had lower APACHE II scores, SOFA scores, serum K+, blood urea nitrogen (BUN), serum creatine (SCr), partial pressure of carbon dioxide (PCO2), and higher partial pressure of oxygen (PO2) than those of children in group C after CBP. (P < 0.05). SOFA scores ≥5 after CBP treatment and the time intervals between the time point of serum Cys C level began to increase (>15 mg/L) and the time point of CBP began ≥24 h were the independent influence factors on the prognosis by multivariate regression analysis. Conclusion: There are significant evidences that continuous blood purification technology within 24 h of serum Cys C level may better control the condition of children with severe sepsis.

Circular RNAs in the pathogenesis of sepsis and their clinical implications: A narrative review.

INTRODUCTION: Sepsis is defined as a life-threatening complication that occurs when the body responds to an infection attacking the host. Sepsis rapidly progresses and patients deteriorate and develop septic shock, with multiple organ failure, if not promptly treated. Currently no effective therapy is available for sepsis; therefore, early diagnosis is crucial to decrease the high mortality rate. Genome-wide expression analyses of patients in critical conditions have confirmed that the expression levels of the majority of genes are changed, suggesting that the molecular basis of sepsis is at the gene level. This review aims to elucidate the role of circular (circ) RNAs in the pathogenesis of sepsis and sepsis-induced organ damage. In addition, the feasibility of using circRNAs as novel diagnostic biomarkers for sepsis is also discussed, as well as circRNA-based therapy. METHOD: This narrative review is based on a literature search using Medline database. Search terms used were "circular RNAs and sepsis", "circRNAs and sepsis", "non-coding RNAs and sepsis", "ncRNAs and sepsis", "circRNAs and septic pathogenesis", "circRNAs and septic model", "circRNAs and septic shock" and "circRNAs, biomarker, and sepsis". RESULTS: Numerous studies indicate that circRNAs might exert pivotal roles in regulating the immune system of the host against various pathogens, such as bacteria and viruses. Dysregulation of circRNA expression levels has been confirmed as an early event in sepsis and associated with the inflammatory response, immunosuppression and coagulation dysfunction. This impairment in regulation eventually leads to multiple organ dysfunctions, including of the kidneys, lungs and heart. CONCLUSION: By investigating the regulation of circRNAs in sepsis, new molecular targets for the diagnosis and intervention of sepsis can be identified. Such an understanding will be important for the development of therapeutic drugs.