Sequential radical and cationic reactivity at separated sites within one molecule in solution.

Distonic radical cations (DRCs) with spatially separated charge and radical sites are expected to show both radical and cationic reactivity at different sites within one molecule. However, such "dual" reactivity has rarely been observed in the condensed phase. Herein we report the isolation of crystalline 1λ2,3λ2-1-phosphonia-3-phosphinyl-cyclohex-4-enes 2a,b˙+, which can be considered delocalized DRCs and were completely characterized by crystallographic, spectroscopic, and computational methods. These DRCs contain a radical and cationic site with seven and six valence electrons, respectively, which are both stabilized via conjugation, yet remain spatially separated. They exhibit reactivity that differs from that of conventional radical cations (CRCs); specifically they show sequential radical and cationic reactivity at separated sites within one molecule in solution.

Invasive pneumococcal diseases in Chinese children: a multicentre hospital-based active surveillance from 2019 to 2021.

This study aimed to provide data for the clinical features of invasive pneumococcal disease (IPD) and the molecular characteristics of Streptococcus pneumoniae isolates from paediatric patients in China. We conducted a multi-centre prospective study for IPD in 19 hospitals across China from January 2019 to December 2021. Data of demographic characteristics, risk factors for IPD, death, and disability was collected and analysed. Serotypes, antibiotic susceptibility, and multi-locus sequence typing (MLST) of pneumococcal isolates were also detected. A total of 478 IPD cases and 355 pneumococcal isolates were enrolled. Among the patients, 260 were male, and the median age was 35 months (interquartile range, 12-46 months). Septicaemia (37.7%), meningitis (32.4%), and pneumonia (27.8%) were common disease types, and 46 (9.6%) patients died from IPD. Thirty-four serotypes were detected, 19F (24.2%), 14 (17.7%), 23F (14.9%), 6B (10.4%) and 19A (9.6%) were common serotypes. Pneumococcal isolates were highly resistant to macrolides (98.3%), tetracycline (94.1%), and trimethoprim/sulfamethoxazole (70.7%). Non-sensitive rates of penicillin were 6.2% and 83.3% in non-meningitis and meningitis isolates. 19F-ST271, 19A-ST320 and 14-ST876 showed high resistance to antibiotics. This multi-centre study reports the clinical features of IPD and demonstrates serotype distribution and antibiotic resistance of pneumococcal isolates in Chinese children. There exists the potential to reduce IPD by improved uptake of pneumococcal vaccination, and continued surveillance is warranted.

Tribological Performance and Enhancing Mechanism of 3D Printed PEEK Coated with In Situ ZIF-8 Nanomaterial.

Polyether ether ketone (PEEK) is esteemed as a high-performance engineering polymer renowned for its exceptional mechanical properties and thermal stability. Nonetheless, the majority of polymer-based lubricating materials fail to meet the contemporary industrial demands for motion components regarding high speed, heavy loading, temperature resistance, and precise control. Utilizing 3D printing technology to design and fabricate intricately structured components, developing high-performance polymer self-lubricating materials becomes imperative to fulfill the stringent operational requirements of motion mechanisms. This study introduces a novel approach employing 3D printing technology to produce PEEK with varying filling densities and conducting in situ synthesis of zeolitic imidazolate framework (ZIF-8) nanomaterials on its surface to enhance PEEK's frictional performance. The research discusses the synthetic methodology, characterization techniques, and tribological performance evaluation of in situ synthesized ZIF-8 nanomaterials on PEEK surfaces. The findings demonstrate a significant enhancement in frictional performance of the composite material under low-load conditions, achieving a minimum wear rate of 4.68 × 10-6 mm3/N·m compared to the non-grafted PEEK material's wear rate of 1.091 × 10-5 mm3/N·m, an approximately 1.3 times improvement. Detailed characterization and analysis of the worn surface of the steel ring unveil the lubrication mechanism of the ZIF-8 nanoparticles, thereby presenting new prospects for the diversified applications of PEEK.

The case of a µ2-P aromatic phosphinine as a 4-electron donor forming σ- and π-three-center-two-electron bonds.

Profound insight into the electronic structures of occasionally observed µ2-P bridging phosphinines remains limited. In this work, we present the isolation and X-ray crystallographic characterization of a dimeric Rh(I) phosphinine complex exhibiting both η1-P and µ2-P phosphinine coordination modes. Variable temperature NMR analyses and DOSY spectrum measurement confirmed the presence of two types of fluxional phenomena in solution: η1-P phosphinine bonding and dissociation, and η1-P and µ2-P equilibrium. DFT calculations in conjunction with single crystal X-ray diffraction studies suggest that the µ2-P phosphinines donate four electrons via a σ-lone pair and a high-lying π-type electron pair, instead of two σ-lone pairs, forming σ- and π-three-center-two-electron bonds. The stronger π-type interactions lead to longer P-C bonds and larger negative coordination chemical shifts for µ2-P phosphinines. However, the binding interactions of µ2-P are thermodynamically weaker than those of η1-P. Reactivity studies further confirm the labile nature of the µ2-P phosphinine bonds, which could be easily converted to an η1-P phosphinine.

Room temperature stable E,Z-diphosphenes: their isomerization, coordination, and cycloaddition chemistry.

E,Z-isomers display distinct physical properties and chemical reactivities. However, investigations on heavy main group elements remain limited. In this work, we present the isolation and X-ray crystallographic characterization of N-heterocyclic vinyl (NHV) substituted diphosphenes as both E- and Z-isomers (L[double bond, length as m-dash]CH-P[double bond, length as m-dash]P-CH[double bond, length as m-dash]L, E,Z-2b; L = N-heterocyclic carbene). E-2b is thermodynamically more stable and undergoes reversible photo-stimulated isomerization to Z-2b. The less stable Z-isomer Z-2b can be thermally reverted to E-2b. Theoretical studies support the view that this E ↔ Z isomerization proceeds via P[double bond, length as m-dash]P bond rotation, reminiscent of the isomerization observed in alkenes. Furthermore, both E,Z-2b coordinate to an AuCl fragment affording the complex [AuCl(η2-Z-2b)] with the diphosphene ligand in Z-conformation, exclusively. In contrast, E,Z-2b undergo [2 + 4] and [2 + 1] cycloadditions with dienes or diazo compounds, respectively, yielding identical cycloaddition products in which the phosphorus bound NHV groups are in trans-position to each other. DFT calculations provide insight into the E/Z-isomerisation and stereoselective formation of Au(i) complexes and cycloaddition products.

The Comparison between Cemented and Uncemented Hemiarthroplasty in Patients with Femoral Neck Fractures: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Hemiarthroplasty is the standard treatment for patients with femoral neck fractures (FNFs). Controversy exists over the use of bone cement in hip fractures treated with hemiarthroplasty. OBJECTIVE: We performed an updated systematic review and meta-analysis to compare cemented and uncemented hemiarthroplasty in patients with femoral neck fractures. METHODS: A literature review was conducted using Cochrane Library, ScienceDirect, PubMed, Embase, Medline, Web of Science, CNKI, VIP, Wang Fang, and Sino Med databases. Studies comparing cemented with uncemented hemiarthroplasty for FNFs in elderly patients up to June 2022 were included. Data were extracted, meta-analyzed, and pooled as risk ratios (RRs) and weighted mean differences (WMDs) with a 95% confidence interval (95% CI). RESULTS: Twenty-four RCTs involving 3471 patients (1749 cement; 1722 uncemented) were analyzed. Patients with cemented intervention had better outcomes regarding hip function, pain, and complications. Significant differences were found in terms of HHS at 6 weeks (WMD 12.5; 95% CI 6.0-17.0; P < 0.001), 3 months (WMD 3.3; 95% CI 1.6-5.0; P < 0.001), 4 months (WMD 7.3; 95% CI 3.4-11.2; P < 0.001), and 6 months (WMD 4.6; 95% CI 3.3-5.8; P < 0.001) postoperatively. Patients with cemented hemiarthroplasty had lower rates of pain (RR 0.59; 95% CI 0.39-0.9; P = 0.013), prosthetic fracture (RR 0.24; 95% CI 0.16-0.38; P < 0.001), subsidence/loosening (RR 0.29; 95% CI 0.11-0.78; P = 0.014), revisions (RR 0.59; 95% CI 0.40-0.89; P = 0.012), and pressure ulcers (RR 0.43; 95% CI 0.23-0.82; P = 0.01) at the expense of longer surgery time (WMD 7.87; 95% CI 5.71-10.02; P < 0.001). CONCLUSION: This meta-analysis demonstrated that patients with cemented hemiarthroplasty had better results in hip function and pain relief and lower complication rates at the expense of prolonged surgery time. Cemented hemiarthroplasty is recommended based on our findings.

Efficacy and Safety of Ticagrelor versus Aspirin and Clopidogrel for Stroke Prevention in Patients with Vascular Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Currently, it is still controversial to treat stroke with ticagrelor alone. The purpose of our study was to systematically review and analyze the efficacy and safety of ticagrelor on cerebrovascular outcomes in patients with vascular risk factors. METHODS: The PubMed, Cochrane Library, and Embase databases were systematically searched using the keywords stroke, ticagrelor, clopidogrel, and aspirin to identify randomized controlled trials (RCTs). Primary outcomes included reported stroke, ischemic stroke, and complex events; the secondary outcome was hemorrhagic stroke. The safety outcomes included major bleeding events, major or minor bleeding, and intracranial bleeding. The pooled odds ratio (OR), hazard ratios (HRs), and 95% confidence interval (CI) were calculated. We used I2 statistics to assess statistical heterogeneity. RESULTS: This meta-analysis included 15 RCTs involving 63,865 patients. Compared to the control group, ticagrelor reduced the risk of stroke (OR: 0.90; 95% CI: 0.81-0.99, p = 0.03; I2 = 3%), ischemic stroke (OR: 0.81; 95% CI: 0.74-0.90, p < 0.0001; I2 = 0%). Ticagrelor was not associated with an increased risk of all-cause mortality (OR: 0.94; 95% CI: 0.84-1.06, p = 0.31; I2 = 62%), major bleeding (OR: 1.06; 95% CI: 0.97-1.15, p = 0.20; I2 = 17%), hemorrhagic strokes (OR: 1.22, 95% CI: 0.76-1.96, p = 0.41; I2 = 0%), and intracranial hemorrhage (OR: 1.06; 95% CI: 0.78-1.43, p = 0.71; I2 = 12%). There was an increased risk of major or minor bleeding with ticagrelor compared to the control group (OR: 1.40; 95% CI: 1.19-1.66, p < 0.0001; I2 = 56%). Additional analyses demonstrated that ticagrelor reduced the risk of incident recurrent stroke (HR: 0.83; 95% CI: 0.75-0.93, p = 0.0009; I2 = 0%), recurrent ischemic stroke (HR: 0.79; 95% CI: 0.71-0.89, p < 0.0001; I2 = 0%) among patients with a history of acute ischemic stroke (AIS) or transient ischemic attack (TIA). There were no significant differences in safety outcomes. CONCLUSION: Ticagrelor is slightly better than clopidogrel and aspirin in preventing stroke, especially ischemic stroke, with significant safety risks. For patients with a history of AIS/TIA, the use of ticagrelor was superior to the use of clopidogrel or aspirin in reducing the risk of subsequent stroke. We believe that ticagrelor is a potential alternative to aspirin or clopidogrel in some cases, especially for patients with CYP2C19 deficiency.

Case report: Muscular tuberculosis with lower-extremity muscular masses as the initial presentation: Clinicopathological analysis of two cases and review of the literature.

Background: Tuberculosis (TB) is a threat to public health that mostly affects people in developing countries. TB presenting as a soft tissue mass is rare and is usually seen in patients with muscular tuberculosis (MT). Case presentation: In this study, we present the clinical, radiographic, and pathological features of two cases and retrospective evaluations of an additional 28 patients who were diagnosed with MT. More patients were men (60.9%) than women (39.1%), with a male-to-female ratio of 1.6:1. The average age among male and female patients was 38.9 and 30.1 years, respectively. MT usually presents with painful or painless muscular nodules on the lower limbs. Imaging findings, including ultrasound, CT, and MRI, can be used to identify lesions and sites for biopsy. The most typical histopathological feature of MT is granulomatous inflammation with caseous necrosis and epithelioid granulomata. Acid-fast bacilli stain and polymerase chain reaction (PCR) assays are helpful in identifying tubercle bacillus. Conclusion: We describe two MT cases with lower-extremity muscular masses as the initial presentation. The results suggest that muscle biopsy and pathological analysis remain necessary for diagnosis. Most of the patients could be cured with standard antituberculosis therapy.

Long-read sequencing identified intronic (GGCCTG)n expansion in NOP56 in one SCA36 family and literature review.

BACKGROUND: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion detection with long-read sequencing (LRS) feasible. Our study investigated one family with SCA 36 and further summarized the genetic and clinical characteristics of the total of 161 patients across different ethnic groups reported worldwide. METHODS: We enrolled a pedigree of 4 patients. The proband was a 55-year-old male. And he was screened for dynamic mutations of SCA subtypes by Tri-prime PCR (TP-PCR) and capillary electrophoresis, showing NOP56 as the candidate gene. The cosegregation was conducted by screening the NOP56 gene in his daughter and further confirmed by low-coverage (∼15 ×) LRS on the Oxford Nanopore platform. RESULTS: The SCA36 pedigree included a total of 4 patients. The proband showed the initial manifestation at the age of 45 years old, which was characterized by truncal ataxia. Genetic test results showed the (GGCCTG)n expansion in NOP56 gene (3/>15 and 6/>15 times respectively). To clarify the diagnosis genetically, LRS was performed in his daughter showing a large intronic insertion (chr20: 2633004 INS 7603 bp) containing (GGCCTG)n expansion of 782 units in NOP56 as the causative mutation. CONCLUSIONS: We identified one SCA36 pedigree by combining TP-PCR with LRS. Our study suggested LRS as an effective tool for molecular diagnosis. LRS also worked as a supplementary but necessary diagnostic tool for dynamic mutation-related SCA on the basis of repeat-primed PCR as well as capillary electrophoresis.

Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder characterized by hypocalcemia with low parathyroid hormone (PTH) levels and high urinary calcium. Its clinical presentation varies from mild asymptomatic to severe hypocalcemia. It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney. Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant. We comprehensively analyzed the phenotypic features of this presentation and reviewed the current literature to better understand clinical manifestations and the genetic spectrum.

The indirect impact of control measures in COVID-19 pandemic on the incidence of other infectious diseases in China.

Objectives: During COVID-19 pandemic in 2020, China, some public health measures of forced lockdown, closure of school and public meeting places, staying at home, transportation stop, masks wearing, hands washing, environmental disinfection were taken on to control epidemic transmission, these measures have made indirect affect on the other infectious diseases incidence. Study design: During COVID-19 pandemic in 2020, we retrospectively analyzed and compared reported cases of other infectious diseases,in order to found what impact of measures in controlling COVID-19 pandemic on the other infectious diseases in China. Methods: We retrospectively analyzed and compared reported cases of measles, pertussis, scarlet fever, seasonal influenza, mumps, HFMD each month in 2018, 2019 and 2020 from the National Health Commission, PRC. Results: Cases of measles, pertussis, scarlet fever, seasonal influenza, mumps and HFMD in January 2020 were not declined, or even increased compare to 2018 and 2019, but from February to December 2020, began to drop significantly compare with the cases of 2018 and 2019. However, seasonal influenza cases in 2020 were more than in 2018. Conclusion: It shown that how important scientific measures are taken to cut off COVID-19 pandemic transmission, However, these taken measures have led to indirect impact on the diffusion of other infectious diseases, led to measles, pertussis, scarlet fever, seasonal influenza, mumps, HFMD declined.

Characterization of H2O2-Induced Alterations in Global Transcription of mRNA and lncRNA.

Hydrogen peroxide (H2O2) is an important reactive oxygen species that plays a major role in redox signaling. Although H2O2 is known to regulate gene expression and affect multiple cellular processes, the characteristics and mechanisms of such transcriptional regulation remain to be defined. In this study, we utilized transcriptome sequencing to determine the global changes of mRNA and lncRNA transcripts induced by H2O2 in human pancreatic normal epithelial (HPNE) and pancreatic cancer (PANC-1) cells. Promoter analysis using PROMO and TRRUST revealed that mRNAs and lncRNAs largely shared the same sets of transcription factors in response to ROS stress. Interestingly, promoters of the upregulated genes were similar to those of the downregulated transcripts, suggesting that the H2O2-responding promoters are conserved but they alone do not determine the levels of transcriptional outputs. We also found that H2O2 induced significant changes in molecules involved in the pathways of RNA metabolism, processing, and transport. Detailed analyses further revealed a significant difference between pancreatic cancer and noncancer cells in their response to H2O2 stress, especially in the transcription of genes involved in cell-cycle regulation and DNA repair. Our study provides new insights into RNA transcriptional regulation upon ROS stress in cancer and normal cells.

Novel Frameshift Heterozygous Mutation in UBAP1 Gene Causing Spastic Paraplegia-80: Case Report With Literature Review.

Hereditary spastic paraplegia (HSP) represents a group of rare inherited neurodegenerative conditions and is characterized by progressive lower limb spasticity. Ubiquitin-associated protein 1 (UBAP1)-related HSP is classified as spastic paraplegia-80 (SPG80), which is an autosomal-dominant (AD) juvenile-onset neurologic disorder and mainly affects the lower limbs. We described the clinical and genetic features of two patients in the same family caused by heterozygous mutation of the UBAP1 gene. The proband was a 34-year-old woman with progressive spasticity and hyperreflexia in the lower limbs for 26 years. Her mother also had similar symptoms since the age of 6. The proband and her mother only had motor dysfunctions, such as unsteady gait, hypertonia, and hyperreflexia of lower limbs. Other system functions (sensory, urinary, visual, and cognitive impairments) were not involved. WES disclosed a frameshift mutation (c.371dupT) in the UBAP1 gene, which was predicted to be "likely pathogenic" and was co-segregated in the pedigree. c.371dupT, encoding the truncated UBAP1 protein with 72.6% missing of the normal amino acid sequence, is responsible for the spastic paraplegia (SPG) in this family. In combination with clinical characteristics, genetic testing results, and co-segregation analysis, the diagnosis is considered to be pure spastic paraplegia-80 (SPG80), which is an AD disease. By retrospectively analyzing the documented cases, we comprehensively review the phenotypic features and summarize the genotype spectrum of SPG80 to enhance earlier recognition and therapeutic strategies.

Deciphering the roles of miR-16-5p in malignant solid tumors.

MiR-16-5p, a member of the miR-16 family, has been reported to be abnormal expression in tumor tissues and blood of tumor patients, and also downregulated in most cancer cell lines. Aberrant expression of miR-16-5p promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and can also affect the treatment sensitivity, such as radiotherapy and chemotherapy. Generally, miR-16-5p plays an anti-tumor role and these diverse functions of miR-16-5p in tumors collectively indicate that miR-16-5p may become an attractive target for novel anticancer therapies and a powerful diagnostic and prognostic biomarker for early tumor detection and population risk screening. Herein we review the role and utilization of miR-16-5p in malignant tumor in detail.

An in situ quenching electrochemiluminescence biosensor amplified with aptamer recognition-induced multi-DNA release for sensitive detection of pathogenic bacteria.

An in situ quenching electrochemiluminescence (ECL) biosensor sensitized with the aptamer recognition-induced multi-DNA release was designed for pathogenic bacterial detection. Benefitting from the high binding ability of the aptamer to targets and large enrichment capacity of magnetic bead separation, the proposed sensing system not only exhibited outstanding identification to Staphylococcus aureus (S. aureus) among various bacteria, but also released abundant signal transduction DNAs. One S. aureus initiated the dissociation of four kinds of DNA sequences, achieving a one-to-multiple amplification effect. These multi-DNA strands were further hybridized with capture DNA, which were assembled to an electrode modified with Ru(bpy)32+-conjugated silica nanoparticles (RuSi NPs). Then, glucose oxidase (GOD) was introduced via the functional conjugation of GOD-multi-DNA, leading to the presence of H2O2 by in situ catalysis of GOD on glucose. Relying on the ECL quenching of H2O2 in the Ru(bpy)32+ system, S. aureus was quantified with a linear range from 10 to 107 CFU/mL. In addition, the negative results of non-target bacteria and good recovery efficiency in real samples revealed the system's remarkable selectivity and potential application in infectious food tests.

Expanding the clinical spectrum of adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a heterogeneous neurodegenerative disease with multiple clinical subtypes. Recent breakthroughs on neuroimaging, skin biopsy and genetic testing have facilitated the diagnosis. We aim to investigate the clinical characteristics of Chinese NIID patients to further refine the spectrum. We analyzed the clinical features of 25 NIID patients from 24 unrelated families and performed skin biopsy and/or sural nerve biopsy on 24 probands. Repeat-primed PCR and fluorescence amplicon length PCR were conducted to detect GGC repeats of NOTCH2NLC. Onset age ranged from 24 to 72 years old, and the disease duration ranged from 12 h to 25 years with the mode of onset characterized as acute, recurrent or chronic progressive type. Tremor was a common phenotype, often observed in the early stages, next to dementia and paroxysmal encephalopathy. Symptoms infrequently reported such as oromandibular dystonia, recurrent vomiting, dizziness and headache of unknown origin, as well as pure peripheral neuropathy were also suggestive of NIID. Reversible leukoencephalopathy following encephalitic episodes and the absence of apparent DWI abnormality were noticed. Two genetically confirmed NIID patients failed to be identified intranuclear inclusions, and one patient was simultaneously found significant mitochondrial swelling and fingerprint profiles depositing in lysosomes. All the patients were identified abnormal GGC repeats of NOTCH2NLC. We identify some atypical clinicopathological features and consider that pathological examinations combined with genetic testing is the gold standard for diagnosis. Whether lysosomal and mitochondrial dysfunction is involved in the pathogenesis of NIID deserves further study.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Antibiotics prescription for targeted therapy of pediatric invasive pneumococcal diseases in China: a multicenter retrospective study.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. METHODS: A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. RESULTS: 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. CONCLUSIONS: Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.

An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness.

Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.

Long non-coding RNA LEISA promotes progression of lung adenocarcinoma via enhancing interaction between STAT3 and IL-6 promoter.

Long non-coding RNAs (lncRNAs) are emerging as a new class of regulators for a variety of biological processes and have been suggested to play pivotal roles in cancer development and progression. Our current study found that a lncRNA, designated enhancing IL-6/STAT3 signaling activation (LEISA, ENST00000603468), functioned as an oncogenic lncRNA in lung adenocarcinoma (LAD), a major form of non-small cell lung carcinoma, which is one of the most frequently diagnosed malignancies with high morbidity and mortality worldwide, and was involved in the regulation of STAT3 induced IL-6 transcription. Our data showed that LEISA was highly expressed in, and correlated with the clinical progression and prognosis of LAD. Ectopic expression of LEISA promoted the proliferation and suppressed apoptosis of LAD cells in vitro and in vivo. Mechanistically, we demonstrated that LEISA recruited STAT3 to bind the promoter of IL-6 and upregulated IL-6 expression. Taken together, our work identifies LEISA as a potential diagnostic biomarker and therapeutic target for LAD.