Evaluation of prognostic scores for status epilepticus in the neurology ICU: A retrospective study.

OBJECTIVE: Status epilepticus (SE) in the neurology intensive care unit (ICU) is associated with significant morbidity. We aimed to evaluate the utility of existing prognostic scores, namely the Status Epilepticus Severity Score (STESS), Epidemiology Based Mortality Score in Status Epilepticus (EMSE)-EACE and Encephalitis-Nonconvulsive Status Epilepticus-Diazepam Resistance-Image Abnormalities-Tracheal Intubation (END-IT), among SE patients in the neurology ICU. METHODS: Neurology ICU patients with SE requiring continuous electroencephalography (cEEG) monitoring over a 10 year period were included. The STESS, EMSE-EACE and END-IT scores were applied retrospectively. Receiver operating characteristic (ROC) analysis was performed to assess the discriminatory value of the scores for inpatient mortality and functional decline, as measured by increase in the modified Rankin Scale (mRS) on discharge. RESULTS: Eighty-five patients were included in the study, of which 71 (83.5%) had refractory SE. Inpatient mortality was 36.5%. Sixty - seven (78.8%) of patients suffered functional decline, with a median mRS of 5 upon hospital discharge. The AUCs of the STESS, EMSE-EACE and END-IT scores associated with inpatient mortality were 0.723 (95% CI 0.613-0.833), 0.722 (95% CI 0.609-0.834) and 0.560 (95% CI 0.436-0.684) respectively. The AUCs of the STESS, EMSE-EACE and END-IT scores associated with functional decline were 0.604 (95% CI 0.468-0.741), 0.596 (95% CI 0.439-0.754) and 0.477 (95% CI 0.331-0.623). SIGNIFICANCE: SE was associated with high mortality and morbidity in this cohort of neurology ICU patients requiring cEEG monitoring. The STESS and EMSE-EACE scores had acceptable AUCs for prediction of inpatient mortality. However, the STESS, EMSE-EACE and END-IT were poorly-correlated with discharge functional outcomes. Further refinements of the scores may be necessary among neurology ICU patients for predicting discharge functional outcomes.

The cost-effectiveness of a real-time seizure detection application for people with epilepsy.

OBJECTIVES: Automated seizure detection modalities can increase safety among people with epilepsy (PWE) and reduce seizure-related anxiety. We evaluated the potential cost-effectiveness of a seizure detection mobile application for PWE in Singapore. METHODS: We used a Markov cohort model to estimate the expected changes to total costs and health outcomes from a decision to adopt the seizure detection application versus the current standard of care from the health provider perspective. The time horizon is ten years and cycle duration is one month. Parameter values were updated from national databases and published literature. As we do not know the application efficacy in reducing seizure-related injuries, a conservative estimate of 1% reduction was used. Probabilistic sensitivity analysis, scenario analyses, and value of information analysis were performed. RESULTS: At a willingness-to-pay of $45,000/ quality-adjusted life-years (QALY), the incremental cost-effectiveness ratio was $1,096/QALY, and the incremental net monetary benefit was $13,656. Probabilistic sensitivity analyses reported that the application had a 99.5% chance of being cost-effective. In a scenario analysis in which the reduction in risk of seizure-related injury was 20%, there was a 99.8% chance that the application was cost-effective. Value of information analysis revealed that health utilities was the most important parameter group contributing to model uncertainty. CONCLUSIONS: This early-stage modeling study reveals that the seizure detection application is likely to be cost-effective compared to current standard of care. Future prospective trials will be needed to demonstrate the real-world impact of the application. Changes in health-related quality of life should also be measured in future trials.

The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment.

Gemcitabine plus cisplatin (GP) chemotherapy is the standard of care for nasopharyngeal carcinoma (NPC). However, the mechanisms underpinning its clinical activity are unclear. Here, using single-cell RNA sequencing and T cell and B cell receptor sequencing of matched, treatment-naive and post-GP chemotherapy NPC samples (n = 15 pairs), we show that GP chemotherapy activated an innate-like B cell (ILB)-dominant antitumor immune response. DNA fragments induced by chemotherapy activated the STING type-I-interferon-dependent pathway to increase major histocompatibility complex class I expression in cancer cells, and simultaneously induced ILB via Toll-like receptor 9 signaling. ILB further expanded follicular helper and helper type 1 T cells via the ICOSL-ICOS axis and subsequently enhanced cytotoxic T cells in tertiary lymphoid organ-like structures after chemotherapy that were deficient for germinal centers. ILB frequency was positively associated with overall and disease-free survival in a phase 3 trial of patients with NPC receiving GP chemotherapy ( NCT01872962 , n = 139). It also served as a predictor for favorable outcomes in patients with NPC treated with GP and immunotherapy combined treatment (n = 380). Collectively, our study provides a high-resolution map of the tumor immune microenvironment after GP chemotherapy and uncovers a role for B cell-centered antitumor immunity. We also identify and validate ILB as a potential biomarker for GP-based treatment in NPC, which could improve patient management.

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma.

The molecular basis underlying nasopharyngeal carcinoma (NPC) remains unclear. Recent progress in transcriptional regulatory network analysis helps identify the master regulator (MR) proteins that transcriptionally define malignant tumor phenotypes. Here, we investigated transcription factor-target interactions and identified TEA domain transcription factor 4 (TEAD4) as an MR of high-risk NPC. Precisely, TEAD4 promoted NPC migration, invasion and cisplatin resistance, depending on its autopalmitoylation. Mechanistically, YTHDF2 (YTH domain family 2) recognized WTAP (Wilms tumor 1-associating protein)-mediated TEAD4 m6A methylation to facilitate its stability and led to aberrant up-regulation of TEAD4. Up-regulated TEAD4 further drove NPC progression by transcriptionally activating BZW2 (basic leucine zipper and W2 domains 2) to induce the oncogenic AKT pathway. Moreover, the transcriptional activity of TEAD4 was independent of its canonical coactivators YAP/TAZ. Clinically, TEAD4 serves as an independent predictor of unfavorable prognosis and cisplatin response in NPC. Our data revealed the crucial role of TEAD4 in driving tumor malignancy, thus, may provide therapeutic vulnerability in NPC.

Repairing TALEN-mediated double-strand break by microhomology-mediated recombination in tobacco plastids generates abundant subgenomic DNA.

Transcription activator-like effector nuclease (TALEN) technology has been widely used to edit nuclear genomes in plants but rarely for editing organellar genomes. In addition, ciprofloxacin, commonly used to cause the double-strand break of organellar DNA for studying the repair mechanism in plants, confers no organellar selectivity and site-specificity. To demonstrate the feasibility of TALEN-mediated chloroplast DNA editing and to use it for studying the repair mechanism in plastids, we developed a TALEN-mediated editing technology fused with chloroplast transit peptide (cpTALEN) to site-specifically edit the rpoB gene via Agrobacteria-mediated transformation of tobacco leaf. Transgenic plants showed various degrees of chlorotic phenotype. Repairing damaged plastid DNA resulted in point mutation, large deletion and small inversion surrounding the rpoB gene by homologous recombination and/or microhomology-mediated recombination. In an albino line, microhomology-mediated recombination via a pair of 12-bp direct repeats between rpoC2 and ycf2 genes generated the chimeric ycf2-rpoC2 subgenome, with the level about 3- to 5-fold higher for subgenomic DNA than ycf2. Additionally, the expression of chimeric ycf2-rpoC2 transcripts versus ycf2 mRNA agreed well with the level of corresponding DNA. The ycf2-rpoC2 subgenomic DNA might independently and preferentially replicate in plastids.

Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses.

Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.

Identification of cross-talk between m6A and 5mC regulators associated with onco-immunogenic features and prognosis across 33 cancer types.

Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (m6A) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between m6A and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between m6A and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between m6A and 5mC methylation at the multiomic level. Then, we further established m6A/5mC epigenetic module eigengenes by combining hub m6A/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.

Chemical Structure Characteristics and Bioactivity of Small Molecule FAK Inhibitors.

Focal adhesion kinase (FAK) is a non-receptor tryosine kinase that plays a vital role in tumor cell survival, proliferation and migration. It has been shown that inhibiting the activity of FAK may result in impeding tumor cells invasion and growth. There are several small molecule FAK inhibitors which have been developed with outstanding FAK inhibitory activity. And most of the small molecules are nitrogen-containing aromatic compounds. This review describes the chemical structure characteristics and activity of current small molecule FAK inhibitors that aims to serve as a future reference for the development of potential FAK inhibitors.

A Protocol to Reduce Interobserver Variability in the Computed Tomography Measurement of Orbital Floor Fractures.

Orbital fracture detection and size determination from computed tomography (CT) scans affect the decision to operate, the type of surgical implant used, and postoperative outcomes. However, the lack of standardization of radiological signs often leads to the false-positive detection of orbital fractures, while nonstandardized landmarks lead to inaccurate defect measurements. We aim to design a novel protocol for CT measurement of orbital floor fractures and evaluate the interobserver variability on CT scan images. Qualitative aspects of this protocol include identifying direct and indirect signs of orbital fractures on CT scan images. Quantitative aspects of this protocol include measuring the surface area of pure orbital floor fractures using computer software. In this study, 15 independent observers without clinical experience in orbital fracture detection and measurement measured the orbital floor fractures of three randomly selected patients following the protocol. The time required for each measurement was recorded. The intraclass correlation coefficient of the surface area measurements is 0.999 (0.997-1.000) with p-value < 0.001. This suggests that any observer measuring the surface area will obtain a similar estimation of the fractured surface area. The maximum error limit was 0.901 cm(2) which is less than the margin of error of 1 cm(2) in mesh trimming for orbital reconstruction. The average duration required for each measurement was 3 minutes 19 seconds (ranging from 1 minute 35 seconds to 5 minutes). Measurements performed with our novel protocol resulted in minimal interobserver variability. This protocol is effective and generated reproducible results, is easy to teach and utilize, and its findings can be interpreted easily.

[Research on regulation mechanism of osteoclast differentiation].

Osteoclasts are multinucleated giant cell, which derived from mononuclear myeloid hematopoietic stem cells with the function of bone absorption. Osteoclasts plays a key role in bone metabolism, therefore the body is very strict to regulation of osteoclastogenesis. Mobilization and differentiation of osteoclast maturation is a complex and sophisticated multi-level regulatory processes. In the relevant regulatory mechanisms, OPG/RANKL/RANK system plays a pivotal role in the process of osteoclast differentiation and maturation. Recent studies revealed that immune cells and osteoclasts were closely connect with each other in the field of bone metabolism, also provide a new therapeutic target for the treatment of bone diseases. The apoptosis of osteoclasts in bone metabolism have been payed more attention,while its mechanism is still not clear, which need further research.

Improved conditions for periodate/Schiff's base-based fluorescent staining of glycoproteins with dansylhydrazine in SDS-PAGE.

An improved periodate/Schiff's base based fluorescent stain with dansylhydrazine (DH) for glycoproteins in 1D and 2D SDS-PAGE was described. Down to 4-8 ng of glycoproteins can be selectively detected within 2 h, which is approximately 16-fold higher than that of original protocol, but similar to that of Pro-Q Emerald 488 stain (Invitrogen, Carlsbad, USA). Furthermore, subsequent study of deglycosylation, glycoprotein affinity isolation, and LC-MS/MS analysis were performed to confirm the specificity of the improved method. As a result, improved DH stain may provide a new choice for selective, economic, MS compatible, and convenient visualization of gel-separated glycoproteins.

Computer-assisted navigational surgery improves outcomes in orbital reconstructive surgery.

Orbital reconstruction is a difficult procedure, success of which is dependent on the surgeon's experience. The lack of objective methods requires a fair amount of estimation is its execution. This study evaluates the efficacy of Kolibri (BrainLab, Munich, Germany), an intraoperative navigation device, in improving outcomes. From 2004 to 2009, 58 patients with orbital trauma who underwent surgery at the National University Hospital, Singapore, were included in this prospective matched control trial. Twenty-nine consecutive patients underwent surgery with Kolibri. The control group underwent surgery without the device. Both groups were matched for age, sex, orbital wall fracture, preoperative ophthalmologic features, etiology and severity of trauma, surgical approach, and types of implant used. The postoperative follow-up was at 1, 3, 6, and 12 months. For subjective assessment, the postoperative ophthalmologic features, including diplopia, infraorbital hypoesthesia, ophthalmoplegia, and enophthalmos, were compared. At 1, 3, 6, and 12 months, respectively, there were fewer patients with postoperative ophthalmologic complications in the study group (italicized; n = 29) compared with the control group (n = 29; P < 0.05): 12/29 (41%) versus 21/29 (72%), 8/29 (28%) versus 19/29 (66%), 5/29 (17%) versus 15/29 (52%), and 2/29 (7%) versus 12/29 (41%). For objective assessment, using the Kolibri workstation, operative plans were created and fused with postoperative computed tomographic scans. Vertical distances between the actual reconstructed and planned orbital floors were measured. On average, the vertical distance measured from the boundaries of floor defects for patients in the study group was 3.24 mm (95% confidence interval, 1.56-4.91) lower than the control group (P = 0.001). In conclusion, navigation minimizes postoperative complications, reduces the need for repeat procedures, and helps surgeons with planning, execution, and postoperative assessment.

Traditional Chinese Medical Journals currently published in mainland China.

BACKGROUND: Traditional Chinese Medical (TCM) journals have been playing an important role in scholarly communication in China. However, the information in those periodicals was not enough for international readers. OBJECTIVE: This study aims to provide an overview of TCM journals in China. METHODS: TCM journals currently published in mainland China were identified from Chinese databases and journal subscription catalogs. Data on publication start year, publishing region, language, whether core journals, whether indexed in famous international databases, with/without accessible URL were investigated, and subjects of journals were categorized. RESULTS: One hundred and forty-nine (149) TCM journals are currently published in mainland China; 88.59% of them are academic journals. The subjects of those journals are various, ranging from the general TCM, integrative medicine, herbal medicines, to veterinary TCM. The publishing areas are distributed in 27 regions, with Beijing having the most TCM journals published. One hundred and forty-two (142) of those periodicals are in Chinese, while 4 are also in English, and 3 in other languages. Only 8 TCM journals were recognized as core journals, and 5 were identified as both core journals and journals with high impacted articles by all evaluation systems in China. A few of the TCM journals from mainland China are indexed in PubMed/MEDLINE (10), EMBASE (5), Biological Abstracts (2), or AMED (1). Online full-text Chinese databases CJFD, COJ, and CSTPD cover most of TCM the journals published in the country. One hundred (100) TCM journals have accessible URLs, but only 3 are open access with free full texts. CONCLUSIONS: Publication of TCM journals in China has been active in academic communication in the past 20 years. However, only a few of them received recognized high evaluation. English information from them is not sufficient. Open access is not extensively acceptable. The accessibility of those journals to international readers needs to be improved.