Antivirals for treatment of severe influenza: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: The optimal antiviral drug for treatment of severe influenza remains unclear. To support updated WHO influenza clinical guidelines, this systematic review and network meta-analysis evaluated antivirals for treatment of patients with severe influenza. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023, that enrolled hospitalised patients with suspected or laboratory-confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or another antiviral. Pairs of coauthors independently extracted data on study characteristics, patient characteristics, antiviral characteristics, and outcomes, with discrepancies resolved by discussion or by a third coauthor. Key outcomes of interest were time to alleviation of symptoms, duration of hospitalisation, admission to intensive care unit, progression to invasive mechanical ventilation, duration of mechanical ventilation, mortality, hospital discharge destination, emergence of antiviral resistance, adverse events, adverse events related to treatments, and serious adverse events. We conducted frequentist network meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. This study is registered with PROSPERO, CRD42023456650. FINDINGS: Of 11 878 records identified by our search, eight trials with 1424 participants (mean age 36-60 years for trials that reported mean or median age; 43-78% male patients) were included in this systematic review, of which six were included in the network meta-analysis. The effects of oseltamivir, peramivir, or zanamivir on mortality compared with placebo or standard care without placebo for seasonal and zoonotic influenza were of very low certainty. Compared with placebo or standard care, we found low certainty evidence that duration of hospitalisation for seasonal influenza was reduced with oseltamivir (mean difference -1·63 days, 95% CI -2·81 to -0·45) and peramivir (-1·73 days, -3·33 to -0·13). Compared with standard care, there was little or no difference in time to alleviation of symptoms with oseltamivir (0·34 days, -0·86 to 1·54; low certainty evidence) or peramivir (-0·05 days, -0·69 to 0·59; low certainty evidence). There were no differences in adverse events or serious adverse events with oseltamivir, peramivir, and zanamivir (very low certainty evidence). Uncertainty remains about the effects of antivirals on other outcomes for patients with severe influenza. Due to the small number of eligible trials, we could not test for publication bias. INTERPRETATION: In hospitalised patients with severe influenza, oseltamivir and peramivir might reduce duration of hospitalisation compared with standard care or placebo, although the certainty of evidence is low. The effects of all antivirals on mortality and other important patient outcomes are very uncertain due to scarce data from randomised controlled trials. FUNDING: World Health Organization.

The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial.

BACKGROUND: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. METHODS: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. FINDINGS: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). INTERPRETATION: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. FUNDING: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.

Cross-Priming-Linked Hierarchical Isothermal Amplification Programming Progressive Activating Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a in miRNA Signaling.

Cascade isothermal nucleic acid amplification, which integrates several different amplification protocols to enhance the assay performance, is widely utilized in biosensing, particularly for detecting microRNAs (miRNAs), crucial biomarkers associated with tumor initiation and progression. However, striking a balance between a high amplification efficiency and simplicity in design remains a challenge. Therefore, methods achieving high amplification efficiency without significantly increasing complexity are highly favored. In this study, we propose a novel approach for miRNA detection, employing cross-priming-linked hierarchical isothermal amplification (CP-HIA) to progressively activate the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a system. The CP-HIA method strategically combines nicking-rolling circle amplification (n-RCA) and palindrome-aided circular strand displacement amplification (p-CSDA) for miRNA detection. Remarkably, this method utilizes only two main probes. Its key innovation lies in the interactive cross-priming strategy, wherein the amplification product from n-RCA is recycled to further drive p-CSDA, and vice versa. This interactive process establishes a hierarchical amplification, significantly enriching the activation probes for progressive CRISPR/Cas12a activation and subsequent target signal amplification. Consequently, the method exhibits greatly enhanced analytical performance, including high sensitivity and specificity in detecting low concentrations of miRNA. As low as 1.06 fM miRNA can thus be quantitatively detected, and the linear response of the miRNA is from 10 fM to 10 nM. These features demonstrate its potential for early disease diagnosis and monitoring. We anticipate that the CP-HIA method will serve as a promising platform for developing advanced molecular diagnostic tools for biomedical research.

Single-Nucleotide-Specific Lipidic Nanoflares for Precise and Visible Detection of KRAS Mutations via Toehold-Initiated Self-Priming DNA Polymerization.

Accurate identification of single-nucleotide mutations in circulating tumor DNA (ctDNA) is critical for cancer surveillance and cell biology research. However, achieving precise and sensitive detection of ctDNAs in complex physiological environments remains challenging due to their low expression and interference from numerous homologous species. This study introduces single-nucleotide-specific lipidic nanoflares designed for the precise and visible detection of ctDNA via toehold-initiated self-priming DNA polymerization (TPP). This system can be assembled from only a single cholesterol-conjugated multifunctional molecular beacon (MMB) via hydrophobicity-mediated aggregation. This results in a compact, high-density, and nick-hidden arrangement of MMBs on the surface of lipidic micelles, thereby enhancing their biostability and localized concentrations. The assay commences with the binding of frequently mutated regions of ctDNA to the MMB toehold domain. This domain is the proximal holding point for initiating the TPP-based strand-displacement reaction, which is the key step in enabling the discrimination of single-base mutations. We successfully detected a single-base mutation in ctDNA (KRAS G12D) in its wild-type gene (KRAS WT), which is one of the most frequently mutated ctDNAs. Notably, coexisting homologous species did not interfere with signal transduction, and small differences in these variations can be visualized by fluorescence imaging. The limit of detection was as low as 10 amol, with the system functioning well in physiological media. In particular, this system allowed us to resolve genetic mutations in the KRAS gene in colorectal cancer, suggesting its high potential in clinical diagnosis and personalized medicine.

Natural Polyphenol Delivered Methylprednisolone Achieve Targeted Enrichment for Acute Spinal Cord Injury Therapy.

The strong anti-inflammatory effect of methylprednisolone (MP) is a necessary treatment for various severe cases including acute spinal cord injury (SCI). However, concerns have been raised regarding adverse effects from MP, which also severely limits its clinical application. Natural polyphenols, due to their rich phenolic hydroxyl chemical properties, can form dynamic structures without additional modification, achieving targeted enrichment and drug release at the disease lesion, making them a highly promising carrier. Considering the clinical application challenges of MP, a natural polyphenolic platform is employed for targeted and efficient delivery of MP, reducing its systemic side effects. Both in vitro and SCI models demonstrated polyphenols have multiple advantages as carriers for delivering MP: (1) Achieved maximum enrichment at the injured site in 2 h post-administration, which met the desires of early treatment for diseases; (2) Traceless release of MP; (3) Reducing its side effects; (4) Endowed treatment system with new antioxidative properties, which is also an aspect that needs to be addressed for diseases treatment. This study highlighted a promising prospect of the robust delivery system based on natural polyphenols can successfully overcome the barrier of MP treatment, providing the possibility for its widespread clinical application.

PDGF-BB accelerates TSCC via fibroblast lactates limiting miR-26a-5p and boosting mitophagy.

The tumor microenvironment and cancer-associated fibroblasts (CAFs) play crucial roles in tumor development, and their metabolic coupling remains unclear. Clinical data showed a positive correlation between PDGF-BB, CAFs, and glycolysis in the tumor microenvironment of oral tongue squamous cell carcinoma patients. In vitro, CAFs are derived from hOMF cells treated with PDGF-BB, which induces their formation and promotes aerobic glycolysis. Mitophagy increased the PDGF-BB-induced formation of CAF phenotypes and aerobic glycolysis, while autophagy inhibition blocked PDGF-BB-induced effects. Downregulation of miR-26a-5p was observed in CAFs; upregulation of miR-26a-5p inhibited the expression of mitophagy-related proteins ULKI, Parkin, PINK1, and LC3 and aerobic glycolysis in PDGF-BB-induced CAFs. PDGF-BB-induced CAFs promoted tumor cell proliferation, invasion, metastasis, NF-κB signaling pathway activation, and PDGF-BB secretion. Thus, PDGF-BB is associated with lactate-induced CAF formation and glucose metabolism reprogramming. These findings indicate potential therapeutic targets in oral tongue squamous cell carcinoma.

Maternal overweight and obesity modify the association of serum fibroblast growth factor 21 levels with gestational diabetes mellitus: A nested case-control study.

AIMS: To examine the prospective association between fibroblast growth factor 21 (FGF21) and risk of gestational diabetes mellitus (GDM) and the modifying effect of overweight/obesity for this association. METHODS: Serum FGF21 levels were measured at 6-15 weeks of gestation among 332 GDM cases and 664 matched controls. Conditional logistic regression was used to evaluate its association with GDM risk. Interaction analyses on multiplicative and additive scales were conducted to investigate the modifying effect of overweight/obesity. RESULTS: Elevated FGF21 levels were associated with a higher risk of GDM in multivariable models, but the positive association was attenuated after further adjustment for pre-pregnancy body mass index (BMI). A significant multiplicative interaction was noted between FGF21 (both continuous and dichotomous) and pre-pregnancy BMI (p for interaction = 0.049 and 0.03), and the association was only significant in participants with pre-pregnancy BMI ≥24 kg/m2 . When participants were grouped based on pre-pregnancy BMI (≥24 and <24 kg/m2 ) and FGF21 levels (≥median and

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Advances, challenges, and opportunities for food safety analysis in the isothermal nucleic acid amplification/CRISPR-Cas12a era.

Global food safety stands out as a prominent public concern, affecting populations worldwide. The recurrent challenge of food safety incidents reveals the need for a robust inspection framework. In recent years, the integration of isothermal nucleic acid amplification with CRISPR-Cas12a techniques has emerged as a promising tool for molecular detection of food hazards, presenting next generation of biosensing for food safety detection. This paper provides a comprehensive review of the current state of research on the synergistic application of isothermal nucleic acid amplification and CRISPR-Cas12a technology in the field of food safety. This innovative combination not only enriches the analytical tools, but also improving assay performance such as sensitivity and specificity, addressing the limitations of traditional methods. The review summarized various detection methodologies by the integration of isothermal nucleic acid amplification and CRISPR-Cas12a technology for diverse food safety concerns, including pathogenic bacterium, viruses, mycotoxins, food adulteration, and genetically modified foods. Each section elucidates the specific strategies employed and highlights the advantages conferred. Furthermore, the paper discussed the challenges faced by this technology in the context of food safety, offering insightful discussions on potential solutions and future prospects.

Two new members of the genus Sphingobacterium: Sphingobacterium zhuxiongii sp. nov. and Sphingobacterium luzhongxinii sp. nov.

Four strains, designated dk4302T, dk4209, xlx-73T, and xlx-183, were isolated from Tibetan gazelle and red swamp crawfish collected from the Qinghai-Tibet Plateau and Jiangxi Province, PR China. The strains were Gram-stain-negative, aerobic, rod-shaped, non-motile, mucoid, and yellow-pigmented. Strains dk4302T and dk4209 grew at 10-40 °C and pH 6.0-9.0, while strains xlx-73T/xlx-183 grew at 15-40 °C and pH 6.0-10.0. Both strains exhibited growth in the presence of up to 3.5 % (w/v) NaCl. Phylogenetic and phylogenomic analyses based on the 16S rRNA gene sequences and 652 core genes, respectively, revealed that the four strains formed two distinct clusters in the genus Sphingobacterium. Strains dk4302T and dk4209 formed a distinct clade with Sphingobacterium hotanense XH4T and Sphingobacterium humi D1T. The most closely related strains to xlx-73T and xlx-183 were Sphingobacterium nematocida M-SX103T. The DNA G+C contents were 38.9 and 39.8 mol%. The digital DNA-DNA hybridization (dDDH) values between dk4302T and S. humi D1T and S. hotanense XH4T were 19.2 and 21.8 % (19.0 and 21.6 % for strain dk4209), respectively. The corresponding average nucleotide identity (ANI) values were 74.3 and 78.1 % (74.4 and 78.3 % for strain dk4209), respectively. The dDDH values between xlx-73T (xlx-183) and S. nematocida M-SX103T was 24.6 % (25.7 %). The corresponding ANI value was 85.7 % (85.5 % for strain xlx-183). The major fatty acid and respiratory quinone of dk4302T and xlx-73T were iso-C15:0 and MK7. The polar lipids identified in all of the novel strains were phosphatidylethanolamine, phosphoglycolipids, aminophospholipids, and phospholipids. A total of 61/190 (32.1 %) and 82/190 (43.2 %) carbon substrates were metabolized by strains dk4302T and xlx-73T in the Biolog MicroPlates, respectively. Based on the results from this polyphasic taxonomic study, two novel species in the genus Sphingobacteruim are proposed, namely Sphingobacteruim zhuxiongii sp. nov. (type strain dk4302T=CGMCC 1.16795T=JCM 33600T) and Sphingobacteruimluzhongxinii sp. nov. (type strain xlx-73T=GDMCC 1.1712T=JCM 33886T).

Nocardioides bizhenqiangii sp. nov. and Nocardioides renjunii sp. nov., isolated from soil and faeces of Tibetan antelope (Pantholops hodgsonii) on the Qinghai-Tibet Plateau.

Two novel strain pairs (HM61T/HM23 and S-34T/S-58) were isolated from soil and the faeces of Tibetan antelope (Pantholops hodgsonii) collected at the Qinghai-Tibet Plateau of PR China. All four new isolates were aerobic, non-motile, Gram-stain-positive, catalase-positive, oxidase-negative, and short rod-shaped bacteria. The results of phylogenetic analysis based on the full-length 16S rRNA genes and 283 core genomic genes indicated that the four strains were separated into two independent branches belonging to the genus Nocardioides. Strains HM61T and HM23 were most closely related to Nocardioides pelophilus THG T63T (98.58 and 98.65 % 16S rRNA gene sequence similarity). Strains S-34T and S-58 were most closely related to Nocardioides okcheonensis MMS20-HV4-12T (98.89 and 98.89 % 16S rRNA gene sequence similarity). The G+C contents of the genomic DNA of strains HM61T and S-34T were 70.6 and 72.5 mol%, respectively. Strains HM61T, S-34T and the type strains of closely related species in the analysis had average nucleotide identity values of 75.4-90.5 % as well as digital DNA-DNA hybridization values between 20.1 and 40.8 %, which clearly indicated that the four isolates represent two novel species within the genus Nocardioides. The chemotaxonomic characteristics of strains HM61T and S-34T were consistent with the genus Nocardioides. The major fatty acids of all four strains were iso-C16 : 0, C17 : 1 ω8c or C18 : 1 ω9c. For strains HM61T and S-34T, MK-8(H4) was the predominant respiratory quinone, ll-2,6-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan, and the polar lipids profiles were composed of diphosphatidylglycerol and phosphatidylglycerol. Based on phylogenetic, phenotypic, and chemotaxonomic data, we propose that strains HM61T and S-34T represent two novel species of the genus Nocardioides, respectively, with the names Nocardioides bizhenqiangii sp. nov. and Nocardioides renjunii sp. nov. The type strains are HM61T (=GDMCC 4.343T=JCM 36399T) and S-34T (=CGMCC 4.7664T=JCM 33792T).

Planococcus shenhongbingii sp. nov., Planococcus shixiaomingii sp. nov. and Planococcus liqunii sp. nov., isolated from soil of the Qinghai-Tibet Plateau.

Six novel bacterial strains, designated N016T, N017, N022T, N028, N056T, and N064, were isolated from soil sampled on the Qinghai-Tibet Plateau. Cells were aerobic, orange or yellow, globular or rod-shaped, non-motile, non-spore-forming, Gram-stain-positive, catalase-positive and oxidase-negative. All the isolates were salt-tolerant and could grow in the range of 4-42 °C. Results of phylogenomic analyses based on 16S rRNA gene sequences and core genomic genes showed that the three pairs of strains (N016T/N017, N022T/N028, and N056T/N064) were closely related to the members of the genus Planococcus, and clustered with Planococcus ruber, Planococcus glaciei, and Planococcus chinensis. The digital DNA-DNA hybridization and average nucleotide identity values of the six novel strains with other members of the genus Planococcus were within the ranges of 18.7-53 % and 70.58-93.49 %, respectively, all below the respective recommended thresholds of 70.0 % and 95-96 %. The genomic DNA G+C content of the six strains ranged from 43.5 to 46.0 mol%. The major fatty acids of the six strains were anteiso-C15 : 0, iso-C14 : 0, and C16 : 1 ω7c alcohol. The predominant polar lipids of strains N016T, N022T, and N056T were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. Menaquinones 7 and 8 were the respiratory quinones. The results of the above analyses indicated that the six strains represent three novel species of the genus Planococcus, for which the names Planococcus shenhongbingii sp. nov. (type strain N016T=GDMCC 1.4062T=JCM 36224T), Planococcus shixiaomingii sp. nov. (type strain N022T=GDMCC 1.4063T=JCM 36225T), and Planococcus liqunii sp. nov. (type strain N056T=GDMCC 1.4064T=JCM 36226T) are proposed.

Automated, fast, robust brain extraction on contrast-enhanced T1-weighted MRI in presence of brain tumors: an optimized model based on multi-center datasets.

OBJECTIVES: Existing brain extraction models should be further optimized to provide more information for oncological analysis. We aimed to develop an nnU-Net-based deep learning model for automated brain extraction on contrast-enhanced T1-weighted (T1CE) images in presence of brain tumors. METHODS: This is a multi-center, retrospective study involving 920 patients. A total of 720 cases with four types of intracranial tumors from private institutions were collected and set as the training group and the internal test group. Mann-Whitney U test (U test) was used to investigate if the model performance was associated with pathological types and tumor characteristics. Then, the generalization of model was independently tested on public datasets consisting of 100 glioma and 100 vestibular schwannoma cases. RESULTS: In the internal test, the model achieved promising performance with median Dice similarity coefficient (DSC) of 0.989 (interquartile range (IQR), 0.988-0.991), and Hausdorff distance (HD) of 6.403 mm (IQR, 5.099-8.426 mm). U test suggested a slightly descending performance in meningioma and vestibular schwannoma group. The results of U test also suggested that there was a significant difference in peritumoral edema group, with median DSC of 0.990 (IQR, 0.989-0.991, p = 0.002), and median HD of 5.916 mm (IQR, 5.000-8.000 mm, p = 0.049). In the external test, our model also showed to be robust performance, with median DSC of 0.991 (IQR, 0.983-0.998) and HD of 8.972 mm (IQR, 6.164-13.710 mm). CONCLUSIONS: For automated processing of MRI neuroimaging data presence of brain tumors, the proposed model can perform brain extraction including important superficial structures for oncological analysis. CLINICAL RELEVANCE STATEMENT: The proposed model serves as a radiological tool for image preprocessing in tumor cases, focusing on superficial brain structures, which could streamline the workflow and enhance the efficiency of subsequent radiological assessments. KEY POINTS: • The nnU-Net-based model is capable of segmenting significant superficial structures in brain extraction. • The proposed model showed feasible performance, regardless of pathological types or tumor characteristics. • The model showed generalization in the public datasets.

Development of predictive model for the neurological deterioration among mild traumatic brain injury patients using machine learning algorithms.

BACKGROUND: Mild traumatic brain injury (mTBI) comprises a majority of traumatic brain injury (TBI) cases. While some mTBI would suffer neurological deterioration (ND) and therefore have poorer prognosis. This study was designed to develop the predictive model for the ND among mTBI using machine learning algorithms. METHODS: mTBI patients recorded in the Medical Information Mart for Intensive Care-III were selected for the study. The ND was defined as a drop of Glasgow Coma Scale ≥ 2 within the first 7 day after admission. Eight machine learning algorithms were trained and validated with 5-fold cross validation including extreme gradient boosting, logistic regression, light gradient boosting machine, random forest, adaptive boosting, decision tree, complement naïve Bayes, and support vector machine. The value of eight machine learning algorithms was compared by the area under the receiver operating characteristic curve (AUC). RESULTS: 361 mTBI patients suffered the ND with the incidence of 30.7%. The ND group had higher 30-day mortality (p = 0.001). In the training cohort of mTBI patients, the random forest performed the best on predicting the ND with the AUC of 1.000. The XGBoost and AdaBoost had an AUC of 0.827 and 0.815, respectively. The logistic regression performed the best on predicting the ND in the validation cohort with the AUC of 0.741. The XGBoost, random forest and AdaBoost had an AUC of 0.729, 0.735, 0.736 in the validation cohort, respectively. After adjusting confounding effects, the multivariate logistic regression found only two independent risk factors for the ND including Sequential Organ Failure Assessment (SOFA) (p < 0.001) and hypertension (p = 0.001). The logistic regression predictive model composed of SOFA and hypertension had an AUC of 0.741. CONCLUSIONS: SOFA score and complicated hypertension are two independent risk factors for the neurological deterioration among mTBI patients. The logistic regression predictive model incorporating SOFA and hypertension is helpful to identify mTBI patients with the high risk of ND.

Smartwatch-Detected Arrhythmias in Patients After Transcatheter Aortic Valve Replacement (TAVR): Analysis of the SMART TAVR Trial.

BACKGROUND: There are limited data available on the development of arrhythmias in patients at risk of high-degree atrioventricular block (HAVB) or complete heart block (CHB) following transcatheter aortic valve replacement (TAVR). OBJECTIVE: This study aimed to explore the incidence and evolution of arrhythmias by monitoring patients at risk of HAVB or CHB after TAVR using smartwatches. METHODS: We analyzed 188 consecutive patients in the prospective SMART TAVR (smartwatch-facilitated early discharge in patients undergoing TAVR) trial. Patients were divided into 2 groups according to the risk of HAVB or CHB. Patients were required to trigger a single-lead electrocardiogram (ECG) recording and send it to the Heart Health App via their smartphone. Physicians in the central ECG core lab would then analyze the ECG. The incidence and timing of arrhythmias and pacemaker implantation within a 30-day follow-up were compared. All arrhythmic events were adjudicated in a central ECG core lab. RESULTS: The mean age of the patients was 73.1 (SD 7.3) years, of whom 105 (55.9%) were men. The mean discharge day after TAVR was 2.0 (SD 1.8) days. There were no statistically significant changes in the evolution of atrial fibrillation or atrial flutter, Mobitz I, Mobitz II, and third-degree atrial ventricular block over time in the first month after TAVR. The incidence of the left bundle branch block (LBBB) increased in the first week and decreased in the subsequent 3 weeks significantly (P<.001). Patients at higher risk of HAVB or CHB received more pacemaker implantation after discharge (n=8, 9.6% vs n=2, 1.9%; P=.04). The incidence of LBBB was higher in the group with higher HAVB or CHB risk (n=47, 56.6% vs n=34, 32.4%; P=.001). The independent predictors for pacemaker implantation were age, baseline atrial fibrillation, baseline right bundle branch block, Mobitz II, and third-degree atrioventricular block detected by the smartwatch. CONCLUSIONS: Except for LBBB, no change in arrhythmias was observed over time in the first month after TAVR. A higher incidence of pacemaker implantation after discharge was observed in patients at risk of HAVB or CHB. However, Mobitz II and third-degree atrioventricular block detected by the smartwatch during follow-ups were more valuable indicators to predict pacemaker implantation after discharge from the index TAVR. TRIAL REGISTRATION: ClinicalTrials.gov NCT04454177; https://clinicaltrials.gov/study/NCT04454177.

Interface-constrained catalytic hairpin assembly permits highly sensitive SERS signaling of miRNA.

The rapid and precise monitoring of peripheral blood miRNA levels holds paramount importance for disease diagnosis and treatment monitoring. In this study, we propose an innovative research strategy that combines the catalytic hairpin assembly reaction with SERS signal congregation and enhancement. This combination can significantly enhance the stability of SERS detection, enabling stable and efficient detection of miRNA. Specifically, our paper-based SERS detection platform incorporates a streptavidin-modified substrate, biotin-labeled catalytic hairpin assembly reaction probes, 4-ATP, and primer-co-modified gold nanoparticles. In the presence of miRNA, the 4-ATP and primer-co-modified gold nanoparticles can specifically recognize the miRNA and interact with the biotin-labeled CHA probes to initiate an interfacial catalytic hairpin assembly reaction. This enzyme-free high-efficiency catalytic process can accumulate a large amount of biotin on the gold nanoparticles, which then bind to the streptavidin on the substrate with the assistance of the driving liquid, forming red gold nanoparticle stripes. These provide a multitude of hotspots for SERS, enabling enhanced signal detection. This innovative design achieves a low detection limit of 3.47 fM while maintaining excellent stability and repeatability. This conceptually innovative detection platform offers new technological possibilities and solutions for clinical miRNA detection.

Dual Enzymolysis Assisted by Acrylate or Phosphate Grafting: Influences on the Structural and Functional Properties of Jujube Residue Dietary Fiber.

Jujube residue is an abundant and low-cost dietary fiber resource, but its relatively lower hydration and functional properties limit its utilization as an ingredient of functional food. Thus, cellulase and hemicellulase hydrolysis, enzymatic hydrolysis assisted by phosphate grafting (EPG), and enzymatic hydrolysis assisted by acrylate grafting (EAG) were used to improve the functional properties of jujube residue dietary fiber (JRDF) in this study. The results evidenced that these modifications all increased the porosity of the microstructure of JRDF and increased the soluble fiber content, surface area, and hydration properties, but reduced its brightness (p < 0.05). Moreover, JRDF modified by enzymolysis combined with acrylate grafting offered the highest extractable polyphenol content, oil, sodium cholate, and nitrite ion sorption abilities. Meanwhile, JRDF modified via enzymolysis assisted by phosphate grafting showed the highest soluble fiber content (23.53 g∙100 g-1), water-retention ability (12.84 g∙g-1), viscosity (9.37 cP), water-swelling volume (10.80 mL∙g-1), and sorption ability of copper (II) and lead (II) ions. Alternatively, JRDF modified with cellulase hydrolysis alone exhibited the highest glucose adsorption capacity (21.9 g∙100 g-1) at pH 7.0. These results indicate that EPG is an effective way to improve the hypolipidemic effects of JRDF, while EAG is a good choice to enhance its hydration and hypoglycemic properties.

RAGE Is a Receptor for SARS-CoV-2 N Protein and Mediates N Protein-induced Acute Lung Injury.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (N-protein) increases early in body fluids during infection and has recently been identified as a direct inducer for lung injury. However, the signal mechanism of N-protein in the lung inflammatory response remains poorly understood. The goal of this study was to determine whether RAGE (receptor for advanced glycation endproducts) participated in N-protein-induced acute lung injury. The binding between N-protein and RAGE was examined via assays for protein-protein interaction. To determine the signaling mechanism in vitro, cells were treated with recombinant N-protein and assayed for the activation of the RAGE/MAPK (mitogen-activated protein kinase)/NF-ĸB pathway. RAGE deficiency mice and antagonist were used to study N-protein-induced acute lung injury in vivo. Binding between N-protein and RAGE was confirmed via flow cytometry-based binding assay, surface plasmon resonance, and ELISA. Pull-down and coimmunoprecipitation assays revealed that N-protein bound RAGE via both N-terminal and C-terminal domains. In vitro, N-protein activated the RAGE-ERK1/2-NF-ĸB signaling pathway and induced a proinflammatory response. RAGE deficiency subdued N-protein-induced proinflammatory signaling and response. In vivo, RAGE was upregulated in the BAL and lung tissue after recombinant N-protein insult. RAGE deficiency and small molecule antagonist partially protected mice from N-protein-induced acute lung injury. Our study demonstrated that RAGE is a receptor for N-protein. RAGE is partially responsible for N-protein-induced acute lung injury and has the potential to become a therapeutic target for treating coronavirus disease.

Clinical Forms of Japanese Spotted Fever from Case-Series Study, Zigui County, Hubei Province, China, 2021.

We report a case-series study of 5 patients with Japanese spotted fever from the Three Gorges Area in China, including 1 fatal case. Seroprevalence of Rickettsia japonica was ≈21% among the local population. Our report highlights the emerging potential threat to human health of Japanese spotted fever in the area.

Intramolecular Accelerated Assembly of Molecular Beacons: A DNA Nanoarchitecture-based Spatial Confinement Strategy toward Terminal Deoxynucleotidyl Transferase Biosensing.

Physiological function analysis of terminal deoxynucleotidyl transferase (TdT) in clinical medicine and hematopathology highlights its significance to be extensively utilized as a diagnostic biomarker for leukemia diagnosis. Herein, taking advantage of the spatial-confinement effect on a three-dimensional (3D) DNA nanoarchitecture, we reported a target-triggered intramolecular accelerated molecular beacon (MB) assembly for rapid and real-time analysis of TdT activity. In this strategy, the 3D DNA nanoarchitecture is first engineered via a cross-linking network hybridization chain reaction (HCR). A number of MBs, which were designed with a polythymine (poly-T) loop, were then conjugated on the scaffold DNA nanoarchitecture, allowing the obtained MB-DNA nanoarchitecture to contain lots of free 3'-hydroxyl (OH) termini inside or outside the super DNA nanostructure. Moreover, the distance between different MBs is closed, and the local concentration of MB is significantly improved owing to the confinement of MBs on this DNA nanoarchitecture. Once encountered with target TdT, the free -OH groups can be recognized by TdT immediately to catalyze the template-independent incorporation of adenine nucleotides, which results in the generation of multiple poly-A chains that rapidly react with many MBs via an intramolecular accelerated assembly process. The time-dependent substantial enhancement of the fluorescence from MBs can thus be applied for robustly analyzing TdT. Our observations suggest that the DNA nanostructure-based spatial confinement effect enables a high molecular collision frequency to accelerate the reaction kinetics, and the super DNA nanoarchitecture exhibits a better nuclease resistance to maintain signal stability. With these advantages, TdT can be rapidly detected with high sensitivity, specificity, and biostability.