Wet-Chemical Synthesis of Concave Hexoctahedral Pd and Pd@Pt Nanocrystals for Methanol Electrooxidation.

Nanocrystals (NCs) exposed with high-index facets usually show enhanced electrocatalytic performances. However, it is a great challenge to persevere with high-index facets against their high surface energy during the synthesis. Herein, we successfully synthesize concave hexoctahedral (c-HOH) Pd NCs exposed with 48 high-index {741} facets using a facile one-pot wet-chemical protocol. Control experiments illustrate that l-ascorbic acid plays a critical role in the formation of the c-HOH morphology, acting as both reducing and capping agents. Moreover, we can extend the synthesis for fabricating c-HOH Pd@Pt core-shell NCs by simply introducing a Pt precursor into the reaction solution, attaining remarkably boosted electrocatalysis for methanol electrooxidation reaction (MOR). Integrating the merits of {741} facets, concave structure, and ligand and strain effect of the core-shell structure, c-HOH Pd4@Pt1 core-shell NCs showed an excellent MOR mass activity of 1.18 A mgPGM-1 or 3.60 A mgPt-1, which is 3.80 or 11.61 times higher than that of commercial Pt/C, respectively.

A humanized Anti-YKL-40 antibody inhibits tumor development.

Drugs specifically targeting YKL-40, an over-expressed gene (CHI3L1) in various diseases remain developed. The current study is to create a humanized anti-YKL-40 neutralizing antibody and characterize its potentially therapeutic signature. We utilized in silico CDR-grafting bioinformatics to replace the complementarity determining regions (CDRs) of human IgG1 with mouse CDRs of our previously established anti-YKL-40 antibody (mAY). In fifteen candidates (VL1-3/VH1-5) of heavy and light chain variable region combination, one antibody L3H4 named Rosazumab demonstrated strong binding affinity with YKL-40 (KD = 4.645 × 10-8 M) and high homology with human IgG (80 %). In addition, we established different overlapping amino acid peptides of YKL-40 and found that Rosazumab specifically bound to residues K337, K342, and R344, the KR-rich functional domain of YKL-40. Rosazumab inhibited migration and tube formation of YKL-40-expressing tumor cells and induced tumor cell apoptosis. Mechanistically, Rosazumab induced interaction of N-cadherin with ß-catenin and activation of downstream MST1/RASSF1/Histone H2B axis, leading to chromosomal DNA breakage and cell apoptosis. Treatment of xenografted tumor mice with Rosazumab twice a week for 4 weeks inhibited tumor growth and angiogenesis, but induced tumor apoptosis. Rosazumab injected in mice distributed to blood, tumor, and other multiple organs, but did not impact in function or structure of liver and kidney, indicating non-detectable toxicity in vivo. Collectively, the study is the first one to demonstrate that a humanized YKL-40 neutralizing antibody offers a valuable means to block tumor development.

Dynamic Interchain Motion in 1D Tetrathiafulvalene-Based Coordination Polymers for Highly Sensitive Molecular Recognition.

The application of electrically conductive 1D coordination polymers (1D CPs) in nanoelectronic molecular recognition is theoretically promising yet rarely explored due to the challenges in their synthesis and optimization of electrical properties. In this regard, two tetrathiafulvalene-based 1D CPs, namely [Co(m-H2TTFTB)(DMF)2(H2O)]n (Co-m-TTFTB), and {[Ni(m-H2TTFTB)(CH3CH2OH)1.5(H2O)1.5]·(H2O)0.5}n (Ni-m-TTFTB) are successfully constructed. The shorter S···S contacts between the [M(solvent)3(m-H2TTFTB)]n chains contribute to a significant improvement in their electrical conductivities. The powder X-ray diffraction (PXRD) under different organic solvents reveals the flexible and dynamic structural characteristic of M-m-TTFTB, which, combined with the 1D morphology, lead to their excellent performance for sensitive detection of volatile organic compounds. Co-m-TTFTB achieves a limit of detection for ethanol vapor down to 0.5 ppm, which is superior to the state-of-the-art chemiresistive sensors based on metal-organic frameworks or organic polymers at room temperature. In situ diffuse reflectance infrared Fourier transform spectroscopy, PXRD measurements and density functional theory calculations reveal the molecular insertion sensing mechanism and the corresponding structure-function relationship. This work expands the applicable scenario of 1D CPs and opens a new realm of 1D CP-based nanoelectronic sensors for highly sensitive room temperature gas detection.

The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway.

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

Selectively superior production of docosahexaenoic acid in Schizochytrium sp. through engineering the fatty acid biosynthetic pathways.

BACKGROUND: Schizochytrium sp. is commercially used for production of docosahexaenoic acid (DHA). Schizochytrium sp. utilizes the polyketide synthase complex (PKS) and a single type I fatty acid synthase (FAS) to synthesize polyunsaturated fatty acids and saturated fatty acids, respectively. The acyl carrier protein (ACP) domains of FAS or PKS are used to load acyl groups during fatty acids biosynthesis. Phosphopantetheinyl transferase (PPTase) transfers the pantetheine moiety from Coenzyme A to the conserved serine residue of an inactive ACP domain to produce its active form. RESULTS: In this study, in order to improve production and content of DHA, we decreased the expression of fas, strengthened the expression of the PKS pathway, and enhanced the supply of active ACP in Schizochytrium sp. ATCC20888. Weakening the expression of fas or disruption of orfA both led to growth defect and reduction of lipid yields in the resulting strains WFAS and DPKSA, indicating that both FAS and PKS were indispensable for growth and lipid accumulation. Although WFAS had a higher DHA content in total fatty acids than the wild-type strain (WT), its growth defect and low DHA yield hinders its use for DHA production. Overexpression of the orfAB, orfC, orfC-DH (truncated orfC), or ppt promoted DHA and lipid production, respectively. The yields and contents of DHA were further increased by combined overexpression of these genes. Highest values of DHA yield (7.2 g/L) and DHA content (40.6%) were achieved in a recombinant OPKSABC-PPT, ⁓56.5% and 15.3% higher than the WT values, respectively. CONCLUSIONS: This study demonstrates that genetic engineering of the fatty acid biosynthetic pathways provides a new strategy to enhance DHA production in Schizochytrium.

Association of blood urea nitrogen with all-cause and cardiovascular mortality in hyperlipidemia: NHANES 1999-2018.

OBJECTIVE: Although blood urea nitrogen (BUN) has a crucial impact on many diseases, its effect on outcomes in patients with hyperlipidemia remains unknown. The study aimed to investigate the relationships between BUN levels and all-cause and cardiovascular disease (CVD) mortality in individuals with hyperlipidemia. METHODS: This analysis comprised 28,122 subjects with hyperlipidemia from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The risk of BUN on mortality was evaluated using weighted Cox regression models. Additionally, to illustrate the dose-response association, the restricted cubic spline (RCS) was used. RESULTS: During the observation period, 4276 participant deaths were recorded, of which 1206 were due to CVD. Compared to patients with hyperlipidemia in the third BUN quintile, the hazard ratios (HRs) for all-cause mortality were 1.26 (95% CIs: 1.09, 1.45) and 1.22 (95% CIs: 1.09, 1.37) for patients in the first and fifth quintiles of BUN, respectively. The HRs for CVD mortality among patients in the fifth quintile of BUN were 1.48 (95% CIs: 1.14, 1.93). BUN levels were found to have a U-shaped association with all-cause mortality and a linear association with CVD mortality using restricted triple spline analysis. CONCLUSIONS: This study revealed that both low and high BUN levels in patients with hyperlipidemia are associated with heightened all-cause mortality. Furthermore, elevated BUN levels are also associated with increased CVD mortality. The findings indicate that patients with hyperlipidemia may face an elevated risk of death if they have abnormal BUN levels.

Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3ß interaction.

Introduction: Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3ß (GSK-3ß). Since ketamine activates GSK-3ß, we examined the impact of ketamine on DISC1 and GSK-3ß expression. Methods: Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3ß antagonist, lithium. Cleaved-caspase-3, GSK-3ß and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3ß was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium. Results: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3ß, which implicates increased GSK-3ß activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3ß and axonal length. Conclusion: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.

Machine learning for the identification of neoantigen-reactive CD8 + T cells in gastrointestinal cancer using single-cell sequencing.

BACKGROUND: It appears that tumour-infiltrating neoantigen-reactive CD8 + T (Neo T) cells are the primary driver of immune responses to gastrointestinal cancer in patients. However, the conventional method is very time-consuming and complex for identifying Neo T cells and their corresponding T cell receptors (TCRs). METHODS: By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumour-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. RESULTS: In both training and validation sets, the model performed admirably. We discovered that the majority of Neo T cells exhibited notable differences in the biological processes of amide-related signal pathways. The analysis of potential cell-to-cell interactions, in conjunction with spatial transcriptomic and multiplex immunohistochemistry data, has revealed that Neo T cells possess potent signalling molecules, including LTA, which can potentially engage with tumour cells within the tumour microenvironment, thereby exerting anti-tumour effects. By sequencing CD8 + T cells in tumour samples of patients undergoing neoadjuvant immunotherapy, we determined that the fraction of Neo T cells was significantly and positively linked with the clinical benefit and overall survival rate of patients. CONCLUSION: This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.

Inhibiting arachidonic acid generation mitigates aging-induced hyperinsulinemia and insulin resistance in mice.

BACKGROUND: Aging-related type 2 diabetes (T2DM) is characterized by hyperinsulinemia, insulin resistance, and ß-cell dysfunction. However, the underlying molecular mechanisms remain to be unclear. METHODS: We conducted non-targeted metabolomics to compare human serum samples from young adults (YA), elderly adults (EA), and elderly adults with diabetes (EA + DM) of Chinese population. Adult mice and aged mice were intragastrically administered with varespladib every day for two weeks and metabolic characteristics were monitored. Serum levels of arachidonic acid, insulin, and C-peptide, as well as serum activity of secretory phospholipase A2 (sPLA2) were detected in mice. Mouse islet perfusion assays were used to assess insulin secretion ability. Phosphorylated AKT levels were measured to evaluate insulin sensitivities of peripheral tissues in mice. RESULTS: Non-targeted metabolomics analysis of human serum samples revealed differential metabolic signatures among the YA, EA, and EA + DM groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enhancement of arachidonic acid metabolism and glycerophospholipid metabolism in the EA group compared with the YA group. Further analysis identified two metabolic fluxes that favored the accumulation of arachidonic acid in the elderly. Increased levels of arachidonic acid were also confirmed in aged mice with hyperinsulinemia and insulin resistance, together with subsequent glucose intolerance. Conversely, inhibiting the generation of arachidonic acid with varespladib, an inhibitor of sPLA2, reduced aging-associated diabetes by improving hyperinsulinemia and hepatic insulin resistance in aged mice but not in adult mice. Islet perfusion assays also showed that varespladib treatment suppressed the enhanced insulin secretion observed in aged islets. CONCLUSIONS: Collectively, our findings uncover that arachidonic acid serves as a metabolic hub in Chinese elderly population. Our results also suggest that arachidonic acid plays a fundamental role in regulating ß-cell function during aging and point to a novel therapy for aging-associated diabetes.

Does subclinical hypothyroidism affect the prognosis of patients with chronic systolic heart failure: A systematic review and meta-analysis.

BACKGROUND: Chronic systolic heart failure (CSHF) is a significant health burden with high morbidity and mortality. The role of subclinical hypothyroidism (SCH) in the prognosis of CSHF patients remains a critical area of inquiry. This systematic review and meta-analysis aim to elucidate the impact of SCH on the prognosis of patients with CSHF. METHODS: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, this meta-analysis employed a comprehensive search strategy across major databases including PubMed, Embase, Web of Science, and the Cochrane Library. The Patient, Intervention, Comparison, Outcome framework guided the inclusion of studies focusing on patients with CSHF, comparing those with and without SCH. Quality assessment was performed using the Newcastle-Ottawa scale. Statistical analyses assessed heterogeneity and publication bias, employing fixed-effect or random-effects models based on heterogeneity levels. RESULTS: From an initial pool of 1439 articles, 8 studies met the stringent inclusion criteria. These studies, conducted across diverse geographical regions, highlighted the relationship between SCH and all-cause mortality, cardiac events, and subgroup differences in CSHF patients. The meta-analysis revealed SCH as a significant risk factor for all-cause mortality (HR = 1.42) and cardiac events (HR = 1.46). Subgroup analysis indicated variability in risk based on region, sample size, age, and follow-up duration. Sensitivity analysis confirmed the stability of these findings, and publication bias assessment indicated symmetric funnel plot and nonsignificant Egger test results. CONCLUSIONS: SCH emerges as a predictive factor for all-cause mortality, cardiovascular events, and rehospitalization in CSHF patients. This finding underscores the importance of screening for SCH in CSHF patients, highlighting its potential role in improving patient prognosis.

Viscoelasticity quantification of cancerous tongue using intraoral optical coherence elastography: a preliminary study.

Quantifying the biomechanical properties of the tongue is significant for early diagnosis of tongue carcinoma. Therefore, an intraoral optical coherence elastography system based on a miniature probe was proposed here to evaluate the viscoelasticity of in vivo tongue for the first time. Results of experiments with Sprague-Dawley rats indicate that considerable elasticity diversity occurred between cancerous and normal tongues, and the corresponding ratio of their Young's modulus was evaluated to be 3.74. It is also found that, viscosity in diseased tissue is smaller than that in normal tissue. Additionally, healthy, transitional and cancerous regions in the cancerous tongue can be distinguished easily by calculating viscoelasticity characteristics. Based on this preliminary attempt, our method with advantages of noninvasive, high-resolution, high-sensitivity and real-time detection and convenient operation may have good potential to become a useful tool for tongue carcinoma assessment after further optimization.

BTLA deficiency promotes HSC activation and protects against hepatic ischemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery. APPROACH AND RESULT: A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. "Loss-of-function" experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA-/-) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA-/- mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA-/- mice with hepatic IRI. Furthermore, the TGF-ß1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro. CONCLUSIONS: These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.

Homochiral Tetraphenylethene-Based Metal-Organic Frameworks with Circularly Polarized Luminescence for Enantioselective Recognition.

A pair of water-stable and highly porous homochiral fluorescent silver-organic framework enantiomers, namely, R-Ag-BPA-TPyPE (R-1) and S-Ag-BPA-TPyPE (S-1), had been prepared as enantioselective fluorescence sensors. Combining homochiral 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BPA) with an AIE-based ligand tetrakis[4-(pyridin-4-yl)phenyl]ethene (TPyPE) in complexes R-1 and S-1 made them possess favorable circularly polarized luminescence (CPL) properties, and their CPL spectra were almost mirror images of each other. The luminescence dissymmetry factors (glum) are ±2.2 × 10-3 for R-1 and S-1, and the absolute fluorescence quantum yields (ΦFs) are 32.0% for R-1 and S-1, respectively. Complex R-1 could enantioselectively recognize two enantiomers of amino acids in water or DMF with high Stern-Volmer constants of 236-573 M-1 and enantioselectivity ratios of 1.40-1.78.

Structure information analysis and relative content determination of protein and chitin from yellow mealworm larvae using Raman spectroscopy.

Insect protein extract is one of the high-quality protein sources and is frequently viewed as a potential nutrition alternative. However, a more precise method for protein measurement is still needed due to protein overestimation by the Kjeldahl method due to the presence of a large amount of chitin in insects. Therefore, we demonstrated the monitoring of chitin and protein extracted from yellow mealworm larvae through the information on molecular vibration obtained using Raman spectroscopy and infrared (IR) spectroscopy. The NH vibration at 3475 cm-1 is the characteristic peak of chitin in defatted product observed in the Raman spectra. The nitrogen-to-protein conversion factor in protein extracted from larvae by the Raman method was determined based on the NH vibration and found to be 5.66 ± 0.01. We also compared these experimental data to theoretical Raman and IR spectra and determined the possible reasons for why nitrogen elements in chitin affect the determination of protein content. The method of sequentially removing fat and protein could provide more accurate quantification of protein and chitin. Raman spectroscopy is feasible for various types of insects with high chitin content. Compared with the Kjeldahl method, the Raman method is a faster and more accurate measurement method. Moreover, it provides the content of impurities, purity, and structural information.

The mechanisms of natural products for eye disorders by targeting mitochondrial dysfunction.

The human eye is susceptible to various disorders that affect its structure or function, including glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction has been identified as a critical factor in the pathogenesis and progression of eye disorders, making it a potential therapeutic target in the clinic. Natural products have been used in traditional medicine for centuries and continue to play a significant role in modern drug development and clinical therapeutics. Recently, there has been a surge in research exploring the efficacy of natural products in treating eye disorders and their underlying physiological mechanisms. This review aims to discuss the involvement of mitochondrial dysfunction in eye disorders and summarize the recent advances in the application of natural products targeting mitochondria. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products.

Heterogenetic mechanism in high-temperature Daqu fermentation by traditional craft and mechanical craft: From microbial assembly patterns to metabolism phenotypes.

The mechanical process has a widely usage in large-scale high-temperature Daqu (HTD) enterprises, however, the quality of the mechanical HTD is gapped with the HTD by traditional process. Currently, the understanding of the mechanism behind this phenomenon is still over-constrained. To this end, the discrepancies in fermentation parameters, enzymatic characteristics, microbial assembly and succession patterns, metabolic phenotypes were compared between traditional HTD and mechanical HTD in this paper. The results showed that mechanical process altered the temperature ramping procedure, resulting in a delayed appearance of the peak temperature. This alteration shifted the assembly pattern of the initial bacterial community from determinism to stochasticity, while having no impact on the stochastic assembly pattern of the fungal community. Concurrently, mechanical pressing impeded the accumulation of arginase, tetramethylpyrazine, trimethylpyrazine, 2-methoxy-4-vinylphenol, and butyric acid, as the target dissimilarities in metabolism between traditional HTD and mechanical HTD. Pearson correlation analysis combined with the functional prediction further demonstrated that Bacillus, Virgibacillus, Oceanobacillus, Kroppenstedtia, Lactobacillus, and Monascus were mainly contributors to metabolic variances. The Redundancy analysis (RDA) of fermented environmental factors on functional ASVs indicated that high temperature, high acid and low moisture were key positive drivers on the microbial metabolism for the characteristic flavor in HTD. Based on these results, heterogeneous mechanisms between traditional HTD and mechanical HTD were explored, and controllable metabolism targets were as possible strategies to improve the quality of mechanical HTD.

Single-Cell Transcriptome Landscape and Cell Fate Decoding in Human Brain Organoids after Transplantation.

Human stem cells and derivatives transplantation are widely used to treat nervous system diseases, while the fate determination of transplanted cells is not well elucidated. To explore cell fate changes of human brain organoids before and after transplantation, human brain organoids are transplanted into prefrontal cortex (PFC) and hippocampus (HIP), respectively. Single-cell sequencing is then performed. According to time-series sample comparison, transplanted cells mainly undergo neural development at 2 months post-transplantation (MPT) and then glial development at 4MPT, respectively. A different brain region sample comparison shows that organoids grafted to PFC have obtained cell fate close to those of host cells in PFC, other than HIP, which may be regulated by the abundant expression of dopamine (DA) and acetylcholine (Ach) in PFC. Meanwhile, morphological complexity of human astrocyte grafts is greater in PFC than in HIP. DA and Ach both activate the calcium activity and increase morphological complexity of astrocytes in vitro. This study demonstrates that human brain organoids receive host niche factor regulation after transplantation, resulting in the alignment of grafted cell fate with implanted brain regions, which may contribute to a better understanding of cell transplantation and regenerative medicine.

Comprehensive comparison between conservative therapy and surgical management for completely displaced and comminuted mid-shaft clavicle fractures.

PURPOSE: It is still controversial whether complete displaced mid-shaft clavicle fractures should be treated with internal fixation or conservative therapy. This retrospective study aims to compare clinical outcomes of two treatment protocols. MATERIALS AND METHODS: 105 patients with displaced and comminuted mid-shaft clavicle fractures were included in this study, among which 55 patients were treated conservatively and 50 patients accepted surgical fixation and were followed up for over 20 months on average. Rate of union, malunion, time taken for union, functional outcome, self-reported satisfaction and complications were compared. RESULTS: Union rate of operative group (n=49, 98.0%) was higher than the non-operative group (n=48, 87.3%). Time taken for union in operative group (2.37±1.06 months) was shorter than the non-operative group (3.69±1.01 months). Malunion and asymmetric were only seen in the conservative group. Numbness of the shoulder was only reported in the operative group (n=23, 46.0%). Most of patients in the operative group (n=45, 90%) accepted a second operation to remove the implant. No statistically difference was found in self-reported satisfaction, Quick-DASH and Constant-Murley score. The operative group returned to work faster (1.47±0.89 to 3.34±1.37 months), regained full range of motion earlier (1.66±0.78 to 3.83±1.24 months) and regained strength faster (3.86±2.45 to 8.03±2.78 months) than the non-operative group. CONCLUSION: Complete displaced and comminuted mid-shaft clavicle fractures treated surgically have more reliable union and faster recovery when compared to conservatively treated fractures.

Artificial intelligence enhances whole-slide interpretation of PD-L1 CPS in triple-negative breast cancer: A multi-institutional ring study.

BACKGROUND AND AIMS: Evaluation of the programmed cell death ligand-1 (PD-L1) combined positive score (CPS) is vital to predict the efficacy of the immunotherapy in triple-negative breast cancer (TNBC), but pathologists show substantial variability in the consistency and accuracy of the interpretation. It is of great importance to establish an objective and effective method which is highly repeatable. METHODS: We proposed a model in a deep learning-based framework, which at the patch level incorporated cell analysis and tissue region analysis, followed by the whole-slide level fusion of patch results. Three rounds of ring studies (RSs) were conducted. Twenty-one pathologists of different levels from four institutions evaluated the PD-L1 CPS in TNBC specimens as continuous scores by visual assessment and our artificial intelligence (AI)-assisted method. RESULTS: In the visual assessment, the interpretation results of PD-L1 (Dako 22C3) CPS by different levels of pathologists have significant differences and showed weak consistency. Using AI-assisted interpretation, there were no significant differences between all pathologists (P = 0.43), and the intraclass correlation coefficient (ICC) value was increased from 0.618 [95% confidence interval (CI) = 0.524-0.719] to 0.931 (95% CI = 0.902-0.955). The accuracy of interpretation result is further improved to 0.919 (95% CI = 0.886-0.947). Acceptance of AI results by junior pathologists was the highest among all levels, and 80% of the AI results were accepted overall. CONCLUSION: With the help of the AI-assisted diagnostic method, different levels of pathologists achieved excellent consistency and repeatability in the interpretation of PD-L1 (Dako 22C3) CPS. Our AI-assisted diagnostic approach was proved to strengthen the consistency and repeatability in clinical practice.