Measurement of Electron Antineutrino Oscillation Amplitude and Frequency via Neutron Capture on Hydrogen at Daya Bay.

This Letter reports the first measurement of the oscillation amplitude and frequency of reactor antineutrinos at Daya Bay via neutron capture on hydrogen using 1958 days of data. With over 3.6 million signal candidates, an optimized candidate selection, improved treatment of backgrounds and efficiencies, refined energy calibration, and an energy response model for the capture-on-hydrogen sensitive region, the relative ν[over ¯]_{e} rates and energy spectra variation among the near and far detectors gives sin^{2}2θ_{13}=0.0759_{-0.0049}^{+0.0050} and Δm_{32}^{2}=(2.72_{-0.15}^{+0.14})×10^{-3} eV^{2} assuming the normal neutrino mass ordering, and Δm_{32}^{2}=(-2.83_{-0.14}^{+0.15})×10^{-3} eV^{2} for the inverted neutrino mass ordering. This estimate of sin^{2}2θ_{13} is consistent with and essentially independent from the one obtained using the capture-on-gadolinium sample at Daya Bay. The combination of these two results yields sin^{2}2θ_{13}=0.0833±0.0022, which represents an 8% relative improvement in precision regarding the Daya Bay full 3158-day capture-on-gadolinium result.

Search for a Sub-eV Sterile Neutrino Using Daya Bay's Full Dataset.

This Letter presents results of a search for the mixing of a sub-eV sterile neutrino with three active neutrinos based on the full data sample of the Daya Bay Reactor Neutrino Experiment, collected during 3158 days of detector operation, which contains 5.55×10^{6} reactor ν[over ¯]_{e} candidates identified as inverse beta-decay interactions followed by neutron capture on gadolinium. The analysis benefits from a doubling of the statistics of our previous result and from improvements of several important systematic uncertainties. No significant oscillation due to mixing of a sub-eV sterile neutrino with active neutrinos was found. Exclusion limits are set by both Feldman-Cousins and CLs methods. Light sterile neutrino mixing with sin^{2}2θ_{14}≳0.01 can be excluded at 95% confidence level in the region of 0.01 eV^{2}≲|Δm_{41}^{2}|≲0.1 eV^{2}. This result represents the world-leading constraints in the region of 2×10^{-4} eV^{2}≲|Δm_{41}^{2}|≲0.2 eV^{2}.

Combined radiomics nomogram of different machine learning models for preoperative distinguishing intraspinal schwannomas and meningiomas: a multicenter and comparative study.

AIMS: The objective of our study was to establish and verify a novel combined model based on multiparameter magnetic resonance imaging (MRI) radiomics and clinical features to distinguish intraspinal schwannomas from meningiomas. MATERIALS AND METHODS: This research analyzed the preoperative magnetic resonance (MR) images and clinical characteristics of 209 patients with intraspinal tumors who received tumor resection at three institutions. 159 individuals from institutions 1 and 2 were randomly assigned into a training group (n=111) and a test group (n=48) in a 7-3 ratio. A nomogram was constructed using the training cohort and was internally and externally verified in the test cohort and an independent validation cohort (n=50). Model performance was assessed utilizing the area under the curve (AUC) of receiver operating characteristics (ROC), decision curve analysis (DCA), and calibration curves. RESULTS: The nomogram exhibited superior predictive efficacy in distinguishing between spinal schwannomas and meningiomas when compared to both the radiomics model and the clinical model. The nomogram yielded AUCs of 0.994, 0.962, and 0.949 in the training, test, and external validation cohorts, respectively, indicating its exceptional differentiating ability. The DCAs demonstrated that the nomogram yielded the best net benefit. The calibration curves indicated that the nomogram got good agreement between the predicted and the actual observation. CONCLUSION: This research suggests that the nomogram incorporating clinical and radiomic features may be an effective auxiliary tool for distinguishing between intraspinal schwannomas and meningiomas, and has important clinical significance for clinical decision-making and prognosis prediction.

[Analysis of the effect of early subcutaneous specific immunotherapy on the levels of dust mite allergen-specific antibodies and polyunsaturated fatty acid metabolism].

Objective: To investigate the effects of subcutaneous immunotherapy (SCIT) on patients' immune markers and metabolic levels in the early stage of allergen treatment, and to gain insight into the role of SCIT in regulating immune responses and metabolic levels, so as to provide reference data for the further discovery of potential biomarkers. Methods: A longitudinal study was used to include 40 subjects who underwent SCIT with dust mite allergens in the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University between November 2017 and February 2022, including 20 subjects each of single mite subcutaneous immunotherapy (SM-SCIT) and double mite subcutaneous immunotherapy (DM-SCIT). In this study, levels of dust mite allergen-specific antibodies and polyunsaturated fatty acid metabolism were measured before and 12 months after treatment, while pulmonary function tests were performed. The therapeutic effects of the patients were followed up by visual analogue scale (VAS), asthma control test (ACT) and total medication scores (TMS). The results were statistically analyzed using t-test and Mann-Whitney U-test. Results: After 12 months of treatment with SCIT, both groups showed a significant decrease in total VAS score (SM-SCIT:Z=-2.298, P<0.05; DM-SCIT:Z=-3.411, P<0.001); total ACT score (SM-SCIT:Z=-2.054, P<0.05; DM-SCIT:Z=-2.014, P<0.05) and total medication scores (SM-SCIT:Z=-3.799, P<0.000 1; DM-SCIT:Z=-3.474, P<0.001) were significantly higher, in addition to significantly higher MMEF75/25 values in the DM-SCIT group (t=-2.253, P<0.05). There was no significant change in sIgE in the SM-SCIT group (P>0.05), and the sIgG4 levels of the Der p, Der f, p 1, p 2, f 2, and p 21 fractions were significantly elevated (Z=-2.651, -3.771, -2.949, -2.912, -2.725, -2.128, and -3.285, respectively, all P<0.05); The sIgE of Der p 2, f 2, p 7 and p 23 fractions(Z=-2.651, -3.771, -2.949, -2.912, -2.725, -2.128, -3.285, all P<0.05) and the sIgG4 levels of the Der p, Der f, p 1, p 2, f 1, f 2, p 10, p 21 and p 23 fractions (Z=-3.808, -3.845, -3.061, -2.688, -2.464, -3.211, -2.371, -2.091, -2.427, all P<0.05) of the DM-SCIT group were significantly elevated. Metabolomics analysis showed that arachidonic acid, docosahexaenoic acid, docosapentaenoic acid, eicosapentaenoic acid, 5, 9, 12-octadecatrienoic acid, 5(S)-hydroxylated eicosatetraenoic acid, and dihomo-gamma-linolenic acid were significantly elevated at the beginning of the treatment period after SM-SCIT treatment (Z of -2.191, -2.497, -1.988, -2.090, -2.19, -2.803, -2.073, all P<0.05); 5(S)-hydroxylated eicosatetraenoic acid showed elevated and alpha-linolenic acid, eicosadienoic acid, and eicosapentaenoic acid were significantly decreased in the DM-SCIT group after treatment (Z=-1.988, -2.090, -2.497, -1.988, respectively, all P<0.05). Correlation analysis showed that arachidonic acid was significantly negatively correlated with changes in dust mite-specific IgG4 (r=-0.499, P<0.05), and that alpha-linolenic acid, 5, 9, 12-octadecatrienoic acid, and eicosapentaenoic acid were positively correlated with the ΔsIgG4 of the dust mite der p 2 (r=0.451, 0.420, 0.474, respectively; all P<0.05). Conclusion: Significant changes in allergen-specific antibody levels and polyunsaturated fatty acid metabolism levels occur during SCIT, and the two may interact and influence each other.

[Spatial distribution pattern of local tumor progression analysis after microwave ablation of hepatocellular carcinoma based on three-dimensional magnetic resonance imaging].

Objective: To investigate the spatial distribution pattern of local tumor progression (LTP) for hepatocellular carcinoma (HCC) ≤5 cm after microwave ablation. Methods: A retrospective analysis was performed on 169 HCCs with matched MRI before and after ablation from December 2009 to December 2019. A tumor MRI was reconstructed using three-dimensional visualization technology. LTP was classified as contact or non-contact, early or late stage, according to whether LTP was in contact with the edge of the ablation zone and the occurrence time (24 months). The tumor-surrounded area was divided into eight quadrants by using the eight-quadrant map method. An analysis was conducted on the spatial correlation between the quadrant where the ablative margin (AM) safety boundary was located and the quadrant where different types of LTP occurred. The t-test, or rank-sum test, was used for the measurement data. 2-test for count data was used to compare the difference between the two groups. Results: The AM quadrant had a distribution of 54.4% LTP, 64.2% early LTP stage, and 69.1% contact LTP, suggesting this quadrant was much more concentrated than the other quadrants (P < 0.001). Additionally, the AM quadrant had only 15.2% of non-contact type LTP and 17.1% of late LTP, which was not significantly different from the average distribution probability of 12.5% (100/8%) among the eight quadrants (P = 0.667, 0.743). 46.6% of early contact type LTP was located at the ablation needle tip, 25.2% at the body, and 28.1% at the caudal, while the location distribution probabilities of non-early contact LTP were 34.8%, 31.8%, and 33.3%, respectively. Conclusion: LTP mostly occurs in areas where the ablation safety boundary is the shortest. However, non-contact LTP and late LTP stages exhibit the feature of uniform distribution. Thus, this type of LPT may result from an inadequate non-ablation safety boundary.

[Curative effect of percutaneous microwave ablation therapy on hepatocellular carcinoma survival: a 15-year real-world study].

Objective: To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma. Methods: 2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival. Results: A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P < 0.001, especially for liver cancer 3.1~5.0 cm (P < 0.001). Conclusion: Microwave ablation therapy is a safe and effective method for BCLC stage 0-B, with significantly enhanced technical efficacy and survival rate over time.

[Correlation analysis between Pirani score and talo-navicular angle,calcaneo-cuboid angle and tibio-calcaneall angle of infant clubfoot under ultrasound].

Objective: To explore the evaluation effect of ultrasonography and Pirani score on tarsal deformity, treatment effect and pseudo-correction of congenital clubfoot in infants and young children, and the correlation between the two methods. Methods: This is a retrospective case series study. The clinical data of 26 children (40 feet) with congenital clubfoot who were evaluated by ultrasonography in the Third Affiliated Hospital of Zhengzhou University from January 2020 to January 2023 were retrospectively collected. There were 16 males and 10 females. The age at the first ultrasound examination was (M(IQR)) 9.0 (18.0) days (range: 1 to 46 days). All patients were treated with Ponseti method by the same physician. The Pirani scores before and after treatment and at the last examination, and the talonavicular angle, calcaneocuboid angle and tibiocalcaneal angle measured by ultrasound were collected, and the treatment and follow-up were recorded. Paired sample t test, repeated measures analysis of variance or Kruskal-Wallis test were used for data comparison, and Spearman correlation analysis was used for correlation analysis. The receiver operating characteristic curve was used to calculate the efficacy of ultrasound in evaluating different Pirani scores. Results: The number of plaster fixation in 26 children was 4.0 (1.0) times (range: 2 to 8 times). The medial talonavicular angle and posterior tibiocalcaneal angle were significantly improved after treatment and at the last follow-up compared with those before treatment, and the differences were statistically significant (all P<0.01). There was no difference in lateral calcaneocuboid angle before and after treatment and at the last follow-up (F=1.971, P>0.05). Pseudo-correction occurred in 2 cases (2 feet) during the treatment, with an incidence of 5%. Correlation analysis showed that there was a moderate positive correlation between talonavicular angle and Pirani midfoot score (r=0.480, P<0.01). There was no correlation between calcaneocuboid angle and Pirani midfoot score (r=0.114, P=0.105). There was a moderate negative correlation between tibial heel angle and Pirani hindfoot score (r=-0.566, P<0.01). The cut-off point of Pirani midfoot score of 1.5 was 38.78°, the sensitivity was 0.90, the specificity was 0.56, and the area under the curve was 0.75. The cut-off value of angle was 27.51 °, the sensitivity was 0.16, the specificity was 0.92, and the area under the curve was 0.44.The cut-off points of Pirani midfoot score of 3.0 were 45.08°and 9.96°, the sensitivity was 0.94 and 0.91, the specificity was 0.37 and 0.42, and the area under the curve was 0.59 and 0.62, respectively. The cut-off values of Pirani hindfoot score of 2.0 and 3.0 were 167.46° and 160.15°, respectively. The sensitivity was 0.75 and 0.67, the specificity was 0.81 and 0.83, and the area under the curve was 0.78 and 0.71, respectively. Conclusion: Ultrasound can complement with Pirani score, visually and dynamically observe the morphology and position changes of talonavicular joint, calcaneocuboid joint and tibiotalocalcaneal joint, monitor the recovery and pseudo-correction of tarsal bones, and better evaluate the therapeutic effect.

Improved Measurement of the Evolution of the Reactor Antineutrino Flux and Spectrum at Daya Bay.

Reactor neutrino experiments play a crucial role in advancing our knowledge of neutrinos. In this Letter, the evolution of the flux and spectrum as a function of the reactor isotopic content is reported in terms of the inverse-beta-decay yield at Daya Bay with 1958 days of data and improved systematic uncertainties. These measurements are compared with two signature model predictions: the Huber-Mueller model based on the conversion method and the SM2018 model based on the summation method. The measured average flux and spectrum, as well as the flux evolution with the ^{239}Pu isotopic fraction, are inconsistent with the predictions of the Huber-Mueller model. In contrast, the SM2018 model is shown to agree with the average flux and its evolution but fails to describe the energy spectrum. Altering the predicted inverse-beta-decay spectrum from ^{239}Pu fission does not improve the agreement with the measurement for either model. The models can be brought into better agreement with the measurements if either the predicted spectrum due to ^{235}U fission is changed or the predicted ^{235}U, ^{238}U, ^{239}Pu, and ^{241}Pu spectra are changed in equal measure.

Precision Measurement of Reactor Antineutrino Oscillation at Kilometer-Scale Baselines by Daya Bay.

We present a new determination of the smallest neutrino mixing angle θ_{13} and the mass-squared difference Δm_{32}^{2} using a final sample of 5.55×10^{6} inverse beta-decay (IBD) candidates with the final-state neutron captured on gadolinium. This sample is selected from the complete dataset obtained by the Daya Bay reactor neutrino experiment in 3158 days of operation. Compared to the previous Daya Bay results, selection of IBD candidates has been optimized, energy calibration refined, and treatment of backgrounds further improved. The resulting oscillation parameters are sin^{2}2θ_{13}=0.0851±0.0024, Δm_{32}^{2}=(2.466±0.060)×10^{-3} eV^{2} for the normal mass ordering or Δm_{32}^{2}=-(2.571±0.060)×10^{-3} eV^{2} for the inverted mass ordering.

Risk factors for diabetic foot ulcers: A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the risk factors for developing diabetic foot ulcers (DFU). METHODS: The Cochrane Library, PubMed, Web of Science, SinoMed, CNKI, VIP, and Wanfang Data were searched for relevant studies on DFU risk factors, and the search time frame was from database creation to March 2022. Meta-analysis was performed using RevMan 5.3. RESULTS: A total of 26 publications were included, including 3 cohort studies, 22 case-control studies, and one cross-sectional study. Meta-analysis showed that advanced age [MD = 6.04, 95% CI (3.92, 8.16)], male [OR = 1.84, 95% CI (1.48, 2.29)], elevated body mass index [MD = 1.58, 95% CI (0.47, 2.69)], prolonged duration of diabetes [MD = 2.72, 95% CI (2.33, 3.11)], comorbid nephropathy [OR = 3.15, 95% CI (2.68, 4.60)], comorbid neuropathy [OR = 4.80, 95% CI (2.79, 8.27)], comorbid retinopathy [OR = 3.37, 95% CI (2.26, 5.02)], elevated systolic blood pressure [OR = 8.19, 95% CI (6.33, 10.05)], elevated fasting glucose [MD = 1.60, 95% CI (0.21, 3.00)], elevated glycated hemoglobin [MD = 1.24, 95% CI (0.94, 1.54)], elevated triglycerides [MD = 0.44 (95% CI (0.15, 0.73)], elevated fibrinogen [MD = 1.35, 95% CI (0.62, 2.08)], elevated white blood cell count [MD = 2.56, 95% CI (2.24, 2.88)], elevated C-reactive protein [MD = 15.08, 95% CI (8.03, 22.13)], decreased ankle-brachial ratio [MD = -0.26, 95% CI (-0.36, -0.16)], and decreased total protein levels [MD = -4.58, 95% CI (-6.91, -2.25)] were risk factors for developing DFU (p < 0.05), and increased HDL cholesterol levels [MD = -0.22, 95% CI (-0.36, -0.08)] were protective factor for developing DFU (p < 0.05). CONCLUSION: There are many risk factors for developing of ulcers in the diabetic feet, and early prevention and intervention should be performed as early as possible to assess the risk of developing diabetic foot patients.

Influence of the concentrate inclusion level in a grass silage-based diet on hepatic transcriptomic profiles in Holstein-Friesian dairy cows in early lactation.

Excessive negative energy balance in early lactation is linked to an increased disease risk but may be mitigated by appropriate nutrition. The liver plays central roles in both metabolism and immunity. Hepatic transcriptomic profiles were compared between 3 dietary groups in each of 40 multiparous and 18 primiparous Holstein-Friesian cows offered isonitrogenous grass silage-based diets with different proportions of concentrates: (1) low concentrate (LC, 30% concentrate + 70% grass silage); (2) medium concentrate (MC, 50% concentrate + 50% grass silage), or (3) high concentrate (HC, 70% concentrate + 30% grass silage). Liver biopsies were taken from all cows at around 14 d in milk for RNA sequencing, and blood metabolites were measured. The sequencing data were analyzed separately for primiparous and multiparous cows using CLC Genomics Workbench V21 (Qiagen Digital Insights), focusing on comparisons between HC and LC groups. More differentially expressed genes (DEG) were seen between the primiparous cows receiving HC versus LC diets than for multiparous cows (597 vs. 497), with only 73 in common, indicating differential dietary responses. Multiparous cows receiving the HC diet had significantly higher circulating glucose and insulin-like growth factor-1 and lower urea than those receiving the LC diet. In response to HC, only the multiparous cows produced more milk. In these animals, bioinformatic analysis indicated expression changes in genes regulating fatty acid metabolism and biosynthesis (e.g., ACACA, ELOVL6, FADS2), increased cholesterol biosynthesis (e.g., CYP7A1, FDPS, HMGCR), downregulation in hepatic AA synthesis (e.g., GPT, GCLC, PSPH, SHMT2), and decreased expression of acute phase proteins (e.g., HP, LBP, SAA2). The primiparous cows on the HC diet also downregulated genes controlling AA metabolism and synthesis (e.g., CTH, GCLC, GOT1, ODC1, SHMT2) but showed higher expression of genes indicative of inflammation (e.g., CCDC80, IL1B, S100A8) and fibrosis (e.g., LOX, LUM, PLOD2). This potentially adverse response to a HC diet in physically immature animals warrants further investigation.

[Effect of SLC7A11 gene downregulation on the gefitinib resistance of lung adenocarcinoma PC9/GR cells and its mechanism].

Objective: To screen the key genes involved in gefitinib resistance of lung adenocarcinoma PC9/GR cells which harbored 19 exon mutation of epidermal growth factor receptor (EGFR) gene, and discuss the effect and mechanism of downregulation of solute carrier family 7 member 11 (SLC7A11) on the gefitinib resistance of PC9/GR cells. Methods: RNA microarray was conducted to detect the gene expressions in PC9 and PC9/GR cells. The differently expressed genes were screened by using limma package of R language and analyzed by Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Western blotting was performed to determine the expression of SLC7A11 protein in PC9 and PC9/GR cells. PC9/GR cells were infected with lentivirus plasmid containing short hairpin RNA (shRNA) targeting SLC7A11 or negative control shRNA (sh-NC), respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the efficacy of shRNA on the expression of SLC7A11 mRNA. Cell counting kit-8 (CCK-8) assay was conducted to determine the suppressing effect of gefitinib on PC9/GR cells. Mito-Tracker Red CMXRos probe and malondialdehyde (MDA) assay kit were used to evaluate gefitinib-induced ferroptosis in PC9/GR cells. Immunohistochemistry (IHC) was conducted to detect the expression of SLC7A11 protein in the tumor tissues of advanced stage lung adenocarcinoma patients harboring 19 exon mutation of EGFR gene. Thirty-six advanced stage lung adenocarcinoma patients who received EGFR-tyrosihe kinase inhibitor(TKI) as first-line treatment in Fourth Hospital of Hebei Medical Unviersity were enrolled. Kaplan-Meier survival curve was drawn to analyze the correlation between SLC7A11 expression and progression-free survival (PFS) of the patients. Results: RNA array demonstrated that 2 888 genes were differently expressed between PC9 and PC9/GR cells. KEGG analysis showed that ferroptosis-related gene was one of the most enriched region of the differently expressed genes between PC9 and PC9/GR cells. These ferroptosis-related gene cohort contained 13 genes, among which SLC7A11 exhibited the most significant difference. Western blotting showed that the expression of SLC7A11 protein in PC9/GR cells was significantly higher than that in PC9 cells (0.76±0.03 vs. 0.19±0.02, P<0.001). The 50% inhibiting concentration (IC(50)) of gefitinib was 35.08 µmol/L and 64.01 µmol/L for sh-SLC7A11 and sh-NC group PC9/GR cells, respectively. PC9/GR cells in sh-SLC7A11 group exhibited significantly lower density of mitochondria fluorescence after gefitinib treatment, compared to the sh-NC group (213.77±26.50 vs. 47.88±4.55, P<0.001). In addition, PC9/GR cells in sh-SLC7A11 group exhibited significantly higher MDA after gefitinib treatment, compared to the sh-NC group [(15.43±1.60) µmol/mg vs. (82.18±7.77) µmol/mg, P<0.001]. The PFS of the patients with low expression of SLC7A11 (n=18) was significantly longer than the patients with high expression of SLC7A11 (n=18, 16.77 months vs. 9.14 months, P<0.001). Conclusion: Downregulation of SLC7A11 could increase the sensitivity of PC9/GR cells to gefitinib by promoting ferroptosis.

[Efficacy analysis of surgical combined with postoperative adjuvant therapy for T3 gallbladder carcinoma: a multicenter retrospective study].

Objective: To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection. Methods: Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A,n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B,n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results: After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A (χ2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% (χ2=4.042,P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% (χ2=0.992,P=0.319). Conclusions: Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

[Effect of postoperative adjuvant chemotherapy on prognosis of patients with intrahepatic cholangiocarcinoma:a multicenter retrospective study].

Objectives: To examine the influence of adjuvant chemotherapy after radical resection on the survival of patients with intrahepatic cholangiocarcinoma(ICC) and to identify patients who may benefit from it. Methods: The clinical and pathological data of 654 patients with ICC diagnosed by postoperative pathology from December 2011 to December 2017 at 13 hospitals in China were collected retrospectively. According to the inclusion and exclusion criteria,455 patients were included in this study,including 69 patients (15.2%) who received adjuvant chemotherapy and 386 patients (84.8%) who did not receive adjuvant chemotherapy. There were 278 males and 177 females,with age of 59 (16) years (M(IQR))(range:23 to 88 years). Propensity score matching (PSM) method was used to balance the difference between adjuvant chemotherapy group and non-adjuvant chemotherapy group. Kaplan-Meier method was used to plot the survival curve,the Log-rank test was used to compare the difference of overall survival(OS) and recurrence free survival(RFS)between the two groups. Univariate analysis was used to determine prognostic factors for OS. Multivariate Cox proportional hazards models were then performed for prognostic factors with P<0.10 to identify potential independent risk factors. The study population were stratified by included study variables and the AJCC staging system,and a subgroup analysis was performed using the Kaplan-Meier method to explore the potential benefit subgroup population of adjuvant chemotherapy. Results: After 1∶1 PSM matching,69 patients were obtained in each group. There was no significant difference in baseline data between the two groups (all P>0.05). After PSM,Cox multivariate analysis showed that lymph node metastasis (HR=3.06,95%CI:1.52 to 6.16,P=0.039),width of resection margin (HR=0.56,95%CI:0.32 to 0.99,P=0.044) and adjuvant chemotherapy (HR=0.51,95%CI:0.29 to 0.91,P=0.022) were independent prognostic factors for OS. Kaplan-Meier analysis showed that the median OS time of adjuvant chemotherapy group was significantly longer than that of non-adjuvant chemotherapy group (P<0.05). There was no significant difference in RFS time between the adjuvant chemotherapy group and the non-adjuvant chemotherapy group (P>0.05). Subgroup analysis showed that,the OS of female patients,without HBV infection,carcinoembryonic antigen<9.6 µg/L,CA19-9≥200 U/ml,intraoperative bleeding<400 ml,tumor diameter>5 cm,microvascular invasion negative,without lymph node metastasis,and AJCC stage Ⅲ patients could benefit from adjuvant chemotherapy (all P<0.05). Conclusion: Adjuvant chemotherapy can prolong the OS of patients with ICC after radical resection,and patients with tumor diameter>5 cm,without lymph node metastasis,AJCC stage Ⅲ,and microvascular invasion negative are more likely to benefit from adjuvant chemotherapy.

[Survival analysis of patients with intrahepatic cholangiocarcinoma treated with adjuvant chemotherapy after radical resection based on CoxPH model and deep learning algorithm].

Objective: To establish a predictive model for survival benefit of patients with intrahepatic cholangiocarcinoma (ICC) who received adjuvant chemotherapy after radical resection. Methods: The clinical and pathological data of 249 patients with ICC who underwent radical resection and adjuvant chemotherapy at 8 hospitals in China from January 2010 to December 2018 were retrospectively collected. There were 121 males and 128 females,with 88 cases>60 years old and 161 cases≤60 years old. Feature selection was performed by univariate and multivariate Cox regression analysis. Overall survival time and survival status were used as outcome indicators,then target clinical features were selected. Patients were stratified into high-risk group and low-risk group,survival differences between the two groups were analyzed. Using the selected clinical features, the traditional CoxPH model and deep learning DeepSurv survival prediction model were constructed, and the performance of the models were evaluated according to concordance index(C-index). Results: Portal vein invasion, carcinoembryonic antigen>5 µg/L,abnormal lymphocyte count, low grade tumor pathological differentiation and positive lymph nodes>0 were independent adverse prognostic factors for overall survival in 249 patients with adjuvant chemotherapy after radical resection (all P<0.05). The survival benefit of adjuvant chemotherapy in the high-risk group was significantly lower than that in the low-risk group (P<0.05). Using the above five features, the traditional CoxPH model and the deep learning DeepSurv survival prediction model were constructed. The C-index values of the training set were 0.687 and 0.770, and the C-index values of the test set were 0.606 and 0.763,respectively. Conclusion: Compared with the traditional Cox model, the DeepSurv model can more accurately predict the survival probability of patients with ICC undergoing adjuvant chemotherapy at a certain time point, and more accurately judge the survival benefit of adjuvant chemotherapy.

[A nomogram for preoperative prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma based on inflammation-related markers].

Objectives: To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification. Methods: Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology. Results: The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively (P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95%CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95%CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test:P=0.082 and 0.510,respectively). Conclusion: The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2.

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2 in NaV1.8-positive neurons (Par2Nav1.8), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par2Nav1.8 and Lgmn deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons from WT female mice. Par2 deletion, LI-1, and inhibitors of adenylyl cyclase or protein kinase A (PKA) prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N terminus of PAR2 at Asn30↓Arg31, proximal to the canonical trypsin activation site. Lgmn activated PAR2 by biased mechanisms in HEK293 cells to induce Ca2+ mobilization, cAMP formation, and PKA/protein kinase D (PKD) activation, but not ß-arrestin recruitment or PAR2 endocytosis. Thus, in the acidified OSCC microenvironment, Lgmn activates PAR2 by biased mechanisms that evoke cancer pain.SIGNIFICANCE STATEMENT Oral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR2) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared with matched normal oral tissue. Lgmn evokes pain-like behavior through PAR2 Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR2 Inhibitors of adenylyl cyclase and protein kinase A (PKA) prevented the effects of Lgmn. Lgmn activated PAR2 to induce calcium mobilization, cAMP formation, and activation of protein kinase D (PKD) and PKA, but not ß-arrestin recruitment or PAR2 endocytosis. Thus, Lgmn is a biased agonist of PAR2 that evokes cancer pain.

First Measurement of High-Energy Reactor Antineutrinos at Daya Bay.

This Letter reports the first measurement of high-energy reactor antineutrinos at Daya Bay, with nearly 9000 inverse beta decay candidates in the prompt energy region of 8-12 MeV observed over 1958 days of data collection. A multivariate analysis is used to separate 2500 signal events from background statistically. The hypothesis of no reactor antineutrinos with neutrino energy above 10 MeV is rejected with a significance of 6.2 standard deviations. A 29% antineutrino flux deficit in the prompt energy region of 8-11 MeV is observed compared to a recent model prediction. We provide the unfolded antineutrino spectrum above 7 MeV as a data-based reference for other experiments. This result provides the first direct observation of the production of antineutrinos from several high-Q_{ß} isotopes in commercial reactors.

Joint Determination of Reactor Antineutrino Spectra from

A joint determination of the reactor antineutrino spectra resulting from the fission of ^{235}U and ^{239}Pu has been carried out by the Daya Bay and PROSPECT Collaborations. This Letter reports the level of consistency of ^{235}U spectrum measurements from the two experiments and presents new results from a joint analysis of both data sets. The measurements are found to be consistent. The combined analysis reduces the degeneracy between the dominant ^{235}U and ^{239}Pu isotopes and improves the uncertainty of the ^{235}U spectral shape to about 3%. The ^{235}U and ^{239}Pu antineutrino energy spectra are unfolded from the jointly deconvolved reactor spectra using the Wiener-SVD unfolding method, providing a data-based reference for other reactor antineutrino experiments and other applications. This is the first measurement of the ^{235}U and ^{239}Pu spectra based on the combination of experiments at low- and highly enriched uranium reactors.

Bifocal 532/1064 nm alternately illuminated photoacoustic microscopy for capturing deep vascular morphology in human skin.

BACKGROUND: As a promising technology, photoacoustic microscopy (PAM) plays a critical role in diagnosis and assessment of dermatological conditions by providing subtle vascular networks non-invasively. However, the established PAMs are insufficient for clinical dermatology when faced with complex structures of human skin instead of animal models owing to high melanin content and superimposed vasculature for Asians, which cannot balance the spatial resolution and the imaging depth. OBJECTIVES: To evaluate the ability of bifocal 532/1064-nm alternately illuminated photoacoustic microscopy (BF-PAM) to non-invasively reveal the morphological structure of human skin for improving the diagnosis and therapeutic efficacy of skin diseases. METHODS: A BF-PAM was developed to capture biopsy-like information of human skin from epidermis to hypodermis. The optical foci of the two excitation beams are staggered in the axial direction to form an extended depth-of-field, which can maintain the lateral resolution and the contrast of PA image. RESULTS: The imaging capability of the BF-PAM was demonstrated by depicting the vascular morphology of multilayered skin with imaging depth of ˜3 mm. Furtherly, vascular malformations in port-wine stains skin were quantitatively assessed without the need for any contrast agent, and the distribution, depth and diameter of the ectatic vessels can determine an optimal treatment protocol for port-wine stains lesions. CONCLUSIONS: The quantitative vascular morphology in the dermis can be used to accurately assess vascular characteristics, in which case it enables clinicians to determine optimum treatment parameters in individual patients. As a non-invasive imaging technique, BF-PAM holds great potential to provide objective assessment to enhance the therapeutic efficacy. ETHICAL STATEMENT: The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20200184) and registered with Chinese Clinical Trial Registry (ChiCTR2000034400). Before skin imaging, written informed consent was taken from all individual participants.