Spin-orbit-driven band inversion in bilayer graphene by the van der Waals proximity effect.

Spin-orbit coupling (SOC) is the key to realizing time-reversal-invariant topological phases of matter1,2. SOC was predicted by Kane and Mele3 to stabilize a quantum spin Hall insulator; however, the weak intrinsic SOC in monolayer graphene4-7 has precluded experimental observation in this material. Here we exploit a layer-selective proximity effect-achieved via a van der Waals contact with a semiconducting transition-metal dichalcogenide8-21-to engineer Kane-Mele SOC in ultra clean bilayer graphene. Using high-resolution capacitance measurements to probe the bulk electronic compressibility, we find that SOC leads to the formation of a distinct, incompressible, gapped phase at charge neutrality. The experimental data agree quantitatively with a simple theoretical model in which the new phase results from SOC-driven band inversion. In contrast to Kane-Mele SOC in monolayer graphene, the inverted phase is not expected to be a time-reversal-invariant topological insulator, despite being separated from conventional band insulators by electric-field-tuned phase transitions where crystal symmetry mandates that the bulk gap must close22. Our electrical transport measurements reveal that the inverted phase has a conductivity of approximately e2/h (where e is the electron charge and h Planck's constant), which is suppressed by exceptionally small in-plane magnetic fields. The high conductivity and anomalous magnetoresistance are consistent with theoretical models that predict helical edge states within the inverted phase that are protected from backscattering by an emergent spin symmetry that remains robust even for large Rashba SOC. Our results pave the way for proximity engineering of strong topological insulators as well as correlated quantum phases in the strong spin-orbit regime in graphene heterostructures.

TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.

Nomogram based on MRI and clinical features to predict progression-free survival in patients with stage IIIC1r cervical squamous cell carcinoma: A two-center study.

PURPOSE: To develop a nomogram based on MRI and clinical features to predict progression-free survival (PFS) of 2018 FIGO stage ⅢC1r cervical squamous cell carcinoma (CSCC). METHODS: 144 consecutive patients with stage ⅢC1r CSCC from two independent institutions were stratified into training cohort (from Institution 1, n=100) and independent validation cohort (from Institution 2, n=44). Univariate and multivariate Cox regression analyses of MRI and clinical features before treatment were performed to determine independent risk factors for PFS in training cohort. Nomogram was developed based on them. Concordance index (C-index), calibration curves, and receiver operating characteristic (ROC) analyses were performed to assess and validate the nomogram. RESULTS: In training cohort, 2009 FIGO stage, maximum length of the primary tumor, short diameter and roundness index of the maximum metastatic lymph node were independent risk factors of PFS in patients with stage IIIC1r CSCC (all P-values < 0.05). Nomogram based on them to predict 1- and 3-year PFS achieved C-indexes of 0.835 (95% confidence interval (CI): 0.809-0.862) and 0.789 (95%CI: 0.683-0.895) in the training and validation cohorts, respectively. Areas under ROC curves for the nomogram to predict 1- and 3-year PFS were 0.891 (95%CI: 0.829-0.954), 0.921 (95%CI: 0.861-0.981) in training cohort, and 0.902 (95%CI: 0.803-0.999), 0.885 (95%CI: 0.778-0.992) in validation cohort, respectively. Calibration curves indicated the nomogram predictions were in good agreement with actual observations. CONCLUSIONS: The nomogram based on MRI and clinical features has high accuracy and stability in predicting PFS of patients with stage IIIC1r CSCC.

Prediction of programmed death-1 expression status in non-small cell lung cancer based on intratumoural and peritumoral computed tomography (CT) radiomics nomogram.

AIMS: This study aimed to predict the expression of programmed death-1 (PD-1) in non-small cell lung cancer (NSCLC) using intratumoral and peritumoral computed tomography (CT) radiomics nomogram. MATERIALS AND METHODS: Two hundred patients pathologically diagnosed with NSCLC from two hospitals were retrospectively analyzed. Of these, 159 NSCLC patients from our hospital were randomly divided into a training cohort (n=96) and an internal validation cohort (n=63) at a ratio of 6:4, while 41 NSCLC patients from another medical institution served as the external validation cohort. The radiomic features of the gross tumor volume (GTV) and peritumoral volume (PTV) were extracted from the CT images. Optimal radiomics features were selected using least absolute shrinkage and selection operator regression analysis. Finally, a CT radiomics nomogram of clinically independent predictors combined with the best rad-score was constructed. RESULTS: Compared with the 'GTV' and 'PTV' radiomics models, the combined 'GTV + PTV' radiomics model showed better predictive performance, and its area under the curve (AUC) values in the training, internal validation, and external validation cohorts were 0.90 (95% confidence interval [CI]: 0.83-0.97), 0.85 (95% CI: 0.74-0.96) and 0.78 (95% CI: 0.63-0.92). The nomogram constructed by the rad-score of the 'GTV + PTV' radiomics model combined with clinical independent predictors (prealbumin and monocyte) had the best performance, with AUC values in each cohort being 0.92 (95% CI: 0.85-0.98), 0.88 (95% CI: 0.78-0.97), and 0.80 (95% CI: 0.66-0.94), respectively. CONCLUSION: The intratumoral and peritumoral CT radiomics nomogram may facilitate individualized prediction of PD-1 expression status in patients with NSCLC.

Apparent diffusion coefficient and its standard deviation from diffusion-weighted imaging in preoperative predicting liver invasion by T3-staged resectable gallbladder carcinoma.

AIM: To evaluate apparent diffusion coefficient (ADC) and its standard deviation (SDADC) in preoperative predicting liver invasion by T3-staged gallbladder carcinoma (GBC). MATERIALS AND METHODS: Forty-one consecutive patients with T3-staged resectable GBC were included and divided into two sets with (n=27) and without (n=14) liver invasion. All patients underwent DWI at b-values of 0, 20, 50, 80, 100, 200, 400, 600, 800, and 1,000 s/mm2 with a 3 T magnetic resonance imaging scanner before surgery. ADC and SDADC of tumour-adjacent and tumour-distant liver tissues were measured on DWI, and were compared by Mann-Whitney U-tests. If there was a significant difference in any derived parameter, the area under the receiver operating characteristic curve (AUC) was used to assess performance of this parameter to predict liver invasion. RESULTS: DWI could differentiate between patients with and without liver invasion when b = 0, 1,000 s/mm2 (AUCs of ADC and SDADC were 0.697 and 0.714, respectively). In patients with liver invasion, mean ADC and SDADC of tumour-adjacent liver tissue were lower than of tumour-distant liver tissue when b = 0, 800 s/mm2, and = 0, 1,000 s/mm2 (all p-values <0.05). To differentiate tumour-adjacent from tumour-distant liver tissues in patients with liver invasion, AUCs of ADC were 0.687 (b = 0, 800 s/mm2) and 0.680 (b = 0, 1,000 s/mm2), and AUCs of SDADC were 0.673 (b = 0, 800 s/mm2) and 0.731 (b = 0, 1,000 s/mm2). CONCLUSIONS: DWI could have potential value in preoperative predicting liver invasion by T3-staged GBC.

A revisit of drugs and potential therapeutic targets against non-alcoholic fatty liver disease: learning from clinical trials.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. Although numerous clinical trials have been conducted over the last few decades, an effective treatment has not been approved yet. Extensive research has accumulated a large amount of data and experience; however, the vast number of clinical trials and new therapeutic targets for NAFLD make it impossible to keep abreast of the relevant information. Therefore, a systematic analysis of the existing trials is necessary. METHODS: Here, we reviewed clinical trials on NAFLD registered in the mandated federal database, ClinicalTrials.gov, to generate a detailed overview of the trials related to drugs and therapeutic targets for NAFLD treatment. Following screening for pertinence to therapy, a total of 440 entries were identified that included active trials as well as those that have already been completed, suspended, terminated, or withdrawn. RESULTS: We summarize and systematically analyze the state, drug development pipeline, and discovery of treatment targets for NAFLD. We consider possible factors that may affect clinical outcomes. Furthermore, we discussed these results to explore the mechanisms responsible for clinical outcomes. CONCLUSION: We summarised the landscape of current clinical trials and suggested the directions for future NAFLD therapy to assist internal medicine specialists in treating the whole clinical spectrum of this highly prevalent liver disease.

[The clinical significance of lateral pelvic sentinel lymph node biopsy using indocyanine green fluorescence navigation in laparoscopic lateral pelvic lymph node dissection].

Objectives: This study aims to explore the clinical significance of lateral pelvic sentinel lymph node biopsy (SLNB) using indocyanine green (ICG) fluorescence navigation in laparoscopic lateral pelvic lymph node dissection (LLND) and evaluate the accuracy and feasibility of this technique to predict the status of lateral pelvic lymph nodes (LPLNs). Methods: The clinical and pathological characteristics, surgical outcomes, lymph node findings and perioperative complications of 16 rectal cancer patients who underwent SLNB using ICG fluorescence navigation in laparoscopic LLND in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during April 2017 and October 2022 were retrospectively collected and analyzed. The patients did not receive preoperative neoadjuvant radiotherapy and presented with LPLNs but without LPLN enlargement (MRI showed the maximum short axes of the LPLNs were ≥5 mm and <10 mm at first visit). Results: All 16 patients were successfully performed SLNB using ICG fluorescence navigation in laparoscopic LLND. Three patients underwent bilateral LLND and 13 patients underwent unilateral LLND. The lateral pelvic sentinel lymph nodes (SLNs) were clearly fluorescent before dissection in 14 patients and the detection rate of SLNs for these patients was 87.5%. Lateral pelvic SLN metastasis was diagnosed in 2 patients and negative results were found in 12 patients by frozen pathological examinations. Among the 14 patients in whom lateral pelvic SLNs were detected, the dissected lateral pelvic non-SLNs were all negative. All dissected LPLNs were negative in two patients without fluorescent lateral pelvic SLNs. The specificity, sensitivity, negative predictive value, and accuracy was 85.7%, 100%, 100%, and 100%, respectively. Conclusions: This study indicates that lateral pelvic SLNB using ICG fluorescence navigation shows promise as a safe and feasible procedure with good accuracy. This technique may replace preventive LLND for locally advanced lower rectal cancer.

[Role of neoadjuvant rectal score in prognosis and adjuvant chemotherapy decision-making in locally advanced rectal cancer following neoadjuvant short-course radiotherapy and consolidation chemotherapy].

Objectives: To assess the prognostic impact of the neoadjuvant rectal (NAR) score following neoadjuvant short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer (LARC), as well as its value in guiding decisions for adjuvant chemotherapy. Methods: Between August 2015 and August 2018, patients were eligible from the STELLAR phase III trial (NCT02533271) who received short-course radiotherapy plus consolidation chemotherapy and for whom the NAR score could be calculated. Based on the NAR score, patients were categorized into low (＜8), intermediate (8-16), and high (＞16) groups. The Kaplan-Meier method, log rank tests, and multivariate Cox proportional hazard regression models were used to evaluate the impact of the NAR score on disease-free survival (DFS). Results: Out of the 232 patients, 24.1%, 48.7%, and 27.2% had low (56 cases), intermediate (113 cases), and high NAR scores (63 cases), respectively. The median follow-up period was 37 months, with 3-year DFS rates of 87.3%, 68.3%, and 53.4% (P＜0.001) for the low, intermediate, and high NAR score groups. Multivariate analysis demonstrated that the NAR score (intermediate NAR score: HR, 3.10, 95% CI, 1.30-7.37, P=0.011; high NAR scores: HR=5.44, 95% CI, 2.26-13.09, P＜0.001), resection status (HR, 3.00, 95% CI, 1.64-5.52, P＜0.001), and adjuvant chemotherapy (HR, 3.25, 95% CI, 2.01-5.27, P＜0.001) were independent prognostic factors for DFS. In patients with R0 resection, the 3-year DFS rates were 97.8% and 78.0% for those with low and intermediate NAR scores who received adjuvant chemotherapy, significantly higher than the 43.2% and 50.6% for those who did not (P＜0.001, P=0.002). There was no significant difference in the 3-year DFS rate (54.2% vs 53.3%, P=0.214) among high NAR score patients, regardless of adjuvant chemotherapy. Conclusions: The NAR score is a robust prognostic indicator in LARC following neoadjuvant short-course radiotherapy and consolidation chemotherapy, with potential implications for subsequent decisions regarding adjuvant chemotherapy. These findings warrant further validation in studies with larger sample sizes.

[Prognostic value of the Second Revision of the International Staging System in patients with newly diagnosed transplant-eligible multiple myeloma].

Objective: To verify the predictive value of the Second Revision of the International Staging System (R2-ISS) in newly diagnosed patients with multiple myeloma (MM) who underwent first-line autologous hematopoietic stem cell transplantation (ASCT) in a new drug era in China. Methods: This multicenter retrospective cohort study enrolled patients with newly diagnosed MM from three centers in China (Beijing Chao-Yang Hospital, Capital Medical University; the First Affiliated Hospital, Sun Yat-Sen University, and the Second Affiliated Hospital of Naval Medical University) from June 2008 to June 2018. A total of 401 newly diagnosed patients with MM who were candidates for ASCT were enrolled in this cohort, all received proteasome inhibitor and/or immunomodulator-based induction chemotherapy followed by ASCT. Baseline and follow-up data were collected. The patients were regrouped using R2-ISS. Progression-free survival (PFS) and overall survival (OS) were analyzed. The Kaplan-Meier method was used to analyze the survival curve and two survival curves were compared using the log-rank test. Cox regression analysis were performed to analyze the relationship between risk factors and survival. Results: The median age of the patients was 53 years (range 25-69 years) and 59.5% (240 cases) were men. Newly diagnosed patients with renal impairment accounted for 11.5% (46 cases). According to Revised-International Staging System (R-ISS), 74 patients (18.5 %) were diagnosed with stage Ⅰ, 259 patients (64.6%) with stage Ⅱ, and 68 patients (17.0%) with stage Ⅲ. According to the R2-ISS, the distribution of patients in each group was as follows: 50 patients (12.5%) in stage Ⅰ, 95 patients (23.7%) in stage Ⅱ, 206 patients (51.4%) in stage Ⅲ, and 50 patients (12.5%) in stage Ⅳ. The median follow-up time was 35.9 months (range, 6-119 months). According to the R2-ISS stage, the median PFS in each group was: 75.3 months for stage Ⅰ; 62.0 months for stage Ⅱ, 39.2 months for stage Ⅲ, and 30.3 months for stage Ⅳ; and the median OS was not reached, 86.6 months, 71.6 months, and 38.5 months, respectively. There were statistically significant differences in PFS and OS between different groups (both P<0.001). Multivariate Cox regression analysis showed that stages Ⅲ and Ⅳ of the R2-ISS were independent prognostic factors for PFS (HR=2.37, 95%CI 1.30-4.30; HR=4.50, 95%CI 2.35-9.01) and OS (HR=4.20, 95%CI 1.50-11.80; HR=9.53, 95%CI 3.21-28.29). Conclusions: The R2-ISS has significant predictive value for PFS and OS for transplant-eligible patients with MM in the new drug era. However, the universality of the R2-ISS still needs to be further verified in different populations.

[Clinical characteristics of posterior malleolus fracture in adults].

Objective: To explore the latest clinical characteristics and development trends of posterior malleolus fracture. Methods: Clinical information of inpatients with posterior malleolus fracture in Shanghai Tongji Hospital and Karamay Central Hospital from January 2014 to December 2022 were reviewed and collected. The imaging data of patients were acquired using the Picture Archiving and Communication Systems. A statistical analysis was performed as to gender, current age, year of admission, injury mechanism, fracture type, and posterior malleolus fracture classification. Moreover, a comparative analysis was conducted on the injury mechanisms and morphological differences of posterior malleolus fracture at different periods, regions, and age groups. Results: A total of 472 patients (210 patients from Shanghai Tongji Hospital and 262 patients from Karamay Central Hospital) with posterior malleolus fracture with a mean age of (48.7±15.6) years were included in this study. The peak of posterior malleolus fracture occurs in the age group of 50-59 years. The injury mechanisms mainly involve low-energy fall and sprain (411 cases, 87.1%), followed by traffic accidents (52 cases, 11.0%), and fall injury from height (9 cases, 1.9%). The number of cases according to different fracture types showed the following descending order: trimalleolar fracture-supination extorsion (335 cases, 71.0%), bimalleolar fracture (60 cases, 12.7%), trimalleolar fracture-pronation extorsion (43 cases, 9.1%), posterior malleolus+tibial shaft fracture (19 cases, 4.0%), simple posterior malleolus fracture (15 cases, 3.2%). The numbers of cases corresponding to the Haraguchi Ⅰ, Ⅱ and Ⅲ type of posterior malleolus fractures was 369 (78.2%), 49 (10.4%), and 54 (11.4%), respectively. The Tongji ⅡA type represented the highest number of cases (249 cases, 52.8%), followed by the ⅡB type (120 cases, 25.4%), Ⅰ type (54 cases, 11.4%), ⅢB type (36 cases, 7.6%), and ⅢA type (13 cases, 2.8%). However, no obvious statistical difference was observed in the injury mechanism, Haraguchi classification, and Tongji classification of posterior malleolus fractures among different years and regions from the year of 2014 to 2022 (all P>0.05). Conclusions: The injury mechanism of posterior malleolus fracture mainly involves low-energy fall and sprain cases. The trimalleolar fracture-supination extorsion, Haraguchi Ⅰ type and Tongji ⅡA type of posterior malleolus fracture are predilection fracture types, and all present an obvious incidence peak in the age group of 50-59 years. There has been no significant change in the development trend of clinical characteristics of posterior malleolus fractures in recent years.

[Drug research and development and unmet needs for advanced-stage hepatocellular carcinoma].

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is a global health challenge. Radical surgical resection is the most effective method to achieve long-term survival for HCC. Regrettably, the vast majority of HCC patients lose the opportunity for radical resection at the time of diagnosis due to advanced tumors or poor liver reserve capacity. HCC is resistant to conventional chemotherapy, and in the past, there have been no definite and effective systemic therapeutic drugs. Fortunately, over the last decade, the research and development of molecular targeted therapy and immunotherapy drugs for HCC have made rapid progress, and a variety of drugs and combination therapy regimens have been successively approved for clinical use. However, the overall therapeutic effect is still not ideal and needs further improvement.

[Correlation between the mutation spectrum of the UGT1A1 gene and clinical phenotype in patients with inherited hyperunconjugated bilirubinemia].

Objective: To analyze the distribution characteristics of UGT1A1 mutant genes (including enhancers, promoters, and exons 1-5) and further explore the correlation between UGT1A1 genotype and clinical phenotypes in patients with inherited hyperunconjugated bilirubinemia. Methods: Patients diagnosed with hereditary hyperunconjugated bilirubinemia at Nanjing Second Hospital from June 2015 to December 2022 were retrospectively analyzed. The UGT1A1 gene was examined using Sanger sequencing in all patients. Complete blood count, liver function, and abdominal imaging examinations were performed. Comparison of categorical variable data using χ(2) testor Fisher percision tests. Comparison of continaous veriable data with normal distribution using t-test. Results: 112 cases (male:female ratio 81:31, aged 9-70 years) had inherited hyperunconjugated bilirubinemia, with a total of 14 mutation sites identified, of which seven were confirmed mutations, and the frequency ranged from high to low: (TA)n accounted for 50%, c.211G>A (p.G71R) accounted for 49.10%, 1456T>G (p.Y486D) accounted for 16.96%, c.686C>A (p.R229W) accounted for 12.5%, 1091C>T (p.P364L) accounted for 8.04%, and c- 3279T>G accounted for 0.982%. Simultaneously, all patients had one to four mutations, of which only one mutation was the most common (55.36%), followed by two mutations (37.5%), and rare three and four mutations (5.36% and 1.78%). There was no statistical significance in total bilirubin (TBil) levels among the four groups (F=0.652, P=0.583). One mutation was most common in (TA)n and c.211G>A (p.G71R), among which TA6/TA7 (n=10) and TA7/TA7 (n=14) mutations were statistically significant in TBil (t=2.143, P=0.043). The c.211G>A (p.G71R) heterozygous (n=9) and isolated (n=15) mutation had no statistical significance in TBil (t=0.382, P=0.706). The GS group accounted for 75%, the intermediate group accounted for 16.9%, and the CNS-Ⅱ group accounted for 8%. TBil was statistically significant among the three groups (F=270.992, P<0.001). There was no statistically significant difference (χ(2)=3.317, P=0.19) between mutation 1 (44 cases, 14 cases, and 4 cases, respectively) and mutations ≥ 2 (40 cases, 5 cases, and 5 cases, respectively) in the GS group, intermediate group, and CNS-II group. Conclusion: The number of UGT1A1 gene mutation sites may have no synergistic effect on TBil levels in patients with inherited hyperunconjugated bilirubinemia. TA7/TA7 mutations are not uncommon, and TBil levels are relatively high.

Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.

Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) ß = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW ß = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.

Tunable interacting composite fermion phases in a half-filled bilayer-graphene Landau level.

Non-Abelian anyons are a type of quasiparticle with the potential to encode quantum information in topological qubits protected from decoherence. Experimental systems that are predicted to harbour non-Abelian anyons include p-wave superfluids, superconducting systems with strong spin-orbit coupling, and paired states of interacting composite fermions that emerge at even denominators in the fractional quantum Hall (FQH) regime. Although even-denominator FQH states have been observed in several two-dimensional systems, small energy gaps and limited tunability have stymied definitive experimental probes of their non-Abelian nature. Here we report the observation of robust even-denominator FQH phases at half-integer Landau-level filling in van der Waals heterostructures consisting of dual-gated, hexagonal-boron-nitride-encapsulated bilayer graphene. The measured energy gap is three times larger than observed previously. We compare these FQH phases with numerical and theoretical models while simultaneously controlling the carrier density, layer polarization and magnetic field, and find evidence for the paired Pfaffian phase that is predicted to host non-Abelian anyons. Electric-field-controlled level crossings between states with different Landau-level indices reveal a cascade of FQH phase transitions, including a continuous phase transition between the even-denominator FQH state and a compressible composite fermion liquid. Our results establish graphene as a pristine and tunable experimental platform for studying the interplay between topology and quantum criticality, and for detecting non-Abelian qubits.

Prognostic value of plaque volume combined with CT fractional flow reserve in patients with suspected coronary artery disease.

AIM: To investigate the prognostic value of quantitative plaque volume on coronary computed tomography (CT) angiography (CTA) combined with CT fractional flow reserve (CT-FFR) for major adverse cardiac events (MACE) in suspected coronary artery disease (CAD) patients. MATERIALS AND METHODS: Patients who underwent coronary CTA with clinically suspected CAD were enrolled retrospectively in this study. Patients' baseline, Framingham Risk Score (FRS), coronary CTA plaque assessment, and CT-FFR were analysed retrospectively. Study outcomes included rehospitalisation and MACE (ST-segment elevation myocardial infarction, unstable angina, or non-ST-segment elevation myocardial infarction, revascularisation, and cardiac death). RESULTS: There were 251 patients in the study, with a follow-up period of 1-6.58 years. Mean age was 61.16 ± 10.45 years and 146 (58%) patients were male. Higher CT-adapted Leaman score and quantitative plaque volume were found in patients with FRS >0.2 regardless of categorical or continuous variables. Coronary scores, quantitative plaque parameters, and CT-FFR were associated with MACE and rehospitalisation in univariate analysis. In model 1, CT-FFR was associated with MACE in multivariate Cox analysis when adjusted for FRS and CT-adapted Leaman score. Quantitative plaque parameters including calcified plaque volume, fibro-fatty plaque volume, low-attenuation plaque volume, non-calcified plaque volume, and total plaque volume were significantly associated with MACE and improved overall prognostic performance in a model adjusted for CT-FFR. CONCLUSION: Additional quantitative plaque volume and CT-FFR further improve the predictive incremental value based on risk factor scores for prognostic prediction in patients. Adding quantitative plaque volume combined with CT-FFR analysis to anatomical and clinical assessment will be further beneficial to predict patients' prognosis of MACE.

Facial expression of patients with Graves' orbitopathy.

PURPOSE: Patients with Graves' orbitopathy (GO) have characteristic facial expressions that are different from those of healthy individuals due to the combination of somatic and psychiatric symptoms. However, the facial expressions of GO patients have not yet been described and analyzed systematically. Thus, the present study aimed to present the facial expressions of GO patients and explore their applications in clinical practice. METHODS: Facial image and clinical data of 943 GO patients were included, and 126 patients answered quality of life (GO-QOL) questionnaires. Each patient was labeled for one facial expression. Then, a portrait was drawn for every facial expression. Logistic and linear regression was performed to analyze the correlation between facial expression and clinical indicators, including QOL, disease activity and severity. The VGG-19 network model was utilized to discriminate facial expressions automatically. RESULTS: Two groups, i.e., the non-negative emotion (neutral, happy) and the negative emotion (disgust, angry, fear, sadness, surprise), and seven expressions of GO patients were systematically analyzed. Facial expression was statistically associated with GO activity (P = 0.002), severity (P < 0.001), QOL visual functioning subscale scores (P = 0.001), and QOL appearance subscale score (P = 0.012). The deep learning model achieved satisfactory results (accuracy 0.851, sensitivity 0.899, precision 0.899, specificity 0.720, F1 score 0.899, and AUC 0.847). CONCLUSIONS: As a novel clinical sign, facial expression holds the potential to be incorporated into GO assessment system in the future. The discrimination model may assist clinicians in real-life patient care.

[Clinical tolerability and pharmacokinetics of troxacitabine].

Objective: To investigate the safety and efficacy of troxatabine in advanced or relapsed malignant tumors resistant to standard therapy in China. Methods: This is a phase Ⅰ prospective study. During dose escalation, patients in Cancer Hospital, Chinese Academy of Medical Sciences received a single-dose intravenous infusion of troxacitabine. The planned dosing groups were 1.8, 3.6, 4.8, 6.4 and 8.0 mg/m(2) on days 1 and 8 every 3 weeks. The data of all patients were collected for safety analyses. Safety and tolerability were evaluated by monitoring adverse events. Results: Nineteen patients were enrolled from April 2018 to May 2019. The major adverse events were fatigue (89.5%, 17/19), leukopenia (84.2%, 16/19) and neutropenia (78.9%, 15/19). The dose limiting toxicity was neutropenia. The maximum tolerated dose was 6.4 mg/m(2). The best effect was stable disease (43.8%). The half-life of elimination phase from 15.91 hours to 76.63 hours in each dose group. Conclusions: The toxicity of troxacitabine is well tolerant. We recommend that the dose for Phase Ⅱ clinical trial should be 6.4 mg/m(2).

[Clinical and endoscopic characteristics of adult celiac disease].

Objective: The study aimed to analyze the clinical and endoscopic characteristics of adult celiac disease (CD) to provide a scientific basis for more effective CD diagnosis and treatment. Methods: In this cross-sectional study, the clinical and endoscopic data of 96 adult CD patients treated in the Department of Gastroenterology of the People's Hospital of Xinjiang Uygur Autonomous Region from March 2016 to December 2021 were retrospectively collected and analyzed. Results: A total of 96 CD patients were diagnosed, including 33 men and 63 women. The average age was 47±14 years (range, 18-81 years). The disease occurred mainly in the age group of 31-60 years. The median course of the disease was 2.0 (0.2-40.0) years. There were 41 (42.7%) classical and 55 (57.3%) non-classical CD patients. All patients with classical CD showed chronic diarrhea, often accompanied by abdominal pain (46.3%, 19/41), abdominal distension (17.1%, 7/41), anemia (65.9%, 27/41), and chronic fatigue (48.8%, 20/41). The main manifestations of non-classical CD were chronic abdominal pain (58.2%, 32/55), abdominal distension (32.7%, 18/55), anemia (40.0%, 22/55), and osteopenia/osteoporosis (38.2%, 21/55). Compared with non-classical CD, anemia developed more frequently in classical CD, and the difference was statistically significant (P = 0.012). The incidence of complications in CD patients was 36.5% (35/96), and the main complications were thyroid disease (19.8%, 19/96), connective tissue disease (6.2%, 6/96), and kidney disease (6.2%, 6/96). There was no significant difference between classical and non-classical CD (P>0.05). The frequency of endoscopic manifestations in CD patients was 84.4% (81/96). Duodenal bulb endoscopy showed nodular changes (72.9%, 70/96), grooved changes (10.4%, 10/96), and focal villous atrophy (9.4%, 9/96). The main manifestations of descending endoscopy were the decrease, flattening, or disappearance of duodenal folds (43.8%, 42/96), scallop-like changes (38.5%, 37/96), and nodular changes (34.4%, 33/96). Conclusions: Adult CD patients are mostly female. CD occurred mainly in the age group of 31-60 years. The clinical manifestations were mainly those of non-classical CD. Some patients often had other autoimmune diseases. Patients with characteristic endoscopic manifestations should be warned about the possibility of developing CD. Clinicians should strengthen the understanding of CD and reduce the related rates of missed diagnosis.

[Prevalence of albuminuria and its association with cardiovascular diseases in Chinese residents aged over 35 years].

Objective: To investigate the prevalence of albuminuria in Chinese residents aged >35 years and its potential association with cardiovascular disease (CVD). Methods: A total of 34 647 Chinese subjects aged ≥35 years were selected by stratified multi-stage random sampling from 2012 to 2015. Data were collected through questionnaires, physical examinations, and laboratory tests. Albuminuria was categorized into 3 types according to urinary albumin-to- creatinine ratio: normal (<30 mg/g), microalbuminuria (MAU, 30-300 mg/g), and macroalbuminuria (≥300 mg/g). Measurement data were expressed as x¯±s, and t-tests were used for comparisons between indicators. Qualitative data were expressed as rate or constituent ratio, and the χ2 test or Kruskal-Wallis test was used to examine differences. Logistic regression was used for multivariate analyses. SAS 9.4 software was used for statistical analyses, and P<0.05 was considered statistically significant. Results: The prevalence of abnormal albuminuria was 19.1%; the prevalence was 17.2% for MAU and lower in males (13.8%) than females (20.1%, P<0.01). The risk of CVD was higher among subjects with MAU (OR=1.23, 95%CI 1.12-1.35) and macroalbuminuria (OR=1.86, 95%CI 1.50-2.32). When MAU was complicated by hypertension and diabetes mellitus, the CVD risk was 1.76 times higher. Conclusions: The prevalence of MAU is high among Chinese subjects aged 35 years and over. Those with MAU have higher CVD risk, especially those with hypertension and diabetes mellitus.

[3D-printed vertebral body in anterior spinal reconstruction after total spondylectomy for patients with cervical chordoma].

OBJECTIVE: To investigate whether 3D-printed artificial vertebral body can reduce prosthesis subsidence rate for patients with cervical chordomas, through comparing the rates of prosthesis subsidence between 3D printing artificial vertebral body and titanium mesh for anterior spinal reconstruction after total spondylectomy. METHODS: This was a retrospective analysis of patients who underwent surgical treatment for cervical chordoma at our hospital from March 2005 to September 2019. There were nine patients in the group of 3D artificial vertebral body (3D group), and 15 patients in the group of titanium mesh cage (Mesh group). The patients' characteristics and treatment data were extracted from the medical records, including age, gender, CT hounsfield unit of cervical vertebra and surgical information, such as the surgical segments, time and blood loss of surgery, frequency and degree of prosthesis subsidence after surgery. Radiographic observations of prosthesis subsidence during the follow-up, including X-rays, CT, and magnetic resonance imaging were also collected. SPSS 22.0 was used to analysis the data. RESULTS: There was no significant difference between the two groups in gender, age, CT hounsfield unit, surgical segments, time of surgery, blood loss of posterior surgery and total blood loss. Blood loss of anterior surgery was 700 (300, 825) mL in 3D group and 1 500 (750, 2 800) mL in Mesh group (P < 0.05). The prosthesis subsidence during the follow-up, 3 months after surgery, there was significant difference between the two groups in mild prosthesis subsidence (P < 0.05). The vertebral height of the 3D group decreased less than 1 mm in eight cases (no prosthesis subsidence) and more than 1 mm in one case (mild prosthesis subsidence). The vertebral height of the Mesh group decreased less than 1 mm in five cases (no prosthesis subsidence), and more than 1 mm in eight cases (mild prosthesis subsidence). Two patients did not have X-rays in 3 months after surgery. There was a statistically significant difference between the two groups in the prosthesis subsidence rate at the end of 12 months (P < 0.01). The vertebral height of eight cases in the 3D group decreased less than 1 mm (no prosthesis subsidence) and one case more than 3 mm (severe prosthesis subsidence). Four of the 15 cases in the Mesh group decreased less than 1 mm (no prosthesis subsidence), two cases more than 1 mm (mild prosthesis subsidence), and nine cases more than 3 mm (severe prosthesis subsidence). There was a statistically significant difference between the two groups in the prosthesis subsidence rate at the end of 24 months (P < 0.01). The vertebral height of seven cases in the 3D group decreased less than 1 mm (no prosthesis subsidence), one case more than 3 mm (severe prosthesis subsidence), and one case died with tumor. One case in the Mesh group decreased less than 1 mm (no prosthesis subsidence), one case more than 1 mm (mild prosthesis subsidence), 11 case more than 3 mm (severe prosthesis subsidence), one case died with tumor and one lost the follow-up. Moreover, at the end of 12 months and 24 months, there was significant difference between the two groups in severe prosthesis subsidence rate (P < 0.01). CONCLUSION: 3D-printed artificial vertebral body for anterior spinal reconstruction after total spondylectomy for patients with cervical chordoma can provide reliable spinal stability, and reduce the incidence of prosthesis subsidence after 2-year follow-up.