Immunogenicity and safety of a severe acute respiratory syndrome coronavirus 2 inactivated vaccine in healthy adults: randomized,double-blind,and placebo-controlled phase 1 and phase 2 clinical trials

Background:The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, KCONVAC, in healthy adults.Methods:Phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in healthy Chinese adults aged 18 to 59 years. The participants in the phase 1 trial were randomized to receive two doses, one each on Days 0 and 14, of either KCONVAC (5 or 10 μg/dose) or placebo. The participants in the phase 2 trial were randomized to receive either KCONVAC (at 5 or 10 μg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following the administration of each dose. In the phase 2 trial, the primary immunogenicity endpoints were neutralization antibody seroconversion and titer and anti-receptor-binding domain immunoglobulin G seroconversion at 28 days after the second dose.Results:In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-μg vaccine (n = 24), 10-μg vaccine (n = 24), or placebo (n = 12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-μg vaccine (n = 100 for 0/14 or 0/28 regimens), 10-μg vaccine (n = 100 for each regimen), or placebo (n = 50 for each regimen). In the phase 1 trial, 13 (54%), 11 (46%), and seven (7/12) participants reported at least one adverse event (AE) after receiving 5-, 10-μg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and nine (18%) 0/14-regimen participants reported at least one AE after receiving 5-, 10-μg vaccine, or placebo, respectively. Similar AE incidences were observed in the three 0/28-regimen treatment groups. No AEs with an intensity of grade 3+ were reported, expect for one vaccine-unrelated serious AE (foot fracture) reported in the phase 1 trial. KCONVAC induced significant antibody responses; 0/28 regimen showed a higher immune responses than that did 0/14 regimen after receiving two vaccine doses.Conclusions:Both doses of KCONVAC are well tolerated and able to induce robust immune responses in healthy adults. These results support testing 5-μg vaccine in the 0/28 regimen in an upcoming phase 3 efficacy trial.Trial Registration:http://www.chictr.org.cn/index.aspx (No. ChiCTR2000038804, http://www.chictr.org.cn/showproj.aspx?proj=62350; No. ChiCTR2000039462, http://www.chictr.org.cn/showproj.aspx?proj=63353).     

Deep learning applied to two-dimensional color Doppler flow imaging ultrasound images significantly improves diagnostic performance in the classification of breast masses: a multicenter study

BackgroundThe current deep learning diagnosis of breast masses is mainly reflected by the diagnosis of benign and malignant lesions. In China, breast masses are divided into four categories according to the treatment method: inflammatory masses, adenosis, benign tumors, and malignant tumors. These categorizations are important for guiding clinical treatment. In this study, we aimed to develop a convolutional neural network (CNN) for classification of these four breast mass types using ultrasound (US) images.MethodsTaking breast biopsy or pathological examinations as the reference standard, CNNs were used to establish models for the four-way classification of 3623 breast cancer patients from 13 centers. The patients were randomly divided into training and test groups (n = 1810 vs. n = 1813). Separate models were created for two-dimensional (2D) images only, 2D and color Doppler flow imaging (2D-CDFI), and 2D-CDFI and pulsed wave Doppler (2D-CDFI-PW) images. The performance of these three models was compared using sensitivity, specificity, area under receiver operating characteristic curve (AUC), positive (PPV) and negative predictive values (NPV), positive (LR+) and negative likelihood ratios (LR−), and the performance of the 2D model was further compared between masses of different sizes with above statistical indicators, between images from different hospitals with AUC, and with the performance of 37 radiologists.ResultsThe accuracies of the 2D, 2D-CDFI, and 2D-CDFI-PW models on the test set were 87.9%, 89.2%, and 88.7%, respectively. The AUCs for classification of benign tumors, malignant tumors, inflammatory masses, and adenosis were 0.90, 0.91, 0.90, and 0.89, respectively (95% confidence intervals [CIs], 0.87–0.91, 0.89–0.92, 0.87–0.91, and 0.86–0.90). The 2D-CDFI model showed better accuracy (89.2%) on the test set than the 2D (87.9%) and 2D-CDFI-PW (88.7%) models. The 2D model showed accuracy of 81.7% on breast masses ≤1 cm and 82.3% on breast masses >1 cm; there was a significant difference between the two groups (P < 0.001). The accuracy of the CNN classifications for the test set (89.2%) was significantly higher than that of all the radiologists (30%).ConclusionsThe CNN may have high accuracy for classification of US images of breast masses and perform significantly better than human radiologists.Trial registrationChictr.org, ChiCTR1900021375; http://www.chictr.org.cn/showproj.aspx?proj=33139.     

Multi-center investigation of the clinical and pathological characteristics of inflammatory breast cancer based on Chinese Society of Breast Surgery (CSBrs-007)

BackgroundInflammatory breast cancer (IBC) is an aggressive type of cancer with poor prognosis and outcomes. This study aimed to investigate clinicopathological features, molecular characteristics, and treatments among Chinese patients diagnosed with IBC.MethodsWe collected data of 95 patients with IBC who were treated by members of the Chinese Society of Breast Surgery, from January 2017 to December 2018. The data, including demographic characteristics, pathological findings, surgical methods, systemic treatment plans, and follow-up, were obtained using a uniform electronic questionnaire. The clinicopathological features of different molecular types in patients without distant metastases were compared using the Kruskal-Wallis (H) test followed by post hoc analyses.ResultsLymph node metastasis was noted in 75.8% of all patients, while distant metastasis was noted in 21.4%. Pathological findings indicated invasive ductal and lobular carcinomas in 86.8% and 5.3% of cases, respectively. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) (41.5%) and HR−/HER2+ (20.1%) were the most common biologic subtypes, followed by HR+/HER2+ (19.1%) and HR−/HER2− (19.1%). Stage III IBC was treated via pre-operative neoadjuvant chemotherapy in 87.7% of the cases, predominantly using anthracycline and taxanes. A total of 91.9% of patients underwent surgical treatment. Among them, 77.0% of the patients underwent modified radical mastectomy, 8.1% of whom also underwent immediate breast reconstruction. The Kruskal-Wallis test revealed that the efficacy of chemotherapy significantly differed among those with HR+/HER2− and HR−/HER2− tumors (adjusted P = 0.008), and Ki-67 expression significantly differed in HR−/HER2+ and HR+/HER2+ molecular subtypes (adjusted P = 0.008).ConclusionOur study provides novel insight into clinicopathological characteristics and treatment status among patients with IBC in China, and might provide a direction and basis for further studies.Trial registrationchictr.org.cn, No. ChiCTR1900027179; http://www.chictr.org.cn/showprojen.aspx?proj=45030     

Safety and efficacy of allogeneic natural killer cell immunotherapy on human immunodeficiency virus type 1 immunological non-responders: a brief report

Background:Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART).Methods:From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People''s Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (10⁸ cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group.Results:From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/μL) in the NK + ART group and (144 to 176 cells/μL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (β = 54.59, P = 0.006) and CD8 level (β = 322.47, P = 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).     

Immunogenicity and safety of a recombinant fusion protein vaccine (V-01) against coronavirus disease 2019 in healthy adults: a randomized,double-blind,placebo-controlled,phase II trial

Background:Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study.Methods:A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18–59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 μg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 μg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization.Results:V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 [95% confidence interval [CI]: 133.3–196.7] and 149.3 [95%CI: 123.9–179.9] in 10 and 25 μg V-01 group of younger adults, respectively; 111.6 [95%CI: 89.6–139.1] and 111.1 [95%CI: 89.2–138.4] in 10 and 25 μg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3–91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 μg V-01 two-dose group, and 50 μg V-01 one-dose group, respectively.Conclusions:The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 μg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy.Trial Registration:http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).     

Investigation of the current situation of nipple-sparing mastectomy: a large multicenter study in China (CSBrs-003)

Background:Mastectomy techniques have been extended to nipple-sparing mastectomy (NSM). This study aimed to assess the actual application of NSM in China and identify the factors influencing postoperative complications.Methods:The clinical data of 615 patients (641 surgeries) undergoing NSM from January 1st, 2018 to December 31st, 2018 at 28 centers nationwide were retrospectively analyzed to obtain the rate of NSM and investigate factors related to NSM surgery.Results:The proportion of NSM surgery performed in this study was 2.67% (17/641). Malignant breast tumors accounted for the majority of NSM surgery (559/641, 87.2%). A total of 475 (77.3%) patients underwent NSM combined with reconstructive surgery. The rate of reconstruction decreased with age in our study, and implants were the most common option (344/641, 53.7%) in reconstruction. Radial incision was the most selected method regardless of reconstruction. However, for those who underwent reconstruction surgery, 18.4% (85/462) of cases also chose curvilinear incision, while in the simple NSM surgery group, more patients chose circumareolar incision (26/136, 19.1%). The tumor-to-nipple distance (TND) influenced postoperative complications (P = 0.004). There were no relationships between postoperative complications and tumor size, tumor location, histologic grade, molecular subtype, nipple discharge, and axillary lymph nodes.Conclusions:NSM surgery is feasible and only TND influenced postoperative complications of NSM surgery. But the proportion of NSM surgery performed is still low in nationwide centers of China. The selection criteria for appropriate surgical methods are important for NSM in clinical practice. To optimize clinical applications of NSM, further multicenter prospective randomized controlled studies are needed.Trial Registration:ChiCTR.org.cn, ChiCTR1900027423; http://www.chictr.org.cn/showprojen.aspx?proj=38739     

A double-blind,double-dummy,randomized controlled,multicenter trial of 99Tc-methylene diphosphonate in patients with moderate to severe rheumatoid arthritis

Background:Clinical observational studies revealed that ⁹⁹Tc-methylene diphosphonate (⁹⁹Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of ⁹⁹Tc-MDP plus methotrexate (MTX) vs. MTX alone or ⁹⁹Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA.Methods:Eligible patients with moderate to severely active RA were randomized to receive ⁹⁹Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or ⁹⁹Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48.Results:At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + ⁹⁹Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or ⁹⁹Tc-MDP group (47.5%) (P = 0.03 for MTX + ⁹⁹Tc-MDP vs. MTX, and MTX + ⁹⁹Tc-MDP vs.⁹⁹Tc-MDP, respectively). The participants in the MTX + ⁹⁹Tc-MDP group and the ⁹⁹Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + ⁹⁹Tc-MDP vs. MTX: P = 0.03, ⁹⁹Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed.Conclusions:This study demonstrated that the combination of ⁹⁹Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and ⁹⁹Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of ⁹⁹Tc-MDP therapy in patients with RA are warranted.Trial Registration:Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.     

A double-blind,randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis

BackgroundBenvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.MethodsWe randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician''s global assessment (sPGA) at week 12.ResultsThe results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.ConclusionDuring this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.Trial RegistrationChinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.     

Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized,controlled, phase 3, non-inferiority TALENT study

BackgroundAlbuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.MethodsWe carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%.ResultsAt the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.ConclusionsThe TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.Trial registrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02369965","term_id":"NCT02369965"}}NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx     

Comparable efficacy of 100 mg aspirin twice daily and rivaroxaban for venous thromboembolism prophylaxis following primary total hip arthroplasty: a randomized controlled trial

Background:Aspirin has demonstrated safety and efficacy for venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA); however, inconsistent dose regimens have been reported in the literature. This study aimed to evaluate and compare the safety and efficacy of 100 mg aspirin twice daily with rivaroxaban in VTE prophylaxis following THA.Methods:Patients undergoing elective unilateral primary THA between January 2019 and January 2020 were prospectively enrolled in the study and randomly allocated to receive 5 weeks of VTE prophylaxis with either oral enteric-coated aspirin (100 mg twice daily) or rivaroxaban (10 mg once daily). Medication safety and efficacy were comprehensively evaluated through symptomatic VTE incidence, deep vein thrombosis (DVT) on Doppler ultrasonography, total blood loss (TBL), laboratory bloodwork, Harris hip score (HHS), post-operative recovery, and the incidence of other complications.Results:We included 70 patients in this study; 34 and 36 were allocated to receive aspirin and rivaroxaban prophylaxis, respectively. No cases of symptomatic VTE occurred in this study. The DVT rate on Doppler ultrasonography in the aspirin group was not significantly different from that in the rivaroxaban group (8.8% vs. 8.3%, χ² = 0.01, P = 0.91), confirming the non-inferiority of aspirin for DVT prophylaxis (χ² = 2.29, P = 0.01). The calculated TBL in the aspirin group (944.9 mL [658.5–1137.8 mL]) was similar to that in the rivaroxaban group (978.3 mL [747.4–1740.6mL]) (χ² = 1.55, P = 0.12). However, there were no significant inter-group differences in HHS at post-operative day (POD) 30 (Aspirin: 81.0 [78.8–83.0], Rivaroxaban: 81.0 [79.3–83.0], χ² = 0.43, P = 0.67) and POD 90 (Aspirin: 90.0 [89.0–92.0], Rivaroxaban: 91.5 [88.3–92.8], χ² = 0.77, P = 0.44), the incidence of bleeding events (2.9% vs. 8.3%, χ² = 0.96, P = 0.33), or gastrointestinal complications (2.9% vs. 5.6%, χ² = 1.13, P = 0.29).Conclusion:In terms of safety and efficacy, the prophylactic use of 100 mg aspirin twice daily was not statistically different from that of rivaroxaban in preventing VTE and reducing the risk of blood loss following elective primary THA. This supports the use of aspirin chemoprophylaxis following THA as a less expensive and more widely available option for future THAs.Trial Registration:Chictr.org, ChiCTR18000202894; http://www.chictr.org.cn/showproj.aspx?proj=33284     

经直肠超声结合剪切波弹性成像在直肠癌诊断及TNM分期中的应用

目的 分析经直肠超声（TRUS）结合剪切波弹性成像（SWE）在直肠癌诊断及TNM分期中的应用。方法 回顾性分析2019年12月—2021年2月中国医科大学附属第四医院收治的86例直肠肿瘤患者临床资料。所有患者术前接受TRUS和SWE检查。记录TRUS与SWE及两者联合诊断直肠癌及其TNM分期的敏感性、特异性及准确率。比较直肠癌与直肠腺瘤患者肿瘤病灶处、周围脂肪和正常直肠壁3个位置E_max值和E_mean值；绘制ROC曲线分析TRUS、SWE及联合诊断直肠癌的价值。结果 联合诊断直肠癌的敏感性为97.18%（95% CI：0.80，0.99），特异性为86.67%（95% CI：0.71，0.98），准确率为95.35%（95% CI：0.78，0.99）。ROC曲线分析结果显示，两者联合诊断直肠癌的AUC为0.968（95% CI：0.89，1.00）。两者联合诊断为T₁期的准确率为94.12%（95% CI：0.76，0.94），T₂期的准确率为90.91%（95% CI：0.72，0.92），T₃期的准确率为100.00%（95% CI：0.99，1.00），T₄期的准确率为100.00%（95% CI：0.99，1.00）。直肠癌组E_max、E_mean值较非直肠癌组高（P <0.05）。不同分期的杨氏模量值比较，差异有统计学意义（P <0.05），且TNM分期越晚，E_max、E_mean值越高。结论 TRUS结合SWE诊断直肠癌及TNM分期的准确性较高，可为临床病变鉴别及病理程度提供一定参考依据。     

Association between blood cadmium and vitamin D levels in the Yangtze Plain of China in the context of rapid urbanization

BackgroundChina has experienced rapid urbanization in the past 30 years. We aimed to report blood cadmium level (BCL) in the rapidly urbanized Yangtze Plain of China, and explore the association between BCL and 25-hydroxyvitamin D (25(OH)D).MethodsOur data source was the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) cross-sectional study (ChiCTR-ECS-14005052, www.chictr.org). We enrolled 3234 subjects from 12 villages in the Yangtze Plain. BCLs were measured by atomic absorption spectrometry. 25(OH)D was measured with a chemiluminescence assay.ResultsA total of 2560 (79.2%) subjects were diagnosed with vitamin D deficiency. The median (interquartile range) BCL was 1.80 μg/L (0.60–3.42) for men and 1.40 μg/L (0.52–3.10) for women. In women, mean 25(OH)D concentrations were inversely associated with BCL (0.401, 95% confidence interval: –0.697 to –0.105 nmol/L lower with each doubling of the BCL) after adjustment for age, educational status, current smoking, body mass index, diabetes, and season. However, there was no significant difference in 25(OH)D across the BCL tertiles for men.ConclusionsBCL in Chinese residents in the Yangtze Plain were much higher than that in developed countries. An inverse association between BCL and 25(OH)D was found in general Chinese women after multivariable adjustment. Future prospective cohort and animal studies are warranted to resolve the direction and temporality of these relationships, and to elucidate the exact mechanisms involved.     

Changes in the Bispectral Index in Response to Loss of Consciousness and No Somatic Movement to Nociceptive Stimuli in Elderly Patients

Background:

Bispectral index (BIS) is considered very useful to guide anesthesia care in elderly patients, but its use is controversial for the evaluation of the adequacy of analgesia. This study compared the BIS changes in response to loss of consciousness (LOC) and loss of somatic response (LOS) to nociceptive stimuli between elderly and young patients receiving intravenous target-controlled infusion (TCI) of propofol and remifentanil.

Methods:

This study was performed on 52 elderly patients (aged 65–78 years) and 52 young patients (aged 25–58 years), American Society of Anesthesiologists physical status I or II. Anesthesia was induced with propofol administered by TCI. A standardized noxious electrical stimulus (transcutaneous electrical nerve stimulation, [TENS]) was applied (50 Hz, 80 mA, 0.25 ms pulses for 4 s) to the ulnar nerve at increasing remifentanil predicted effective-site concentration (Ce) until patients lost somatic response to TENS. Changes in awake, prestimulus, poststimulus BIS, heart rate, mean arterial pressure, pulse oxygen saturation, predicted plasma concentration, Ce of propofol, and remifentanil at both LOC and LOS clinical points were investigated.

Results:

BIS_LOC in elderly group was higher than that in young patient group (65.4 ± 9.7 vs. 57.6 ± 12.3) (t = 21.58, P < 0.0001) after TCI propofol, and the propofol Ce at LOC was 1.6 ± 0.3 μg/ml in elderly patients, which was significantly lower than that in young patients (2.3 ± 0.5 μg/ml) (t = 7.474, P < 0.0001). As nociceptive stimulation induced BIS to increase, the mean of BIS maximum values after TENS was significantly higher than that before TENS in both age groups (t = 8.902 and t = 8.019, P < 0.0001). With increasing Ce of remifentanil until patients lost somatic response to TENS, BIS_LOS was the same as the BIS_LOC in elderly patients (65.6 ± 10.7 vs. 65.4 ± 9.7), and there were no marked differences between elderly and young patient groups in BIS_awake, BIS_LOS, and Ce of remifentanil required for LOS.

Conclusion:

In elderly patients, BIS can be used as an indicator for hypnotic-analgesic balance and be helpful to guide the optimal administration of propofol and remifentanil individually.

Trial Registration:

CTRI Reg. No: ChiCTR-OOC-14005629; http://www.chictr.org.cn/showproj.aspx?proj=9875.     

Anticancer drug synergy prediction in understudied tissues using transfer learning

ObjectiveDrug combination screening has advantages in identifying cancer treatment options with higher efficacy without degradation in terms of safety. A key challenge is that the accumulated number of observations in in-vitro drug responses varies greatly among different cancer types, where some tissues are more understudied than the others. Thus, we aim to develop a drug synergy prediction model for understudied tissues as a way of overcoming data scarcity problems.Materials and MethodsWe collected a comprehensive set of genetic, molecular, phenotypic features for cancer cell lines. We developed a drug synergy prediction model based on multitask deep neural networks to integrate multimodal input and multiple output. We also utilized transfer learning from data-rich tissues to data-poor tissues.ResultsWe showed improved accuracy in predicting synergy in both data-rich tissues and understudied tissues. In data-rich tissue, the prediction model accuracy was 0.9577 AUROC for binarized classification task and 174.3 mean squared error for regression task. We observed that an adequate transfer learning strategy significantly increases accuracy in the understudied tissues.ConclusionsOur synergy prediction model can be used to rank synergistic drug combinations in understudied tissues and thus help to prioritize future in-vitro experiments. Code is available at https://github.com/yejinjkim/synergy-transfer.     

A simple and easily implemented risk model to predict 1-year ischemic stroke and systemic embolism in Chinese patients with atrial fibrillation

Background:Accurate prediction of ischemic stroke is required for deciding anticoagulation use in patients with atrial fibrillation (AF). Even though only 6% to 8% of AF patients die from stroke, about 90% are indicated for anticoagulants according to the current AF management guidelines. Therefore, we aimed to develop an accurate and easy-to-use new risk model for 1-year thromboembolic events (TEs) in Chinese AF patients.Methods:From the prospective China Atrial Fibrillation Registry cohort study, we identified 6601 AF patients who were not treated with anticoagulation or ablation at baseline. We selected the most important variables by the extreme gradient boosting (XGBoost) algorithm and developed a simplified risk model for predicting 1-year TEs. The novel risk score was internally validated using bootstrapping with 1000 replicates and compared with the CHA₂DS₂-VA score (excluding female sex from the CHA₂DS₂-VASc score).Results:Up to the follow-up of 1 year, 163 TEs (ischemic stroke or systemic embolism) occurred. Using the XGBoost algorithm, we selected the three most important variables (congestive heart failure or left ventricular dysfunction, age, and prior stroke, abbreviated as CAS model) to predict 1-year TE risk. We trained a multivariate Cox regression model and assigned point scores proportional to model coefficients. The CAS scheme classified 30.8% (2033/6601) of the patients as low risk for TE (CAS score = 0), with a corresponding 1-year TE risk of 0.81% (95% confidence interval [CI]: 0.41%–1.19%). In our cohort, the C-statistic of CAS model was 0.69 (95% CI: 0.65–0.73), higher than that of CHA₂DS₂-VA score (0.66, 95% CI: 0.62–0.70, Z = 2.01, P = 0.045). The overall net reclassification improvement from CHA₂DS₂-VA categories (low = 0/high ≥1) to CAS categories (low = 0/high ≥1) was 12.2% (95% CI: 8.7%–15.7%).Conclusion:In Chinese AF patients, a novel and simple CAS risk model better predicted 1-year TEs than the widely-used CHA₂DS₂-VA risk score and identified a large proportion of patients with low risk of TEs, which could potentially improve anticoagulation decision-making.Trial Registration:www.chictr.org.cn (Unique identifier No. ChiCTR-OCH-13003729).     

NLR与PCT对直肠癌术后吻合口漏的早期诊断价值

目的 分析中性粒细胞淋巴细胞计数比值（neutrophil to lymphocyte ratio,NLR）与降钙素原（procalcitonin,PCT）在早期诊断直肠癌术后吻合口漏（anastomotic leakage,AL）的价值,为临床工作提供参考依据。方法 以2016年11月~2017年11月220例于西南医科大学附属医院胃肠外科住院的直肠癌患者为纳入对象,将其分为两组,其中术后未发生AL患者205例（无AL组）,发生AL（AL组）的患者15例,分别在术前、术后第1~7天检测外周血NLR、PCT水平,运用受试者工作特性曲线（ROC曲线）评价NLR、PCT在早期诊断直肠癌术后AL方面的价值。结果 220例患者中,15例患者术后发生AL（发生率为6.818%）,两组患者NLR值水平在术后第4天差异有统计学意义（P<0.05）,第5、6、7天差异有统计学意义（P<0.01）,行ROC曲线分析发现术后第6~7天NLR的AUC值>0.800,且在术后第7天出现最大值（AUC=0.848）;两组患者PCT值在术后第2、3天差异有统计学意义（P<0.05）,第4、5、6、7天差异有统计学意义（P<0.01）,行ROC曲线研究时发现术后第4、5、6、7天PCT的AUC值>0.800,且在术后第5天达到最大值（AUC=0.903）。结论 NLR、PCT均可用于早期诊断直肠癌Dixon术后AL,且PCT比NLR更具有诊断价值。     

血清胰岛素样生长因子结合蛋白2在直肠癌早期诊断中的价值

目的 探讨血清胰岛素样生长因子结合蛋白2(IGFBP-2)在早期直肠癌诊断中的价值。 方法 选取肿瘤外科住院TNM分期Ⅰ期与Ⅱ期直肠癌患者84例,同时以性别、年龄匹配的直肠良性病变与健康体检者作为对照。酶联免疫吸附法(ELISA)检测血清IGFBP-2,比较3组间含量的差异。比较直肠癌患者男女之间、不同年龄、不同浸润深度、不同分化程度、不同肿瘤直径、不同临床分期等IGFBP-2水平的差异。采用Pearson相关分析法研究血清IGFBP-2与临床病理参数的相关性;ROC曲线分析IGFBP-2诊断Ⅰ期、Ⅱ期直肠癌敏感度与特异性。 结果 直肠癌组、直肠良性病变组、正常对照组IGFBP-2水平分别为223.7~360.9 ng/ml、158.2~199.6 ng/ml、135.6~184.5 ng/ml,直肠癌组显著高于直肠良性病变组与正常对照组(P<0.05);IGFBP-2在浸润深度为T3~T4患者显著高于深度为T1~T2患者,Mann-Whitney检验Z值为2.28(P=0.02);IGFBP-2诊断直肠癌Ⅰ期、Ⅱ期ROC曲线下面积(AUC)分别为0.701、0.753。当IGFBP-2取值分别为197.33、242.17 ng/ml时诊断Ⅰ期与Ⅱ期直肠癌的灵敏度与特异性分别为0.874、0.643和0.786、0.655。 结论 血清IGFBP-2水平可区分直肠组织早期癌变与良性病变,与癌组织浸润深度有较大关系,但应用于直肠癌早期诊断特异性偏低,临床价值有限。      

基于T2WI与RS-EPI DWI影像组学特征的自动化机器学习模型预测直肠癌术前T分期的价值

  目的  探讨基于磁共振T2加权成像（T2 weighted image, T2WI）和分段读出平面回波成像（readout-segmented EPI, RS-EPI）与扩散加权成像（diffusion weighted image, DWI）的影像组学特征,通过开发和验证自动化机器学习模型,预测直肠癌术前病理T分期的价值。  方法  回顾性分析2016年10月?2018年12月经手术病理结果证实为直肠癌且在我院行术前直肠磁共振的患者131例。采用ITK-SNAP软件从T2WI和RS-EPI DWI图像中手动分割出肿瘤区域。使用PyRadiomics包提取出200个特征〔100个特征来自于T2WI,100个特征来自RS-EPI DWI的表观弥散系数（apparent diffusion coefficient, ADC）图〕。使用mwmote与neater重采样均衡数据,加入13例T_1-2期模拟数据。根据3∶1的比例将总体数据分割成训练集111例和测试集37例。在训练集上使用Tree-based Pipeline Optimization Tool（TPOT）最优化模型参数并选取最重要的组学特征建模,得到5个互相独立的T分期模型。使用准确率和受试者工作特征（ROC）曲线下面积（area under the curve, AUC）筛选出最优模型。在测试集和原数据集上预测直肠癌T分期。  结果  自动化机器学习推荐的5个T分期模型,在训练集上的准确率为0.802～0.838,敏感度为0.762～0.825,特异度为0.833～0.896,AUC范围为0.841～0.893,average precision（AP）范围为0.870～0.901。经过对比后,最终选择的模型的敏感度、特异度、AUC,在训练集上为0.810、0.875、0.893,在测试集上为0.810、0.813、0.810,在原始数据集上为0.810、0.830、0.860。  结论  基于T2WI和RS-EPI DWI的影像组学数据,通过自动化机器学习建立的模型在预测直肠癌T分期上有较高的准确率。     

磁共振影像组学主成分分析法预测直肠癌新辅助放射化学治疗效果

目的 探讨基于MRI高分辨率T2加权图像的影像组学主成分分析（PCA）法对直肠癌新辅助放射化学治疗效果的预测价值。方法 回顾性分析2018年1月1日至2018年12月31日在我院因局部进展期直肠癌接受新辅助放射化学治疗后行直肠癌根治性切除术的80例患者资料,男60例、女20例,年龄为28~74岁,平均年龄为（56.2±9.9）岁。患者行新辅助放射化学治疗前接受3.0 T MRI检查,在高分辨率T2加权图像上提取影像组学特征,再采用PCA法进行特征值降维,使用降维后的特征与病理完全缓解（pCR）标签建立logistic回归分类器模型,将样本随机分为训练集与测试集进行机器学习,分别绘制ROC曲线并计算AUC及灵敏度、特异度、准确度。结果 MRI高分辨率T2加权图像共提取到1 409个影像组学特征,PCA法重新组合并选取了前5个最能代表整个影像组学特征矩阵的新特征,分别能代表整个影像组学特征矩阵中9.926 016 67×10^-1、4.854 545 00×10^-3、2.509 013 91×10^-3、2.489 032 30×10^-5、7.372 984 50×10^-6的信息。Logistic回归分类器模型交叉验证测试集的平均AUC为0.761（95% CI：0.694~0.828）,灵敏度为90.3%,特异度为40.0%,准确度为79.0%。结论 基于MRI高分辨率T2加权影像组学PCA法对直肠癌新辅助放射化学治疗的疗效具有较好的预测价值。     

Secukinumab provided significant and sustained improvement in the signs and symptoms of ankylosing spondylitis: results from the 52-week,Phase III China-centric study,MEASURE 5

BackgroundSecukinumab demonstrated sustained efficacy in patients with ankylosing spondylitis (AS) through 5 years in pivotal Phase III studies. Here, we present efficacy and safety results (52-week) of secukinumab in patients with AS from the MEASURE 5 study.MethodsMEASURE 5 was a 52-week, Phase III, China-centric study. Eligible patients were randomly assigned (2:1) to receive subcutaneous secukinumab 150 mg or placebo weekly for the first five doses and then once every 4 weeks (q4w). All placebo patients switched to secukinumab 150 mg q4w starting at Week 16. Primary endpoint was Assessments of SpondyloArthritis international Society (ASAS) 20 at Week 16. Randomization was stratified by region (China vs. non-China).ResultsOf 458 patients (secukinumab 150 mg, N = 305; placebo, N = 153) randomized, 327 (71.4%) were from China and 131 (28.6%) were not from China. Of these, 97.7% and 97.4% patients completed Week 16 and 91.1% and 95.3% (placebo-secukinumab) patients completed Week 52 of treatment. The primary endpoint was met; secukinumab significantly improved ASAS20 response at Week 16 vs. placebo (58.4% vs. 36.6%; P < 0.0001); corresponding rate in the Chinese population was 56.0% vs. 38.5% (P < 0.01). All secondary efficacy endpoints significantly improved with secukinumab 150 mg in the overall population at Week 16; responses were maintained with a trend toward increased efficacy from Week 16 to 52. No new or unexpected safety signals were reported up to Week 52.ConclusionsSecukinumab 150 mg demonstrated rapid and significant improvement in signs and symptoms of AS. Secukinumab was well tolerated and the safety profile was consistent with previous reports. Efficacy and safety results were comparable between the overall and Chinese populations.Trial registrationClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02896127","term_id":"NCT02896127"}}NCT02896127; https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02896127","term_id":"NCT02896127"}}NCT02896127?term={"type":"clinical-trial","attrs":{"text":"NCT02896127","term_id":"NCT02896127"}}NCT02896127&draw=2&rank=1.