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Ying Wang,1,&ast; Yu Yi,1,&ast; Fan Zhang,1 Yuan-Yuan Yao,2 Yue-Xiu Chen,2 Chao-Min Wu,2 Rui-Yu Wang,2 Min Yan1,2 1Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China; 2Department of Anesthesiology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Yan, Email zryanmin@zju.edu.cnBackground: The lung ultrasound score was developed for rapidly assessing the extent of lung ventilation, and it can predict failure to wean various types of patients off mechanical ventilation. Whether it is also effective for COVID-19 patients is unclear.Methods: This single-center, prospective, observational study was conducted to assess the ability of the 12-region lung ultrasound score to predict failure to wean COVID-19 patients off ventilation. In parallel, we assessed whether right hemidiaphragmatic excursion or previously published predictors of weaning failure can apply to these patients. Predictive ability was assessed in terms of the area under the receiver operating characteristic curve (AUC).Results: The mean age of the 35 patients in the study was (75 ± 9) years and 12 patients (37%) could not be weaned off mechanical ventilation. The lung ultrasound score predicted these failures with an AUC of 0.885 (95% CI 0.770– 0.999, p < 0.001), and a threshold score of 10 provided specificity of 72.7% and sensitivity of 92.3%. AUCs were lower for previously published predictors of weaning failure, and right hemidiaphragmatic excursion did not differ significantly between the two groups.Conclusion: The lung ultrasound score can accurately predict failure to wean critically ill COVID-19 patients off mechanical ventilation, whereas assessment of right hemidiaphragmatic excursion does not appear helpful in this regard.Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05706441.Keywords: lung ultrasound score, diaphragmatic excursion, spontaneous breathing trial, weaning, COVID-19, critical care

Yang X Chen,1 Joshua Meyerov,2 Simon E Skalicky2,3 1St Vincent’s Hospital Clinical School, University of Melbourne, Melbourne, VIC, Australia; 2Department of Surgery Ophthalmology, University of Melbourne, Melbourne, VIC, Australia; 3Glaucoma Investigation and Research Unit, the Royal Victorian Eye and Ear Hospital, Melbourne, VIC, AustraliaCorrespondence: Simon E Skalicky, Royal Victorian Eye and Ear Hospital, 32 Gisborne St, East Melbourne, Melbourne, VIC, 3002, Australia, Tel +9509 4233, Email seskalicky@gmail.comPurpose: To establish a normative database using a central 10-degree grid pattern for the online circular contrast perimetry (OCCP) application.Participants: Fifty participants with mean age 65 ± 13 years were selected for this study. One eye from each participant that met inclusion criteria was randomly included in the cohort.Methods: The web-application delivered online 52-loci perimetry in a central 10-degree pattern using circular flickering targets. These targets consist of concentric sinusoidal alternating contrast rings. Users were guided by the application to the correct viewing distance and head position using in-built blind spot localization and webcam monitoring. A spinning golden star was used as the fixation target and patients performed the test in a darkened room following standard automated perimetry (SAP).Results: The reliability rates and global indices for OCCP were similar to SAP. OCCP mean sensitivity reduced with age at a similar rate to SAP. Mean sensitivity per loci of 10-degree OCCP was greater than SAP by 1.24 log units (95% CI 1.23 to 1.26) and obeyed a physiological hill of vision. Small differences existed in mean sensitivities between OCCP and SAP which increased with increasing spot eccentricity. Mean deviation (MD) displayed good agreement between the two tests.Conclusion: Central 10-degree online circular contrast perimetry via a computer-based application has comparable perimetric results to standard automated perimetry in a normal cohort.Keywords: online perimetry, glaucoma, visual field testing

Gui-Qin Zhong,1,&ast; Bi-Hua Lin,1,&ast; Yu-Xuan Chen,2 Yan-Juan Lin,1 Chun-Mei Chen3 1Department of Neurosurgery Nursing, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 2College of Nursing, Fujian Medical University, Fuzhou, 350108, People’s Republic of China; 3Department of Neurosurgery, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan-Juan Lin, Department of Neurosurgery Nursing, Fujian Medical University Union Hospital, No. 29, Xin Quan Road, Fuzhou, Fujian Province, 350001, People’s Republic of China, Tel +8613365910562, Email linyanjuanlyj9k@126.com Chun-Mei Chen, Department of Neurosurgery, Fujian Medical University Union Hospital, No. 29, Xin Quan Road, Fuzhou City, Fujian Province, 350001, People’s Republic of China, Tel +8613365910678, Email chenchumeiccm0@126.comObjective: To investigate the prevalence of postoperative kinesiophobia in patients with cervical spondylotic myelopathy (CSM) and factors influencing the occurrence of kinesiophobia, to provide relevant basis for making clinical decisions for targeted interventions.Methods: We enrolled a total of 85 patients who underwent CSM surgery at two grade-A general public hospitals in Fujian Province between September 2021 and May 2022. We conducted a questionnaire survey using the Tampa Scale for Kinesiophobia (TSK) and the Zung Self-Rating Anxiety Scale (SAS). Patients evaluated pain using a visual analogue scale. We used one-way ANOVA and logistic multiple regression analysis to identify the relevant influencing factors.Results: The TSK score was (41.88± 4.46) in 85 postoperative CSM patients, 65 males and 20 females, and there were 31 patients under 40 years old, 54 patients over 40 years old, 58 patients below high school education and 27 patients above high school education, and among them, 81.17% were diagnosed with kinesiophobia. Age was positively correlated with TSK score (r = 0.379, P < 0.05) and therefore a risk factor for kinesiophobia (OR = 1.941, 95% CI = 1.021– 3.690). Additionally, the duration of the disease was a protective factor for kinesiophobia (OR = 0.179, 95% CI = 0.053– 0.605).Conclusion: Patients with CSM were at high risk of developing kinesiophobia postoperatively. Age and duration of the disease were factors influencing the occurrence of kinesiophobia in this group.Keywords: cervical spondylotic myelopathy, influencing factors, kinesiophobia, postoperative

Yu-Xing Chen,1,&ast; Jin-Xing Zhang,1,&ast; Chun-Gao Zhou,1 Jin Liu,2 Sheng Liu,1 Hai-Bin Shi,1 Qing-Quan Zu1 1Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Clinical Medicine Research Institution, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing-Quan Zu, Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-25-68306316 ; +86-13913807470, Fax +86-25-83724440, Email zuqingquan@njmu.edu.cnBackground: Combination of angiogenesis inhibitor may achieve better therapeutic synergistic efficacy, considering of tumor hypoxia and promoted angiogenesis after transarterial chemoembolization (TACE). This study aimed to compare the safety and efficacy of TACE plus lenvatinib (TACE-lenvatinib) with TACE alone for patients with unresectable hepatocellular carcinoma (HCC).Methods: Between June 2019 and September 2021, a total of 215 patients diagnosed with unresectable HCC were retrospectively reviewed, including 53 patients who received TACE-lenvatinib and 162 patients who received TACE alone. The patient selection bias between the TACE-lenvatinib group and the TACE group was balanced by propensity score matching analysis at a 1:2 ratio. Progression-free survival (PFS), overall survival (OS) and tumor response were evaluated in the two groups.Results: After propensity score matching analysis, 34 patients receiving TACE-lenvatinib and 68 patients receiving TACE alone were enrolled. The median PFS and OS times in the TACE-lenvatinib group were significantly greater than those in the TACE group (PFS: 8.3 months vs 4.6 months, P = 0.008; OS: 27.7 months vs 18.4 months, P = 0.043). The objective response rate (ORR) in the TACE-lenvatinib group was higher than that in the TACE alone group (64.1% vs 36.5%, P = 0.002). Univariate and multivariate analyses revealed that TACE-lenvatinib treatment was an independent favorable prognostic factor for both PFS and OS.Conclusion: For unresectable HCC patients, the TACE-lenvatinib appeared superior to TACE alone regarding tumor control, PFS, and OS. However, considering the limitations of this study, these results should be interpreted as preliminary and warrant further confirmation.Keywords: carcinoma, hepatocellular, chemoembolization, therapeutic, lenvatinib, survival analysis, propensity score

Yan Chen, Yan-Xia Chen, Chong Huang, Zhi-Bing Duan, Cheng-Yun Xu Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of ChinaCorrespondence: Yan ChenDepartment of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, Jiangxi Province, 330006, People’s Republic of ChinaTel/Fax +86 791 86312319Email chenyan_drcy@163.comObjective: This study aims to investigate the clinical value of serum Klotho and FGF23 in cardiac valve calcification in patients with chronic kidney disease (CKD).Methods: In the present study, 180 patients with CKD, who were admitted to the department of nephrology of our hospital on April 1, 2016 (solstice, 2019), were selected as the main subjects. According to the CKD stage, these patients were divided into three groups: CKD2∼ 3 group, CKD4 group, and CKD5 group. In each group, ultrasound was used to evaluate the cardiac valve calcification, and the independent risk factors for cardiac valve calcification were analyzed by Logistic regression.Results: The levels of hemoglobin and blood calcium in CKD2∼ 3 patients were higher than those in CKD4 and CKD5 patients, and the levels of hemoglobin and blood calcium in CKD5 patients were higher than those in CKD4 patients (P< 0.05). Albumin was lower in CKD2∼ 3 patients when compared to CKD5 patients while albumin was higher in CKD5 patients when compared to CKD4 patients (P< 0.05). The serum levels of FGF23 was lower in CKD2∼ 3 patients when compared to CKD4 and CKD5 patients while the serum levels of FGF23 was lower in CKD4 patients when compared to CKD5 patients (P< 0.05). The serum levels of Klotho was higher in CKD2∼ 3 patients, when compared to CKD4 and CKD5 patients, while the serum levels of Klotho was higher in CKD4 patients, when compared to CKD5 patients (P< 0.05). The logistic regression analysis revealed that GFR, serum creatinine, FGF23 and Klotho were independent risk factors for cardiac valve calcification in patients with CKD.Conclusion: With the decrease of GFR in CKD patients, the serum levels of FGF23 increases, while the serum levels of Klotho decreases. Furthermore, the serum levels of FGF23 and Klotho are affected by various factors, and the levels of FGF23 and Klotho in CKD patients are negatively correlated. GFR, serum creatinine, FGF23 and Klotho are independent risk factors for heart valve calcification in patients with CKD.Keywords: Klotho, FGF23, chronic kidney disease, cardiac valve calcification, logistic regression analysis

Xiang-Jin Wang,1,2,* Zhen Wang,1,3,* Zi-Tao Zhang,3 Xu-Sheng Qiu,3 Ming Chen,2 Yi-Xin Chen1,3 1Department of Orthopedics, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Orthopedics, XuZhou Central Hospital, Xuzhou, People’s Republic of China; 3Department of Orthopedics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi-Xin ChenDepartment of Orthopedics, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, Jiangsu 210008, People’s Republic of ChinaEmail chenyixin93@126.comBackground: The timely and accurate diagnosis of infected nonunion is challenging, and there is a need for more efficient biomarkers. Previous studies have shown that fibrinogen plays an important role in mediating inflammation in bacterial infections and, therefore, could be a valuable biomarker for infected nonunion. The purpose of this study was to evaluate and compare the performance of plasma fibrinogen and other traditional blood markers for the diagnosis of infected nonunion.Materials and Methods: We retrospectively studied 146 patients who underwent surgery for primary nonunion between January 2018 and January 2020. The patients were divided into those with infected nonunion (n = 55) and those with aseptic nonunion (n = 91). The preoperatively analyzed parameters were plasma fibrinogen, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and white blood cell (WBC) count. Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity of the biomarkers, and Youden’s index was calculated to determine their optimal cut-off values.Results: The plasma fibrinogen values were significantly higher (p < 0.001) in the patients with infected nonunion than in those with aseptic nonunion. ROC curve analysis showed that plasma fibrinogen had a high value of area under the curve (0.816), which indicated that it had good diagnostic ability. Further, at the optimal threshold value of 2.75 g/L, plasma fibrinogen had the highest sensitivity (78.2%; 95% CI = 64.6– 87.8) and good specificity (82.4%; 95% CI, 72.7– 89.3).Conclusion: In comparison to the traditional markers of infection, plasma fibrinogen showed good diagnostic ability for the detection of infected nonunion. It may have potential as a practical and cost-efficient biomarker for the diagnosis of infected nonunion.Keywords: infected nonunion, diagnostic test, plasma fibrinogen, blood biomarkers

You-Xin Chen,1 Xiao-Xin Li,2 Young Hee Yoon,3 Xiaodong Sun,4 Yury Astakhov,5 Gezhi Xu,6 Hui Wang,7 Xiaowei Ren,8 Friedrich Asmus9 On behalf of the VIVID-East investigators1Department of Ophthalmology, Peking Union Medical College, Beijing, People’s Republic of China; 2Ophthalmology Department, People’s Eye Center of Peking University People’s Hospital, Beijing, People’s Republic of China; 3Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Department of Ophthalmology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Ophthalmology, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia; 6Department of Ophthalmology and Vision Sciences, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 7Clinical Development, Ophthalmology, Bayer Healthcare Inc, Shanghai, People’s Republic of China; 8Statistics and Data Insights, Bayer Healthcare Inc, Beijing, People’s Republic of China; 9University Hospital of Tübingen, Tübingen, GermanyCorrespondence: Friedrich AsmusCenter for Neurology, University Hospital of Tübingen, Hoppe-Seyler Strasse 3, Tübingen, GermanyTel +49 179 746 3010Email friedrich.asmus@gmail.comPurpose: The prevalence of diabetes and diabetes-related complications, including diabetic macular edema (DME), is increasing in Asia and worldwide.Methods: VIVID-East was a 12-month, double-masked, randomized, active-controlled, Phase 3 trial (NCT01783886) enrolling adult patients (aged ≥ 18 years) with DME at 25 centers across China, Hong Kong, Republic of Korea, and Russia. Eyes were randomized 1:1:1 to 2 mg intravitreal aflibercept (IVT-AFL) every 4 weeks (2q4; N=127), 2 mg IVT-AFL every 8 weeks (after 5 initial monthly doses from baseline to week 16) with sham injections on nontreatment visits (2q8; N=127), or macular laser photocoagulation at baseline and sham injections at every visit (laser control group; N=124). The primary efficacy endpoint was mean change in best corrected visual acuity (BCVA) from baseline to week 52.Results: Compared with baseline, at week 52 the mean (SE) BCVA in the 2q4 and 2q8 groups gained +13.6 (0.9) and +13.1 (1.0) letters, respectively, versus − 0.5 (1.4) letters in the laser group (P< 0.0001 for both). A significantly higher proportion of patients treated with IVT-AFL (2q4 and 2q8) achieved a ≥ 10-letter or ≥ 15-letter gain compared with laser (both P< 0.0001) (≥ 10-letter gain: 70.9%, 62.7%, and 23.4%, respectively; ≥ 15-letter gain: 43.3%, 36.5%, and 12.1%, respectively). Mean reduction in central retinal thickness from baseline to week 52 was significantly greater with IVT-AFL versus laser treatment. Incidence of treatment-emergent adverse events was low and similar across groups; conjunctival hemorrhage (11.8%), retinal hemorrhage (8.7%), retinal aneurysm (7.5%), and retinal exudates (5.5%) being the most frequently reported. Visual and anatomic outcomes in the Chinese subgroup were consistent with the overall population.Conclusion: IVT-AFL treatment resulted in significant visual and anatomic improvements in Asian patients with DME. Treatment benefits observed in the overall study population were mirrored in the subgroup of Chinese patients, who made up the largest population group in the study.Study Registration: NCT01783886.Keywords: Asia, Chinese, intravitreal aflibercept, diabetic macular edema

Yuan Zhuang, Bao-Ying Yuan, Yong Hu, Gen-Wen Chen, Li Zhang, Xiao-Mei Zhao, Yi-Xing Chen,* Zhao-Chong Zeng* Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi-Xing Chen; Zhao-Chong ZengDepartment of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86-139-1605-6575Fax +86-21-6404-8472Email chen.yixing@zs-hospital.sh.cn; zeng.zhaochong@zs-hospital.sh.cnPurpose: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are inflammatory indexes that may reflect immune response to tumors and prognosis. We investigated the prognostic values of pre-treatment and post-treatment NLR and PLR and changes in those ratios in patients with small hepatocellular carcinoma (sHCC) treated with stereotactic body radiation therapy (SBRT).Patients and methods: Sixty patients who received SBRT were retrospectively reviewed. NLR and PLR were calculated by division of neutrophil and platelet counts, respectively, by lymphocyte counts. Independent factors for progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan–Meier method, log-rank test, and Cox multivariate regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) were also calculated.Results: The median follow-up was 36.9 (range: 4.1–73.5) months. Median PFS was 21.4 (range: 1.8–66.9) months. The 1-year and 2-year PFS rates were 76.7% and 55.0%, respectively. The 1-year and 2-year OS rates were 95.0% and 78.3%, respectively. In multivariate analysis, post-treatment PLR ≥263.0 indicated both poor PFS (HR: 3.70; 95% CI: 1.07–12.76, p=0.038) and OS (HR: 3.23; 95% CI: 1.01–9.11, p=0.043) for sHCC patients treated with SBRT. In addition, the presence of hepatitis infection and a low level of red blood cell count were also proved to be significantly associated with patients’ poor prognosis (pp=0.029).Conclusion: High post-treatment PLR and change in NLR ≥2.7-fold were associated with poor prognosis in patients treated with SBRT and might be considered as reliable and independent prognostic biomarkers for patients with sHCC.Keywords: stereotactic body radiation therapy, hepatocellular carcinoma, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, progression-free survival

Sheng-Yuan Yu,1 Bi-Fa Fan,2 Fei Yang,1 Marco DiBonaventura,3 Yu-Xuan Chen,4 Ruo-Yu Li,5 Kristen King-Concialdi,6 Ian Kudel,6 Patrick Hlavacek,3 Markay Hopps,3 Margarita Udall,3 Alesia Sadosky,3 Joseph C Cappelleri7 1Department of Neurology, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Pain Medicine, Pain Management Centre, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Pfizer, New York, NY, USA; 4Pfizer China, Beijing, People’s Republic of China; 5Department of Dermatology, Peking University First Hospital, Beijing, People’s Republic of China; 6Kantar Health, New York, NY, USA; 7Pfizer Inc, Groton, CT, USACorrespondence: Sheng-Yuan YuDepartment of Neurology, Chinese PLA General Hospital, Hai Dian District, Beijing 100853, People’s Republic of ChinaTel +86 105 549 9118Fax +86 108 862 6299Email yusy1963@126.comBackground: Little is known about the patient-reported and economic burdens of postherpetic neuralgia (PHN) among China’s urban population.Methods: This noninterventional study was conducted among adults ≥40 years with PHN who were seeking medical care at eight urban hospitals in China. At one study site, patients completed a questionnaire evaluating the patient-reported disease burden (N=185). The questionnaire consisted of validated patient-reported outcomes including the Brief Pain Inventory (BPI), 5-dimension, 3-level EuroQol (EQ-5D-3L), Medical Outcomes Study Sleep Scale, and Work Productivity and Activity Impairment Questionnaire for Specific Health Problems. Questions on non-pharmacologic therapy and out-of-pocket (OOP) expenses were also included. At all study sites, physicians (N=100) completed a structured review of patient charts (N=828), which was used to derive health care resource utilization and associated costs from the societal perspective. Annual costs in Chinese Yuan Renminbi (RMB) for the year 2016 were converted to US dollars (US$).Results: Patients (N=185, mean age 63.0 years, 53.5% female) reported pain of moderate severity (mean BPI score 4.6); poor sleep quantity (average of 5.3 hrs per night) and quality; and poorer health status on the EQ-5D-3L relative to the general Chinese population. Respondents also reported average annual OOP costs of RMB 16,873 (US$2541) per patient, mainly for prescription PHN medications (RMB 8990 [US$1354]). Substantial work impairment among employed individuals resulted in annual indirect costs of RMB 28,025 (US$4221). In the chart review, physicians reported that patients (N=828) had substantial health resource utilization, especially office visits; 98% had all-cause and 95% had PHN-related office visits. Total annual direct medical costs were RMB 10,002 (US$1507), mostly driven by hospitalizations (RMB 8781 [US$1323]).Conclusion: In urban China, PHN is associated with a patient-reported burden, affecting sleep, quality-of-life, and daily activities including work impairment, and an economic burden resulting from direct medical costs and indirect costs due to lost productivity. These burdens suggest the need for appropriate prevention and management of PHN.Keywords: postherpetic neuralgia, disease burden, health-related quality-of-life, EQ-5D, China, health care costs, productivity

Yanhong Shang,1,2,* Dexi Li,2,* Xinxin Shan,2 Stefan Schwarz,3 Su-Mei Zhang,2 Yu-Xia Chen,2 Wuqing Ouyang,1 Xiang-Dang Du21Department of Basic Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Shaanxi 712100, People’s Republic of China; 2Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, People’s Republic of China; 3Institute of Microbiology and Epizootics, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany*These authors contributed equally to this workBackground: The acquired optrA gene, which encodes a ribosomal protection protein of the ABC-F family, can confer cross-resistance to linezolid and florfenicol, posing a serious therapeutic challenge to both human and veterinary medicine.Purpose: The objective of this study was to investigate the two Enterococcus faecalis (E. faecalis) plasmids for their fine structure, their transferability and the presence of mobile antimicrobial resistance loci.Methods: To elucidate their fine structure, the two plasmids were completely sequenced and the sequences analysed. Besides conjugation experiments, inverse PCR assays were conducted to see whether minicircles are produced from the mobile antimicrobial resistance loci.Results: Two pheromone-responsive conjugative optrA-carrying plasmids from E. faecalis, pE211 and pE508 were identified, which can transfer with frequencies of 2.6 ×10−2 and 3.7 ×10−2 (transconjugant per donor), respectively. In both plasmids, optrA was located on the novel mobile optrA locus with different sizes (12,834 bp in pE211 and 7,561 bp in pE508, respectively), flanked by two copies of IS1216 genes in the same orientation. Inverse PCR revealed that circular forms can be generated, consisting of optrA and one copy of IS1216, indicating they are all active. The 77,562 bp plasmid pE211 also carried Tn558 and a mobile bcrABDR locus, and the 84,468 bp plasmid pE508 also harbored the genes fexA, tet(L), tet(O/W/32/O) and a mobile aac(A)-aph(D) locus.Conclusion: The presence of mobile genetic elements in these plasmids renders them flexible and these elements will aid to the persistence and dissemination of these plasmids among enterococci and potentially also other gram-positive bacteria.Keywords: enterococci, resistance, IS1216, conjugation, mobile genetic elements

Gui-Fen Ma,1,* Hai-Ge Zhang,1,* Juan Liu,1 Yi-Xing Chen,1 Han Xiao,1 Xue-Fei Wang,2 Jian He,1 Zhao-Chong Zeng,1 Jing Sun,1 Tian-Shu Liu3,41Department of Radiotherapy, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 2Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 4Center of Evidence-Based Medicine, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workBackground: For patients with locally advanced gastric cancer (LAGC) after D2 gastrectomy, the survival benefits of receiving adjuvant chemoradiotherapy versus adjuvant chemotherapy are unclear. This study aimed to compare the 5- and 7-year overall survival (OS) in the two groups and to identify which patients can benefit more from adjuvant chemoradiotherapy.Methods: Retrospective data were collected from January 2009 to December 2014. The 5- and 7-year OS and disease-free survival (DFS) were compared between the two groups using the Chi-square test. The association of OS with prognostic factors was identified using the Cox’s proportional hazard model, which was then adjusted for survival coparison using propensity score-matching (PSM) analysis. The association of OS with each clinical/demographic factor was compared between the two groups using the Kaplan–Meier analysis.Results: A total of 415 eligible patients were identified (135 adjuvant chemoradiotherapy, 280 adjuvant chemotherapy). Significant 5- and 7-year OS and DFS benefits were found in the adjuvant chemoradiotherapy group versus chemotherapy group. Multivariate analysis showed that age, TNM stage, lymph node (LN) ratio, tumor deposits, and total/subtotal gastrectomy were independent prognostic factors. When the PSM analysis was adjusting by these factors, 135 patients were matched with an improved survival benefit from adjuvant chemoradiotherapy. Patients in the adjuvant chemoradiotherapy group had a lower locoregional relapse. Subset analysis also identified significant OS benefits of adjuvant chemoradiotherapy in patients with LN ratio

Zhen Wang, Ji Xiao, Zitao Zhang, Xusheng Qiu, Yixin Chen Department of Orthopedics, Drum Tower Hospital Clinical College of Nanjing University, Nanjing, China Background: Preoperative deep vein thrombosis (DVT) is a common complication in patients with hip fractures. Chronic kidney disease (CKD) as a frequent comorbidity in middle-aged and elderly patients with hip fractures is known to promote a proinflammatory and prothrombotic state. We aimed to identify whether CKD can increase the risk of DVT in middle-aged and elderly patients with hip fractures, as well as identify other risk factors.Patients and methods: We retrospectively studied 248 middle-aged and elderly patients with hip fractures who were admitted to our hospital from January 2016 to June 2017, meeting all the inclusion criteria. Doppler ultrasonography was used to diagnose DVT. Patients with CKD were classified into five stages according to the Kidney Diseases Outcomes Quality Initiative. We identified whether CKD could increase the occurrence of preoperative DVT in middle-aged and elderly patients with hip fractures and further investigated other independent risk factors for preoperative DVT by using univariate and multivariate analyses.Results: The mean estimated glomerular filtration rate was 125.7±41.4 mL/min/1.73 m2. Briefly, 82.3% (n=204) had been diagnosed with normal kidney function, 11.7% (n=29) with mildly decreased kidney function, and 6.0% (n=15) with stage 3 and 4 CKD. In addition, of the 248 patients, 11.7% (n=29) developed DVT before surgery. Independent predictors of preoperative DVT identified by multivariate analyses were age, prolonged bedridden time, increased levels of fibrinogen, and lower estimated glomerular filtration rate.Conclusion: CKD can increase the risk rate of preoperative DVT in middle-aged and elderly patients with hip fractures. Additionally, age, prolonged bedridden time, and increased levels of fibrinogen were also independent risk factors for preoperative DVT in these patients. We should take preventive measures for these patients with risk factors in order to reduce the incidence of preoperative DVT. Keywords: CKD, preoperative DVT, hip fractures, middle-aged and elderly patients

Bruce Parsons,1 Xiaoping Pan,2 Li Xie,3 YuXuan Chen,3 Marie Ortiz,1 Ed Whalen1 1Pfizer, New York, NY, USA; 2Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China; 3Pfizer China, Beijing, China Purpose: Pregabalin is indicated for postherpetic neuralgia (PHN) in multiple countries, including China. This analysis compared pregabalin efficacy and safety in Chinese and international patients with PHN. Patients and methods: Data from Chinese and international randomized, double-blind, placebo-controlled trials were compared. Pregabalin was administered at fixed (150, 300, or 600 mg/day) or flexible (150–600 mg/day) doses. The main efficacy measure was mean pain score change at endpoint on an 11-point numeric rating scale ranging from 0 = no pain to 10 = worst possible pain. Secondary efficacy measures included proportions of 30% and 50% pain responders, pain-related sleep interference (PRSI) scores, and proportions of Patient Global Impression of Change (PGIC) responders. The incidences of serious adverse events (SAEs) and adverse events (AEs) were used to assess safety. The effect of baseline pain severity on efficacy was tested. The proportions of patients with severe baseline pain who had moderate or mild pain at endpoint were also assessed. Results: A total of 1166 patients were analyzed: 312 Chinese and 854 international. Overall, results were similar between Chinese and international patients. Pregabalin statistically significantly improved mean pain score versus placebo (least squares mean difference [95% CIs]: Chinese, –0.8 [–1.2, –0.5]; international, –1.3 [–1.6, –1.0]; both p

Li-Ying Tang,1 Mou-Xin Zhang,2 Di-Han Lu,3 Yong-Xiong Chen,1 Zu-Guo Liu,1,2 San-Gang Wu4 1Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Medical College, Xiamen University, Xiamen 361005, People’s Republic of China; 2Xiamen University Affiliated Xiamen Eye Center, Xiamen 361001, People’s Republic of China; 3Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China; 4Department of Radiation Oncology, Xiamen Cancer Hospital, the First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of China Introduction: Orbital embryonal rhabdomyosarcoma is a rare childhood malignancy with a good prognosis, but the optimal treatment remains unclear. Using a population-based cancer registry, we assessed the prognoses and survival outcomes of patients with orbital embryonal rhabdomyosarcoma according to the local treatment strategy.Patients and methods: Patients diagnosed with orbital embryonal rhabdomyosarcoma between 1988 and 2012 as part of the Surveillance Epidemiology and End Results program were included. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors associated with cause-specific survival (CSS) and overall survival (OS).Results: In total, 102 patients were included; their median age was 6 years, 78.4% were white, and 56.9% were male. The median tumor size was 30 mm. Of 20 patients with an available histologic grade, the tumors of 90% were poorly differentiated/undifferentiated. Of 92 patients with available surgical and radiotherapy (RT) statuses, 50 (54.3%), 36 (39.1%), and 6 (6.5%) received surgery and RT, primary RT, and primary surgery, respectively. Ninety-five patients (93.1%) received chemotherapy. The 5- and 10-year CSSs of the entire cohort were 94.3% and 92.2%, respectively. The 5- and 10-year OSs were 93.3% and 91.3%, respectively. In 95 patients who were followed up for at least 12 months, there were no significant prognostic factors related to CSS and OS. Furthermore, the local treatment strategy did not significantly affect CSS (P=0.29) or OS (P=0.468).Conclusion: There is no local treatment of choice for orbital embryonal rhabdomyosarcoma in terms of survival. However, RT is a reasonable alternative treatment to surgery. Keywords: orbital embryonal rhabdomyosarcoma, survival, radiotherapy, surgery, SEER

San-Gang Wu,1,* Wen-Wen Zhang,2,* Zhen-Yu He,2 Jia-Yuan Sun,2 Yong-Xiong Chen,3 Ling Guo4 1Department of Radiation Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 3Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Medical College, Xiamen University, Xiamen, 4Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China *These authors contributed equally to this work. Background: There are few population-based studies of the sites of distant metastasis (DM) and survival from esophageal cancer (EC). The aim of this study was to assess the patterns and survival outcomes for site-specific DM from EC using a population-based approach.Methods: Patients diagnosed with de novo stage IV EC between 2010 and 2014 were identified from the Surveillance, Epidemiology, and End Results program database. Overall survival (OS) was compared according to the site of DM.Results: We included 3218 patients in this study; the most common site of DM was the liver, followed by distant lymph nodes, lung, bone and brain. Median OS for patients with liver, distant lymph node, lung, bone, and brain metastases was 5, 10, 6, 4, and 6 months, respectively (p

San-Gang Wu,1,* Wen-Wen Zhang,2,* Jia-Yuan Sun,2 Feng-Yan Li,2 Yong-Xiong Chen,3 Zhen-Yu He2 1Department of Radiation Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 3Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Medical College, Xiamen University, Xiamen, People’s Republic of China *These authors contributed equally to this work Introduction: Invasive micropapillary carcinoma (IMPC) of the breast poses a high risk of locoregional recurrence, and postoperative radiotherapy (PORT) may be beneficial in IMPC. Hence, we determined the clinical value of PORT in IMPC patients. Patients and methods: We assessed clinicopathological factors extracted from the Surveillance, Epidemiology, and End Results database (2004–2013). Univariate and multivariate Cox proportional hazards regressions were performed to assess the independent prognostic factors on breast cancer-specific survival (BCSS) and overall survival (OS). Results: Of the 881 study patients, 444 (50.4%) and 437 (49.6%) underwent breast-conserving surgery (BCS) and mastectomy (MAST), respectively, of whom 357 (80.4%) and 153 (35.0%) underwent PORT, respectively. Patients with young age, large tumor size, or advanced nodal stage were more likely to undergo MAST and PORT compared with MAST alone. Patients with progesterone receptor-positive disease were more likely to receive BCS and PORT compared with BCS alone. The 5-year BCSS and OS were 95.7% and 90.9%, respectively. On multivariate analyses, tumor size, histological grade, and estrogen receptor status were independent predictors of BCSS and OS. The types of surgical procedures (MAST vs. BCS) were not an independent predictor of survival outcomes. Patients who underwent MAST with or without PORT had similar BCSS and OS in the multivariate analyses. Those who underwent BCS plus PORT did not have better BCSS and OS than those who underwent BCS alone. In the low-, intermediate-, and high-risk groups, PORT was not associated with better BCSS and OS than non-PORT groups in patients who received BCS or MAST. Conclusion: IMPC has favorable BCSS and OS. Regardless of the types of surgical procedures (MAST or BCS), PORT groups were not inferior to non-PORT groups on BCSS and OS. Keywords: invasive micropapillary carcinoma, SEER, radiotherapy, survival

Ningying Mao,1 Beth Lesher,2 Qifa Liu,3 Lei Qin,2 Yixi Chen,4 Xin Gao,2 Stephanie R Earnshaw,5 Cheryl L McDade,5 Claudie Charbonneau,61School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, People's Republic of China; 2Pharmerit International, Bethesda, MD, USA; 3Hematology Department, Nanfang Hospital, Southern Medical University, Guangzhou, 4Pfizer Investment Co. Ltd., Beijing, People's Republic of China; 5RTI Health Solutions, Research Triangle Park, NC, USA; 6Pfizer International Operations, Paris, France Abstract: Invasive fungal infections (IFIs) require rapid diagnosis and treatment. A decision-analytic model was used to estimate total costs and survival associated with a diagnostic-driven (DD) or an empiric treatment approach in neutropenic patients with hematological malignancies receiving chemotherapy or autologous/allogeneic stem cell transplants in Shanghai, Beijing, Chengdu, and Guangzhou, the People's Republic of China. Treatment initiation for the empiric approach occurred after clinical suspicion of an IFI; treatment initiation for the DD approach occurred after clinical suspicion and a positive IFI diagnostic test result. Model inputs were obtained from the literature; treatment patterns and resource use were based on clinical opinion. Total costs were lower for the DD versus the empiric approach in Shanghai (¥3,232 vs ¥4,331), Beijing (¥3,894 vs ¥4,864), Chengdu, (¥4,632 vs ¥5,795), and Guangzhou (¥8,489 vs ¥9,795). Antifungal administration was lower using the DD (5.7%) than empiric (9.8%) approach, with similar survival rates. Results from one-way and probabilistic sensitivity analyses were most sensitive to changes in diagnostic test sensitivity and IFI incidence; the DD approach dominated the empiric approach in 88% of scenarios. These results suggest that a DD compared to an empiric treatment approach in the People’s Republic of China may be cost saving, with similar overall survival in immunocompromised patients with suspected IFIs. Keywords: aspergillosis, cost-effectiveness analysis, voriconazole, caspofungin, itraconazole

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.

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.

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_{β} isotopes in commercial reactors.

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.

The prediction of reactor antineutrino spectra will play a crucial role as reactor experiments enter the precision era. The positron energy spectrum of 3.5 million antineutrino inverse beta decay reactions observed by the Daya Bay experiment, in combination with the fission rates of fissile isotopes in the reactor, is used to extract the positron energy spectra resulting from the fission of specific isotopes. This information can be used to produce a precise, data-based prediction of the antineutrino energy spectrum in other reactor antineutrino experiments with different fission fractions than Daya Bay. The positron energy spectra are unfolded to obtain the antineutrino energy spectra by removing the contribution from detector response with the Wiener-SVD unfolding method. Consistent results are obtained with other unfolding methods. A technique to construct a data-based prediction of the reactor antineutrino energy spectrum is proposed and investigated. Given the reactor fission fractions, the technique can predict the energy spectrum to a 2% precision. In addition, we illustrate how to perform a rigorous comparison between the unfolded antineutrino spectrum and a theoretical model prediction that avoids the input model bias of the unfolding method.

The establishment of a possible connection between neutrino emission and gravitational-wave (GW) bursts is important to our understanding of the physical processes that occur when black holes or neutron stars merge. In the Daya Bay experiment, using the data collected from December 2011 to August 2017, a search was performed for electron-Antineutrino signals that coincided with detected GW events, including GW150914, GW151012, GW151226, GW170104, GW170608, GW170814, and GW170817. We used three time windows of 10, 500, and 1000 s relative to the occurrence of the GW events and a neutrino energy range of 1.8 to 100 MeV to search for correlated neutrino candidates. The detected electron-Antineutrino candidates were consistent with the expected background rates for all the three time windows. Assuming monochromatic spectra, we found upper limits (90% confidence level) of the electron-Antineutrino fluence of (1.13-2.44)×1011 cm-2 at 5 MeV to 8.0×107 cm-2 at 100 MeV for the three time windows. Under the assumption of a Fermi-Dirac spectrum, the upper limits were found to be (5.4-7.0)×109 cm-2 for the three time windows.

The prediction of reactor antineutrino spectra will play a crucial role asreactor experiments enter the precision era. The positron energy spectrum of3.5 million antineutrino inverse beta decay reactions observed by the Daya Bayexperiment, in combination with the fission rates of fissile isotopes in thereactor, is used to extract the positron energy spectra resulting from thefission of specific isotopes. This information can be used to produce aprecise, data-based prediction of the antineutrino energy spectrum in otherreactor antineutrino experiments with different fission fractions than DayaBay. The positron energy spectra are unfolded to obtain the antineutrino energyspectra by removing the contribution from detector response with the Wiener-SVDunfolding method. Consistent results are obtained with other unfolding methods.A technique to construct a data-based prediction of the reactor antineutrinoenergy spectrum is proposed and investigated. Given the reactor fissionfractions, the technique can predict the energy spectrum to a 2% precision. Inaddition, we illustrate how to perform a rigorous comparison between theunfolded antineutrino spectrum and a theoretical model prediction that avoidsthe input model bias of the unfolding method.

To maximize the light yield of the liquid scintillator (LS) for the Jiangmen Underground Neutrino Observatory (JUNO), a 20 t LS sample was produced in a pilot plant at Daya Bay. The optical properties of the new LS in various compositions were studied by replacing the gadolinium-loaded LS in one antineutrino detector. The concentrations of the fluor, PPO, and the wavelength shifter, bis-MSB, were increased in 12 steps from 0.5 g/L and

Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θ_{μe} mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm_{41}^{2}, excluding the 90% C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90% CL_{s} for Δm_{41}^{2}

A high precision calibration of the nonlinearity in the energy response of the Daya Bay Reactor Neutrino Experiment's antineutrino detectors is presented in detail. The energy nonlinearity originates from the particle-dependent light yield of the scintillator and charge-dependent electronics response. The nonlinearity model is constrained by γ calibration points from deployed and naturally occurring radioactive sources, the β spectrum from 12B decays, and a direct measurement of the electronics nonlinearity with a new flash analog-to-digital converter readout system. Less than 0.5% uncertainty in the energy nonlinearity calibration is achieved for positrons of kinetic energies greater than 1 MeV.

This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.

This work reports a precise measurement of the reactor antineutrino flux using 2.2 million inverse beta decay (IBD) events collected with the Daya Bay near detectors in 1230 days. The dominant uncertainty on the neutron detection efficiency is reduced by 56% with respect to the previous measurement through a comprehensive neutron calibration and detailed data and simulation analysis. The new average IBD yield is determined to be (5.91±0.09)×10-43 cm2/fission with total uncertainty improved by 29%. The corresponding mean fission fractions from the four main fission isotopes U235, U238, Pu239, and Pu241 are 0.564, 0.076, 0.304, and 0.056, respectively. The ratio of measured to predicted antineutrino yield is found to be 0.952±0.014±0.023 (1.001±0.015±0.027) for the Huber-Mueller (ILL-Vogel) model, where the first and second uncertainty are experimental and theoretical model uncertainty, respectively. This measurement confirms the discrepancy between the world average of reactor antineutrino flux and the Huber-Mueller model.

This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.

The Daya Bay Collaboration responds to comments posted by S. Parke and R.Zukanovich Funchal regarding our use of Delta(m^2_ee).

We report a measurement of electron antineutrino oscillation from the Daya Bay Reactor Neutrino Experiment with nearly 4 million reactor ν[over ¯]_{e} inverse β decay candidates observed over 1958 days of data collection. The installation of a flash analog-to-digital converter readout system and a special calibration campaign using different source enclosures reduce uncertainties in the absolute energy calibration to less than 0.5% for visible energies larger than 2 MeV. The uncertainty in the cosmogenic ^{9}Li and ^{8}He background is reduced from 45% to 30% in the near detectors. A detailed investigation of the spent nuclear fuel history improves its uncertainty from 100% to 30%. Analysis of the relative ν[over ¯]_{e} rates and energy spectra among detectors yields sin^{2}2θ_{13}=0.0856±0.0029 and Δm_{32}^{2}=(2.471_{-0.070}^{+0.068})×10^{-3}  eV^{2} assuming the normal hierarchy, and Δm_{32}^{2}=-(2.575_{-0.070}^{+0.068})×10^{-3}  eV^{2} assuming the inverted hierarchy.

A search for a time-varying νe signal was performed with 621 days of data acquired by the Daya Bay Reactor Neutrino Experiment over 704 calendar days. The time spectrum of the measured νe flux normalized to its prediction was analyzed with a Lomb-Scargle periodogram, which yielded no significant signal for periods ranging from 2 hours to nearly 2 years. The normalized time spectrum was also fit for a sidereal modulation under the Standard Model Extension (SME) framework to search for Lorentz and CPT violation (LV-CPTV). Limits were obtained for all six flavor pairs ēμ,ēτ, μτ, ēē,μμ and ττ by fitting them one at a time, constituting the first experimental constraints on the latter three. Daya Bay's high statistics and unique layout of multiple directions from three pairs of reactors to three experimental halls allowed the simultaneous constraint of individual SME LV-CPTV coefficients without assuming others contribute negligibly, a first for a neutrino experiment.

Neutrons produced by cosmic ray muons are an important background forunderground experiments studying neutrino oscillations, neutrinoless doublebeta decay, dark matter, and other rare-event signals. A measurement of theneutron yield in the three different experimental halls of the Daya Bay ReactorNeutrino Experiment at varying depth is reported. The neutron yield in DayaBay's liquid scintillator is measured to be $Y_n=(10.26\pm 0.86)\times10^{-5}$, $(10.22\pm 0.87)\times 10^{-5}$, and $(17.03\pm 1.22)\times10^{-5}~\mu^{-1}~$g$^{-1}~$cm$^2$ at depths of 250, 265, and 860meters-water-equivalent. These results are compared to other measurements andthe simulated neutron yield in Fluka and Geant4. A global fit including theDaya Bay measurements yields a power law coefficient of $0.77 \pm 0.03$ for thedependence of the neutron yield on muon energy.

The Daya Bay Experiment consists of eight identically designed detectors located in three underground experimental halls named as EH1, EH2, EH3, with 250, 265 and 860 meters of water equivalent vertical overburden, respectively. Cosmic muon events have been recorded over a two-year period. The underground muon rate is observed to be positively correlated with the effective atmospheric temperature and to follow a seasonal modulation pattern. The correlation coefficient α, describing how a variation in the muon rate relates to a variation in the effective atmospheric temperature, is found to be αEH1 = 0.362±0.031, αEH2 = 0.433±0.038 and αEH3 = 0.641±0.057 for each experimental hall.

The disappearance of reactor $\bar{\nu}_e$ observed by the Daya Bayexperiment is examined in the framework of a model in which the neutrino isdescribed by a wave packet with a relative intrinsic momentum dispersion$\sigma_\text{rel}$. Three pairs of nuclear reactors and eight antineutrinodetectors, each with good energy resolution, distributed among threeexperimental halls, supply a high-statistics sample of $\bar{\nu}_e$ acquiredat nine different baselines. This provides a unique platform to test theeffects which arise from the wave packet treatment of neutrino oscillation. Themodified survival probability formula was used to fit Daya Bay data, providingthe first experimental limits: $2.38 \cdot 10^{-17} < \sigma_{\rm rel} < 0.23$.Treating the dimensions of the reactor cores and detectors as constraints, thelimits are improved: $10^{-14} \lesssim \sigma_{\rm rel} < 0.23$, and an upperlimit of $\sigma_{\rm rel}

The Daya Bay experiment has observed correlations between reactor core fuel evolution and changes in the reactor antineutrino flux and energy spectrum. Four antineutrino detectors in two experimental halls were used to identify 2.2 million inverse beta decays (IBDs) over 1230 days spanning multiple fuel cycles for each of six 2.9 GW_{th} reactor cores at the Daya Bay and Ling Ao nuclear power plants. Using detector data spanning effective ^{239}Pu fission fractions F_{239} from 0.25 to 0.35, Daya Bay measures an average IBD yield σ[over ¯]_{f} of (5.90±0.13)×10^{-43}  cm^{2}/fission and a fuel-dependent variation in the IBD yield, dσ_{f}/dF_{239}, of (-1.86±0.18)×10^{-43}  cm^{2}/fission. This observation rejects the hypothesis of a constant antineutrino flux as a function of the ^{239}Pu fission fraction at 10 standard deviations. The variation in IBD yield is found to be energy dependent, rejecting the hypothesis of a constant antineutrino energy spectrum at 5.1 standard deviations. While measurements of the evolution in the IBD spectrum show general agreement with predictions from recent reactor models, the measured evolution in total IBD yield disagrees with recent predictions at 3.1σ. This discrepancy indicates that an overall deficit in the measured flux with respect to predictions does not result from equal fractional deficits from the primary fission isotopes ^{235}U, ^{239}Pu, ^{238}U, and ^{241}Pu. Based on measured IBD yield variations, yields of (6.17±0.17) and (4.27±0.26)×10^{-43}  cm^{2}/fission have been determined for the two dominant fission parent isotopes ^{235}U and ^{239}Pu. A 7.8% discrepancy between the observed and predicted ^{235}U yields suggests that this isotope may be the primary contributor to the reactor antineutrino anomaly.

A measurement of electron antineutrino oscillation by the Daya Bay Reactor Neutrino Experiment is described in detail. Six 2.9-GWth nuclear power reactors of the Daya Bay and Ling Ao nuclear power facilities served as intense sources of νe's. Comparison of the νe rate and energy spectrum measured by antineutrino detectors far from the nuclear reactors (∼1500-1950 m) relative to detectors near the reactors (∼350-600 m) allowed a precise measurement of νe disappearance. More than 2.5 million νe inverse beta-decay interactions were observed, based on the combination of 217 days of operation of six antineutrino detectors (December, 2011-July, 2012) with a subsequent 1013 days using the complete configuration of eight detectors (October, 2012-July, 2015). The νe rate observed at the far detectors relative to the near detectors showed a significant deficit, R=0.949±0.002(stat)±0.002(syst). The energy dependence of νe disappearance showed the distinct variation predicted by neutrino oscillation. Analysis using an approximation for the three-flavor oscillation probability yielded the flavor-mixing angle sin22θ13=0.0841±0.0027(stat)±0.0019(syst) and the effective neutrino mass-squared difference of |Δmee2|=(2.50±0.06(stat)±0.06(syst))×10-3 eV2. Analysis using the exact three-flavor probability found Δm322=(2.45±0.06(stat)±0.06(syst))×10-3 eV2 assuming the normal neutrino mass hierarchy and Δm322=(-2.56±0.06(stat)±0.06(syst))×10-3 eV2 for the inverted hierarchy.

A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9 GWth nuclear reactors and detected by eight antineutrino detectors deployed in two near (560 m and 600 m flux-weighted baselines) and one far (1640 m flux-weighted baseline) underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay (IBD) candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be 0.946±0.020 (0.992±0.021) for the Huber+Mueller (ILL+Vogel) model. A 2.9σ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4-6 MeV was found in the measured spectrum, with a local significance of 4.4σ. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions.

This Letter reports an improved search for light sterile neutrino mixing in the electron antineutrino disappearance channel with the full configuration of the Daya Bay Reactor Neutrino Experiment. With an additional 404 days of data collected in eight antineutrino detectors, this search benefits from 3.6 times the statistics available to the previous publication, as well as from improvements in energy calibration and background reduction. A relative comparison of the rate and energy spectrum of reactor antineutrinos in the three experimental halls yields no evidence of sterile neutrino mixing in the 2×10^{-4}≲|Δm_{41}^{2}|≲0.3  eV^{2} mass range. The resulting limits on sin^{2}2θ_{14} are improved by approx imately a factor of 2 over previous results and constitute the most stringent constraints to date in the |Δm_{41}^{2}|≲0.2  eV^{2} region.

Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the Liquid Scintillator Neutrino Detector (LSND) and MiniBooNE experiments in a minimally extended four-neutrino flavor framework. Stringent limits on sin^{2}2θ_{μe} are set over 6 orders of magnitude in the sterile mass-squared splitting Δm_{41}^{2}. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for Δm_{41}^{2}

This article reports an improved independent measurement of neutrino mixing angle θ13 at the Daya Bay Reactor Neutrino Experiment. Electron antineutrinos were identified by inverse β-decays with the emitted neutron captured by hydrogen, yielding a data set with principally distinct uncertainties from that with neutrons captured by gadolinium. With the final two of eight antineutrino detectors installed, this study used 621 days of data including the previously reported 217-day data set with six detectors. The dominant statistical uncertainty was reduced by 49%. Intensive studies of the cosmogenic muon-induced Li9 and fast neutron backgrounds and the neutron-capture energy selection efficiency, resulted in a reduction of the systematic uncertainty by 26%. The deficit in the detected number of antineutrinos at the far detectors relative to the expected number based on the near detectors yielded sin22θ13=0.071±0.011 in the three-neutrino-oscillation framework. The combination of this result with the gadolinium-capture result is also reported.

The Daya Bay experiment was the first to report simultaneous measurements of reactor antineutrinos at multiple baselines leading to the discovery of ν¯e oscillations over km-baselines. Subsequent data has provided the world's most precise measurement of sin22θ13 and the effective mass splitting Δmee2. The experiment is located in Daya Bay, China where the cluster of six nuclear reactors is among the world's most prolific sources of electron antineutrinos. Multiple antineutrino detectors are deployed in three underground water pools at different distances from the reactor cores to search for deviations in the antineutrino rate and energy spectrum due to neutrino mixing. Instrumented with photomultiplier tubes, the water pools serve as shielding against natural radioactivity from the surrounding rock and provide efficient muon tagging. Arrays of resistive plate chambers over the top of each pool provide additional muon detection. The antineutrino detectors were specifically designed for measurements of the antineutrino flux with minimal systematic uncertainty. Relative detector efficiencies between the near and far detectors are known to better than 0.2%. With the unblinding of the final two detectors' baselines and target masses, a complete description and comparison of the eight antineutrino detectors can now be presented. This paper describes the Daya Bay detector systems, consisting of eight antineutrino detectors in three instrumented water pools in three underground halls, and their operation through the first year of eight detector data-taking.

This Letter reports a measurement of the flux and energy spectrum of electron antineutrinos from six 2.9 GWth nuclear reactors with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls in the Daya Bay experiment. Using 217 days of data, 296 721 and 41 589 inverse β decay (IBD) candidates were detected in the near and far halls, respectively. The measured IBD yield is (1.55±0.04) ×10(-18)  cm(2) GW(-1) day(-1) or (5.92±0.14) ×10(-43)  cm(2) fission(-1). This flux measurement is consistent with previous short-baseline reactor antineutrino experiments and is 0.946±0.022 (0.991±0.023) relative to the flux predicted with the Huber-Mueller (ILL-Vogel) fissile antineutrino model. The measured IBD positron energy spectrum deviates from both spectral predictions by more than 2σ over the full energy range with a local significance of up to ∼4σ between 4-6 MeV. A reactor antineutrino spectrum of IBD reactions is extracted from the measured positron energy spectrum for model-independent predictions.

We report a new measurement of electron antineutrino disappearance using the fully constructed Daya Bay Reactor Neutrino Experiment. The final two of eight antineutrino detectors were installed in the summer of 2012. Including the 404 days of data collected from October 2012 to November 2013 resulted in a total exposure of 6.9×10^{5} GW_{th}  ton days, a 3.6 times increase over our previous results. Improvements in energy calibration limited variations between detectors to 0.2%. Removal of six ^{241}Am-^{13}C radioactive calibration sources reduced the background by a factor of 2 for the detectors in the experimental hall furthest from the reactors. Direct prediction of the antineutrino signal in the far detectors based on the measurements in the near detectors explicitly minimized the dependence of the measurement on models of reactor antineutrino emission. The uncertainties in our estimates of sin^{2}2θ_{13} and |Δm_{ee}^{2}| were halved as a result of these improvements. An analysis of the relative antineutrino rates and energy spectra between detectors gave sin^{2}2θ_{13}=0.084±0.005 and |Δm_{ee}^{2}|=(2.42±0.11)×10^{-3}  eV^{2} in the three-neutrino framework.

The Daya Bay experiment consists of functionally identical antineutrino detectors immersed in pools of ultrapure water in three well-separated underground experimental halls near two nuclear reactor complexes. These pools serve both as shields against natural, low-energy radiation, and as water Cherenkov detectors that efficiently detect cosmic muons using arrays of photomultiplier tubes. Each pool is covered by a plane of resistive plate chambers as an additional means of detecting muons. Design, construction, operation, and performance of these muon detectors are described.

A new measurement of the $\theta_{13}$ mixing angle has been obtained at theDaya Bay Reactor Neutrino Experiment via the detection of inverse beta decaystagged by neutron capture on hydrogen. The antineutrino events for hydrogencapture are distinct from those for gadolinium capture with largely differentsystematic uncertainties, allowing a determination independent of thegadolinium-capture result and an improvement on the precision of $\theta_{13}$measurement. With a 217-day antineutrino data set obtained with sixantineutrino detectors and from six 2.9 GW$_{th}$ reactors, the rate deficitobserved at the far hall is interpreted as $\sin^22\theta_{13}=0.083\pm0.018$in the three-flavor oscillation model. When combined with thegadolinium-capture result from Daya Bay, we obtain$\sin^22\theta_{13}=0.089\pm0.008$ as the final result for thesix-antineutrino-detector configuration of the Daya Bay experiment.

A new measurement of the $\theta_{13}$ mixing angle has been obtained at theDaya Bay Reactor Neutrino Experiment via the detection of inverse beta decaystagged by neutron capture on hydrogen. The antineutrino events for hydrogencapture are distinct from those for gadolinium capture with largely differentsystematic uncertainties, allowing a determination independent of thegadolinium-capture result and an improvement on the precision of $\theta_{13}$measurement. With a 217-day antineutrino data set obtained with sixantineutrino detectors and from six 2.9 GW$_{th}$ reactors, the rate deficitobserved at the far hall is interpreted as $\sin^22\theta_{13}=0.083\pm0.018$in the three-flavor oscillation model. When combined with thegadolinium-capture result from Daya Bay, we obtain$\sin^22\theta_{13}=0.089\pm0.008$ as the final result for thesix-antineutrino-detector configuration of the Daya Bay experiment.

A search for light sterile neutrino mixing was performed with the first 217 days of data from the Daya Bay Reactor Antineutrino Experiment. The experiment's unique configuration of multiple baselines from six 2.9 GW(th) nuclear reactors to six antineutrino detectors deployed in two near (effective baselines 512 m and 561 m) and one far (1579 m) underground experimental halls makes it possible to test for oscillations to a fourth (sterile) neutrino in the 10(-3) eV(2)

A measurement of the energy dependence of antineutrino disappearance at the Daya Bay reactor neutrino experiment is reported. Electron antineutrinos (ν¯(e)) from six 2.9  GW(th) reactors were detected with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls. Using 217 days of data, 41 589 (203 809 and 92 912) antineutrino candidates were detected in the far hall (near halls). An improved measurement of the oscillation amplitude sin(2)2θ(13)=0.090(-0.009)(+0.008) and the first direct measurement of the ν¯(e) mass-squared difference |Δm(ee)2|=(2.59(-0.20)(+0.19))×10(-3)  eV2 is obtained using the observed ν¯(e) rates and energy spectra in a three-neutrino framework. This value of |Δm(ee)2| is consistent with |Δm(μμ)2| measured by muon neutrino disappearance, supporting the three-flavor oscillation model.