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Jing Zhao,* Jiuxiang He,* Xiaoyan Ding, Yuxin Zhou, Minchi Liu, Xiaozhong Chen, Wenxuan Quan, Dong Hua, Jun Tong, Jintao Li College of Basic Medicine, Army Medical University, Chongqing, 400038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jintao Li, College of Basic Medicine, Army Medical University, Gaotanyan Street, No. 30, Shapingba District, Chongqing, 400038, People’s Republic of China, Tel +1-86-23-68771389, Fax +1-86-23-68771391, Email ljtqms@tmmu.edu.cnBackground: The global prevalence of Dengue virus (DENV) infection poses a significant health risk, urging the need for effective vaccinations. Peptide vaccines, known for their capacity to induce comprehensive immunity against multiple virus serotypes, offer promise due to their stability, safety, and design flexibility. Spherical nucleic acid (SNA), particularly those with gold nanoparticle cores, present an attractive avenue for enhancing peptide vaccine efficacy due to their modularity and immunomodulatory properties.Methods: The spherical nucleic acid-TBB (SNA-TBB), a novel nanovaccine construct, was fabricated through the co-functionalization process of SNA with epitope peptide, targeting all four serotypes of the DENV. This innovative approach aims to enhance immunogenicity and provide broad-spectrum protection against DENV infections. The physicochemical properties of SNA-TBB were characterized using dynamic light scattering, zeta potential measurement, and transmission electron microscopy. In vitro assessments included endocytosis studies, cytotoxicity evaluation, bone marrow-dendritic cells (BMDCs) maturation and activation analysis, cytokine detection, RNA sequencing, and transcript level analysis in BMDCs. In vivo immunization studies in mice involved evaluating IgG antibody titers, serum protection against DENV infection and safety assessment of nanovaccines.Results: SNA-TBB demonstrated successful synthesis, enhanced endocytosis, and favorable physicochemical properties. In vitro assessments revealed no cytotoxicity and promoted BMDCs maturation. Cytokine analyses exhibited heightened IL-12p70, TNF-α, and IL-1β levels. Transcriptomic analysis highlighted genes linked to BMDCs maturation and immune responses. In vivo studies immunization with SNA-TBB resulted in elevated antigen-specific IgG antibody levels and conferred protection against DENV infection in neonatal mice. Evaluation of in vivo safety showed no signs of adverse effects in vital organs.Conclusion: The study demonstrates the successful development of SNA-TBB as a promising nanovaccine platform against DENV infection and highlights the potential of SNA-based peptide vaccines as a strategy for developing safe and effective antiviral immunotherapy.Keywords: nanovaccine, dengue virus, spherical nucleic acid, immunogenicity, peptide antigen

Song Song,1,* Honghong Xu,1,* Jiawei Cao,2,* Guanghong Wu,2 Haiyan Sun,1 Xiaoqi Dai,1 Xuekui Li,1 Meng Chen,1 Menghan Zhang,1 Yueming Yan,1 Jingfeng Tong,3 Zhongdong Wang1 1Institute of Tuberculosis Control, Qingdao Preventive Medicine Research Institute, Qingdao Municipal Center for Disease Control and Prevention, Qingdao, People’s Republic of China; 2Department of Laboratory Medicine, Qingdao Chest Hospital, Qingdao, Shandong, People’s Republic of China; 3Department of Medical Affairs, Shanghai Conlight Medical Co., Ltd., Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhongdong Wang, Institute of Tuberculosis Control, Qingdao Preventive Medicine Research Institute, Qingdao Municipal Center for Disease Control and Prevention, No. 8, Fengxian Road, Jinhu Road Street, Shinan District, Qingdao City, Shandong Province, 266000, People’s Republic of China, Email jkzxtb1@163.comPurpose: Nucleotide-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (nucleotide MALDI-TOF MS) is an emerging molecular technology used for the diagnosis of tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB)and its drug resistance. This study aimed to compare the ability of nucleotide MALDI-TOF MS to detect rifampicin (RIF) resistance in drug-resistant TB (DR-TB) patients with Xpert MTB/RIF and to analyze the disparate results individually. Additionally, potential factors associated with rifampicin resistance among DR-TB patients in Qingdao were investigated.Patients and Methods: A retrospective study was conducted at Qingdao Chest Hospital, and patients with DR-TB were enrolled. Corresponding frozen isolates were recovered and subjected to nucleotide MALDI-TOF MS, Xpert MTB/RIF, and phenotypic drug susceptibility testing (pDST). Sanger sequencing was performed for the discordant results of nucleotide MALDI-TOF MS and Xpert MTB/RIF. Univariate and multivariate logistic regression analyses were used to identify potential factors associated with rifampicin resistance among patients with DR-TB.Results: A total of 125 patients with DR-TB (18.8%, 125/668) were enrolled in this study from May 1 to July 31, 2023. Rifampicin-resistant (DR-TB/RR, 29) and rifampicin-sensitive (DR-TB/RS, 96) groups were divided according to the pDST results. Nucleotide MALDI-TOF MS performed better than Xpert MTB/RIF in terms of sensitivity, specificity, accuracy, and agreement with pDST. Only six cases had inconsistent results, and the sequencing results of five cases were identical to nucleotide MALDI-TOF MS. Furthermore, chest pain (aOR=12.84, 95% CI, 2.29– 91.97, p=0.005), isoniazid sensitivity (aOR=0.14, 0.02– 0.59, p=0.013), and ethambutol sensitivity (aOR=0.02, 0.00– 0.10, p=0.000) were potential factors associated with rifampicin resistance among DR-TB patients in Qingdao.Conclusion: The overall concordance between nucleotide MALDI-TOF MS and Xpert MTB/RIF was 95.2%, with the former performing better in determining rifampicin susceptibility among DR-TB cases in Qingdao. Chest pain, isoniazid, and ethambutol resistance might be factors associated with RIF resistance among patients with DR-TB in Qingdao.Keywords: MTB, rifampicin, nucleotide MALDI-TOF MS, Xpert MTB/RIF, comparison, risk factors

Dan Liu, Juan Tong, Erling Chen, Li Wang, Lei Xue, Xuhan Zhang, Na Zhao, Xing Hu, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, People’s Republic of ChinaCorrespondence: Changcheng Zheng, Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, Anhui Province, 230001, People’s Republic of China, Email zhengchch1123@ustc.edu.cnBackground: The aim of the study was to evaluate the efficacy and safety of induction and consolidation with all-trans retinoic acid (ATRA) +arsenic trioxide (ATO) +anthracyclines and maintenance with ATRA +Realgar-Indigo naturalis formula (RIF) for high-risk APL.Methods: Twenty-one patients with high-risk APL treated with ATRA+ATO+ anthracyclines for induction and consolidation and ATRA+RIF for maintenance from 2012 to 2021 were analyzed. Endpoints include morphological complete remission (CR) and complete molecular remission (CMR), early death (ED) and relapse, survival and adverse events (AEs).Results: After induction treatment, all 21 patients (100%) achieved morphological CR and 14 people (66.7%) achieved CMR. Five of the 21 patients did not undergo immunological minimal residual disease (MRD) examination after induction; however, 14 of the remaining 16 patients were MRD negative (87.5%). The median time to achieve CR and CMR was 26 days (range: 16– 44) and 40 days (range: 22– 75), respectively. The cumulative probability of achieving CR and CMR in 45 days was 100% and 76.2% (95% CI: 56.9– 91.3%), respectively. All patients achieved CMR and MRD negativity after the three courses of consolidation treatment. The median follow-up was 66 months (25– 142), with no central nervous system relapse and bone marrow morphological or molecular relapse until now, and all patients survived with 100% overall survival and 100% event-free survival. Grade 4 adverse events (AEs) were observed in 3 patients (14.3%) during the induction period including arrhythmia (n = 1), pulmonary infection (n = 1) and respiratory failure (n = 1); and the most frequent grade 3 AEs were pulmonary infection, accounting for 62.0% and 28.6%, respectively, during induction and consolidation treatment, followed by neutropenia, accounting for 42.9% and 38.1%, respectively.Conclusion: For newly diagnosed high-risk APL patients, induction and consolidation with ATRA+ATO+anthracyclines and maintenance with ATRA+RIF is a highly curative treatment approach.Keywords: high-risk acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, realgar–Indigo naturalis formula, anthracyclines, event-free survival

Yan Chen,1 Jiahuan Tong,2 Jianfeng Wang2 1Department of General Practice, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310018, People’s Republic of China; 2Department of Respiratory Diseases, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310018, People’s Republic of ChinaCorrespondence: Jianfeng Wang, Department of Respiratory Diseases, the First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Shangcheng District, Hangzhou, 310018, People’s Republic of China, Email 2001m@163.comAbstract: The clinical severity of Chlamydia psittaci infection ranges from asymptomatic to severe pneumonia. Diagnosis poses challenges due to its similarity to other respiratory infections. Treatment includes tetracyclines, macrolides, and fluoroquinolones, with limited evidence on the efficacy of omadacycline. We report a case of an 86-year-old male with severe psittacosis treated with omadacycline, resulting in significant improvement. This highlights the necessity for further research on omadacycline’s role in psittacosis treatment.Keywords: Chlamydia psittaci, omadacycline, pneumonia

Background: Postoperative ileus (POI) is a common complication after colorectal surgery, leading to increased hospital stay and costs. This study aimed to explore patient comorbidities that contribute to the development of POI in the colorectal surgical population and compare machine learning (ML) model accuracy to existing risk instruments. Study Design: In a retrospective study, data were collected on 316 adult patients who underwent colorectal surgery from January 2020 to December 2021. The study excluded patients undergoing multi-visceral resections, re-operations, or combined primary and metastatic resections. Patients lacking follow-up within 90 days after surgery were also excluded. Eight different ML models were trained and cross-validated using 29 patient comorbidities and four comorbidity risk indices (ASA Status, NSQIP, CCI, and ECI). Results: The study found that 6.33% of patients experienced POI. Age, BMI, gender, kidney disease, anemia, arrhythmia, rheumatoid arthritis, and NSQIP score were identified as significant predictors of POI. The ML models with the greatest accuracy were AdaBoost tuned with grid search (94.2%) and XG Boost tuned with grid search (85.2%). Conclusions: This study suggests that ML models can predict the risk of POI with high accuracy and may offer a new frontier in early detection and intervention for postoperative outcome optimization. ML models can greatly improve the prediction and prevention of POI in colorectal surgery patients, which can lead to improved patient outcomes and reduced healthcare costs. Further research is required to validate and assess the replicability of these results.

Yan Chen,* Xiaohuan Huang,* Hongfei Chen, Junru Tong, Lingling Huang, Junyou Su, Li Deng Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Deng; Junyou Su, Email dengli@gxmu.edu.cn; sujunyou@sr.gxmu.edu.cnBackground: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive activation of NK cells and cytotoxic T lymphocytes, subsequently leading to macrophage activation and increased cytokine production. Misdiagnosis due to nonspecific clinical presentations and inadequate understanding of the disease can significantly jeopardize the safety of both the mother and the infant. We report a case of pregnancy combined with HLH and conduct a literature review to provide insights into the diagnosis and treatment of pregnancy-related HLH.Case Presentation: We discussed a case of a pregnant woman with persistent postpartum fever, serum ferritin, and elevated liver function, who failed to respond to repeated anti-infective therapy and was diagnosed with HLH after multidisciplinary diagnostic treatment. We gave dexamethasone treatment, and the patient’s temperature and blood cells quickly returned to normal. Finally, exome sequencing revealed heterozygous variation in UNC13D gene, so we considered this case as pregnancy combined with primary HLH (pHLH).Conclusion: We report the case of HLH diagnosed during pregnancy and show that early diagnosis and timely intervention can prevent rapid disease progression, reduce maternal mortality rates, and improve survival rates. Additionally, molecular genetic testing can confirm pathogenic gene mutations, providing essential genetic counseling for patients with pHLH who plan to conceive a healthy child.Keywords: hemophagocytic lymphohistiocytosis, hemophagocytic syndrome, pregnancy, case report

Xiaoyu Wang,* Yingqiao Zhu,* Dan Liu, Lijun Zhu, Juan Tong, Changcheng Zheng Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changcheng Zheng, Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China, Tel/Fax +86-551-62284476, Email zhengchch1123@ustc.edu.cnIntroduction: COVID-19 infection has brought new challenges to the treatment of adult patients with immune thrombocytopenia (ITP). In adult ITP patients, there have been no relevant reports exploring the incidence, clinical characteristics, and risk factors of platelet elevation after COVID-19 infection.Materials and Methods: A total of 66 patients with previously diagnosed ITP from December 2022 to February 2023 in a single-center were collected and analyzed for this real-world clinical retrospective observational study.Results: In the platelet count increased group (n = 19), 13 patients (68.4%) were using thrombopoietin receptor agonists (TPO-RA) treatment at the time of COVID-19 infection; the median platelet count was 52 (2– 207) × 109/L at the last visit before infection and 108 (19– 453) × 109/L at the first visit after infection. In the platelet count stable group (n = 19) and platelet count decreased group (n = 28), 9 (47.4%) and 8 (28.6%) patients were using TPO-RA at the time of infection, respectively. ITP patients treated with TPO-RA had a significantly higher risk of increased platelet count than those not treated with TPO-RA at the time of infection (platelet count increased group vs platelet count decreased group: OR: 5.745, p = 0.009; platelet count increased group vs the non-increased group: OR: 3.616, p = 0.031). In the platelet count increased group, the median platelet count at 6 months post-infection was 67 (14– 235) × 109/L, which was significantly higher than the platelet level at the last visit before infection (p = 0.040).Conclusion: This study showed that some adult ITP patients had an increase in platelet count after COVID-19 infection, and this phenomenon was strongly associated with the use of TPO-RA at the time of infection. Although no thrombotic events were observed in this study, it reminds clinicians that they should be alert to the possibility of thrombotic events in the long-term management of adult ITP patients during the COVID-19 pandemic.Keywords: immune thrombocytopenia, thrombopoietin receptor agonists, COVID-19, thrombosis

Ying Qin,1 Jingwen Zhao,1 Yong Yang,1 Yanjing Liu,1 Hui Xiang,2 Jingfeng Tong,3 Chengchen Huang3 1Department of Psychiatry, the Second People’s Hospital of Guizhou Province, Guiyang, 550004, People’s Republic of China; 2Department of Psychology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China; 3Shanghai Conlight Medical Laboratory, Co, Ltd, Shanghai, 200032, People’s Republic of ChinaCorrespondence: Chengchen Huang, Shanghai Conlight Medical Laboratory Co, Ltd, Shanghai, People’s Republic of China, Email huangcc@kangliyixue.comPurpose: We investigate the association of HTR1A rs10042486 and rs6295 with efficacy and plasma concentrations of atypical antipsychotics in the treatment of male patients with schizophrenia.Patients and Methods: A total of 140 male patients diagnosed with schizophrenia who were treated with any single atypical antipsychotic between May 2020 and May 2022 were retrospectively included. Clinical symptoms were assessed using Positive and Negative Syndrome Scale (PANSS). All SNPs were typed using Agena Bioscience MassARRAY DNA mass spectrometry. Plasma concentrations of antipsychotics at week 3, 6 and 12 after treatment commence were analyzed using mass spectrometry.Results: For efficacy of atypical antipsychotics, we observed no significant difference between HTR1A rs10042486, rs6295 and positive symptom improvement, where the patients with heterozygous mutant at the rs10042486 and rs6295 locus were superior to those with wild-type or homozygous mutant genotypes on negative symptom improvement, especially at 12 weeks of follow-up when the difference between genotypes at the rs6295 locus have statistical significance (P = 0.037). For plasma concentration, we found that quetiapine plasma concentrations were significantly lower in patients with mutation-heterozygous types than in wild-type and homozygous mutation genotypes at week 6. In contrast, higher plasma concentrations were found for mutant heterozygous than wild genotypes in the risperidone monotherapy analysis, and the difference among genotypes at the rs6295 locus was statistically significant at 6 weeks of follow-up.Conclusion: The assessment of the correlation of genetic polymorphisms of HTR1A rs6295 and rs10042486 in male patients with schizophrenia with the monitoring of therapeutic drug concentrations and therapeutic efficacy provides a constructive foundation for the clinical individualization of antipsychotics, such as quetiapine and risperidone, which is important in selecting the dose of the medication and improving the improvement of negative symptoms.Keywords: schizophrenia, HTR1A, polymorphism, plasma concentration, atypical antipsychotics, asian male patients

Jiqian Jiang,1 Yan Wang,1 Dan Liu,1 Xiaoyu Wang,1 Yingqiao Zhu,1 Juan Tong,1 Erling Chen,1 Lei Xue,1 Na Zhao,1 Tingting Liang,2 Changcheng Zheng1 1Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 2The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng Zheng, Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of China, Tel/Fax +86-551-62284476, Email zhengchch1123@ustc.edu.cnIntroduction: The BCL-2 inhibitor venetoclax has been widely used in the treatment of acute myeloid leukemia (AML); however, AML patients treated with venetoclax gradually develop resistance. The exportin-1 (XPO1) inhibitor selinexor can synergistically promote the antileukemia activity of venetoclax, but the mechanism remains unclear.Methods and Results: Annexin V/7-aminoactinomycin D assays were used to examine the effects of a combination of venetoclax and selinexor (VEN+SEL) on AML cell lines and primary AML cells. RNA sequencing and oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) determinations by a Seahorse XF analyzer were employed to investigate the molecular mechanism of the toxicity of the VEN+SEL combination to AML cells. The cytotoxicity of NK cell combined with VEN+SEL combination was assessed in vitro using flow cytometry. VEN+SEL enhanced the apoptosis of AML cells (KG-1A and THP-1) and primary AML samples in vitro. The ECAR and OCR results demonstrated that the VEN+SEL combination significantly inhibited glycolytic function. RNA sequencing of THP-1 cells demonstrated that DNA replication-related genes were downregulated after treatment with the VEN+SEL combination.Conclusion: This study indicated that selinexor can synergistically enhance the antileukemia activity of venetoclax in AML cells in vitro by inhibiting glycolytic function and downregulating DNA replication-related genes. Based on our experimental data, combining selinexor with venetoclax is an appropriate advanced treatment option for AML patients.Keywords: venetoclax, selinexor, acute myeloid leukemia, glycolytic function, DNA replication-related genes

Jie Tong,1,* Tingting Zhang,1,* Qiang Wang,1 Xudong Zhao,2 Xirong Sun,1 Manji Hu1 1Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Manji Hu; Xirong Sun, Email hmj2008tj@qq.com; xirongsun@163.comBackground: To promote the balanced development with the population, China has phased out a one-child policy in 2016, and a two-child policy was launched, which has led to dramatic changes in family structure. The transition could be a huge challenge for adolescents who are in a period of psychological vulnerability.Purpose: This study explored the differences and predictors of family dynamics and functioning between two-child and one-child families in the context of China’s two-child policy.Methods: We used the Self-rating scale of Systemic Family Dynamics (SSFD) and Family Assessment Device-General Functioning (FAD-GF) to investigate the family dynamics, family functioning, and family structure and status of 3289 adolescents under the background of China’s two-child policy.Results: Results revealed that the mean scores for family atmosphere, personalization, disease concept, overall family dynamics, and family functioning health rate of the one-child families were higher than those of the two-child families. Parental marital status, mother’s education, annual household income, and family economic satisfaction in two-child and one-child families was positively correlated with family dynamics and functioning, but not significantly associated with living style, parental age and employment. Family financial satisfaction, parental marital status, and distress in the family were predictors of family dynamics and functioning, and parental preference was also an important factor in two-child families.Conclusion: The findings suggest family atmosphere, personality, disease concept, family dynamics, and family functioning of the one-child families were better than those of the two-child families. Unlike one-child families, parental preference is an important predictor of family dynamics and functioning in two child families. This study increases our understanding of adolescents psychological problems during family structure transitions under the background of fertility policy, providing psychologists with more evidence-based evidence and intervention directions.Keywords: family structure, family dynamics, family functioning, adolescents, two-child families

Abstract Background In the early postoperative period, respiratory compromise is a significant problem. Standard-of-care monitoring includes respiratory rate (RR) and pulse oximetry, which are helpful; however, low SpO2 is often a late sign during decompensation. The FDA-approved Capnostream-20p monitor records four variables (SpO2, RR, End-tidal CO2, heart rate), which are combined by fuzzy logic into a single, unit-less value (range 1–10) called the integrated pulmonary index (IPI). No published studies have assessed the performance of a low IPI to predict impending respiratory events. Methods In this investigator-initiated study, adult patients undergoing general anesthesia were monitored with the Capnostream-20p monitor for up to 2 h during their recovery room stay. The study coordinator, who along with clinicians, was blinded to IPI values, recorded the time of any respiratory event, defined a priori as any one of eight respiratory-related interventions/conditions. The primary sensitivity endpoint (early detection success) was defined as at least 80% of events predicted by at least 2 consecutive low IPI (≤ 7) values within 2–15 min before an event occurred. Late detection was defined as low IPI values occurring with 2 min prior to or 2 min after the event occurred. Discussion Of 358 patients, ≥ 1 respiratory event occurred in 183 (51.1%) patients. Of 802 total events, 606 were detected early (within 2–15 min prior to the event), and 653 were detected either early or late. Therefore, the sensitivity for early detection was 75.6% (95% confidence interval [CI]: 72.6–78.5%), which differed significantly from the 80% sensitivity goal by 4.4% (p = 0.0016). Sensitivity for total success (early or late) was 81.4% (95% CI: 78.7–84.1%), which was significantly different from the 90% on time sensitivity goal by 8.6% (p

Xiaoyu Zhu,1 Ran Li,1 Yu Zhu,1 Jia Zhou,1 Junchao Huang,1 Yanfang Zhou,1 Jinghui Tong,1 Ping Zhang,1 Xingguang Luo,2 Song Chen,1 Yanli Li,1 Baopeng Tian,1 Shu-Ping Tan,1 Zhiren Wang,1 Xiaole Han,1 Li Tian,3 Chiang-Shan R Li,2 Yun-Long Tan1 1Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China; 2Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; 3Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, EstoniaCorrespondence: Yun-Long Tan, Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China, Tel +86-10-83024319, Fax +86-10-62710156, Email yltan21@126.comObjective: Accumulating evidence suggested that immune system activation might be involved in the pathophysiology of schizophrenia. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) can measure inflammation. This study aimed to investigate the inflammatory state in patients with schizophrenia by using these indicators.Methods: In this study, the complete blood count data for 187 continuing hospitalized patients with schizophrenia and 187 age- and sex-matched healthy participants was collected annually from 2017 to 2019. Platelet (PLT), lymphocyte (LYM), monocyte (MON) and neutrophil (NEU) counts were aggregated and NLR, MLR, PLR, and SII were calculated. Using a generalized linear mixed model, we assessed the impact of age, sex, diagnosis, and sampling year on the above indicators and evaluated the interaction between the factors.Results: According to the estimation results of the generalized linear mixed model, the NLR increased by 0.319 (p = 0.004), the MLR increased by 0.037 (p < 0.001), and the SII increased by 57.858 (p = 0.018) in patients with schizophrenia. Data after two years of continuous antipsychotic treatment showed that the NLR and MLR were higher in patients with schizophrenia than those in healthy controls, while the PLT and LYM counts were decreased in patients with schizophrenia. The schizophrenia diagnosis was correlated to the MON and LYM count, NLR, MLR, and SII (p < 0.05).Conclusion: The differences in these markers were stable and cannot be eliminated by a full course of treatment. This study provides impetus for the inflammatory hypothesis of schizophrenia.Keywords: schizophrenia, systemic immune-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio

Shiying Li,1 Jin Tong,2 Hu Li,1 Chenxue Mao,3 Wei Shen,1 Yu Lei,1 Peng Hu1 1Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Respiratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Laboratory Diagnosis, ChongQing KingMed Center for Clinical Laboratory Co., Ltd, Chongqing, 400050, People’s Republic of ChinaCorrespondence: Peng Hu, Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74&num; Linjiang Road, Chongqing, 400010, People’s Republic of China, Email hp_cq@163.com; hupengcq@hospital.cqmu.edu.cnAbstract: We report a case of a 34-year-old lady with multiple joint pain. Autoimmune diseases were considered first with a positive result of anti-Ro antibody and her right knee joint cavity effusion. Later, bilateral interstitial changes in her lungs and mediastinal lymphadenopathy were found after chest CT scanning. Empirical quinolone therapy was given although pathological examinations of blood, sputum and bronchoalveolar lavage fluid (BALF) did not find anything. Finally, Legionella pneumophila was identified by target next-generation sequencing (tNGS) detection. This case highlighted the timely use of tNGS, a new tool with fast speed, high accuracy and effective cost, could help to identify atypical infection and start an early therapy.Keywords: case report, Legionella pneumophila, targeted next-generation sequencing, tNGS, precision treatment, levofloxacin

Xiaoou Li,1 Wei Gao,2 Zhonglan Jia,3 Kaihu Yao,2 Jinyan Yang,1 Jingjing Tong,4 Yajuan Wang5 1Department of Neonatology, Haidian District Maternal and Child Health Care Hospital, Beijing, 100080, People’s Republic of China; 2Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics (Capital Medical University), Laboratory of Dermatology, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 3Department of Clinical Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, 100080, People’s Republic of China; 4Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, People’s Republic of China; 5Department of Neonatology, Children’s Hospital, Capital Institute of Pediatrics, Beijing, 100020, People’s Republic of ChinaCorrespondence: Yajuan Wang, Department of Neonatology, Children’s Hospital, Capital Institute of Pediatrics, No. 2 Yabao Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86-10-85695631, Email cxswyj@vip.sina.comPurpose: We investigate the drug resistance, serotype and multilocus sequence typing (MLST) of Group B streptococcus (GBS) strains obtained from pregnant women and neonates in a hospital in Beijing.Patients and Methods: In this cross-sectional study, 1470 eligible pregnant women at a gestational age of 35– 37 weeks presented to our department between May 2015 and May 2016 were included. Vaginal and rectal samples from pregnant women together with sampling from neonatal samples were collected to screen GBS. GBS strains were subject to drug resistance and serotype analysis and MLST.Results: GBS strains were isolated from 111 pregnant women (7.6%) and 6 neonates (0.99%) from 606 matched neonates. 102 strains from pregnant women and 3 strains from neonates were included in the drug sensitivity test, serotyping and MLST typing. All these strains were susceptible to ampicillin, penicillin, ceftriaxone, vancomycin, linezolid, and meropenem. Sixty strains (58.8%) showed multi-drug resistance. Serious cross-resistance was seen between erythromycin and clindamycin. There were eight serotypes, and 37 strains (36.3%) showed a serotype of type III serving as the major type. All 102 GBS strains isolated from pregnant samples could be divided into 18 STs types. They belonged to five clonal complexes and five single clones, with the predominant type of ST19/III, ST10/Ib, and ST23/Ia, with CC19 as the most common type. Three GBS strains isolated from neonates covered two serotypes (ie type III and Ia) that were consistent with those of the mothers.Conclusion: Serotype III was the predominant serotype of GBS in this study. The predominant MLST type was ST19, ST10, and ST23, with ST19/III, ST10/Ib, and ST23/Ia serving as the most prevalent and CC19 as the most common clonal complex. GBS strains from neonates were consistent in the clonal complex, serotype, and MLST with these isolated from the mothers.Keywords: Group B streptococcus, multilocus sequence typing, drug resistance, molecular epidemiology

Fan Zhang, Huan Chang, Wenxiang Qing, Rili Yu, Qin Liao, Jianbin Tong Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of ChinaCorrespondence: Jianbin Tong; Qin Liao, Department of Anesthesiology, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Email jianbintong@csu.edu.cn; xy3yyliaoqin@sina.comBackground: Propofol is widely used for sedation of hysteroscopy. It can cause injection pain, respiratory depression, and hypotension. Remimazolam is a novel ultra-short-acting benzodiazepine. Clinical practice has found that the use of remimazolam alone often leads to body movement during hysteroscopy, which decreases the safety and comfort. Here this study is to investigate whether remimazolam combined with low-dose propofol can improve the sedation effect and safety of hysteroscopy.Patients and Methods: In this prospective, randomized, parallel-controlled trial, women (18 to 60 years) undergoing hysteroscopy were randomly assigned to receive propofol (Group P), remimazolam tosylate (Group R), or remimazolam tosylate plus propofol (Group RP). Intraoperative sedation depth was kept at the bispectral index (BIS) value of 40– 60. 6 μg/kg alfentanil was used for analgesic before sedation. Intraoperative low pulse oxygen saturation (SpO2), body movement, injection pain, mean arterial pressure (MAP), heart rate (HR), and postoperative recovery time, dizziness, nausea and vomiting were recorded and compared.Results: From February to July 2022, 193 patients were recruited and randomly assigned to group P (n=64), group R (n=64), or group RP (n=65). There was no significant inter-group difference of the intraoperative BIS values. The incidence of low SpO2, injection pain, hypotension, and postoperative dizziness in group RP were less than that in group P, and had no significant difference from group R. The incidence of body movement in group RP was less than that in group R, and had no significant difference from group P. Postoperative recovery time of group RP was shorter than that of the other two groups. No significant inter-group difference in bradycardia, nausea and vomiting was observed.Conclusion: Remimazolam tosylate combined with low dose of propofol improved sedation and safety in hysteroscopy, and may be a more ideal sedative method for hysteroscopy.Keywords: remimazolam tosylate, propofol, sedation, hysteroscopy

Junlu Tong1,2 &ast;, Li Cong1 &ast;, Yingbin Jia,3 Bai-Liang He,4 Yifan Guo,1 Jianzhong He,5 Decheng Li,3 Baojia Zou,3 Jian Li3 1Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 3Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Biomedical Imaging, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 5Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Li; Baojia Zou, Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China, Tel +86-756-252-8781, Email lijian5@mail.sysu.edu.cn; zoubj6@mail.sysu.edu.cnPurpose: In this study, we aimed to investigate the effect of follistatin (FST) on hepatic steatosis in NAFLD and the underlying mechanism, which has rarely been reported before.Methods: Liver samples from NAFLD patients and normal liver samples (from liver donors) were collected to investigate hepatic FST expression in humans. Additionally, human liver cells (LO2) were treated with free fatty acid (FFA) to induce lipid accumulation. Furthermore, lentivirus with FST overexpression or knockdown vectors were used to generate stable cell lines, which were subsequently treated with FFA or FFA and rapamycin. In the animal experiments, male C57BL/6J mice were fed with a high-fat diet (HFD) to induce NAFLD, after which the adeno-associated virus (AAV) gene vectors for FST overexpression were administered. In both cell culture and mice, we evaluated morphological changes and the protein expression of sterol regulatory element-binding protein1 (SREBP1), acetyl-CoA carboxylase1 (ACC1), carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase (FASN), and Akt/mTOR signaling. The body weight and serum parameters of the mice were also measured.Results: Hepatic FST expression level was higher in NAFLD patients compared to normal samples. In LO2 cells, FST overexpression alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis. FST could regulate Akt/mTOR signaling, and the mTOR inhibitor rapamycin abolished the effect of FST knockdown on hepatic de novo lipogenesis (DNL). Furthermore, FST expression was increased in HFD mice compared to the corresponding controls. FST overexpression in mice reduced body weight gain, hyperlipidemia, hepatic DNL, and suppressed Akt/mTOR signaling.Conclusion: Hepatic FST expression increases in NAFLD and plays a protective role in hepatic steatosis. FST overexpression gene therapy alleviates hepatic steatosis via the mTOR pathway.Therefore, gene therapy for FST is a promising treatment in NAFLD.Keywords: follistatin, non-alcoholic fatty liver disease, free fatty acid, lipid synthesis

Yong Zhou,1,&ast; Yongfei Fan,1,&ast; Binzhe Qiu,1 Ming Lou,1 Xiaoshuang Liu,2 Kai Yuan,1,3 Jichun Tong1 1The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China; 2Nanjing Jinling Hospital: East Region Military Command General Hospital, Nanjing, People’s Republic of China; 3Heart and Lung Disease Laboratory, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jichun Tong; Kai Yuan, Email tongjichun2021@163.com; yuankai202001@163.comBackground: NSCLC (non-small cell lung cancer) has become the malignancy with the highest incidence and mortality rate worldwide. Fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a key regulator of glycolysis with both kinase and phosphatase activities. The Warburg effect, or increased glycolysis in tumors, provides the metabolic basis for cancer cell proliferation and metastasis, and the Warburg pathway enzyme PFKFB4 is a newly identified important kinase. This study aimed to elucidate the poor prognostic relevance of PFKFB4 in non-small cell lung cancer tissues and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints.Methods: In this study, immunohistochemical methods were used to assess PFKFB4 expression levels in 140 surgical specimens from patients with histologically confirmed non-small cell lung cancer and to investigate the relationship between PFKFB4 expression levels and the patients’ clinicopathological characteristics. The impact of PFKFB4 expression on prognosis was evaluated using Kaplan–Meier survival analysis and Cox regression analysis.Results: When compared to normal paracrine tissues, PFKFB4 expression was enhanced in lung cancer tissues, and Kaplan–Meier survival analysis revealed that patients with high PFKFB4 expression had a worse prognosis. In NSCLC, PFKFB4 was found to be associated with immune cell infiltration and immunological checkpoints.Conclusion: PFKFB4 expression may be upregulated as a sign of poor prognosis in NSCLC, and PFKFB4 may be implicated not only in the genesis and progression of NSCLC but also in its immunological control.Keywords: PFKFB4, NSCLC, prognostic marker, immune cells

Jinjin Tong,1,&ast; Xintong Ji,1,&ast; Hua Zhang,1 Benhai Xiong,2 Defeng Cui,3 Linshu Jiang1 1Beijing Key Laboratory for Dairy Cow Nutrition, Beijing University of Agriculture, Beijing, People’s Republic of China; 2State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of China; 3Beijing Key Laboratory of TCVM, Beijing University of Agriculture, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Defeng Cui, Beijing Key Laboratory of TCVM, Beijing University of Agriculture, Beijing, People’s Republic of China, Tel +86 (10)-81798091, Email cdfffff@163.com Linshu Jiang, Beijing Key Laboratory for Dairy Cow Nutrition, Beijing University of Agriculture, Beijing, People’s Republic of China, Tel +86 (10)-81798091, Email linshujiangbua@163.comPurpose: Streptococcus agalactiae is one of the primary pathogens responsible for subclinical mastitis, a significant economic burden for dairy farms. An essential component of the immune response to infection is ubiquitination, which plays important roles in the complex interactions between the pathogen and host.Materials and Methods: In the present study, quantitative ubiquitylomics was performed to profile changes in the global ubiquitinome of bovine mammary gland epithelial cells (BMECs) infected with S. agalactiae.Results: The most notable changes in the BMEC ubiquitinome were related to the adherens junction, ribosome, and tight junction pathways. Ubiquitination of CTNNB1, EGFR, ITGB1, CTNNA1, CTNNA2, CDH1, YES1, and SLC9A3R1 appears to be fundamental for regulating multiple cellular processes in BMECs in response to S. agalactiae infection. In addition, broad ubiquitination of various effectors and outer membrane proteins was observed. Ubiquitinated proteins in S. agalactiae-infected BMECs were associated with regulating cell junctions in the host, with potential implications for susceptibility to infection.Conclusion: The preliminary findings suggest that extensive ubiquitination of CTNNB1, CDH1 and SLC9A3R1 and proteins closely related to cell junctions might play an important role in mastitis progression in dairy cows. The results provide evidence that ubiquitin modification of certain proteins in S. agalactiae-infected BMECs could be a promising therapeutic strategy for reducing mammary gland injury and mastitis.Keywords: ubiquitination, protein degradation, mastitis, dairy cows

Abstract Advances in cardiac surgical operative techniques and myocardial protection have dramatically improved outcomes in the past two decades. An unfortunate and unintended consequence is that 80% of the preventable morbidity and mortality following cardiac surgery now originates outside of the operating room. Our hope is that a renewed emphasis on evidence-based best practice and standardized perioperative care will reduce overall morbidity and mortality and improve patient-centric care. The Perioperative Quality Initiative (POQI) and Enhanced Recovery After Surgery–Cardiac Society (ERAS® Cardiac) have identified significant evidence gaps in perioperative medicine related to cardiac surgery, defined as areas in which there is significant controversy about how best to manage patients. These five areas of focus include patient blood management, goal-directed therapy, acute kidney injury, opioid analgesic reduction, and delirium.

Li Wang, Na Zhao, Li Zhou, Juan Tong, Lei Xue, Lei Zhang, Yongsheng Han, Xingbing Wang, Liangquan Geng, Baolin Tang, Huilan Liu, Weibo Zhu, Xiaoyan Cai, Xin Liu, Xiaoyu Zhu, Zimin Sun, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng ZhengDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of ChinaTel/Fax +86-551-62284476Email zhengchch1123@ustc.edu.cnBackground: There is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients.Methods: A total of 149 consecutive newly diagnosed elderly AML patients (aged ≥ 60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed.Results: After the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035).Conclusion: Our results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR.Keywords: acute myeloid leukemia, elderly patients, minimal residual disease, standard-intensity chemotherapy, intermediate or high dose cytarabine

Yubin Tian,1,2,&ast; Yong Zhou,2,&ast; Junhui Liu,1,2 Lei Yi,2 Zhaojia Gao,2,3 Kai Yuan,1,3 Jichun Tong2,3 1School of Medical, Dalian Medical University, Dalian, People’s Republic of China; 2The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China; 3Heart and Lung Disease Laboratory, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kai Yuan; Jichun Tong, Email yuankai202001@163.com; tongjichun2012@163.comPurpose: To investigate the expression profile of systemic RNA interference deficient-1 transmembrane family member 1 (SIDT1) in patients with non-small cell lung cancer (NSCLC) and assess its prognostic value and immune infiltration.Materials and Methods: A tissue microarray (TMA) was purchased containing 60 paired NSCLC tissues and matched para-tumor tissues, and another TMA was constructed comprising 140 NSCLC tissues. Then, immunohistochemical staining and scoring were performed. Finally, we evaluated the expression profiles and prognostic values of SIDT1 in NSCLC. Correlation between SIDT1 gene expression and the immune microenvironment of NSCLC was investigated using the ESTIMATE and CIBERSORT algorithms.Results: SIDT1 was mainly detected in the cytoplasm and the cell membrane. SIDT1 expression was significantly higher in tumor tissues than in para-tumor tissues. High expression of SIDT1 was correlated with the NSCLC stage. High SIDT1 expression signals worsening overall survival (OS) in NSCLC patients, especially in stage I. In LUSC, high SIDT1 expression is an independent prognostic factor for worsening OS.Conclusion: High SIDT1 expression predicted a low survival rate in LUSC patients, suggesting it may be a potential target for prognostic assessment of NSCLC patients.Keywords: NSCLC, prognosis, TMA, immune infiltration, SIDT1

Junwei Tong,1– 3,&ast; Xiangui Meng,1– 3,&ast; Qingyang Lv,1– 3,&ast; Hongwei Yuan,1– 3 Weiquan Li,1– 3 Wen Xiao,1– 3 Xiaoping Zhang1– 3 1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, People’s Republic of China; 3Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoping Zhang; Wen XiaoDepartment of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of ChinaFax +86 85776343Email xzhang@hust.edu.cn; xiaowenx11@163.comBackground: Increasing evidence indicated that the aberrant expression of the cytoplasmic FMR1-interacting protein (CYFIP) family might possess critical role and potential functions in cancer. But the role of CYFIP2 in clear cell renal cell carcinoma (ccRCC) is still uncharacteristic.Methods: We investigated the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for the expression profile, clinicopathological variables, clinical prognosis information, and promoter methylation levels of CYFIPs in ccRCC. The aberrant CYFIP2 protein expression was validated by the Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to uncover CYFIP2 mRNA levels in 28 pairs of ccRCC cancer tissues. Kaplan–Meier analysis, univariate and multivariate Cox proportional hazard regression were performed to assess CYFIPs’ prognosis value. Gene set enrichment analysis (GSEA) was used to determined hallmark functions, gene ontology of CYFIP2. TIMER database was utilized to assess the correlation with immune infiltration in ccRCC.Results: Results showed CYFIP2 was downregulated in ccRCC, relative to paired normal tissues in TCGA-KIRC database and 28 pairs of clinical samples (P < 0.0001). Similarly, a decreased CYFIP2 protein expression was confirmed by ccRCC tissues. The results showed CYFIP2 was negatively regulated by promoter DNA methylation. Survival analysis results showed CYFIP2 could be an independent biomarker for ccRCC and its reduction predicted a poor overall survival (OS) and disease-free survival (DFS). GSEA showed CYFIP2 was involved in metabolic pathways and epithelial–mesenchymal transition (EMT). Immune infiltration analysis revealed that a list of immune markers was significantly correlated with CYFIP2 expression especially with CD4+ cells and CD8+ cells in ccRCC.Conclusion: These results show that CYFIP2 was downregulated in ccRCC patients and predicted an unfavorable prognosis. CYFIP2 might be a potential novel prognostic molecule, and related to immune infiltration, the metabolism, as well as EMT process in ccRCC. CYFIP2 could act as tumor suppressor gene in ccRCC and positive modulation of CYFIP2 might lead to development of a novel strategy for ccRCC treatment.Keywords: CYFIP2, ccRCC, methylation, prognosis, immune infiltration

Jiepeng Tong,1 Yiheng Jiang,2 Hao Xu,1 Xuehang Jin,1 Li Zhang,1 Shuaibing Ying,1 Wei Yu,1 Yunqing Qiu1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Clinical Medicine, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Wei Yu; Yunqing Qiu Email wyu@zju.edu.cn; qiuyq@zju.edu.cnPurpose: The emergence of vancomycin resistant Enterococci (VRE) is shortening the choices for clinical anti-infective therapy. The aim of this study was to investigate the mechanism of vancomycin resistance and evaluate the effect of fosfomycin (FM), rifampin (RIF), vancomycin (VAN), linezolid (LNZ), daptomycin (DAP) alone or in combination against VRE.Methods: Eight VRE isolates were collected. A total of 18 antibiotics susceptibility tests were further done for VRE. Whole genome sequencing and bioinformatics analysis were performed. The effect of FM, RIF, VNA, LNZ, DAP alone or in combination was determined using anti-biofilm testing and the time-kill assay.Results: All isolates were susceptible to LNZ and DPA. The high-level resistance determinant of VAN in these strains was due to VanA-type cassette. MLST revealed two different STs for vancomycin-resistant Enterococcus faecium (VREm) and four different STs for vancomycin-resistant E. faecalis (VREs). Virulence genes in VREs were more than VREm, especially for 4942 isolated from blood. Gene acm and uppS were only identified in VREm, while virulence genes related to cytolysin were only found in E. faecalis. Further in vitro studies indicated FM (83 mg/L) combined with DAP (20.6 mg/L) and DAP monotherapy (47.1 mg/L) had bactericidal effect against VRE isolates at 24h.Conclusion: High-level resistance determinant of VAN in tested isolates was due to VanA-type cassette. FM combined with DAP is a potential therapeutic option for VRE infections.Keywords: vancomycin, daptomycin, combination therapy, biofilm

Juan Tong, Na Zhao, Xing Hu, Wen Yao, Yaxin Cheng, Li Zhou, Huilan Liu, Liangquan Geng, Zimin Sun, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng ZhengDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of ChinaTel +86-551-62284476Fax +86-551-62284476Email zhengchch1123@ustc.edu.cnPurpose: We report the efficacy and safety of venetoclax plus decitabine-based treatment in heavily pre-treated relapsed or refractory acute myeloid leukaemia (RR-AML) in a real-world setting.Patients and Methods: There were 22 patients in this study and the median age was 47.5 (12– 84) years old, including 11 males and 11 females. Among them, 8 patients were relapsed AML including 2 patients relapsed after HSCT and 14 patients with primary refractory AML including 4 secondary AML. The median number of cycles of previous chemotherapy was 4 (range, 2– 10).Results: After a course of venetoclax plus decitabine-based treatment, 9 patients achieved complete remission (CR) and 1 patient achieved complete remission with incomplete haematological recovery (CRi). The overall response rate (ORR) was 45.5% and the CR rate was 40.9%, and the median time to reach CR/CRi was 21 (13– 46) days. Four of the 10 CR/CRi patients relapsed again, and the median time of relapse was 5 (1.0– 24) months. The one-year overall survival rate was 31.8%, and the median survival time was 6 months (95% CI, 1– 9 months). The one-year overall survival rate of 10 CR/CRi patients was 59.1%, and the 12 NR patients was 10.4% (p=0.001). Nausea and vomiting occurred in 11 patients (50.0%). All patients had grade IV neutropenia and IV thrombocytopenia (100%). Pneumonia occurred in 14 patients (63.6%) and septicaemia occurred in 2 patients (9.0%). The cause of death in all patients was primary disease progression, and no patients died due to the side effects.Conclusion: The efficacy of venetoclax plus decitabine-based treatment in the real-world treatment of heavily pre-treated RR-AML is similar to that in clinical trials, and the side effects are controllable.Keywords: venetoclax, hypomethylating agents, acute myeloid leukaemia

Yue Qiu,1,&ast; Daojiong Lin,2,&ast; Yi Xu,3,&ast; Yibing Cheng,4 Fang Wang,5 Qingxiong Zhu,6 Chunhui Zhu,6 Chaomin Wan,7 Yu Zhu,7 Jianning Tong,8 Rui Li,8 Qionghua Zhou,2 Minxia Chen,3 Qingwen Shan,9 Zhiqiang Zhuo,10 Caihong Wang,10 Shiyong Zhao,11 Wen Song,11 Mei Zeng1 1Department of Infectious Diseases, Children’s Hospital of Fudan University, ShangHai, People’s Republic of China; 2Department of Infectious Diseases, Hainan Women and Children’s Medical Center, Haikou, People’s Republic of China; 3Department of Infections Disease, Guangzhou Women and Children’s Medical Center, Guangzhou, People’s Republic of China; 4Department of Emergency, Children’s Hospital Affiliated to Zhengzhou University (Henan Children’s Hospital), Zhengzhou, People’s Republic of China; 5Department of Infections Disease, Children’s Hospital Affiliated to Zhengzhou University (Henan Children’s Hospital), Zhengzhou, People’s Republic of China; 6Department of Infection Diseases, Children’s hospital of Jiangxi Province, Nanchang, People’s Republic of China; 7Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China; 8Department of Pediatric, Gastroenterology and Infectious Diseases, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China; 9Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 10Department of Infectious Diseases, Xiamen Children’s Hospital, Xiamen, People’s Republic of China; 11Department of Infectious Diseases, Hangzhou Children’s Hospital, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mei ZengDepartment of Infectious Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, People’s Republic of ChinaTel +86-21-64931132Email zengmeigao@aliyun.comObjective: To assess clinical characteristics, outcomes and antimicrobial resistance of invasive Klebsiella pneumoniae (KP) infections in Chinese pediatric patients in hospital and community settings.Methods: This retrospective study was conducted in the nine tertiary hospitals during 2016– 2018. The 324 pediatric inpatients who had KP isolated from blood and cerebrospinal fluid and had complete medical records reviewed were included. We analyzed the risk factors, outcomes and antimicrobial resistance pattern of KP-infected patients based on comparison between healthcare-associated KP infections (HAI) and community-acquired infections.Results: Of the 324 enrolled patients, 275 (84.9%) were clinically defined as HAI, including 175 (63.6%) neonates and 100 (36.4%) aged > 28 days. The overall prevalence of CRKP was 38.2% (43.4% in HAI verse 8.7% in CAI, P < 0.05). Prematurity (odds ratio (OR): 37.07, 95% CI: 8.29– 165.84), hematologic malignancies (OR: 15.52, 95% CI: 1.89– 127.14) and invasive mechanical ventilation (OR: 13.09, 95% CI: 1.66– 103.56) were independent risk factors for HAI. Patients from rural area (OR: 1.94, 95% CI: 1.12– 3.35), invasive mechanical ventilation (OR: 2.33, 95% CI: 1.25– 4.33), antibiotic therapy prior to admission (OR: 2.33, 95% CI: 1.25– 4.33) and prior hospital stay in the past 30 days (OR: 3.46, 95% CI: 1.87– 6.41) were associated with healthcare-associated CRKP infections. Organ dysfunction was independently correlated with poor outcomes (OR: 2.92, 95% CI: 1.23– 6.95).Conclusion: Pediatric invasive KP infections and high prevalence of CRKP infections largely occurred in healthcare settings in China. The adequate and intensified infection control measures should be focused on high-risk hematologic patients, neonatal patients and intubated patients.Keywords: Klebsiella pneumoniae, healthcare-associated infections, children

Abstract Background Carbohydrate-containing drinks (CCD) are administered preoperatively in most enhanced recovery after surgery (ERAS) programs. It is not known which types of CCDs are used, e.g., simple vs. complex carbohydrate, and if the choice of drink differs in patients with diabetes. Methods A national survey was performed to characterize the use of preoperative CCDs within the context of adult colorectal ERAS programs. The survey had questions regarding the use of preoperative CCDs, the types of beverages used, and the timing of beverage administration. The survey was administered electronically to members of the American Society for Enhanced Recovery (ASER) and manually to participants at the 2018 Perioperative Quality and Enhanced Recovery Conference in San Francisco, CA. Results Responses were received from 78 unique hospitals with a colorectal ERAS program of which 68 (87.2%) reported administering a preoperative drink. Of these, 98.5%, 80.9%, and 60.3% of hospitals administered a beverage to patients without diabetes, patients with diabetes not taking insulin, and patients with diabetes taking insulin, respectively. Surprisingly, one third of programs that administered a beverage to patients with diabetes used a simple carbohydrate drink. Conclusions This survey finds a high use of CHO-containing beverages in colorectal ERAS programs. More than half of all programs administer a CHO-containing beverage to patients with diabetes, and surprisingly, there is significant use of simple carbohydrate beverages in patients with diabetes receiving insulin.

Abstract Background Enhanced Recovery After Surgery (ERAS) programs have gained traction across US hospitals in the past two decades. Initially implemented for elective colorectal surgical procedures, ERAS has expanded to a variety of surgical service lines. There is little information regarding the extent to which various surgical service lines use ERAS. Methods A survey was performed to describe the prevalence of ERAS programs across surgical service lines in the USA. The survey had questions regarding the number of ERAS programs, operating rooms (ORs) and presence of anesthesia and/or surgery residency program at an institution. The survey was administered electronically to members of the American Society for Enhanced Recovery (ASER) and manually to participants at the 2018 Perioperative Quality and Enhanced Recovery Conference in San Francisco, CA. Results Responses were received from 88 unique institutions. The most commonly reported surgical service lines were colorectal (87%), gynecology (51%), orthopedic (49%), surgical oncology (39%), and urology (35%). A significant positive association was observed between the number of ORs and the number ERAS programs (Spearman’s Rho 0.5, p

Abstract Background Health care workers (HCW) such as anesthesiologists, surgeons, and intensivists face high rates of exposure to SARS-CoV-2 through direct contact with COVID-19 patients. While there are initial reports of the prevalence of COVID-19 antibodies among the general population, there are few reports comparing the seroprevalence of IgM/IgG COVID-19 antibodies in HCW of different exposure levels as well as different HCW professions. Methods A convenience sample of health care workers provided blood for COVID-19 antibody testing and a review of medical history and work exposure for correlative analyses. Results Overall, 474 HCW were enrolled in April 2020 including 102 front-line physicians (e.g., anesthesiologists, surgeons, intensivists, emergency medicine), 91 other physicians, 135 nurses, 134 other clinical staff, and 12 non-clinical HCW. The prevalence of IgM or IgG antibodies to SARS-CoV-2 was 16.9% (95% CI 13.6–20.6) (80/474). The proportion of positive antibodies in the PCR + group was significantly higher than health care workers without symptoms (84.6% [95% CI 54.6–98.1] vs. 12.3% [95% CI 8.5–17.2], p < 0.001). No significant differences in proportions of COVID-19 antibodies were observed among the different exposure groups (e.g., high vs minimal/no exposure) and among the different HCW professionals. Conclusions Despite exposure to COVID-19 patients, the prevalence of antibodies in our HCW was similar to what has been reported for the general population of New York State (14%) and for another New York HCW cohort (13.7%). Health care workers with higher exposure rates were not more likely to have been infected with COVID-19. Therefore, these data suggest that infection of HCW may result from exposure in the community rather than at work. Trial registration This investigator-initiated study was observational; therefore, no registration was required. Not applicable.

Chen Wang,1,* Jiaqi Tong,2,* Mengqiu Tang,3 Yunyun Lu,3 Gaofeng Liang,4 Zhanchun Zhang,3 Tian Chen3 1Department of Gastroenterology, Ningbo Medical Center, Lihuili Hospital, Ningbo, People’s Republic of China; 2Department of Hematology, Ningbo Medical Center, Lihuili Hospital, Ningbo, People’s Republic of China; 3Department of Radiation Oncology, Ningbo Medical Center, Lihuili Hospital, Ningbo, People’s Republic of China; 4Department of Thoracic Surgery, Ningbo Medical Center, Lihuili Hospital, Ningbo, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tian Chen Email lhldbyyct@126.comBackground: Various inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have been well authenticated to predict clinical outcomes in numerous types of cancer. The optimal treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC) located in the middle or upper region is still inconclusive. The aim of the study was to examine pretreatment NLR and PLR to select from radical surgery or definitive chemoradiotherapy (dCRT) for these patients. The linkage between pretreatment NLR/PLR and prognosis was also analyzed.Methods: NLR and PLR were calculated in 113 locally advanced ESCC located in the middle or upper esophagus of patients who underwent radical surgery or dCRT between January 2014 and December 2019. A receiver operating characteristic curve was plotted to select the best cut-off value of NLR and PLR for predicting survival. A survival curve was plotted using the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were applied to assess predictors for survival.Results: NLR and PLR were associated with the extent of lymph node metastasis (NLR: P = 0.045; PLR: P = 0.002). Additionally, high PLR and recurrence with distant organ metastasis were closely related (P = 0.014), and NLR was related to the tumor stage (P = 0.043). The results of the multivariate analysis revealed that NLR (> 2.07) and PLR (> 183.06) were independently associated with poor prognosis. It is noteworthy that surgery was associated with a superior OS compared with dCRT in the low NLR population (P = 0.045).Conclusion: Low pretreatment NLR patients are fit to undergo radical surgery with a substantial therapeutic benefit. Pretreatment NLR and PLR are independent predictors for patients with locally advanced ESCC located in the middle and upper esophagus who underwent radical surgery or dCRT.Keywords: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, esophageal squamous cell carcinoma, definitive chemoradiotherapy, surgery, prognostic factor, reference marker

Jialu Guo,1,2 Jinyi Tong,1,2 Jianfeng Zheng2,3 1Department of the Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310008, People’s Republic of China; 2Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital, Hangzhou, Zhejiang Province, 310008, People’s Republic of China; 3Department of Obstetrics and Gynecology, Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, Zhejiang Province, 310008, People’s Republic of ChinaCorrespondence: Jinyi TongDepartment of the Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, Zhejiang Province, 310008, People’s Republic of ChinaTel +86 13588818180Email tongjinyi252@zju.edu.cnAbstract: Endometrial cancer (EC) is one of the most common malignant tumors of the female reproductive tract. EC patients have high morbidity and mortality rates and remain an important cause of cancer-related morbidity and mortality worldwide. More and more studies have shown that a large number of non-coding RNAs (such as microRNAs and long non-coding RNAs) are associated with the occurrence of diseases. Circular RNAs (circRNAs) is an endogenous non-coding RNA. It has a unique covalent structure. Many studies in recent years have found circRNAs differential expression in a variety of tumor tissues compared to matched normal tissues. In endometrial carcinoma, there also are multiple circRNAs differentially expressed and therefore circRNAs perhaps can be used as a diagnostic and prognosis biomarkers of EC. In this review, we described the biogenesis, function and characteristics of circRNAs, and the circRNAs with potential influence and clinical significance on the development of EC were summarized. Adenocarcinoma is the most common form of EC, so this review focuses on endometrioid adenocarcinoma.Keywords: circRNA, biogenesis, back-splicing, function, endometrial cancer, biomarker

Yuhong Jin,1 Haiyan Mao,1 Bingyang Liu,1 Fen Zhou,1 Junjie Yang,1 Lei Xu,1 Jingtao Tong,2 Chen Huang,3 Yi Ding1 1Department of Intensive Care, Lihuili Hospital, Ningbo Medical Center, Ningbo, People’s Republic of China; 2Department of Radiotherapy, Lihuili Hospital, Ningbo Medical Center, Ningbo, People’s Republic of China; 3Department of Respiratory Medicine, Lihuili Hospital, Ningbo Medical Center, Ningbo, People’s Republic of ChinaCorrespondence: Chen HuangDepartment of Respiratory Medicine, Lihuili Hospital, Ningbo Medical Center, Ningbo 315000, People’s Republic of ChinaTel +86-574-87018701Fax +86- 574-87392232Email drhchen@163.comYi DingDepartment of Intensive Care, Lihuili Hospital, Ningbo Medical Center, Ningbo 315000, People’s Republic of ChinaTel +86-574-87018661Email dingdingnb@163.comObjective: There is a paucity of published data to evaluate the efficacy and safety of imipenem (IPM) and piperacillin-tazobactam (PT) dosing regimens in the treatment of septic patients acquiring continuous renal replacement therapy (CRRT).Methods and Materials: Critically-ill patients were grouped into short-stay and long-stay intensive care unit (ICU) patients. Pathogens were isolated from bloodstream infections in these patients. Minimum inhibitory concentration (MIC) value was determined by agar dilution method. Population PK models were introduced in this study, and differences in the likelihood of achieving efficacious and toxic exposures of IPM and PT for critically-ill patients were assessed.Results: A total of 86 K. pneumoniae bloodstream infection associated isolates were collected, and the MIC50 and MIC90 for short-stay ICU patients were 0.5/4 mg/L and 32/128 mg/L, respectively. IMP 0.5g q8h reached 90% probability of target attainment (PTA) against isolates with MICs ≤ 2 mg/L and was recommended to empirically treat short-stay ICU patients during CRRT based on the target of 40% ƒT>MIC. However, based on a more aggressive target of 100% ƒT>MIC, all the simulated IMP regimens except for IMP 1g q6h failed to achieve > 80% cumulative fraction of response (CFR) in such patients. Unfortunately, the risk of drug-related toxicity for IMP 1g q6h was relatively high (50– 85%). For PT, even the regimen of 4/0.5g q6h failed to provide sufficient antimicrobial exposure in short-stay ICU patients acquiring CRRT.Conclusion: No dose adjustment was required for the conventional IMP and PT regimens in the critically-ill population acquiring CRRT. Empirical treatment of IMP 0.5g q8h/q6h, not for PT, may provide sufficient antimicrobial exposure for short-stay ICU patients during CRRT. PT should be used in the knowledge of MIC results.Keywords: Klebsiella pneumoniae infection, pharmacokinetic/pharmacodynamic, continuous renal replacement therapy; CRRT, intensive care unit; ICU

Jinfei Tong,1,2 Xiao Zhang,1,2 Yunlong Fan,3 Lingfeng Chen,1– 3 Xudong Ma,1,2 Hailan Yu,1,2 Jianqiong Li,1,2 Xiaojing Guan,1,2 Peiya Zhao,1,2 Jianhua Yang1,2 1Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, People’s Republic of China; 3Department of Gynaecology and Obstetrics, First People’s Hospital of Wenling, Wenling, People’s Republic of ChinaCorrespondence: Jianhua Yang Email yjh2006@zju.edu.cnPurpose: Ovarian cancer is the leading cause of death in gynecologic malignancies. Growing evidences demonstrate that a complicated relationship exists between the gut microbiota and cancer treatment. However, there are few studies explored the alterations of gut microbiota in ovarian cancer patients following anti-cancer treatments. Therefore, we aim to analyze the changes of the gut microbiota in ovarian cancer patients treated with radical surgery and chemotherapy.Patients and Methods: The microbial genes were examined from a total of 75 fecal samples from 18 ovarian cancer patients, including 10 preoperative fecal samples (Group B), 4 postoperative fecal samples (Group M0), as well as 61 fecal samples after first to fifth cycles of chemotherapy, using 16S rRNA sequencing.Results: Our results showed that fecal samples collected in postoperative (Group M0) exhibited significant decreases in abundance of Bacteroidetes and Firmicutes, while a significant increase in abundance of Proteobacteria compared with preoperative (Group B) fecal samples. LEfSe analysis identified that Bilophila and Faecalibacterium are the key genera in Group B, while Klebsiella and Enterococcus are the key genus in Group M0. Compared with before chemotherapy, the abundance of Bacteroidetes and Firmicutes increased, and the abundance of Proteobacteria decreased after chemotherapy. In addition, anaerobic bacteria, such as Bacteroides, Collinsella and Blautia, exhibited significant increases after chemotherapy. Moreover, we observed that certain bacterial genera were significantly correlated with clinicopathological characteristics of ovarian cancer patients.Conclusion: Our study suggested that radical surgery and chemotherapy altered the composition of gut microbiota in ovarian cancer patients. Therapeutic strategies targeting the gut microbiota may be beneficial for the clinical treatment of ovarian cancer.Keywords: ovarian cancer, intestinal microbiota, radical surgery, chemotherapy, 16S rRNA sequencing

Abstract Background Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.

Man-Yu Dong, Bao-Lin Tang, Xiao-Yu Zhu, Si-Qi Cheng, Xin-Chen Fang, Juan Tong, Xiang Wan, Chang-Cheng Zheng, Hui-Lan Liu, Zi-Min Sun Department of Hematology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Zi-Min SunDepartment of Hematology, The First Affiliated Hospital of University of Science and Technology of China, No. 17, Lujiang Road, Hefei, Anhui 230001, People’s Republic of ChinaTel +86 551 6228 2992Fax +86 551 6228 2121Email zmsun_vip@163.comIntroduction: Current consensus recommends a protective effect of cytomegalovirus (CMV) infection on relapse after peripheral blood or bone marrow hematopoietic stem cell transplantation. However, in cord blood transplantation (CBT), studies of CMV infection, especially CMV viral load, on relapse are limited.Patients and Methods: Wct e retrospectively analyzed the effect of CMV infection on 3-year outcomes in 249 AML patients according to CMV DNA load (DNA copies < 1000/mL and DNA copies ≧1000/mL) within 100 days after CBT. Furthermore, eight-colour flow cytometry was used to detect peripheral blood lymphocyte subsets in 38 patients who received CBT in the last year, and 10 healthy volunteers were included as controls.Results: The results showed that CMV DNA load did not affect the cumulative incidence of relapse in the whole study population. However, in patients with complete remission status before transplantation, the high CMV DNA load group showed a significantly reduction of relapse than the low CMV DNA load group (3.9% vs 14.6%, p=0.012, respectively), which was confirmed by multivariate analysis (HR 0.23; 95% CI, 0.07– 0.73, p = 0.012). Surprisingly, high or low CMV DNA load did not significantly affect non-relapse mortality or overall survival (18.0% vs 17.0%, p=0.777 and 79.0% vs 74.6%, p=0.781, respectively). Besides, the absolute number of CD8+ T cells were increased in the high CMV DNA load group compared with the low DNA load group 1 month after CBT (0.20× 10 9/L vs 0.10× 10 9/L, p=0.021, respectively).Conclusion: DNA copies ≧1000/mL for AML patients in complete remission was associated with a lower incidence of relapse after CBT, which might partly result from the expansion of CMV-related CD8+ T cells.Keywords: cord blood transplantation, cytomegalovirus, DNA load, relapse, acute myeloid leukemia, complete remission

Background: Several continuous monitoring solutions, including wireless wearable sensors, are available or being developed to improve patient surveillance on surgical wards. We designed a survey to understand the current perception and expectations of anaesthesiologists who, as perioperative physicians, are increasingly involved in postoperative care. Methods: The survey was shared in 40 university hospitals from Western Europe and the USA. Results: From 5744 anaesthesiologists who received the survey link, there were 1158 valid questionnaires available for analysis. Current postoperative surveillance was mainly based on intermittent spot-checks of vital signs every 4–6 h in the USA (72%) and every 8–12 h in Europe (53%). A majority of respondents (91%) considered that continuous monitoring of vital signs should be available on surgical wards and that wireless sensors are preferable to tethered systems (86%). Most respondents indicated that oxygen saturation (93%), heart rate (80%), and blood pressure (71%) should be continuously monitored with wrist devices (71%) or skin adhesive patches (54%). They believed it may help detect clinical deterioration earlier (90%), decrease rescue interventions (59%), and decrease hospital mortality (54%). Opinions diverged regarding the impact on nurse workload (increase 46%, decrease 39%), and most respondents considered that the biggest implementation challenges are economic (79%) and connectivity issues (64%). Conclusion: Continuous monitoring of vital signs with wireless sensors is wanted by most anaesthesiologists from university hospitals in Western Europe and in the USA. They believe it may improve patient safety and outcome, but may also be challenging to implement because of cost and connectivity issues.

BackgroundAs patients are discharged from the hospital more quickly, the ability to monitor patient recovery between hospital discharge and the first follow-up clinic visit is becoming increasingly important. Despite substantial increase in both internet use and smartphone ownership over the past 5 years, clinicians have been slow to embrace the use of these devices to capture patient recovery information in the period between hospital discharge and the first clinical follow-up appointment. ObjectiveThis study aims to investigate the generalizability of using a web-based platform to capture patient recovery in a broad surgical patient population and compare response rates for 3 different web-based strategies for delivering recovery surveys over the perioperative period: email, SMS text messaging, and a concurrent mixed approach of using both email and SMS text messaging. MethodsPatients undergoing surgeries managed with an enhanced recovery after surgery pathway were asked to participate in a web-based quality assurance monitoring program at the time of their preoperative surgery appointment. Different follow-up methods were implemented over 3 sequential phases. Patients received Health Insurance Portability and Accountability Act–compliant web-based survey links via email (phase 1), SMS text messaging (phase 2), or concurrently using both email and SMS text messaging (phase 3) using REDCap and Twilio software. Recovery assessments using the established Quality of Recovery-9 instrument were performed 4 days before surgery and at 7 and 30 days postoperatively. Generalizability of the web-based system was examined by comparing characteristics of those who participated versus those who did not. Differences in response rates by the web-based collection method were analyzed using adjusted models. ResultsA total of 615 patients were asked to participate, with 526 (85.5%) opting for the follow-up program. Those who opted in were younger, slightly healthier, and more likely to be in a partnership. The concurrent mixed modes method was the most successful for obtaining responses at each time point compared with text or email alone (pre: 119/160, 74.4% vs 116/173, 67.1% vs 56/130, 43.1%, P

Chad Moretz1, Lindsay GS Bengtson2, Lucie Sharpsten2, Eleena Koep2, Lisa Le2, Junliang Tong2, Richard H Stanford1, Beth Hahn1, Riju Ray1 1Glaxo Smith Kline, Research Triangle Park, Durham, NC, USA; 2Optum, Eden Prairie, MN, USACorrespondence: Chad MoretzGlaxoSmithKline, Research Triangle Park, 5 Moore Drive, Durham, NC, USATel +1 828 442 6294Email chad.x.moretz@gsk.comBackground: This was the first real-world head-to-head study comparing inhaled long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination treatments as maintenance therapy.Methods: Retrospective observational study including commercial, Medicare Advantage with Part D or Part D-only enrollees aged ≥40 years from the Optum Research Database. Patients initiated umeclidinium/vilanterol (UMEC/VI) or tiotropium bromide/olodaterol (TIO/OLO) between June 1, 2015 and November 30, 2016 (index date) with 12 months of pre- and post-index continuous enrollment. Outcomes were modeled following the inverse probability of treatment weighting. The primary endpoint, rescue medication use, was modeled using weighted ordinary least squares regression with bootstrapped variance estimation. Intent-to-treat analysis evaluated non-inferiority and superiority of UMEC/VI to TIO/OLO with thresholds of 0.30 and 0 units, respectively. On-treatment sensitivity analysis evaluated the superiority of UMEC/VI to TIO/OLO for rescue medication use. The secondary endpoint, medication adherence (proportion of days covered [PDC]≥80%), was evaluated using weighted logistic regression. Post hoc weighted Cox proportional hazards regression analysis evaluated escalation to multiple inhaler triple therapy (MITT).Results: The study population included 14,324 patients; 9549 initiated UMEC/VI and 4775 initiated TIO/OLO. During the 12-month post-index period, UMEC/VI initiators used 0.16 fewer adjusted mean units of rescue medication than TIO/OLO initiators (95% CI: −0.28, −0.04), meeting pre-specified non-inferiority (P

Chad Moretz,1 Lucie Sharpsten,2 Lindsay GS Bengtson,2 Eleena Koep,2 Lisa Le,2 Junliang Tong,2 Richard H Stanford,1 Beth Hahn,1 Riju Ray31US Value Evidence and Outcomes, GSK, Durham, NC, USA; 2Health Economics and Outcomes Research, Optum, Eden Prairie, MN, USA; 3US Medical Affairs, GSK, Durham, NC, USABackground and objective: Retrospective claims data in patients with chronic obstructive pulmonary disease (COPD) initiating maintenance therapy with inhaled fixed-dose combinations of long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) versus inhaled corticosteroid (ICS)/LABA have not been reported.Methods: Retrospective observational study in a COPD-diagnosed population of commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years from a US health insurer database. Patients initiated umeclidinium/vilanterol (UMEC/VI [62.5/25 μg]) or fluticasone propionate/salmeterol (FP/SAL [250/50 μg]) between April 1, 2014 and August 31, 2016 (index date) and had 12 months continuous enrollment pre- and post-index. Exclusion criteria included an asthma diagnosis in the pre-index period/index date; ICS-, LABA-, or LAMA-containing therapy during the pre-index period; or pharmacy fills for both UMEC/VI and FP/SAL, multiple-inhaler triple therapy, a non-index therapy, or COPD exacerbation on the index date. Adherence (proportion of days covered [PDC] ≥80%) was modeled using weighted logistic regression following inverse probability of treatment weighting (IPTW). Weighted Kaplan–Meier and Cox proportional hazards regression following IPTW were performed for incidence of COPD exacerbation and escalation to multiple-inhaler triple therapy.Results: The study population included 5306 patients (1386 initiating UMEC/VI and 3920 initiating FP/SAL). Adjusted odds of adherence were 2.00 times greater among UMEC/VI than FP/SAL initiators (95% confidence interval [CI]: 1.62─2.46; P

Jinfei Tong,1,2 Xudong Ma,1,2 Hailan Yu,1,2 Jianhua Yang1,21Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, People’s Republic of ChinaAbstract: Cancer is expected to rank as the leading cause of death worldwide due to increasing morbidity and mortality. Long noncoding RNAs (lncRNAs) have been found to play pivotal roles in multiple biological processes, such as transcriptional interference, posttranscriptional regulation and epigenetic modification. Small nucleolar RNA host gene 15 (SNHG15), a snoRNA host gene which produces a short half-lived lncRNA, was reported to be upregulated in tumor cells and participate in the occurrence and development of multiple cancers. And more than half of the SNHG15 research in cancers has been published within the last 2 years. In this review, we summarized the current evidence concerning the biological functions and molecular mechanisms of SNHG15 in various cancers, including gastric, hepatocellular, pancreatic, colorectal, breast, and thyroid cancer, osteosarcoma, glioma, lung cancer, renal cell carcinoma, and epithelial ovarian cancer. SNHG15 plays critical roles in regulation of cell proliferation, migration and invasion of tumors via different potential mechanisms. Moreover, the abnormal expression of SNHG15 was associated with clinical features of patients with cancers. Consequently, SNHG15 could be considered as a promising biomarker for cancer diagnosis, prognosis or treatment.Keywords: SNHG15, long noncoding RNA, cancer, biomarker

Charlie Strange,1 Valery Walker,2 Michael DePietro,3 Junliang Tong,2 Jonathan Kurlander,2 Maureen Carlyle,2 Lauren A Millette,3 Eric Wittbrodt41Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA; 2Health Economics and Outcomes Research, Optum, Inc., Eden Prairie, MN, USA; 3US Medical Affairs, AstraZeneca, Wilmington, DE, USA; 4Health Economics and Outcomes Research, AstraZeneca, Wilmington, DE, USABackground: This study compared real-world patient-reported outcomes (PROs) measured by the Clinical COPD Questionnaire (CCQ), the London Chest Activities of Daily Living (LCADL) scale, and the Work Productivity and Activity Impairment (WPAI) questionnaire between individuals with COPD initiating LAMA/LABA fixed-dose combination (FDC) dual therapy versus either long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) monotherapy.Methods: Individuals with COPD aged ≥40 years initiating a LAMA/LABA FDC dual therapy or a LAMA or LABA monotherapy (index date = first prescription date) between January 1, 2016 and December 31, 2016 were identified from a large US administrative claims database. Individuals were excluded if they were prescribed an inhaled corticosteroid (ICS) or ICS/LABA two months prior to the index date or were diagnosed with cystic fibrosis, idiopathic pulmonary fibrosis, or asthma. The cohorts were propensity score matched (PSM) 1:1 for COPD severity using baseline measures. Each participant completed a survey.Results: Surveys were completed by 399 participants in the dual therapy cohort, and 718 participants in the monotherapy cohort. Following PSM, 379 participants remained in each cohort for analysis (monotherapy: 369 LAMA and 10 LABA). The dual therapy cohort reported fewer COPD-related symptoms (CCQ symptom score 2.75 vs 2.97, respectively, P=0.023), and, fewer limitations in leisure activities (LCADL leisure score 4.78 vs 5.17, respectively, P=0.021) versus the monotherapy cohort. No significant differences were found in the WPAI. A greater percentage of participants in the dual therapy cohort stayed on index therapy (63.1%) when compared with the monotherapy cohort (30.3%, P

Abstract Background There is a paucity of literature regarding the implementation of enhanced recovery after surgery (ERAS) protocols for open lumbar spine fusions. We implemented an ERAS program for 1–2-level lumbar spine fusion surgery and identified areas that might benefit from perioperative interventions to improve patient satisfaction and outcomes. Methods This institutionally approved quality improvement (QI) ERAS program for lumbar spine fusion was designed for all neurosurgical patients 18 years and older scheduled for 1 or 2 level primary lumbar fusions. The ERAS bundle contained elements such as multimodal analgesia including preoperative oral acetaminophen and gabapentin, postoperative early mobilization and physical therapy, and a prophylactic multimodal antiemetic regimen to decrease postoperative nausea and vomiting. No fluid management or hemodynamic parameters were included. Pre-ERAS and post-ERAS data were compared with regard to potential confounders, compliance with the ERAS bundle, and postoperative outcomes. Results A total of 230 patients were included from October 2013 to May 2017. The pre-ERAS phase consisted of 123 patients, 11 patients during the transition period, and 96 serving as post-ERAS patients. The pre-ERAS and post-ERAS groups had comparable demographics and comorbidities. Compliance with preoperative and intraoperative medication interventions was relatively good (~ 80%). Compliance with postoperative elements such as early physical therapy, early mobilization, and early removal of the urinary catheter was poor with no significant improvement in post-ERAS patients. There was no significant change in the amount of short-acting opioids used, but there was a decrease in the use of long-acting opioids in the post-ERAS phase (14.6 to 5.2%, p = 0.025). Post-ERAS patients required fewer rescue antiemetic medications in the recovery room compared to pre-ERAS patients (40 to 24%). There was no significant difference in postoperative pain scores or hospital length of stay between the two groups. Conclusions Implementing an ERAS bundle for 1–2-level lumbar fusion had minimal effect in decreasing length of stay, but a significant decrease in postoperative opioid and rescue antiemetic use. This ERAS bundle showed mixed results likely secondary to poor ERAS protocol compliance. Going forward, this QI project will look to improve post-operative ERAS implementation to improve patient outcomes.

Abstract Background Buffered intravenous fluid preparations contain substrates to maintain acid-base status. The objective of this systematic review was to compare the effects of buffered and non-buffered fluids administered during the perioperative period on clinical and biochemical outcomes. Methods We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library until May 2017 and included all randomised controlled trials that evaluated buffered versus non-buffered fluids, whether crystalloid or colloid, administered to surgical patients. We assessed the selected studies for risk of bias and graded the level of evidence in accordance with Cochrane recommendations. Results We identified 19 publications of 18 randomised controlled trials, totalling 1096 participants. Mean difference (MD) in postoperative pH was 0.05 units lower immediately following surgery in the non-buffered group (12 studies of 720 participants; 95% confidence interval (CI) 0.04 to 0.07; I 2 = 61%). This difference did not persist on postoperative day 1. Serum chloride concentration was higher in the non-buffered group at the end of surgery (10 trials of 530 participants; MD 6.77 mmol/L, 95% CI 3.38 to 10.17). This effect persisted until postoperative day 1 (5 trials of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). Quality of this evidence was moderate. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Outcome data was variably reported at disparate time points and with heterogeneous patient groups. Consequently, the effect size and overall confidence interval was reduced, despite the relatively low inherent risk of bias. There was insufficient evidence on the effect of fluid composition on mortality and organ dysfunction. Confidence intervals of this outcome were wide and the quality of evidence was low (3 trials of 276 participants for mortality; odds ratio (OR) 1.85, 95% CI 0.37 to 9.33; I 2 = 0%). Conclusions Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Buffered fluid may have biochemical benefits, including a significant reduction in postoperative hyperchloraemia and metabolic acidosis.

Abstract Introduction The management of acute postoperative pain remains a significant challenge for physicians. Poorly controlled postoperative pain is associated with poorer overall outcomes. Methods Between April and May 2017, physicians from an online database who regularly prescribe intravenous (IV) medications for acute postoperative pain completed a 47-question survey on topics such as patient demographics, IV analgesia preferences, factors that influence prescribing decisions, and the challenges and unmet needs for the treatment of acute postoperative pain. Results Of 501 surveyed physicians, 55% practiced in community hospitals, 60% had been in practice for > 10 years, and 60% were surgeons. The three categories of IV pain medications most likely to be prescribed to patients with moderate-to-severe pain immediately after surgery were morphine, hydromorphone, or fentanyl (95.8% of respondents); COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (73.7%); and acetaminophen (60.5%). Past clinical experience (81.6%), surgery type (78.2%), and onset of analgesia (67.1%) were practice-related factors that most determined their medication choice. Key patient-related risk factors, such as avoidance of medication-related adverse events (AEs), each influenced prescription decisions in > 75.0% of physicians. Nausea and vomiting were among the most common challenges associated with postoperative pain management (76.2 and 60.3%, respectively), and avoidance of analgesic medication-related AEs was among the three most influential patient-related factors that determined prescribing decision (75%). Physicians reported the top unmet need for acute pain management in patients experiencing moderate-to-severe postoperative pain was more medications with fewer side effects (i.e., nausea, vomiting, and respiratory depression; 80.7%). Conclusions Opioids remain an integral component of multimodal acute analgesic therapy for acute postoperative pain in hospitalized patients. The use of all IV analgesic medications is limited by concerns over AEs, particularly with opioids and in high-risk patients. There remains a key unmet need for effective analgesic medications that are associated with a lower risk of AEs. Funding Trevena, Inc.

Haishen Kong,1,2 Lingmei Fang,3 Rujin Jiang,4 Jixiang Tong2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 2Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 3Clinical Laboratory, Chunan First People’s Hospital, Zhejiang Province People’s Hospital Chunan Branch, Hangzhou, China; 4Clinical Laboratory, Yuhang Hospital of Traditional Chinese Medicine, Hangzhou, China Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Various virulence and antiseptic-resistant factors increase the pathogenicity of MRSA strains and allow for increased infection rates.Purpose: The purpose of this study was to investigate the prevalence and distribution of virulence-associated and antiseptic-resistant genes from epidemic MRSA strains isolated from East China.Methods: A newly designed multiplex PCR assay was used to assess whether the virulence-associated genes sasX and pvl and the chlorhexidine tolerance gene qacA/B were present in 189 clinical isolates of MRSA. Multilocus sequence typing (MLST) and Staphylococcal protein A (spa) typing of these isolates were also performed. The frequency of these genes in isolates with epidemic sequence types (STs) was investigated. Results: Twenty STs and 36 spa types with five epidemic clones (ST5-t311, ST59-t437, ST5-t002, ST239-t030, and ST239-t037) were identified. The prevalence of sasX, pvl, and qacA/B in all isolates was 5.8%, 10.1%, and 20.1%, respectively. The prevalences of these genes in isolates with ST5, ST59, ST239, and other ST genetic backgrounds were all significantly different (P

Abstract Background Goal-directed hemodynamic therapy (GDHT) has been used in the clinical setting for years. However, the evidence for the beneficial effect of GDHT on postoperative recovery remains inconsistent. The aim of this systematic review and meta-analysis was to evaluate the effect of perioperative GDHT in comparison with conventional fluid therapy on postoperative recovery in adults undergoing major abdominal surgery. Methods Randomized controlled trials (RCTs) in which researchers evaluated the effect of perioperative use of GDHT on postoperative recovery in comparison with conventional fluid therapy following abdominal surgery in adults (i.e., >16 years) were considered. The effect sizes with 95% CIs were calculated. Results Forty-five eligible RCTs were included. Perioperative GDHT was associated with a significant reduction in short-term mortality (risk ratio [RR] 0.75, 95% CI 0.61–0.91, p = 0.004, I 2 = 0), long-term mortality (RR 0.80, 95% CI 0.64–0.99, p = 0.04, I 2 = 4%), and overall complication rates (RR 0.76, 95% CI 0.68–0.85, p

Abstract Background Within an enhanced recovery pathway (ERP), the approach to treating pain should be multifaceted and the goal should be to deliver “optimal analgesia”, which we define in this paper as a technique that optimizes patient comfort and facilitates functional recovery with the fewest medication side effects. Methods With input from a multidisciplinary, international group of experts and through a structured review of the literature and use of a modified Delphi method, we achieved consensus surrounding the topic of optimal analgesia in the perioperative period for colorectal surgery patients. Discussion As a part of the first Perioperative Quality Improvement (POQI) workgroup meeting, we sought to develop a consensus document describing a comprehensive, yet rational and practical, approach for developing an evidence-based plan for achieving optimal analgesia, specifically for a colorectal surgery within an ERP. The goal was twofold: (a) that application of this process would lead to improved patient outcomes and (b) that investigation of the questions raised would identify knowledge gaps to aid the direction for research into analgesia within ERPs in the years to come. This document details the evidence for a wide range of analgesic components, with particular focus on care in the post-anesthesia care unit, general care ward, and transition to home after discharge. The preoperative and operative consensus statement for analgesia was covered in Part 1 of this paper. The overall conclusion is that the combination of analgesic techniques employed in the perioperative period is not important as long as it is effective in delivering the goal of “optimal analgesia” as set forth in this document.

Abstract Background Within an enhanced recovery pathway (ERP), the approach to treating pain should be multifaceted and the goal should be to deliver “optimal analgesia,” which we define in this paper as a technique that optimizes patient comfort and facilitates functional recovery with the fewest medication side effects. Methods With input from a multi-disciplinary, international group of clinicians, and through a structured review of the literature and use of a modified Delphi method, we achieved consensus surrounding the topic of optimal analgesia in the perioperative period for colorectal surgery patients. Discussion As a part of the first Perioperative Quality Improvement (POQI) workgroup meeting, we sought to develop a consensus document describing a comprehensive, yet rational and practical, approach for developing an evidence-based plan for achieving optimal analgesia, specifically for a colorectal surgery ERP. The goal was two-fold: (a) that application of this process would lead to improved patient outcomes and (b) that investigation of the questions raised would identify knowledge gaps to aid the direction for research into analgesia within ERPs in the years to come. This document details the evidence for a wide range of analgesic components, with particular focus from the preoperative period to the post-anesthesia care unit. The overall conclusion is that the combination of analgesic techniques employed in the perioperative period is not important as long as it is effective in delivering the goal of optimal analgesia as set forth in this document.