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Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged.• Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence.• The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

To investigate the factors influencing postoperative femoral head collapse (FHC) in patients with Ficat I, II, and III stages of aseptic necrosis of the femoral head (ANFH).Retrospective analysis of 178 patients with ANFH admitted to our hospital from October 2018 to October 2021 was studied, and patients were categorized into the FHC group and no FHC group according to whether FHC occurred after surgery. The influencing factors causing postoperative FHC were analyzed by univariate and multifactor logistic regression.In the collapsed group, there were statistically significant differences in etiology, extent of necrosis, mechanism of injury, preoperative waiting time, Japanese Femoral Necrosis Research Society staging, distance from the tip of the tantalum rod to the center of necrosis, and Harris score after treatment ( P0.05). The etiology, extent of necrosis, mechanism of injury, preoperative waiting time, Japanese Femoral Osteonecrosis Research Society classification, distance between the tantalum rod tip and the center of necrosis, and Harris score after treatment were set as independent variables, and postoperative FHC in patients with Ficat I, II, and III stages of ANFH was used as the dependent variable in the univariate logistic regression analysis.Hormonal osteonecrosis of the femur, extent of necrosis, type C1 and type C2 in the Japanese Society for the Study of Femoral Osteonecrosis staging, and distance of the tip of the tantalum rod from the center of necrosis are risk factors for postoperative FHC in patients with Ficat I, II, and III stages of ANFH.

Long non-coding RNA H19 (lncRNA H19) is transcribed from the H19 gene. We previously reported the role of lncRNA H19 in the pathogenesis of cerebral ischemic stroke. The present study aimed to elucidate the relationship between lncRNA H19 and blood-brain barrier breakdown induced by cerebral ischemic stroke. We observed that plasma levels of lncRNA H19 were positively associated with the extent of blood-brain barrier damage. In cellular co-culture models, neurons expressed and transported lncRNA H19 to astrocytes via exosomes and contributed to an increase in endothelium permeability induced by oxygen-glucose deprivation. Inhibition of neuronal exosomal lncRNA H19 regulated astrocytic microRNA (miR)-18a and vascular endothelial growth factor (VEGF) expression. Further, lncRNA H19 induced a decrease in tight junction proteins expression via the lncRNA H19/miR-18a/VEGF axis. This study highlights the transportation of lncRNA H19 by exosomes and the relationship between lncRNA H19 and blood-brain barrier breakdown.

With the ongoing COVID-19 pandemic, growing evidence shows that a considerable proportion of people who have recovered from COVID-19 have long-term effects on multiple organs and systems. A few longitudinal studies have reported on the persistent health effects of COVID-19, but the follow-up was limited to 1 year after acute infection. The aim of our study was to characterise the longitudinal evolution of health outcomes in hospital survivors with different initial disease severity throughout 2 years after acute COVID-19 infection and to determine their recovery status.We did an ambidirectional, longitudinal cohort study of individuals who had survived hospitalisation with COVID-19 and who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. We measured health outcomes 6 months (June 16-Sept 3, 2020), 12 months (Dec 16, 2020-Feb 7, 2021), and 2 years (Nov 16, 2021-Jan 10, 2022) after symptom onset with a 6-min walking distance (6MWD) test, laboratory tests, and a series of questionnaires on symptoms, mental health, health-related quality of life (HRQoL), return to work, and health-care use after discharge. A subset of COVID-19 survivors received pulmonary function tests and chest imaging at each visit. Age-matched, sex-matched, and comorbidities-matched participants without COVID-19 infection (controls) were introduced to determine the recovery status of COVID-19 survivors at 2 years. The primary outcomes included symptoms, modified British Medical Research Council (mMRC) dyspnoea scale, HRQoL, 6MWD, and return to work, and were assessed in all COVID-19 survivors who attended all three follow-up visits. Symptoms, mMRC dyspnoea scale, and HRQoL were also assessed in controls.2469 patients with COVID-19 were discharged from Jin Yin-tan Hospital between Jan 7 and May 29, 2020. 1192 COVID-19 survivors completed assessments at the three follow-up visits and were included in the final analysis, 1119 (94%) of whom attended the face-to-face interview 2 years after infection. The median age at discharge was 57·0 years (48·0-65·0) and 551 (46%) were women. The median follow-up time after symptom onset was 185·0 days (IQR 175·0-197·0) for the visit at 6 months, 349·0 days (337·0-360·0) for the visit at 12 months, and 685·0 days (675·0-698·0) for the visit at 2 years. The proportion of COVID-19 survivors with at least one sequelae symptom decreased significantly from 777 (68%) of 1149 at 6 months to 650 (55%) of 1190 at 2 years (p0·0001), with fatigue or muscle weakness always being the most frequent. The proportion of COVID-19 survivors with an mMRC score of at least 1 was 168 (14%) of 1191 at 2 years, significantly lower than the 288 (26%) of 1104 at 6 months (p0·0001). HRQoL continued to improve in almost all domains, especially in terms of anxiety or depression: the proportion of individuals with symptoms of anxiety or depression decreased from 256 (23%) of 1105 at 6 months to 143 (12%) 1191 at 2 years (p0·0001). The proportion of individuals with a 6MWD less than the lower limit of the normal range declined continuously in COVID-19 survivors overall and in the three subgroups of varying initial disease severity. 438 (89%) of 494 COVID-19 survivors had returned to their original work at 2 years. Survivors with long COVID symptoms at 2 years had lower HRQoL, worse exercise capacity, more mental health abnormality, and increased health-care use after discharge than survivors without long COVID symptoms. COVID-19 survivors still had more prevalent symptoms and more problems in pain or discomfort, as well as anxiety or depression, at 2 years than did controls. Additionally, a significantly higher proportion of survivors who had received higher-level respiratory support during hospitalisation had lung diffusion impairment (43 [65%] of 66 vs 24 [36%] of 66, p=0·0009), reduced residual volume (41 [62%] vs 13 [20%], p0·0001), and total lung capacity (26 [39%] vs four [6%], p0·0001) than did controls.Regardless of initial disease severity, COVID-19 survivors had longitudinal improvements in physical and mental health, with most returning to their original work within 2 years; however, the burden of symptomatic sequelae remained fairly high. COVID-19 survivors had a remarkably lower health status than the general population at 2 years. The study findings indicate that there is an urgent need to explore the pathogenesis of long COVID and develop effective interventions to reduce the risk of long COVID.

This study aimed to establish a multiplex quantitative polymerase chain reaction (MQ-PCR) assay for 12 bacterial pathogens found in lower respiratory tract infection (LRTI) and to evaluate its performance in a cohort of 211 patients with LRTI.The study was divided into two stages: a pilot study to establish the methodology and a clinical validation study to evaluate its performance. In the pilot study, we established the MQ-PCR and analyzed its performance regarding limits of detection, reproducibility, specificity, and efficiency. In the clinical validation study, we obtained 211 sputum and/or bronchoalveolar lavage fluid (BALF) samples and detected pathogens by MQ-PCR. The MQ-PCR time was 3 h from sample collection to complete pathogen detection.The limit of detection was 1000 copies/ml, and the maximum efficiency was95%. When cutoffs of ≥10This study demonstrates that the new MQ-PCR assay is time-saving, more effective and sensitive, and brings us closer to mainstream adoption of quantitative molecular detection of bacteria.

Objectives: This study aimed to assess the current incidence and risk factors for polymyxin B-associated acute kidney injury (AKI) in Chinese hospitals for a more effective clinical use for polymyxin B. Methods: This multicenter, retrospective cohort study included patients from 14 Chinese teaching hospitals who received polymyxin B therapy. Univariate and multivariate logistic regression models were used to determine the factors associated with polymyxin B-associated incident AKI. Furthermore, a multivariate logistic regression model was used to identify the independent risk factors for AKI. Results: A total of 251 patients were included in the analysis. The overall incidence of AKI was 33.5%. A multivariate logistic regression model identified the loading dose (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.01–3.38; P = 0.0491) and the use of two or more nephrotoxic drugs (HR, 3.56; 95% CI, 1.55–8.18; P = 0.0029) as independent risk factors for the occurrence of AKI. Meanwhile, the estimated glomerular filtration rate had a protective effect (HR, 0.99; 95% CI, 0.98–0.99; P = 0.0006) on the occurrence of AKI. The daily dose, cumulative dose, and treatment duration of polymyxin B did not affect the occurrence of AKI. Conclusions: The use of polymyxin B loading doses and the combined use of multiple nephrotoxic drugs are independent risk factors for polymyxin B-associated AKI. The severity of AKI may be higher in patients with elevated baseline creatinine levels.

Xiudi Han,1 Liang Chen,2 Hui Li,3 Fei Zhou,3 Xiqian Xing,4 Chunxiao Zhang,5 Lijun Suo,6 Jinxiang Wang,7 Xuedong Liu,1 Bin Cao3 On behalf of the CAP-China network1Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital Group, Qingdao City, Shandong Province, 266011, People’s Republic of China; 2Department of Infectious Diseases, Nanjing Lishui People’s Hospital, Nanjing City, Jiangsu Province, 211213, People’s Republic of China; 3National Clinical Research Center of Respiratory Diseases, Center for Respiratory Diseases, China-Japan Friendship Hospital; Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, 100020, People’s Republic of China; 4Department of Respiratory Medicine, Yan’an Hospital Affiliated to Kunming Medical University, Kunming City, Yunnan Province, 652199, People’s Republic of China; 5Department of Respiratory Medicine, Beijing Huimin Hospital, Beijing, 100054, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, Zibo Municipal Hospital, Zibo City, Shandong Province, 255000, People’s Republic of China; 7Department of Respiratory Medicine, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, People’s Republic of ChinaCorrespondence: Xuedong Liu, Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital Group, Jiaozhou Road, Qingdao City, Shandong Province, 266011, People’s Republic of China, Tel +86-18661678256, Fax +86-532-82789055, Email xuedongliu@263.net Bin Cao, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Yinghuayuan East Street, Chao-Yang District, Beijing, 100020, People’s Republic of China, Tel +86-13911318339, Fax +86-10-84206264, Email caobin_ben@163.comBackground: Limited data were available about the burden of cardiovascular events (CVEs) during hospitalization in elderly patients with community-acquired pneumonia (CAP). The aim was to assess the incidence, characteristics, predictive factors and outcomes of CVEs in elderly patients with CAP during hospitalization.Methods: This study was a multicenter, retrospective research on hospitalized elderly patients with CAP from the CAP-China network. Predictive factors for the occurrence of CVEs and 30-day mortality were identified by multivariable logistic regression analysis.Results: Of 2941 hospitalized elderly patients, 402 (13.7%) developed CVEs during hospitalization with the median age of 81 years old. Compared with non-CVEs patients, patients with CVEs were older, more comorbidities, and higher disease severity; use of glucocorticoids, leukocytosis, azotemia, hyponatremia, multilobe infiltration and pleural effusion were more common; the rate of clinical failure (CF), in-hospital mortality and 30-day mortality were higher, which significantly increased with age and the number of CVEs (p < 0.001). Multivariable logistic regression showed previous history of congestive heart failure (odds ratio [OR], 6.16; 95% CI, 4.14– 9.18), CF (OR, 4.69; 95% CI, 3.392– 6.48), previous history of ischemic heart disease (OR, 2.22; 95% CI, 1.61– 3.07), use of glucocorticoids (OR, 2.0; 95% CI, 1.39– 2.89), aspiration (OR, 1.88; 95% CI, 1.26– 2.81), pleural effusion (OR, 1.66; 95% CI, 1.25– 2.20), multilobe infiltration (OR, 1.50; 95% CI, 1.15– 1.96), age (OR, 1.05; 95% CI, 1.04– 1.07), and blood urea nitrogen (OR, 1.03; 95% CI, 1.01– 1.06) were independent predictors for the occurrence of CVEs, while level of blood sodium (OR, 0.98; 95% CI, 0.97– 0.99) was protective factor. Renal failure (OR, 9.46; 95% CI, 4.17– 21.48), respiratory failure (OR, 9.32; 95% CI, 5.91– 14.71), sepsis/septic shock (OR, 7.87; 95% CI, 3.58– 17.31), new cerebrovascular diseases (OR, 5.94; 95% CI, 1.78– 19.87), new heart failure (OR, 4.04; 95% CI, 1.15– 14.14), new arrhythmia (OR, 2.38; 95% CI, 1.11– 5.14), aspiration (OR, 1.95; 95% CI, 1.09– 3.50), CURB-65 (OR, 1.57; 95% CI, 1.21– 2.02), and white blood cell count (OR, 1.05; 95% CI, 1.02– 1.09) were independent predictors for 30-day mortality in elderly patients with CAP, while lymphocyte count (OR, 0.63; 95% CI, 0.46– 0.87) was protective factor.Conclusion: Patients with CVEs had heavier disease burden and worse prognosis. Early recognition of risk factors is meaningful to strengthen the management in elderly patients with CAP.Keywords: community-acquired pneumonia, cardiovascular events, prognostic factors, elderly

Little is known about Subgenomic RNA (sgRNA) dynamics in patients with Coronavirus diseases 2019 (COVID-19). We collected 147 throat swabs, 74 gut swabs and 46 plasma samples from 117 COVID-19 patients recruited in the LOTUS China trial (ChiCTR2000029308) and compared E and orf7a sgRNA load in patients with different illness duration, outcome, and comorbidities. Both sgRNAs were detected in all the three types of samples, with longest duration of 25, 13, and 17 days for E sgRNA, and 32, 28, and 17 days for orf7a sgRNA in throat, gut, and plasma, respectively. A total of 95% (57/60) of patients had no E sgRNA detected after 10 days post treatment, though 86% of them were still E RNA positive. High correlation on titer was observed between sgRNA encoding E and orf7a gene. sgRNA showed similar variation in the standard care and Lopinavir-Ritonavir group. Patients with diabetes and heart diseases showed higher pharyngeal E sgRNA at the first day (P ​= ​0.016 and 0.013, respectively) but no difference at five days after treatment, compared with patients without such commodities. Patients with hypertension and cerebrovascular diseases showed no difference in the pharyngeal sgRNA levels at both one and five days after treatment, compared with patients without these two commodities. E sgRNA levels in the initial infection showed no correlation with the serum antibody against spike, nucleoprotein, and receptor binding domains at ten days later. sgRNA lasted a long period in COVID-19 patients and might have little effect on humoral response.

To investigate the regulatory effect and mechanism of vitamin D on the local renin-angiotensin system at maternal-fetal interface in the pathological process of preeclampsia (PE).The mRNA and protein expression of renin in decidua of normal pregnancy and PE placentas was determined by RT-PCR and Western blot. Normal decidual tissues were treated with active and inactive vitamin D for 48 hThe expression of renin in PE decidua was significantly higher than that of normal control at transcriptional and translational levels (The expression of renin in placental decidua is up-regulated in patients with PE, and the activation of local renin-angiotensin system at the maternal-fetal interface may be involved in the pathogenesis of PE. Vitamin D can specifically down-regulate renin expression in human decidual gland epithelial cells by competing with the PKA pathway. Vitamin D supplementation may have potential value for clinical intervention of PE.

Background Whether procalcitonin (PCT) or C-reactive protein (CRP) combined with certain clinical characteristics can better distinguish viral from bacterial infections remains unclear. The aim of the study was to assess the ability of PCT or CRP combined with clinical characteristics to distinguish between viral and bacterial infections in hospitalized non-intensive care unit (ICU) adults with lower respiratory tract infection (LRTI). Methods This was a post-hoc analysis of a randomized clinical trial previously conducted among LRTI patients. The ability of PCT, CRP and PCT or CRP combined with clinical symptoms to discriminate between viral and bacterial infection were assessed by portraying receiver operating characteristic (ROC) curves among patients with only a viral or a typical bacterial infection. Results In total, 209 infected patients (viral 69%, bacterial 31%) were included in the study. When using CRP or PCT to discriminate between viral and bacterial LRTI, the optimal cut-off points were 22 mg/L and 0.18 ng/mL, respectively. When the optimal cut-off for CRP (≤ 22 mg/L) or PCT (≤ 0.18 ng/mL) combined with rhinorrhea was used to discriminate viral from bacterial LRTI, the AUCs were 0.81 (95% CI: 0.75–0.87) and 0.80 (95% CI: 0.74–0.86), which was statistically significantly better than when CRP or PCT used alone (p p = 0.011 and p = 0.021). Conclusions Either CRP ≤ 22 mg/L or PCT ≤ 0.18 ng/mL combined with rhinorrhea could help distinguish viral from bacterial infections in hospitalized non-ICU adults with LRTI. When rhinorrhea was combined together, discrimination ability was further improved.

Background The full range of long-term health consequences of COVID-19 in patients who are discharged from hospital is largely unclear. The aim of our study was to comprehensively compare consequences between 6 months and 12 months after symptom onset among hospital survivors with COVID-19. Methods We undertook an ambidirectional cohort study of COVID-19 survivors who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. At 6-month and 12-month follow-up visit, survivors were interviewed with questionnaires on symptoms and health-related quality of life (HRQoL), and received a physical examination, a 6-min walking test, and laboratory tests. They were required to report their health-care use after discharge and work status at the 12-month visit. Survivors who had completed pulmonary function tests or had lung radiographic abnormality at 6 months were given the corresponding tests at 12 months. Non-COVID-19 participants (controls) matched for age, sex, and comorbidities were interviewed and completed questionnaires to assess prevalent symptoms and HRQoL. The primary outcomes were symptoms, modified British Medical Research Council (mMRC) score, HRQoL, and distance walked in 6 min (6MWD). Multivariable adjusted logistic regression models were used to evaluate the risk factors of 12-month outcomes. Findings 1276 COVID-19 survivors completed both visits. The median age of patients was 59·0 years (IQR 49·0–67·0) and 681 (53%) were men. The median follow-up time was 185·0 days (IQR 175·0–198·0) for the 6-month visit and 349·0 days (337·0–361·0) for the 12-month visit after symptom onset. The proportion of patients with at least one sequelae symptom decreased from 68% (831/1227) at 6 months to 49% (620/1272) at 12 months (p

The coronavirus disease 2019 (COVID‐19) pandemic is ongoing and many drugs have been studied in clinical trials. From a pathophysiological perspective, anti‐viral drugs may be more effective in the early stage while immunomodulators may be more effective in severe patients in later stages of infection. While drugs such as lopinavir‐ritonavir, hydroxychloroquine and azithromycin have proved to be ineffective in randomized controlled trials, corticosteroids, neutralizing monoclonal antibodies, remdesivir, tocilizumab and baricitinib have been reported to benefit certain groups of patients with COVID‐19. In this review, we will present the key clinical evidence and progress in promising COVID‐19 therapeutics, as well as summarize the experience and lessons learned from the development of the current therapeutics.

Pneumonia causes a significant burden of disease worldwide. Although all populations are at risk of pneumonia, those at extremes of age and those with immunosuppressive disorders, underlying respiratory disease, and critical illness are particularly vulnerable. Although clinical practice guidelines addressing the management and treatment of pneumonia exist, few of the supporting studies focus on the crucial contributions of the host in pneumonia pathogenesis and recovery. Such essential considerations include the host risk factors that lead to susceptibility to lung infections; biomarkers reflecting the host response and the means to pursue host-directed pneumonia therapy; systemic effects of pneumonia on the host; and long-term health outcomes after pneumonia. To address these gaps, the Pneumonia Working Group of the Assembly on Pulmonary Infection and Tuberculosis led a workshop held at the American Thoracic Society meeting in May 2018 with overarching objectives to foster attention, stimulate research, and promote funding for short-term and long-term investigations into the host contributions to pneumonia. The workshop involved participants from various disciplines with expertise in lung infection, pneumonia, sepsis, immunocompromised patients, translational biology, data science, genomics, systems biology, and clinical trials. This workshop report summarizes the presentations and discussions and important recommendations for future clinical pneumonia studies. These recommendations include establishing consensus disease and outcome definitions, improved phenotyping, development of clinical study networks, standardized data and biospecimen collection and protocols, and development of innovative trial designs.

Summary Background Inappropriate antibiotic use greatly accelerates antimicrobial resistance. The appropriateness of antibiotic prescriptions is well evaluated, using big observational data, in some high-income countries, whereas the evidence of this appropriateness is scarce in China. We aimed to assess the appropriateness of antibiotic prescriptions in ambulatory care settings in China to inform future antimicrobial stewardship. Methods We used data from the Beijing Data Center for Rational Use of Drugs, which was a national database designed for monitoring rationality of drug use. 139 hospitals that uploaded diagnosis and prescription information were included from 28 provincial-level regions of mainland China. Outpatient prescriptions were classified as appropriate, potentially appropriate, inappropriate, or not linked to any diagnosis for antibiotic use by following a published classification scheme. Antibiotic prescription rates for various diagnosis categories and proportions of inappropriate antibiotic prescriptions for different subgroups were estimated. Antibiotic prescribing patterns and proportions of individual antibiotics prescribed for different diagnosis categories were analysed and reported. Findings Between Oct 1, 2014, and April 30, 2018, 18 848 864 (10·9%) of 172 704 117 outpatient visits ended with antibiotic prescriptions. For conditions for which antibiotic use was appropriate, potentially appropriate, and inappropriate, 42·2%, 30·6%, and 7·6% of visits were associated with antibiotic prescriptions, respectively. Of all 18 848 864 antibiotic prescriptions, 9 689 937 (51·4%) were inappropriate, 5 354 224 (28·4%) were potentially appropriate, 2 893 102 (15·3%) were appropriate, and 911 601 (4·8%) could not be linked to any diagnosis. A total of 23 266 494 individual antibiotics were prescribed, of which 18 620 086 (80·0%) were broad-spectrum and the top four most prescribed antibiotics were third-generation cephalosporins (5 056 058 [21·7%]), second-generation cephalosporins (3 823 410 [16·4%]), macrolides (3 554 348 [15·3%]), and fluoroquinolones (3 285 765 [14·1%]). Interpretation Inappropriate antibiotic prescribing was highly prevalent nationwide in China. Over half of the antibiotic prescriptions were inappropriate in secondary-level and tertiary-level hospitals, suggesting an urgent need for outpatient antibiotic stewardship aimed at optimising antibiotic prescribing to achieve the goals set in China's 2016 national action plan to contain antimicrobial resistance. Funding The National Natural Science Foundation of China.

Objective This study investigated changes of plasma cytokines and aimed to build a dynamic nomogram for diabetic macular edema (DME) in type 2 diabetes mellitus (T2DM). Methods In a pilot cohort, plasma samples were selected from 9 T2DM patients and 9 DME patients to screen for cytokine differences. The screening cytokines were then validated by enzyme-linked immunoassay in a cohort, which contained 100 DME (DME group) and 100 T2DM patients without DME (T2DM group). A dynamic nomogram for predicting DME was developed, based on the plasma cytokines. Results In the pilot cohort, 11 plasma cytokines were significantly increased in the DME group. In the validation cohort, platelet-derived growth factor (PDGF)-BB, tissue inhibitors of metalloproteinase (TIMP)-1, angiopoietin (ANG-1), and vascular endothelial cell growth factor receptor (VEGFR)-2 were confirmed to be significantly elevated in the DME group. The dynamic nomogram demonstrated good calibration and discrimination, with an area under the receiver operating characteristic curve (AUC) of 0.88. In the test set, sensitivity, specificity, and AUC were 73.3%, 80.0%, and 0.84, respectively. Conclusion Plasma cytokines were closely associated with DME. A novel dynamic monogram including ANG-1, PDGF-BB, TIMP-1, and VEGFR2 was a novel tool for predicting DME.

By the beginning of November 2020, almost 50 million cases of coronavirus disease 2019 (COVID-19) had been reported worldwide, with over 35 million people defined as recovering from the disease [1]. According to the Centers for Disease Control and Prevention (CDC), updated on 10 September 2020, there were no confirmed reports to date of a person being reinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the initial infection [2]. In the absence of solid human data, Rhesus monkeys were challenged 28 days after first SARS-CoV-2 infection with same virus strain and did not establish reinfection [3]. However, on 21 September 2020 the European CDC issued a report addressing SARS-CoV-2 reinfection, citing several case studies and calling for a case definition [4]. Defining reinfection, relapsed infection and recurrence of positive (re-positive) nucleic acid detection might have clinical and epidemiological implications for treatment and infection control measures, respectively. In this commentary, we aimed to provide such definitions, including a microbiologically confirmed definition of reinfection, as well as clinical and epidemiological ones. Reinfections are observed with many respiratory viruses, including human coronaviruses. Reinfections with respiratory viruses may be due to weak or waning initial immune response (e.g. respiratory syncytial virus), reinfection with another genotype/species (e.g. rhinoviruses) or the high variability of the viruses (e.g. influenza virus). Following the SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) epidemics, specific antibodies were detected in survivors up to 24 and 34 months, respectively. The negligible risk of a second exposure to these viruses has not allowed for a clinical determination as to the immunity against reinfection [5,6]. For endemic coronaviruses, immunity was shown to be temporary, lasting from several months to a few years, and reinfection has been reported after experimental and natural infection [7]. It is assumed that the immune response following a natural viral infection is incomplete and reinfections are possible [8]. Currently tested COVID-19 vaccine platforms such as RNA and viral vector vaccines are designed to elicit antibody and T-cell responses, whereas subunit vaccines are more restricted to antibody responses, precluding the effect of active effector T cells and memory T cells. However, it is one of the subunit vaccine candidates that shows so far the highest neutralizing antibody titres and it is still unclear if a future COVID-19 vaccine will provide sustained and sterilizing immunity.

Pancreatic ductal adenocarcinoma (PDA) is aggressive cancer characterized by rapid progression, metastatic recurrence, and highly resistant to treatment. PDA cells exhibit aerobic glycolysis, or the Warburg effect, which reduces the flux of pyruvate into mitochondria. As a result, more glycolytic metabolites are shunted to pathways for the production of building blocks (e.g., ribose) and reducing agents (e.g., NADPH) for biosynthesis that are necessary for cell proliferation. In addition, PDA cells are highly addicted to glutamine for both maintaining biosynthetic pathways and achieving redox balance. Mitochondrial uncoupling facilitates proton influx across the mitochondrial inner membrane without generating ATP, leading to a futile cycle that consumes glucose metabolites and glutamine. We synthesized a new mitochondrial uncoupler MB1-47 and tested its effect on cancer cell metabolism and the anticancer activity in pancreatic cancer cell models and murine tumor transplantation models. MB1-47 uncouples mitochondria in the pancreatic cancer cells, resulting in: (1) the acceleration of pyruvate oxidation and TCA turnover; (2) increases in AMP/ATP and ADP/AMP ratios; and (3) a decrease in the synthesis rate of nucleotides and sugar nucleotides. Moreover, MB1-47 arrests cell cycle at G0-G1 phase, reduces clonogenicity, and inhibits cell growth of murine and human pancreatic cancer cells. In vivo studies showed that MB1-47 inhibits tumor growth in murine tumor transplantation models, and inhibits the hepatic metastasis when tumor cells were transplanted intrasplenically. Our results provide proof of concept for a potentially new strategy of treating PDA, and a novel prototype experimental drug for future studies and development.

Aims This study aimed to investigate changes of plasma cytokines and to develop machine learning classifiers for predicting non-proliferative diabetic retinopathy among type 2 diabetes mellitus patients. Results There were 12 plasma cytokines significantly higher in the non-proliferative diabetic retinopathy group in the pilot cohort. The validation cohort showed that angiopoietin 1, platelet-derived growth factor-BB, tissue inhibitors of metalloproteinase 2 and vascular endothelial growth factor receptor 2 were significantly higher in the NPDR group. Machine learning algorithms using the random forest yielded the best performance, with sensitivity of 92.3%, specificity of 75%, PPV of 82.8%, NPV of 88.2% and area under the curve of 0.84. Conclusions Plasma angiopoietin 1, platelet-derived growth factor-BB, and vascular endothelial growth factor receptor 2 were associated with presence of non-proliferative diabetic retinopathy and may be good biomarkers that play important roles in pathophysiology of diabetic retinopathy. Materials and methods In pilot cohort, 60 plasma cytokines were simultaneously measured. In validation cohort, angiopoietin 1, CXC-chemokine ligand 16, platelet-derived growth factor-BB, tissue inhibitors of metalloproteinase 1, tissue inhibitors of metalloproteinase 2, and vascular endothelial growth factor receptor 2 were validated using ELISA kits. Machine learning algorithms were developed to build a prediction model for non-proliferative diabetic retinopathy.

BACKGROUND Community-acquired pneumonia (CAP) is one of the major global health problems worldwide. However, the epidemiological information of CAP is limited in China. This study aimed to estimate the incidence rate of CAP and describe the epidemiologic characteristics among the Chinese population. METHODS We conducted a retrospective analysis of CAP incidence using the Chinese Urban Basic Medical Insurance database of 23 provinces in 2016, which covered 427.52 million urban beneficiaries of all age groups in Mainland China. CAP episodes were identified using a diagnosis-term-derived algorithm, and multiple CAP records of one single person within 90 continuous days were considered as one single episode. The incidence rates were calculated and described by sex, age, region, and season. RESULTS A total of 1.42 million patients were identified as having one or more CAP episodes, and finally a sum of 1.48 million CAP episodes were counted. The overall incidence of CAP was 7.13 (95% CI: 6.11-8.15) per 1000 person-years, in males 7.32 (95% CI: 6.28-8.35) and females 6.93 (95% CI: 5.92-7.94) per 1000 person-years, respectively. The incidence varied by age with a U-shaped curve peaking in children aged

Handling the infections by extensively drug-resistant Pseudomonas aeruginosa (XDRPA) strains is challenging due to their complicated antibiotic resistance mechanisms in immunosuppressed patients with pulmonary diseases (e.g., cystic fibrosis, chronic obstructive pulmonary disease, and lung transplant), ventilator-associated pneumonia, and bloodstream infections. The current study suggested the potentiality of the ceftazidime-avibactam-imipenem combination against XDRPA with bla AmpC overexpression or mutation, decreased OprD porin, and/or upregulated efflux pumps.

We characterized the first NDM-5 and MCR-8.2 co-harboring ST656

T cell lymphopenia was a significant characteristic of severe influenza infection and it was associated with the functional changes of T cells. It is necessary to clarify the T cells characteristics of kinetic changes and their correlation with disease severity.In a cohort of hospitalized influenza patients with varying degrees of severity, we characterized lymphocyte populations using flow cytometry.The numbers of cycling (Ki67The increased numbers of cycling memory (Ki67

We aimed to establish an easy-to-use screening questionnaire with risk factors and suspected symptoms of COPD for primary health care settings.Based on a nationwide epidemiological study of pulmonary health among adults in mainland China (China Pulmonary Health, CPH study) between 2012 and 2015, participants ≥40 years who completed the questionnaire and spirometry tests were recruited and randomly divided into development set and validation set by the ratio of 2:1. Parameters including sex, age, BMI, residence, education, smoking status, smoking pack-years, biomass exposure, parental history of respiratory diseases and daily respiratory symptoms were initially selected for the development of scoring system. Receiver operating characteristic (ROC) curve, area under curve (AUC), positive and negative predictive values were calculated in development set and validation set.After random split by 2:1 ratio, 22443 individuals were assigned to development set and 11221 to validation set. Ten variables were significantly associated with COPD independently in development set after a stepwise selection by multivariable logistic model and used to develop scoring system. The scoring system yielded good discrimination, as measured by AUC of 0.7737, and in the validation set, the AUC was 0.7711. When applying a cutoff point of ≥16, the sensitivity in development set was 0.69 (0.67 - 0.71); specificity 0.72 (0.71 - 0.73), PPV 0.25 (0.24 - 0.26) and NPV 0.94 (0.94 - 0.95).We developed and validated a comprehensive screening questionnaire, COPD-CPHS, with good discrimination. The score system still needs to be validated by large cohort in the future.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2022.2042504 .

Background The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection. Methods In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms. Findings We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection. Interpretation SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time.

The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m6A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m6A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m6A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.

Influenza A virus still represents a noticeable epidemic risk to international public health at present, despite the extensive use of vaccines and anti-viral drugs. In the fight against pathogens, the immune defence lines consisting of diverse lymphocytes are indispensable for humans. However, the role of virus infection of lymphocytes and subsequent abnormal immune cell death remains to be explored. Different T cell subpopulations have distinct characterizations and functions, and we reveal the high heterogeneity of susceptibility to viral infection and biological responses such as apoptosis in various CD4

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 is profoundly influencing the global healthcare system and people's daily lives. The high resource consumption of coronavirus disease 2019 (COVID-19) is resulting in insufficient surveillance of coinfection or resurgence of other critical respiratory epidemics, which is of public concern. To facilitate evaluation of the current coinfection situation, a microfluidic system (MAPnavi) is developed for the rapid (40 min) and sensitive diagnosis of multiple respiratory viruses from swab samples in a fully sealed and automated manner, in which a nested-recombinase polymerase amplification and the CRISPR-based amplification system is first proposed to ensure the sensitivity and specificity. This novel system has a remarkably low limit of detection (50-200 copies mL

Pigeon paramyxovirus type 1 (PPMV-1), an antigenic variant of avian paramyxovirus type 1 (APMV-1), mainly infects pigeons. PPMV-1 genotype VI is the dominant genotype infecting pigeons in China. Human infection of avian paramyxovirus was rarely reported, and usually developed mild symptoms, such as conjunctivitis. We detected PPMV-1 in the lower respiratory sample from a fatal case with severe pneumonia; this patient aged 64 years presented cough, fever, and haemoptysis for 8 days and was admitted to hospital on Dec 26, 2020. He developed acute respiratory distress syndrome and sepsis in the following days and died of multiple organ failure on Jan 7, 2021. Sputum and blood culture reported multidrug-resistant

Objective Maisonneuve fracture is a special type of injury which are rare in clinic. The manifestation of such fractures is variable. The aim of this study is to describe the pathoanatomical features of typical Maisonneuve fracture on the basis of radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI), and intraoperative exploration findings, and to investigate the injury mechanism of this variety. Methods The data of 41 patients with Maisonneuve fracture from April 2014 to September 2019 were retrospectively analyzed. There were 32 males and nine females, the average age was 37.9 years (range, 18 to 61 years), the fractures occurred on the left side in 20 patients and on the right side in 21 patients. The cause of injuries were traffic accident in five patients, sprain injury in 20 patients, and falling injury from height in 16 patients. All patients underwent posteroanterior and lateral X-ray examinations of the ankle and calf. CT scan of the ankle was performed in 38 patients, including three-dimensional reconstruction in 33 patients. MRI examination of the ankle and calf was performed in 28 and five patients, respectively. Forty patients were treated with open reduction and internal fixation. The features of proximal fibular fracture, injuries of the medial and posterior structures of the ankle, injuries of the anterior inferior tibiofibular ligament and the interosseous membrane were recorded and analyzed. Results Forty-one patients had proximal one-third fractures of the fibula including six patients with fracture involving the fibular neck, 30 with proximal one-third fractures of the fibular shaft, and five with proximal-medial one-third junction fracture of the fibular shaft. Thirty-five patients (35/41, 85.37%) with injury of posterior structures, 34 patients had posterior malleolar fracture (34/41, 82.93%), and one patient had posterior inferior tibiofibular ligament rupture (1/41, 2.44%). There were 20 patients with type I fracture, four patients with type II fracture, and 10 patients with type III fracture according to the Haraguchi classification of posterior malleolus fracture. The fracture of the medial malleolus was in 30 patients (30/41, 73.17%), rupture of the deltoid ligament was in 10 patients (10/41, 24.39%), and medial structures intact were in one patient (1/41, 2.44%). All 41 patients had injury of the anterior inferior tibiofibular ligament. Conclusions Maisonneuve fracture is characterized by fractures of the proximal fibula and the complete rupture of the anterior inferior tibiofibular ligament. Pronation-external rotation is the main injury mechanism. The manifestations of typical Maisonneuve fracture including that the fibular fracture located in proximal one-third diaphysis and the fracture line was from anterosuperior to posteroinferior.

Few studies were conducted to assess safety and efficacy of continuous antiviral therapy administrated from preconception. In the present study, 136 eligible women with chronic HBV infection were recruited, and assigned to active chronic hepatitis B (CHB) (Group A, B or C) or chronic HBV carrier (Group D). Antiviral therapy was administrated in preconception (Group A), in early (Group B) or late pregnancy (Group C and Group D). Immunoprophylaxis was administrated to all infants. Mothers’ HBV status and ALT were assessed at delivery and 7 months postpartum. Offspring’s HBV status was examined at 7 months old. Group A women showed low HBV DNA level and normal ALT throughout pregnancy. All women at delivery had an HBV DNA level of less than 106 IU/ml, but the proportion of patients with lower HBV DNA level in Group A was higher than any of other three groups (P

In December 2019, a novel coronavirus was identified in Wuhan City, Hubei Province, China and later the disease was named coronavirus disease 2019 (COVID-19). On March 11, 2020, the World Health Organization (WHO) officially announced that COVID-19 had reached global pandemic status. This article summarized the understanding of the etiology, pathogenesis, epidemiology, clinical characteristics, diagnosis, treatment, rehabilitation, and prevention and control measures of COVID-19 based on the available data and anti-epidemic experience in China.

Hereditary spherocytosis (HS) is often misdiagnosed due to lack of specific diagnostic methods. Our study summarized clinical characteristics and described the diagnostic workflow for mild and moderate HS in Chinese individuals, using data from 20 adults, 8 of whom presented a familial history for HS. We used scanning electron microscopy (SEM) to diagnose HS. We observed reduced eosin maleimide fluorescence activity (5.50 mean channel fluorescence (MCF) units) in the 10 cases of HS, which differed significantly when compared with 10 normal adults (15.50 units), iron deficiency anemia (15.50 MCF units), and megaloblastic anemia (12.00 MCF units) values (P

Influenza virus infection poses a heavy burden on global health and economics. With the advancement in viral pathogen detection methods, the role of virus infection in community-acquired pneumonia has been increasingly recognized. The disease spectrum of influenza ranges from asymptomatic infection to severe or even fatal illness. Progress has been made in recent years to identify risk factors including lymphopenia and hypoxia for influenza mortality. Immunopathology plays an important role in influenza pathogenesis. The disturbed homeostasis after virus infection consists of both an excessive inflammatory phase and an immune suppression phase, collectively described as viral sepsis. Multiple antiviral therapies have been tested and some were advanced to late-phase clinical trials, including polymerase inhibitors, hemagglutinin inhibitors, host-acting antivirals, monoclonal antibodies, and adjunctive immunomodulatory therapies. Combination therapies have been shown to increase antiviral efficacy and genetic resistance barrier. In this review, we summarized the recent advances in our understanding of the disease pathogenesis, as well as the progress in antiviral therapy development. We also pointed out current key knowledge gaps in influenza research. Hopefully, experience gained from seasonal influenza research will prepare us for the next influenza pandemic and emerging respiratory pathogens.

Background The competing endogenous RNA (ceRNA) networks of long non-coding RNAs (lncRNAs) and microRNAs (miRs) have aroused wide concerns. The study aims to investigate the roles of lncRNA DANCR-associated ceRNA network in the growth and behaviors of colon cancer (CC) cells. Methods Differentially expressed lncRNAs between CC and paracancerous tissues were analyzed using microarrays and RT-qPCR. Follow-up studies were conducted to evaluate the correlation between DANCR expression and prognosis of CC patients. Loss-of-functions of DANCR were performed to identify its role in the malignant behaviors of CC cells. Sub-cellular localization of DANCR and the potential targets of DANCR were predicted and validated. Cells with inhibited DANCR were implanted into nude mice to evaluate the tumor formation and metastasis in vivo. Results DANCR was highly-expressed in CC tissues and cell lines, and higher levels of DANCR were linked with worse prognosis and less survival time of CC patients. Silencing of DANCR inhibited proliferation, viability, metastasis and resistance to death of CC cells. DANCR was found to be sub-localized in cytoplasmic matrix and to mediate murine double minute 2 (MDM2) expression through sponging miR-518a-3p in CC cells, during which the Smad2/3 signaling was activated. Likewise, silencing of DANCR in CC cells inhibited tumor formation and metastasis in vivo. Conclusion This study provided evidence that silencing of DANCR might inhibit the growth and metastasis of CC cells through the DANCR/miR-518a-3p/MDM2 ceRNA network and the defect of Smad2/3 while activation of the p53 signaling pathways. This study may offer novel insights in CC treatment.

Background Respiratory syncytial virus (RSV) is an important cause of medically attended acute respiratory illnesses in older adults but awareness of the relevance of RSV in older people remains lower than that of influenza, which exhibits similar clinical characteristics to those of RSV. Objectives This study was performed to assess the clinical significance of RSV in respiratory samples from hospitalized adults. Methods Characteristics and outcomes in adults (≥18 years) hospitalized for RSV infection (n = 51) were compared with a cohort hospitalized for influenza A infection (n = 279) in a single‐center retrospective cohort study in Beijing, China. Results Respiratory syncytial virus patients were slightly older, with no significant differences in underlying chronic conditions. Lower respiratory tract infection and cardiovascular complications were more frequent (P

The 2019 novel coronavirus (2019-nCoV) is an emerging pathogen and is threatening the global health. Strikingly, more than 28 000 cases and 550 deaths have been reported within two months from disease emergence. Armed with experience from previous epidemics in the last two decades, clinicians, scientists, officials, and citizens in China are all contributing to the prevention of further 2019-nCoV transmission. Efficient preliminary work has enabled us to understand the basic characteristics of 2019-nCoV, but there are still many unanswered questions. It is too early now to judge our performance in this outbreak. Continuous and strengthened efforts should be made not only during the epidemic, but also afterwards in order to prepare for any incoming challenges.

Summary Background Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. Methods INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28–32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , numbers NCT01799993 and NCT00805168 . Findings Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28–32 (odds ratio 0·841, 95% CI 0·554–1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). Interpretation Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. Funding Bayer AG.

Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days.The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

BACKGROUND AND AIM No predictive model for lymph node metastasis (LNM) of superficial esophagogastric junction (EGJ) cancer exists. This study aimed to evaluate incidence, identify risk factors, and develop a predictive nomogram for LNM in patients with superficial EGJ cancers. METHODS Data were extracted from the Surveillance, Epidemiology, and End Results database for model development and internal validation. Another data set was obtained from two hospitals for external validation. A nomogram was developed based on independent risk factors that resulted from a multivariate logistic regression analysis. Internal and external validations were performed to assess the performance of nomogram model by receiver operating characteristic and calibration plot. RESULTS Prevalence of LNM was 11.41% for intramucosal cancer and increased to 26.50% for submucosal cancer. On the multivariate analysis, large tumor size (odds ratio [OR] = 1.42; P

Background Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death in China with a reported prevalence of 8.2% people aged ≥40 years. It is recommended that Chinese physicians follow Global Initiative for Chronic Obstructive Lung Disease (GOLD) and national guidelines, yet many patients with COPD in China remain undiagnosed. Furthermore, missed diagnoses and a lack of standardized diagnosis and treatment remain significant problems. The situation is further complicated by a lack of large-scale, long-term, prospective studies of real-world outcomes, including exacerbation rates, disease severity, efficacy of treatment, and compliance of COPD patients in China. Methods/design The REALizing and improving management of stable COPD in China (REAL) study is a 52-week multi-center, prospective, observational trial. REAL aims to recruit approximately 5000 outpatients aged ≥40 years with a clinical diagnosis of COPD per GOLD 2016. Outpatients will be consecutively recruited from approximately 50 tertiary and secondary hospitals randomly selected across six geographic regions to provide a representative population. Patients will receive conventional medical care as determined by their treating physicians. The primary objective is to evaluate COPD patient outcomes including lung function, health status, exacerbations, hospitalization rate, and dyspnea following 1 year of current clinical practice. Secondary objectives are to assess disease severity, treatment patterns, adherence to medication, and associated risk factors. Data will be collected at two study visits, at patients’ usual care visits, and by telephone interview every 3 months. Discussion Knowledge of COPD among physicians in China is poor. The REAL study will provide reliable information on COPD management, outcomes, and risk factors that may help improve the standard of care in China. Patient recruitment began on 30 June 2017 and the estimated primary completion date is 30 July 2019. Trial registration ClinicalTrials.gov identifier: NCT03131362. Registered on 20 March 2017.

To identify the association between the kinetics of viral load and clinical outcome in severe coronavirus disease 2019 (COVID-19) patients, a retrospective study was performed by involved 188 hospitalized severe COVID-19 patients in the LOTUS China trial. Among the collected 578 paired throat swab (TS) and anal swab (AS) samples, viral RNA was detected in 193 (33.4%) TS and 121 (20.9%) AS. A higher viral RNA load was found in TS than that of AS, with means of 1.0 × 106 and 2.3 × 105 copies/ml, respectively. In non-survivors, the viral RNA in AS was detected earlier than that in survivors (median of 14 days vs 19 days, P = 0.007). The positivity and viral load in AS were higher in non-survivors than that of survivors at week 2 post symptom onset (P = 0.006). A high initial viral load in AS was associated with death (OR 1.368, 95% CI 1.076–1.741, P = 0.011), admission to the intensive care unit (OR 1.237, 95% CI 1.001–1.528, P = 0.049) and need for invasive mechanical ventilation (OR 1.340, 95% CI 1.076–1.669, P = 0.009). Our findings indicated viral replication in extrapulmonary sites should be monitored intensively during antiviral therapy.

The impacts of the current COVID-19 pandemic on maternal and foetal health are enormous and of serious concern. However, the influence of SARS-CoV-2 infection at early-to-mid gestation on maternal and foetal health remains unclear.Here, we report the follow-up study of a pregnant woman of her whole infective course of SARS-CoV-2, from asymptomatic infection at gestational week 20 to mild and then severe illness state, and finally cured at Week 24. Following caesarean section due to incomplete uterine rupture at Week 28, histological examinations on the placenta and foetal tissues as well as single-cell RNA sequencing (scRNA-seq) for the placenta were performed.Compared with the gestational age-matched control placentas, the placenta from this COVID-19 case exhibited more syncytial knots and lowered expression of syncytiotrophoblast-related genes. The scRNA-seq analysis demonstrated impaired trophoblast differentiation, activation of antiviral and inflammatory CD8 T cells, as well as the tight association of increased inflammatory responses in the placenta with complement over-activation in macrophages. In addition, levels of several inflammatory factors increased in the placenta and foetal blood.These findings illustrate a systematic cellular and molecular signature of placental insufficiency and immune activation at the maternal-foetal interface that may be attributed to SARS-CoV-2 infection at the midgestation stage, which highly suggests the extensive care for maternal and foetal outcomes in pregnant women suffering from COVID-19.

Severe Community Acquired Pneumonia (SCAP) challenges public health globally. Considerable improvements in molecular pathogen testing emerged in the last few years. Our prospective study combinedly used traditional culture, antigen tests, PCR and mNGS in SCAP pathogen identification with clinical outcomes. From June 2018 to December 2019, we conducted a multi-centre prospective study in 17 hospitals of SCAP patients within 48 hours of emergency room stay or hospitalization in China. All clinical data were uploaded into an online database. Blood, urine and respiratory specimens were collected for routine culture, antigen detection, PCR and mNGS as designed appropriately. Aetiology confirmation was made by the local attending physician group and scientific committee according to microbiological results, clinical features, and response to the treatment. Two hundred seventy-five patients were included for final analysis. Combined detection methods made identification rate up to 74.2% (222/299), while 14.4% (43/299) when only using routine cultures and 40.8% (122/299) when not using mNGS. Influenza virus (23.2%, 46/198), S. pneumoniae (19.6%, 39/198), Enterobacteriaceae (14.6%, 29/198), Legionella pneumophila (12.6%, 25/198), Mycoplasma pneumoniae (11.1%, 22/198) were the top five common pathogens. The in-hospital mortality of patients with pathogen identified and unidentified was 21.7% (43/198) and 25.9% (20/77), respectively. In conclusion, early combined detection increased the pathogen identification rate and possibly benefitted survival. Influenza virus, S. pneumoniae, Enterobacteriaceae was the leading cause of SCAP in China, and there was a clear seasonal distribution pattern of influenza viruses. Physicians should be aware of the emergence of uncommon pathogens, including Chlamydia Psittaci and Leptospira.

Objective To investigate the effectiveness and safety of transparent cap‐assisted endoscopy in removing foreign bodies in the esophagus. Methods Patients with foreign body lodged in the esophagus who received a transparent cap‐assisted or conventional endoscopy between October 2004 and July 2018 were retrospectively enrolled. Propensity score matching was performed. The success rate of the endoscopic procedure, procedure time, clearness of endoscopic view and adverse event rate were compared between the two groups. Results Of the 838 patients who had a foreign body lodged in the esophagus, 728 (86.9%) underwent endoscopic intervention. After matched by prospensity score, 224 patients each received either transparent cap‐assisted endoscopy or conventional endoscopy. No difference was noted between the two groups in terms of the success rate (100% vs 99.1%, P = 0.499). Transparent cap‐assisted endoscopy was associated with shorter procedure time for removing jujube pits ([4.24 ± 2.81] min vs [7.62 ± 8.15] min, P = 0.001), fish bones ([2.99 ± 2.15] min vs [6.49 ± 6.54] min, P

BackgroundImported malaria has been an important challenge for China. Fatality rates from malaria increased in China, particularly in Henan Province, primarily due to malpractice and misdiagnoses in healthcare institutions, and the level of imported malaria. This study aims to investigate the relationship between the state of diagnosis and subsequent complications among imported malaria cases at healthcare institutions, based on malaria surveillance data in Henan Province from 2012 to 2017.MethodsA retrospective descriptive analysis was performed using data from the Centre for Disease Control and Prevention, Zhengzhou City, the capital of Henan Province. A decision tree method was exploited to provide valuable insight into the correlation between imported malaria cases and healthcare institutions.ResultsFrom 2012 to 2017, there were 371 imported malaria cases, mostly in males aged between 20 and 50 years, including 319Plasmodium falciparumcases. First visits of 32.3%, 19.9% and 15.9% malaria cases for treatment were to provincial, municipal and county healthcare institutions, respectively. The time interval between onset and initial diagnosis of 284 cases (76.5%) and the time interval between initial diagnosis and final diagnosis of 197 cases (53.1%) was no more than 72 h. An apparent trend was found that there were notably fewer patients misdiagnosed at first visit to healthcare institutions of a higher administrative level; 12.5% of cases were misdiagnosed in provincial healthcare institutions compared to 98.2% in private clinics, leading to fewer complications at healthcare institutions of higher administrative level due to correct initial diagnosis. In the tree model, the rank of healthcare facilities for initial diagnosis, and number of days between onset and initial diagnosis, made a major contribution to the classification of initial diagnosis, which subsequently became the most significant factor influencing complications developed in the second tree model. The classification accuracy were 82.2 and 74.1%, respectively for the tree models of initial diagnosis and complications developed.ConclusionInadequate seeking medical care by imported malaria patients, and insufficient capacity to diagnose malaria by healthcare institutions of lower administrative level were identified as major factors influencing complications of imported malaria cases in Henan Province. The lack of connection between uncommon imported malaria cases and superior medical resources was found to be the crucial challenge. A web-based system combined with WeChat to target imported malaria cases was proposed to cope with the challenge.

BackgroundStriking similarities have been found between coronavirus disease 2019 (COVID-19) and anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-related dermatomyositis, implying a shared autoinflammatory aberrance. Herein, we aim to investigate whether the anti-MDA5 Ab is present in COVID-19 and correlates with the severity and adverse outcome of COVID-19 patients.Methods and FindingsWe retrospectively recruited 274 adult inpatients with COVID-19 in this study, including 48, 164, and 62 cases of deaths, severe, and non-severe patients respectively. The anti-MDA5 Ab was determined by ELISA and verified by Western Blotting, which indicated that the positive rate of anti-MDA5 Ab in COVID-19 patients was 48.2% (132/274). The clinical and laboratory features, as well as outcomes between patients with positive and negative anti-MDA5 Ab were compared and we found that the anti-MDA5 Ab positive patients tended to represent severe disease (88.6% vs 66.9%, Pvs 8.22 ± 6.64, P=0.030) and the positive rate was also higher than that in the survivals (23.5% vs 12.0%, P=0.012). Regarding severe COVID-19 patients, we found that high titer of anti-MDA5 Ab (≥10.0 U/mL) was more prevalent in the non-survivals (31.2% vs 14.0%, P=0.006). Moreover, a dynamic analysis of anti-MDA5 Ab was conducted at different time-points of COVID-19, which revealed that early profiling of anti-MDA5 Ab could distinguish severe patients from those with non-severe ones.ConclusionsAnti-MDA5 Ab was prevalent in the COVID-19 patients and high titer of this antibody is correlated with severe disease and unfavorable outcomes.