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Introduction Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury. Objectives In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs). Methods Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155−/− and miR-155wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart. Results When both miR-155−/− and miR-155wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart. Conclusion In this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.

Background In COVID-19 patients, information regarding superinfection, antimicrobial assessment, and the value of metagenomic sequencing (MS) could help develop antimicrobial stewardship. Method This retrospective study analyzed 323 laboratory-confirmed COVID-19 patients for co-infection rate and antimicrobial usage in the Shanghai Public Health Clinical Center (SPHCC) from January 23rd to March 14th 2020. The microbiota composition was also investigated in patients with critically severe COVID-19. Results The total population co-infection rate was 17/323 (5.3%) and 0/229 (0), 4/78 (5.1%), and 13/16 (81.3%) for the mild, severe, and critically severe subgroups, respectively. Proven fungal infection was significantly associated with a higher mortality rate (p = 0.029). In critically severe patients, the rate of antimicrobials and carbapenem usage were 16/16 (100%) and 13/16 (81.3%), respectively, in which the preemptive and empiric antimicrobial days accounted for 51.6% and 30.1%, respectively. Targeted therapy only accounted for 18.3%. MS was implemented to detect non-COVID-19 virus co-existence and the semi-quantitative surveillance of bacteremia, with clear clinical benefit seen in cases with MS-based precision antimicrobial management. Airway microbiome analysis suggested that the microbiota compositions in critically severe COVID-19 patients were likely due to intubation and mechanical ventilation. Conclusions In the SPHCC cohort, we observed a non-negligible rate of super-infection, especially for the critically ill COVID-19 patients. Fungal co-infection requires intensive attention due to the high risk of mortality, and the clinical benefit of MS in guiding antimicrobial management warrants further investigation.

Background: Cardiac hypertrophy is an important prepathology of, and will ultimately lead to, heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. This study aims to elucidate the effects and mechanisms of HINT1 (histidine triad nucleotide–binding protein 1) in cardiac hypertrophy and heart failure. Methods: HINT1 was downregulated in human hypertrophic heart samples compared with nonhypertrophic samples by mass spectrometry analysis. Hint1 knockout mice were challenged with transverse aortic constriction surgery. Cardiac-specific overexpression of HINT1 mice by intravenous injection of adeno-associated virus 9 (AAV9)–encoding Hint1 under the cTnT (cardiac troponin T) promoter were subjected to transverse aortic construction. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against Hoxa5 (homeobox A5) was administrated to investigate whether the effects of HINT1 on cardiac hypertrophy were HOXA5-dependent. RNA sequencing analysis was performed to recapitulate possible changes in transcriptome profile.Coimmunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5. Results: The reduction of HINT1 expression was observed in the hearts of hypertrophic patients and pressure overloaded–induced hypertrophic mice, respectively. In Hint1 -deficient mice, cardiac hypertrophy deteriorated after transverse aortic construction. Conversely, cardiac-specific overexpression of HINT1 alleviated cardiac hypertrophy and dysfunction. Unbiased profiler polymerase chain reaction array showed HOXA5 is 1 target for HINT1, and the cardioprotective role of HINT1 was abolished by HOXA5 knockdown in vivo. Hoxa5 was identified to affect hypertrophy through the TGF-β (transforming growth factor β) signal pathway. Mechanically, HINT1 inhibited PKCβ1 (protein kinase C β type 1) membrane translocation and phosphorylation via direct interaction, attenuating the MEK/ERK/YY1 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/yin yang 1) signal pathway, downregulating HOXA5 expression, and eventually attenuating cardiac hypertrophy. Conclusions: HINT1 protects against cardiac hypertrophy through suppressing HOXA5 expression. These findings indicate that HINT1 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene ( Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β-β-catenin-Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.

To control the spread of COVID-19, rigorous restrictions have been implemented in China, resulting in a great reduction in pollutant emissions. In this study, we evaluated the air quality in the Yangtze River Delta during the COVID-19 lockdown period using satellite and ground-based data, including particle matter (PM), trace gases, water-soluble ions (WSIs) and black carbon (BC). We found that the impacts of lockdown policy on air quality cannot be accurately assessed using MODIS aerosol optical depth (AOD) data, whereas the tropospheric nitrogen dioxide (NO2) vertical column density can well reflect the influences of these restrictions on human activities. Compared to the pre-COVID period, the PM2.5, PM10, NO2, carbon monoxide (CO), BC and WSIs during the lockdown in Suzhou were observed to decrease by 37.2%, 38.3%, 64.5%, 26.1%, 53.3% and 58.6%, respectively, while the sulfur dioxide (SO2) and ozone (O3) increased by 1.5% and 104.7%. The WSIs ranked in the order of NO3− > NH4+ > SO42- > Cl− > Ca2+ > K+ > Mg2+ > Na+ during the lockdown period. By comparisons with the ion concentrations during the pre-COVID period, we found that the ions NO3−, NH4+, SO42−, Cl−, Ca2+, K+ and Na+ decreased by 66.3%, 48.8%, 52.9%, 56.9%, 57.9% and 76.3%, respectively, during the lockdown, in contrast to Mg2+, which increased by 30.2%. The lockdown policy was found to have great impacts on the diurnal variations of Cl−, SO42−, Na+ and Ca2+., Graphical absract Image, graphical abstract

The aim of this study is to assess the efficacy of multiple treatments, especially hydroxychloroquine, used in different disease stages of coronavirus disease 2019 (COVID-19). All consecutive patients with COVID-19 admitted to Shanghai Public Health Clinical Center (Shanghai, China) between January 20, 2020, and April 30, 2020, were enrolled, and their clinical data were retrospectively collected. Binary logistic regression was used to screen the factors associated with disease aggravation, and multivariable analyses with the Cox proportional hazards model were used to estimate the effects of prognostic factors on the improvement time and PCR conversion days in throat swabs and stool swabs. A total of 616 patients, including 50 (8.11%) severe and 18 (2.92%) critical patients, were enrolled in our retrospective cohort study. The early use of hydroxychloroquine was a protective factor associated with disease aggravation (95% CI: 0.040-0.575, p = 0.006). Clinical improvement by 20 days was significantly different between patients with hydroxychloroquine used early and those with hydroxychloroquine not used (p = 0.016, 95% CI: 1.052-1.647). The median time to clinical improvement was 6 days in the hydroxychloroquine used early group, compared with 9 days in the without hydroxychloroquine used group and 8 days in the with hydroxychloroquine not used early group (p < 0.001). Hydroxychloroquine used early was associated with earlier PCR conversion in both throat swabs (HR = 1.558, p = 0.001) and stool swabs (HR = 1.400, p = 0.028). The use of hydroxychloroquine at an early stage is a potential therapeutic strategy for treating patients before irreversible severe respiratory complications occur. The early use of hydroxychloroquine decreased the improvement time and the duration of COVID-19 detection in throat and stool swabs.

Highlights • T-cell responses in term of frequency and intensity are clearly distinct between mild illness and severe pneumonia patients. • High levels of IFNᵧ production observed with all CoV proteins support that SARS-CoV-2 elicit potent memory immune responses. • Recent history of COVID-19 did not hamper viral memory T-cell pool against common viruses., Adaptive Immune responses generated by SARS-CoV-2 virus in convalescent patients according to disease severity remain poorly characterized. To this end, we designed a prospective study (NCT04365322) that included 60 COVID-19 convalescent patients (1-month post infection) in two cohorts respectively entitled mild illness and severe pneumonia. The monitoring of peripheral immune responses was performed using IFNᵧ ELISpot assay. The serology index of each patient was investigated at the same time. Patients with severe pneumonia were older and had more comorbidities than patients with mild illness. T-cell responses in term of frequency and intensity were clearly distinct between mild illness and severe pneumonia patients. Furthermore, our results demonstrated that recent history of COVID-19 did not hamper viral memory T-cell pool against common viruses (Cytomegalovirus, Epstein-Barr-virus and Flu-virus). The presence of potent adaptive immunity even in patients who underwent severe pneumonia sustain the rationale for the development of protective therapeutics against SARS-CoV-2.

Background The objectives of present study were to examine the level of disagreement between self-reported and objective measurement of sensitization to common inhalant allergens, and to explore the potential risk factors that might contribute to this discrepancy. Methods A total of 215 children were enrolled from pediatric clinics at a tertiary pediatric center in Beijing, China. A survey questionnaires regarding self-perceived sensitization was completed by participants’ parents/caregiver, meanwhile, skin prick testing(SPT) was performed as objective assessment of sensitization. Extent of agreement between self-reported versus SPT-measured sensitization to individual allergen was calculated using Cohen’s kappa (κ) coefficient. Multivariable regression analyses were used to determine the factors associated with discrepancy between self-reported and objective measurement of sensitization. Results 119(55.3%) patients have reported to be sensitized to at least one of inhalant allergen, whereas 167(77.7%) patients had a positive skin testing response. Agreement between self-perceived and actual aeroallergen sensitization was moderate for mites(κ = 0.518) and grass pollen mix(κ = 0.451), moreover, fair agreement was observed for mold(κ = 0.316) and cockroach(κ = 0.297), respectively. There was a least agreement between perceived and actual sensitization observed for pet dander, with a kappa coefficient of 0.005. Subjects’ age, atopy history, ownership of pet may increase the risk of disagreement, moreover, background factors of informant, like: age, education level, and the relationship with enrolled subjects, were linked to the incidence of disagreement between self-reported sensitization in comparison with SPT results. Conclusion Questionnaire-based self-assessment is easy way to collect clinical information on allergen sensitization; however, the accuracy of questionnaire-derived information is more likely to be influenced by respondent’s background factors. The information from the questionnaire report is considered to be more reliable when in combination with objective assessment of sensitization, including blood IgE testing and SPT.

Purpose Our study aimed to construct a visible model to evaluate the risk of infectious complications after gastrectomy. Methods The clinical data of 856 patients who underwent gastrectomy were used to retrieve medical records. Univariate and multivariate analyses were performed to correlate early postoperative NLR and operative variables with postoperative complications, and the construction of the nomogram was based on logistic regression. The concordance index and receiver operating characteristic curves were used to evaluate the model performance. Results The postoperative infectious and noninfectious complication rates after gastrectomy were 18.5% (158/856 cases) and 12.3% (105/856 cases) respectively. Postoperative NLR (within 24 h) independently predicted the development of postoperative infectious complication. Multivariate analysis revealed that age, diabetes, body mass index (BMI), intraoperative blood transfusion and postoperative NLR were independent risk factors. The nomogram model showed a good performance in terms of predicting infectious complications after gastrectomy (concordance index=0.718). Conclusion Age, diabetes, BMI, intraoperative blood transfusion and postoperative NLR were independent risk factors of postoperative infectious complications after gastrectomy, and a novel nomogram based on these results can be used to predict postoperative infection and has the advantages of simple application and easy access.

Acute coronary syndrome (ACS) is the main manifestation of cardiovascular disease and the primary cause of adult hospitalization in China. There is an urgent demand for novel biomarkers for the diagnosis of ACS. Although plasma cysteine-rich protein 61 (Cyr61) has been previously reported to be accurate for ACS diagnosis, the accuracy of exosomal Cyr61 in ACS diagnosis remains unknown. In the present study, the aim was to assess the potential of applying exosomal Cyr61 in ACS diagnosis and to explore the role of Cyr61 in vascular remodeling in vitro. The abundance of Cyr61 in plasma-derived exosomes from patients with unstable angina pectoris (UAP), acute myocardial infarction (AMI) patients in addition to those isolated from healthy individuals were detected using an ELISA kit. The association between exosomal Cyr61 levels and clinical characteristics of ACS patients was analyzed through χ2 test, Fisher's exact test and Student's t-test. Receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using exosomal Cyr61 as a biomarker of ACS diagnosis. Furthermore, independent predictors of the existence of ACS were investigated through a multivariate analysis. Subsequently, the role of Cyr61 on vascular remodeling was evaluated in vascular smooth muscle cells (VSMCs) upon oxidized low-density lipoprotein (ox-LDL) treatment by performing Cyr61 knockdown, Cell Counting Kit-8, flow cytometry and Transwell assays. Exosomal Cyr61 expression was found to be significantly elevated in patients with ACS compared with that in healthy individuals. In addition, exosomal Cyr61 levels were associated with sex, family history of ACS and glucose levels. ROC curve analyzes revealed that exosomal Cyr61 expression could be used to differentiate patients with UAP, AMI and ACS from healthy individuals. Furthermore, exosomal Cyr61 levels were independently correlated with the existence of ACS. In vitro, Cyr61 expression was demonstrated to be significantly increased in VSMCs after ox-LDL exposure in a concentration- and time-dependent manner. Functionally, the elevated cell viability and migration of VSMCs induced by ox-LDL were partially but significantly inhibited by Cyr61 knockdown. By contrast, knocking down Cyr61 expression significantly elevated the apoptosis rate of VSMCs compared with that in the ox-LDL-treated group. In conclusion, data from the present study suggest that Cyr61 serve a regulatory role in vascular remodeling in vitro, where exosomal Cyr61 levels may represent a promising biomarker for ACS diagnosis.

Background Hyperlactatemia is associated with a poor prognosis in cardiac surgery patients. This study explored the impact of target blood pressure management during cardiopulmonary bypass (CPB) on blood lactate levels after cardiac surgery. Methods Adult patients undergoing cardiac valve surgery between 20/1/2020 and 30/6/2020 at Shanghai Chest Hospital were enrolled. The patients were randomized into a low mean arterial pressure (L-MAP) group (target MAP between 50 and 60 mmHg) or a high mean arterial pressure (H-MAP) group (target MAP between 70 and 80 mmHg), n = 20 for each. Norepinephrine was titrated only during CPB to maintain MAP at the target level. Blood lactate levels in the two groups were detected before the operation (T0), at the end of CPB (T1), at the end of the operation (T2), 1 h after the operation (T3), 6 h after the operation (T4) and 24 h after the operation (T5). The primary outcome was the blood lactate level at the end of the operation (T2). The secondary outcomes included the blood lactate level at T1, T3, T4, and T5 and the dose of epinephrine and dopamine within 24 h after the operation, time to extubation, length of stay in the ICU, incidence of readmission within 30 days, and mortality within 1 year. Results Forty patents were enrolled and analyzed in the study. The lactate level in the H-MAP group was significantly lower than that in the L-MAP group at the end of the operation (3.1 [IQR 2.1, 5.0] vs. 2.1 [IQR 1.7, 2.9], P = 0.008) and at the end of CPB and 1 hour after surgery. The dose of epinephrine within 24 h after the operation, time to extubation and length of stay in the ICU in the L-MAP group were significantly higher than those in the H-MAP group. Conclusions Maintaining a relatively higher MAP during CPB deceased the blood lactate level at the end of surgery, reduced epinephrine consumption, and shortened the time to extubation and length of stay in the ICU after surgery. Trial registration This single-center, prospective, RCT has completed the registration of the Chinese Clinical Trial Center at 8/1/2020 with the registration number ChiCTR2000028941. It was conducted from 20/1/2020 to 30/6/2020 as a single, blinded trial in Shanghai Chest Hospital.

BackgroundSolitary intracranial hypothalamic mass occurs rarely. The etiological diagnosis of solitary hypothalamus lesion is challenging and often unachievable. Although previous studies indicated that lesions affecting the hypothalamus often cause significant metabolic disorders, few reports about the metabolic disturbances of patients with solitary hypothalamic mass have been reported.MethodTwenty-five patients with solitary hypothalamus lesions who had been evaluated and treated in Huashan Hospital from January 2010 to December 2020 were retrospectively enrolled. The clinical manifestations, radiological features, endocrine and metabolic disorders, and pathology were analyzed.ResultsThe male to female ratio was 5/20. The median age of onset was 22 (19, 35) years old. The most common initial symptom was polydipsia/polyuria (19/25, 76.0%) and amenorrhea (9/20, 45.0%). A high prevalence of hypopituitarism of different axes was found, with almost all no less than 80%. Central hypogonadism (21/22, 95.5%) and central diabetes insipidus (19/21, 90.5%) were the top two pituitary dysfunctions. Conclusive diagnoses were achieved by intracranial surgical biopsy/resection or stereotactic biopsy in 16 cases and by examining extracranial lesions in 3 cases. The pathological results were various, and the most common diagnoses were Langerhans cell histiocytosis (7/19) and hypothalamitis (5/19). The mean timespan from onset to diagnosis in the 19 cases was 34 ± 26 months. Metabolic evaluations revealed remarkable metabolic disorders, including hyperlipidemia (13/16, 81.3%), hyperglycemia (10/16, 62.5%), hyperuricemia (12/20, 60%), overweight/obesity (13/20, 65.0%), and hepatic adipose infiltration (10/13, 76.6%).ConclusionEither surgical or stereotactic biopsy will be a reliable and relatively safe procedure to help to confirm the pathological diagnosis of solitary hypothalamic mass. Metabolic disorders were severe in patients with solitary hypothalamic mass. The management of such cases should cover both the treatment of the primary disease, as well as the endocrine and metabolic disorders

Background Acromial anatomy has been found to be correlated with degenerative full-thickness rotator cuff tears in current studies. However, research on the relationship between acromial anatomy and articular-sided partial thickness of rotator cuff tears (PTRCTs) is still lacking. The purpose of this study was to evaluate whether these imaging graphic parameters exhibit any association between acromial anatomy and degenerative articular-sided PTRCTs. Methods Between January 2016 and December 2018, a total of 91 patients without a history of trauma underwent arthroscopy as an articular-sided PTRCT group. In the control group, with age- and sex-matched patients, we selected 91 consecutive outpatient patients who underwent shoulder magnetic resonance imaging (MRI) because of shoulder pain and an MRI diagnosis of only synovial hyperplasia and effusion. MRI was used to measure the acromial type, acromiohumeral distance (AHD), lateral acromial angle (LAA), acromion index (AI), and critical shoulder angle (CSA) by 2 independent observers. Results The acromion type, AHD and LAA showed no difference between degenerative articular-sided PTRCTs and controls (P = 0.532, 0.277, and 0.108, respectively). AI and CSA were significantly higher in degenerative articular-sided PTRCTs (P = 0.002 and 0.003, respectively). A good correlation was found between AI and CSA to measurement(Pearson correlation coefficient = 0.631). Conclusions Our study revealed that higher AI and CSA were found in degenerative articular-sided PTRCTs. Acromial anatomy with a large acromial extension was associated with the occurrence of degenerative articular-sided PTRCTs.

Sepsis-induced cardiac injury (SIC) is one of the most common complications in the intensive care unit (ICU) with high morbidity and mortality. Mitochondrial dysfunction is one of the main reasons for SIC, and Interleukin-13 (IL-13) is a master regulator of mitochondria biogenesis. The aim of the present study was to investigate the role of IL-13 in SIC and explore the underlying mechanism. It was found that reactive oxygen species (ROS) production and apoptosis were significantly increased in lipopolysaccharide (LPS)-stimulated primary cardiomyocytes, which was accompanied with obvious mitochondria dysfunction. The results of RNA-sequencing (RNA-seq), mitochondrial membrane potential, fatty acid uptake and oxidation rate suggested that treatment with IL-13 could restore the function and morphology of mitochondria, indicating that it played an important role in protecting septic cardiomyocytes. These findings demonstrated that IL-13 alleviated sepsis-induced cardiac inflammation and apoptosis by improving mitochondrial fatty acid uptake and oxidation, suggesting that IL-13 may prove to be a potential promising target for SIC treatment.

Background The coronavirus disease 2019 (COVID-19) has turned into a pandemic and resulted in huge death tolls and burdens. Integrating Chinese and western medicine has played an important role in the fight against the COVID-19 pandemic. Purpose We aimed to develop a living evidence-based guideline of integrating Chinese and western medicine for COVID-19. Study design Living evidence-based guideline. Methods This living guideline was developed using internationally recognized and accepted guideline standards, dynamically monitoring the release of new clinical evidence, and quickly updating the linked living systematic review, evidence summary tables, and recommendations. Modified Delphi method was used to reach consensus for all recommendations. The certainty of the evidence, resources, and other factors were fully considered, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the certainty of evidence and the strength of recommendations. Results The first version of this living guidance focuses on patients who are mild or moderate COVID-19. A multidisciplinary guideline development panel was established. Ten clinical questions were identified based on the status of evidence and a face-to-face experts' consensus. Finally, nine recommendations were reached consensus, and were formulated from systematic reviews of the benefits and harms, certainty of evidence, public accessibility, policy supports, feedback on proposed recommendations from multidisciplinary experts, and consensus meetings. Conclusion This guideline panel made nine recommendations, which covered five traditional Chinese medicine (TCM) prescription granules/decoction (MXXFJD, QFPD, XFBD, TJQW, and JWDY), three Chinese patent medicines (LHQW granules/capsule, JHQG granules, and LHQK granules), and one Chinese herbal injection (XBJ injection). Of them, two were strongly recommended (LHQW granules/capsule and QFPD decoction), and five were weakly recommended (MXXFJD decoction, XFBD decoction, JHQG granules, TJQW granules, and JWDY decoction) for the treatment of mild and moderate COVID-19; two were weakly recommended against (XBJ injection and LHQK granules) the treatment of mild and moderate COVID-19. The users of this living guideline are most likely to be clinicians, patients, governments, ministries, and health administrators.

The involvement of cardiomyopathy during sepsis means higher mortality and prolonged length of hospital stay. Many efforts have been made to alleviate the apoptosis of cardiomyocytes in sepsis. The huge potential of IL-13 in tissue repair has attracted increasing attention. In the present study, we used LPS-treated mice or primary cardiomyocytes as a sepsis model to explore the anti-apoptotic ability of IL-13. It was found that an increased level of exogenous IL-13 was beneficial to the recovery of heart function in sepsis, and this anti-apoptotic effect of IL-13 was probably through enhancing the phosphorylation of STAT3 Ser727. In addition, we identified that the heart protective effect of IL-13 was associated with type 2 innate lymphocytes (ILC2). All these findings may provide a potential promising treatment for sepsis-induced cardiomyopathy.

ContextHypothalamic obesity (HO) is a severe complication following craniopharyngioma, but studies regarding the sequelae in adult-onset patients with craniopharyngioma are sparse.ObjectiveThe objective of the study was to describe weight changes after surgical treatment in adult-onset craniopharyngioma patients and to analyze risk factors for postoperative weight gain and HO.Subjects and MethodA retrospective analysis was conducted of 120 adult-onset patients who underwent surgery for craniopharyngioma and follow-up at the institution of the authors between January 2018 and September 2020. Clinical characteristics, anthropometric data, image features, treatment modalities, and endocrine indices were collected. Multivariable logistic regression analysis was used to identify independent risk factors for postoperative weight gain and HO.ResultsForty-nine (40.8%) patients had clinically meaningful weight gain (≥5%) in a median follow-up time of 12.0 months (range 1.0–41.0 months) after surgery. The mean postoperative weight gain in this subgroup was 17.59 ± 12.28 (%). Weight gain continued in the first year following surgery. Patients with lower preoperative BMI [OR 0.78, 95% CI (0.67–0.90), P = 0.001] and the adamantinomatous subtype [OR 3.46, 95% CI (1.02–11.76), P = 0.047] were more likely to experience postoperative weight gain ≥5%. The prevalence of HO was 19.2% preoperatively and increased to 29.2% at last follow-up postoperatively. Only preoperative BMI [OR 2.51, 95% CI (1.64–3.85), P < 0.001] was identified as an independent risk factor for postoperative HO.ConclusionsHO is a common complication in patients with adult-onset craniopharyngioma. Patients with higher preoperative BMI had a greater risk for developing HO postoperatively.

Objective To evaluate the efficacy and safety of Hua Shi Bai Du Granule (Q-14) plus standard care compared with standard care alone in adults with coronavirus disease (COVID-19). Study Design A single-center, open-label, randomized controlled trial. Setting Wuhan Jinyintan Hospital, Wuhan, China, February 27 to March 27, 2020. Participants A total of 204 patients with laboratory-confirmed COVID-19 were randomized into the treatment group and control group, consisting of 102 patients in each group. Interventions In the treatment group, Q-14 was administered at 10 g (granules) twice daily for 14 days, plus standard care. In the control group, patients were provided standard care alone for 14 days. Main Outcome Measure The primary outcome was the conversion time for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral assay. Adverse events were analyzed in the safety population. Results Among the 204 patients, 195 were analyzed according to the intention-to-treat principle. A total of 149 patients (71 vs. 78 in the treatment and control groups, respectively) tested negative via the SARS-CoV-2 viral assay. There was no statistical significance in the conversion time between the treatment group and control group (Full analysis set: Median [interquartile range]: 10.00 [9.00-11.00] vs. 10.00 [9.00-11.00]; Mean rank: 67.92 vs. 81.44; P = 0.051). The recovery time for fever was shorter in the treatment group than in the control group. The disappearance rate of symptoms like cough, fatigue, and chest discomfort was significantly higher in the treatment group. In chest computed tomography (CT) examinations, the overall evaluation of chest CT examination after treatment compared with baseline showed that more patients improved in the treatment group. There were no significant differences in the other outcomes. Conclusion The combination of Q-14 and standard care for COVID-19 was useful for the improvement of symptoms (such as fever, cough, fatigue, and chest discomfort), but did not result in a significantly higher probability of negative conversion in the SARS-CoV-2 viral assay. No serious adverse events were observed. Trial Registration ChiCTR2000030288

Background and purpose Effective anti-fibrotic therapeutic solutions are unavailable so far. The heat shock protein 90 (HSP90) exerts deleterious effects in some fibrotic diseases. S-nitrosylation (SNO) of HSP90 affects its own function, however, little is known about its role in pathological stress. Here, we investigated the effect of SNO-HSP90 on cardiac fibrosis. Experimental approach SNO-HSP90 level was measured by biotin-switch. SNO sites were identified through mass spectrometry. S-nitrosylation site-mutated plasmids or adeno-associated virus, gene deletion and pharmacological antagonists were used to identify the contribution of SNO-HSP90 in myocardial fibrosis. Key results SNO-HSP90 level was positively correlated with fibrosis marker expression in hearts from patients and significantly higher in fibrotic hearts from spontaneously hypertensive rats and mice subjected to transverse aortic constriction, as well as in angiotensin II- or isoproterenol-treated neonatal rat cardiac fibroblasts. S-nitrosylated site of HSP90 at cysteine 589 was identified. Inhibition of SNO-HSP90 by Cys589 mutation reduced fibrosis in angiotensin II- or isoproterenol-treated cardiac fibroblasts. Administration of recombinant adeno-associated virus of Cys589 mutation improved heart function and alleviated fibrosis in transverse aortic constriction mice. Mechanismly, SNO-HSP90 stimulated transforming growth factor-β type II receptor (TGFβ RII) binding to HSP90 in response to fibrotic stimuli, subsequently increased phosphorylation and nuclear translocation of SMAD3. Additionally, inducible nitric oxide synthase (iNOS) deficiency or iNOS inhibitor, 1400W, reduced SNO-HSP90 level and the activation of TGFβ/SMAD3 signaling pathway. Conclusions and implications We demonstrate that genetic or pharmacological inhibition of SNO-HSP90 mitigates fibrosis through blocking TGFβ/SMAD3 signaling pathway, providing a potential therapy for cardiac remodeling.

Adiponectin is an adipocyte-secreted protein hormone and prevents the development of insulin resistance. The adiponectin-mediated activation of AMP-activated protein kinase (AMPK) pathway is essential for decreasing the expression of hepatic gluconeogenic enzymes and enhancing the hepatic effects of insulin. However, the resilience factors required to maintain adiponectin-mediated AMPK activation signaling in the liver remain unclear. Recent studies from our laboratory suggest that NgBR plays a previously unrecognized role in preserving AMPK activation. The loss of NgBR in the obesity liver impairs adiponectin-dependent gluconeogenesis and insulin sensitivity. NgBR hepatocyte-specific knockout (hepKO) mice resemble many features of prediabetes, such as moderately increased fasting blood glucose levels and insulin resistance, as well as facilitating the high-fat diet (HFD)-induced onset of T2D. NgBR was identified as a cell surface receptor for soluble Nogo-B (sNogo-B). Also, NgBR binds the farnesylated form of liver kinase B1 (LKB1-farn), a key regulator of AMPK. NgBR depletion in hepatocytes abolishes the localization of LKB1 in the plasma membrane and impairs AMPK activation, the critical signal for adiponectin-mediated insulin sensitivity. NgBR expression is decreased in the liver of diabetic mice. Similar changes also occur in diabetes patients. The NgBR transcript level is reduced in T2D obese patients’ liver compared to non-T2D obese and lean subjects. Additional in vitro studies show that NgBR deficiency in hepatocyte prevents AMPK activation induced by AdipoRon (an agonist of adiponectin receptor) and increases the gluconeogenesis. Our data suggest that NgBR is a potential resilience factor required for preserving adiponectin-mediated insulin sensitivity and preventing the onset of obesity-caused T2D, and disruption of the NgBR-dependent regulation system leads to impairing gluconeogenesis regulation and insulin sensitivity in the liver. Disclosure W. Hu: None. X. Wang: None. Q. Miao: None. Funding National Institutes of Health (R01DK112971)

Background Exercise is generally recognized as beneficial to prevent obesity; however, it is not clear which indicator can better reflect the benefits, especially in adolescents. The aim of this study was to describe the effects of exercise on body mass and fat indexes and to clarify the significance of different indexes in clinical use. Methods We conducted a prospective cohort study involving 1,941 freshmen from 2014, followed-up biennially until 2018. Various body mass and fat indexes, including weight, height, waist and hip circumference and body fat percentage (BFP), were measured. Physical activity and other variables were collected by questionnaire. All study participants were divided into two groups according to the frequency and intensity of exercise. Results Compared with the low frequency and intensity exercise group, the high frequency and intensity exercise group had a lower increase in BFP during the 4-year follow-up, and no significant differences were observed in the changes of other indexes between the groups. Even after adjusting, the high frequency and intensity exercise group still exhibited a higher likelihood of reducing BFP. Conclusions High frequency and intensity exercise provides benefits for reducing BFP. No other body mass or fat indexes showed any association. BFP could be a much more sensitive indicator to detect and control obesity in adolescents.

Background Metagenomic next-generation sequencing (mNGS) is widely applied in the etiological diagnosis of infectious diseases. However, the clinical practice of mNGS in infective endocarditis (IE) is relatively less studied. This research aimed to assess the etiological diagnostic value of valve mNGS in IE. Methods We retrospectively analyzed 49 IE patients who underwent cardiac valve surgery in Zhongshan Hospital, Fudan University, Shanghai from 1 June 2018 to 30 November 2020. Among these IE patients, 28 were culture positive and 21 were culture negative. The culture results of the culture-positive IE patients were set as gold standard to assess the sensitivity and specificity of valve mNGS in the etiological diagnosis of IE. We studied the positive detection rate of pathogens by valve mNGS among the culture-negative IE patients. During the same period, we also collected the resected valves of 8 patients with non-infective valvular diseases for mNGS as negative controls. Results The valve mNGS results of the culture-positive IE patients were the exact same as their culture results. Both the sensitivity and specificity of valve mNGS were 100%. The positive detection rate of pathogens by valve mNGS was 100% among the culture-negative IE patients. The stringent mapped reads number of genera (SMRNG), relative abundance of genera, stringent mapped reads number of species (SMRN), relative abundance of species, and coverage rate of valve mNGS results were significantly higher in culture-positive IE participants than in culture-negative IE participants. The valve mNGS results of the 8 participants with non-infective valvular diseases were all negative. Conclusions Valve mNGS is a promising technology for the etiological diagnosis of IE, especially culture-negative IE, and it may be used to guide precise antibiotic treatment after surgery.

The etiology for liver cancer has been clearly defined. Unfortunately, therapeutic approaches for liver cancer are rather limited, and liver cancer is insensitive to chemotherapy and radiotherapy. Traditional Chinese medicine (TCM) has become a promising strategy for cancer treatment as TCM elicits broad spectrum anticancer activity. In the present study, we evaluated the anticancer efficacy of AB4, an extract from the medical herb Pulsatilla chinensis (Bunge) Regel, in liver cancer in vitro and in vivo. We found that AB4 readily dose- and time-dependently inhibited liver cancer HepG2 and Huh-7 cell proliferation and colony formation. Western blot and flow cytometry analyses suggested that AB4 treatment induced liver cancer cell apoptosis. Moreover, these findings could be readily recaptured in vivo, in which the AB4 regimen resulted in tumor suppression and cancer cell apoptosis in xenograft tumor-bearing nude mice. Importantly, we noted that treatment with a Notch signaling inhibitor DAPT produced very similar anticancer efficacy in both HepG2 and Huh-7 cell lines, and administration of DAPT also efficiently suppressed HepG2 ×enograft outgrowth. To this end, we anticipated that AB4 and DAPT may act on the same signaling pathway, probably through inhibition of the Notch pathway. Indeed, we found decreased expression of Notch1 protein, as well as downstream targets Hes1 and Hey1, after AB4 treatment. Immunohistochemistry analysis further confirmed the suppression of Notch signaling in HepG2 ×enograft-bearing mice. Taken together, our study highlighted the anticancer efficacy of AB4 in liver cancer. We also provided preliminary data showing Notch as a therapeutic target of AB4. It would be interesting to investigate the anticancer efficacy of AB4 in other types of cancer with elevated Notch activity.

Background To evaluate whether a shorter time of lying supine without a pillow and fasting for solids and liquids (LSFSL) after a lumbar puncture (LP) is associated with a higher risk of post-lumbar puncture headache (PLPH) and post-lumbar puncture lower back pain (PLPBP) in a randomized, assessor-blinded, controlled trial. Methods Paediatric patients who underwent their first LP after hospital admission were randomly allocated to either the group with half an hour of LSFSL (0.5 h LSFSL) or 4 h of LSFSL (4 h LSFSL) immediately after LP. The primary outcome is PLPH after LP. The incidence of PLPH, PLPBP, and vomiting; vital signs (respiratory rate, heart rate, blood pressure); and other post-procedure conditions after LP were measured as the outcomes. The Non-inferiority test and Wilcoxon rank-sum test were used to analyse the outcome data. Results In total, 400 patients (201 in the 0.5-h LSFSL group and 199 in the 4-h LSFSL group) were included in this trial. Twelve (5.97%) of 201 patients experienced PLPH in the 0.5 h LSFSL group versus 13 (6.53%) of 199 patients in the 4 h LSFSL group (difference 0.56, 95% CI -4.18 to 5.31; p = 0·0108 for the non-inferiority test). Fourteen (6.97%) of 201 patients experienced PLPBP in the 0.5 h LSFSL group versus 17 (8.54%) of 199 patients in the 4 h LSFSL group (difference 1.57, 95% CI -3.66 to 6.82; p = 0.007 for the non-inferiority test). The changes in heart rate (HR), respiratory rate (RP) and systolic blood pressure (SBP) before and after the LP were not different between the 0.5-h LSFSL group and the 4-h LSFSL group. No other adverse events were reported. Conclusions Compared with 4 h of LSFSL after LP, 0.5 h of LSFSL was not associated with a higher risk of PLPH, PLPBP or other adverse events. In conclusion, 0.5 h of LSFSL is sufficient for children undergoing LP. Trial registration Clinical trial NCT02590718. The date of registration was 08/25/2015.

Malononitrile underwent α-arylation with 2-(2-bromophenyl)-4,5-diphenyl-1H-imidazole to give a subsequent nucleophilic addition and dehydration products of 5-amino-2,3-diphenylimidazo[2,1-a]isoquinoline-6-carbonitriles catalyzed by CuI/l-proline. Under the same reaction conditions, this novel procedure had a good chemoselectivity in cyanacetates for the efficient synthesis of 5-aminoimidazo[2,1-a]isoquinoline-6-carboxylate derivatives in good yields.

Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9−T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.

Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system.Objective: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design.Methods: Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra.Results: Longitudinal [C-11]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [C-11] PBR28 binding from baseline averaging 0.128 +/- 0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed.Conclusion: A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD.

Objective Craniopharyngiomas have traditionally been resected through the transcranial approaches (TCA). The endoscopic endonasal approach (EEA) has recently been developed as an alternative for surgeons, but controversy remains regarding which approach has better outcomes. We compared the endocrine and metabolic outcomes of TCA and EEA in patients who underwent primary resection of craniopharyngiomas. Methods A retrospective analysis was conducted of patients with craniopharyngioma who were treated by the department of endocrinology and metabolism at our institution between 2011 and 2015. Results Of 43 patients assessed, 26 underwent TCA and 17 underwent EEA. After surgery, 29.4% (5/17) of patients in the EEA group had normal anterior pituitary function, whereas none in the TCA group had complete anterior pituitary function. Higher prevalences of corticotropic deficiency (92.3% vs. 52.9%, P = 0.009), thyrotrophic deficiency (96.2% vs. 52.9%, P = 0.003), and hypogonadotropic hypogonadism (100% vs. 70.6%, P = 0.014) were found in the TCA group. The TCA group showed a trend toward having more patients with at least 3 anterior pituitary deficits (88.5% vs. 58.8%, P = 0.060). The mean body mass index at last follow-up tended to be lower in the EEA group (24.13 ± 3.16 kg/m2 vs. 26.79 ± 4.5 kg/m2, P = 0.079), and the preoperative body mass index was comparable between groups. Similar prevalences of overweight/obesity, hypertension, hyperglycemia, and metabolic syndrome were detected in the 2 groups. Moreover, no significant differences were observed in the rates of cerebrospinal fluid leakage and intracranial infection between the 2 groups. Conclusions EEA may provide the same gross total resection rate for craniopharyngioma as TCA while providing better protection of anterior pituitary function.

This paper presents a comprehensive review of high-level control techniques for upper-limb robotic training. It aims to compare and discuss the potentials of these different control algorithms, and specify future research direction. Included studies mainly come from selected papers in four review articles. To make selected studies complete and comprehensive, especially some recently-developed upper-limb robotic devices, a search was further conducted in IEEE Xplore, Google Scholar, Scopus and Web of Science using keywords (‘upper limb*’ or ‘upper body*’) and (‘rehabilitation*’ or ‘treatment*’) and (‘robot*’ or ‘device*’ or ‘exoskeleton*’). The search is limited to English-language articles published between January 2013 and December 2017. Valuable references in related publications were also screened. Comparative analysis shows that high-level interaction control strategies can be implemented in a range of methods, mainly including impedance/admittance based strategies, adaptive control techniques, and physiological signal control. Even though the potentials of existing interactive control strategies have been demonstrated, it is hard to identify the one leading to maximum encouragement from human users. However, it is reasonable to suggest that future studies should combine different control strategies to be application specific, and deliver appropriate robotic assistance based on physical disability levels of human users.

Background Metagenomic next-generation sequencing (mNGS) was suggested to potentially replace traditional microbiological methodology because of its comprehensiveness. However, clinical experience with application of the test is relatively limited. Methods From April 2017 to December 2017, 511 specimens were collected, and their retrospective diagnoses were classified into infectious disease (347 [67.9%]), noninfectious disease (119 [23.3%]), and unknown cases (45 [8.8%]). The diagnostic performance of pathogens was compared between mNGS and culture. The effect of antibiotic exposure on detection rate was also assessed. Results The sensitivity and specificity of mNGS for diagnosing infectious disease were 50.7% and 85.7%, respectively, and these values outperformed those of culture, especially for Mycobacterium tuberculosis (odds ratio [OR], 4 [95% confidence interval {CI}, 1.7-10.8]; P < .01), viruses (mNGS only; P < .01), anaerobes (OR, ∞ [95% CI, 1.71-∞]; P < .01) and fungi (OR, 4.0 [95% CI, 1.6-10.3]; P < .01). Importantly, for mNGS-positive cases where the conventional method was inconclusive, 43 (61%) cases led to diagnosis modification, and 41 (58%) cases were not covered by empirical antibiotics. For cases where viruses were identified, broad-spectrum antibiotics were commonly administered (14/27), and 10 of 27 of these cases were suspected to be inappropriate. Interestingly, the sensitivity of mNGS was superior to that of culture (52.5% vs 34.2%; P < .01) in cases with, but not without, antibiotic exposure. Conclusions mNGS could yield a higher sensitivity for pathogen identification and is less affected by prior antibiotic exposure, thereby emerging as a promising technology for detecting infectious diseases.

Cattail pollen (CP) and pine pollen (PP) are traditional Chinese medicine, which are used for bleeding blood and immunity enhancement activity respectively. Due to the economic benefits, they are occasionally adulterated with bee pollen. In this study, CP, PP and 6 kinds of bee pollen (dandelion pollen, sunflower pollen, lotus pollen, rhus pollen, buckwheat pollen, corn pollen) were collected and observed by the scanning electron microscope. And then, Fourier transform infrared (FT-IR) spectroscopy and two-dimensional correlation infrared (2D-IR) spectroscopy were used to identify and analyze these 8 kinds of pollens. It is found that PP and CP could be identified from bee pollen through the position, intensity and shape of saccharide and protein characteristic peaks in the FT-IR spectra. The FT-IR spectra of PP, CP and bee pollen are almost similar. 2D-IR spectra exhibited significant differences in automatic peak positions, especially in the range of 760–1400 cm−1. CP and PP have three consistently strong automatic peaks around 1150, 1204, and 1233 cm−1. The sequences of the absorption intensities of them all are 1204 cm−1 > 1233 cm−1 > 1150 cm−1. While CP has no obvious strong automatic peaks compared with PP in the range of 830–1140 cm−1. In conclusion, FT-IR and 2D-IR technology are the effective method for distinguish CP and PP from these 6 kinds of bee pollen.

Escherichia coli (E. coli) is the most common pathogen in both hospital and community settings, and is capable of causing infections that can lead to serious consequences. Quinolones, one of the most common antibiotics in clinical use, are effective weapons to treat E. coli infections. However, the resistance of E. coli to quinolones develops rapidly and spreads widely. Thus, it has become increasingly urgent to enhance the potency of quinolones against both drug-susceptible and drug-resistant E. coli. This review aims to summarize the recent developments of quinolone derivatives with potential activity against E. coli, and to discuss the structure-activity relationship for further rationale design of this kind of derivatives.