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Transplanting cell cultured brown adipocytes (BAs) represents a promising approach to prevent and treat obesity (OB) and its associated metabolic disorders, including type 2 diabetes mellitus (T2DM). However, transplanted BAs have a very low survival rate in vivo. The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells. There is a critical need for novel methods that can avoid cell death during cell preparation, transplantation, and in vivo. Here, we reported that preparing BAs as injectable microtissues could overcome the problem. We found that 3D culture promoted BA differentiation and UCP-1 expression, and the optimal initial cell aggregate size was 100 μm. The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved. Fabricated microtissues could survive in vivo for long term. They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet (HFD)-induced OB and T2DM mice. Transplanted microtissues impacted multiple organs, secreted protein factors, and influenced the secretion of endogenous adipokines. To our best knowledge, this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice. The proposal of transplanting fabricated BA microtissues, the microtissue fabrication method, and the demonstration of efficacy in T2DM mice are all new. Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability, storage, purity, safety, dosage, survival, and efficacy.

INTRODUCTION: Acute myocardial infarction (AMI) accounts for the majority of deaths caused by coronary artery disease (CAD). Early warning of AMI, especially for patients with stable coronary artery disease (sCAD), is urgently needed. Our previous study showed that alterations in the gut microbiota were correlated with CAD severity. OBJECTIVES: Herein, we tried to discover accurate and convenient biomarkers for AMI by combination of gut microbiota and fecal/blood/urinary metabolomics. METHODS: We recruited 190 volunteers including 93 sCAD patients, 49 AMI patients, and 48 subjects with normal coronary artery (NCA), and measured their blood biochemical parameters, 16S rRNA-based gut microbiota and NMR-based fecal/blood/urinary metabolites. We further selected 20 subjects from each group and analyzed their gut microbiota by whole-metagenome shotgun sequencing. RESULTS: Multi-omic analyses revealed that AMI patients exhibited specific changes in gut microbiota and serum/urinary/fecal metabolites as compared to subjects with sCAD or NCA. Fourteen bacterial genera and 30 metabolites (11 in feces, 10 in blood, 9 in urine) were closely related to AMI phenotypes and could accurately distinguish AMI patients from sCAD patients. Some species belonging to Alistipes, Streptococcus, Ruminococcus, Lactobacillus and Faecalibacterium were effective to distinguish AMI from sCAD and their predictive ability was confirmed in an independent cohort of CAD patients. We further selected nine indicators including 4 bacterial genera, 3 fecal and 2 urinary metabolites as a noninvasive biomarker set which can distinguish AMI from sCAD with an AUC of 0.932. CONCLUSION: Combination of gut microbiota and fecal/urinary metabolites provided a set of potential useful and noninvasive predictive biomarker for AMI from sCAD.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles.Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining.We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423GA (p.Leu141=) and c.839+5GA variants impaired the normal splicing of TBX6 messenger RNA, c.422TC (p.Leu141Pro) and c.745GA (p.Val249Met) led to decreased protein expression, c.10CT (p.Pro4Ser) and c.400GA (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356GA (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance.Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

Nucleocapsid (N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the formation of ribonucleoprotein (RNP) complex with the viral RNA. Here we reported the crystal structures of the N-terminal domain (NTD) and C-terminal domain (CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.

Background and aims Host–microbiota interactions involving metabolic pathways have been linked to the pathogenesis of atherosclerotic disease and type 2 diabetes. As stable coronary artery disease (SCAD) patients combined with type 2 diabetes have significantly increased risk for cardiac event, we focused on elucidating the role of microbiota affecting cardiometabolic disease development. Methods and results We used multi-omics analyses (metagenomics and metabolomics) of fecal and serum samples from a prospective cohort including stable coronary artery disease combined with diabetes mellitus (SCAD + T2DM, n = 38), SCAD (n = 71), and healthy control (HC, n = 55). We linked microbiome features to disease severity in a three-pronged association analysis and identified prognostic bacterial biomarkers. We identified that bacterial and metabolic signatures varied significantly between SCAD and SCAD + T2DM groups. SCAD + T2DM individuals were characterized by increased levels of aromatic amino acids and carbohydrates, which correlate with a gut microbiome with enriched biosynthetic potential. Our study also addressed how metformin may confound gut dysbiosis and increase the potential for nitrogen metabolism. In addition, we found that specific bacterial taxa Ruminococcus torques [HR: 2.363 (08–4.56), P = 0.03] was predictive of cardiac survival outcomes. Conclusion Overall, our study identified relationships between features of the gut microbiota (GM) and circulating metabolites, providing a new direction for future studies aiming to understand the host–GM interplay in atherosclerotic cardiovascular pathogenesis.

Highlights • Myocardial injury is common in critically ill COVID-19 patients. • COVID-19 patients with myocardial injury are more likely to develop adverse events and fatal outcomes during the hospitalization. • Myocardial injury and advanced age (≥75 yrs old) are independent risk factors for 28-day in-ICU mortality., Objective The aim of this study was to investigate the incidence, clinical presentation, cardiovascular (CV) complications and mortality risk of myocardial injury on admission in critically ill ICU inpatients with COVID-19. Design A single-center, retrospective, observational study. Setting A new-built ICU in Tongji hospital (Sino-French new city campus), Huazhong University of Science and Technology, Wuhan, China. Participants Seventy-seven critical COVID-19 patients. Interventions Patients were divided into myocardial injury group and non-myocardial injury group according to the on-admission levels of high-sensitivity cardiac troponin I. Measurements and Main Results Demographic data, clinical characteristics, laboratory tests, treatment and clinical outcome were evaluated stratified by the presence of myocardial injury on admission. Compared with non-myocardial injury patients, patients with myocardial injury were older (68.4 ± 10.1 vs. 62.1 ± 13.5 years; P=0.02), had higher prevalence of underlying CV disease (34.1% vs. 11.1%; P=0.02) and in-ICU CV complications (41.5% vs13.9%; P=0.008), higher Acute Physiology and Chronic Health Evaluation II scores (20.3 ± 7.3 vs 14.4 ± 7.4; P=0.001) and Sequential Organ Failure Assessment scores [7, interquartile range (IQR) 5-10 vs. 5,IQR 3-6; P

Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs.Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis.One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P.001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P.001).Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.

Receptor-interacting serine-threonine kinase 3 (RIP3) is a key mediator of programmed necrosis (necroptosis), and is implicated in cardiac remodeling and heart failure (HF) triggered by ischemia-reperfusion or oxidative stress in animal study. However, its value in the diagnosis and prognosis of human HF remains unclear.Plasma RIP3 concentrations in 91 HF patients and 95 healthy volunteers were detected by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic value of RIP3. Follow-up was conducted, and the composite endpoint was defined as all-cause mortality/readmission due to decompensated HF/worse New York Heart Association (NYHA) functional class. The relationship between RIP3 and patient outcome was examined.Plasma concentrations of RIP3 were significantly increased in patients with HF compared to controls (P 0.001). ROC analysis supported plasma RIP3 as a good diagnostic marker for HF, with an optimal cutoff value of 357 pg/ml (AUC = 0.934, sensitivity = 0.846, specificity = 0.905). Kaplan-Meier survival analysis also supported increased plasma RIP3 as a predictor for a poor prognosis in HF (cutoff value = 622.2 pg/ml, P 0.05). Additionally, binary logistic regression analysis revealed RIP3 to be an independent risk factor for all-cause mortality (OR = 11.844, P = 0.02), worse NYHA (OR = 9.013, P = 0.009) and a composite endpoint (OR = 5.065, P = 0.013).Plasma concentration of RIP3 is significantly elevated in HF and associated with the prognosis. Plasma RIP3 possibly constitutes a valuable diagnostic and prognostic biomarker for HF.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25% in Chinese and 16% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6(+/−)) resulted in 13% solitary kidneys. Remarkably, this incidence increased to 29% in a compound heterozygous model (Tbx6(mh/‒)) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.

Objectives Apatinib showed efficacy in non-small cell lung cancer (NSCLC). We conducted this phase II clinical study to assess the efficacy and safety of apatinib in combination with pemetrexed-platinum chemotherapy in non-squamous NSCLC (Clinical Trial Registration: ChiCTR1800015920). Materials and methods Patients received oral apatinib (250 mg/d) with intravenous pemetrexed (500 mg/m2)-platinum (carboplatin AUC = 5 or cisplatin 75 mg/m2) chemotherapy every 21 days for 6 treatment cycles, and then maintained with apatinib 250 mg/d until progressive disease or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included the progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results Twenty advanced and chemo-naive non-squamous NSCLC patients were enrolled and evaluated. The ORR and DCR was 80% and 100%, respectively. The median PFS (mPFS) and median OS (mOS) for total patients was 7.7 (95%CI: 3.1-12.3) and 20.1 (95%CI: not available, NA) months. In the TKI-pretreated and treatment-naive subgroup, the ORR was 90% vs.70%, and the mPFS was 8.9 (95%CI: 5.5-12.3) vs.5.7 (95%CI: 0.1-11.3) months, respectively (P = 0.433). The mPFS in the responders without central nervous system (CNS) metastasis at baseline was 10.0 (95%CI: 6.1-13.9) months, and it was 3.8 (95%CI: 0.9-6.7) months in those with presence of CNS metastasis at baseline (P = 0.041, HR = 0.283, 95%CI: 0.084-0.948). Toxicities mainly included grade I-II hand-foot syndrome, hypertension, proteinuria and myelosuppression. Conclusion Apatinib in combination with pemetrexed-platinum chemotherapy showed good efficacy and tolerable toxicity in advanced non-squamous NSCLC, especially for those who failed to prior TKI targeted therapies.

Background The long-term outcomes and optimal treatment strategy for patients with Takayasu arteritis (TA) and significant coronary stenosis remain unclear. We aim to investigate the prognosis of these patients according to the initial management strategy. Methods A total of 57 consecutive patients with TA and significant coronary stenosis were included between 2002 and 2018. The cohort was divided into the percutaneous coronary intervention (PCI) group (n = 18), coronary artery bypass graft (CABG) group (n = 10), and medical-therapy group (n = 29). The primary outcome was major adverse cardiac events (MACEs) defined as a composite of cardiac death, myocardial infarction, and coronary revascularization. Results Over a median follow-up of 4.5 (IQR 3.5–8.0) years, 24 (42.1%) patients experienced at least one MACE. The long-term rates of MACEs and re-revascularization were significantly higher in the PCI group than in the other 2 groups (HR 5.306, 95% CI 2.160–13.036, p Conclusions The initial baseline active disease is an important predictor of long-term outcome and subsequent revascularization in patients with TA and significant coronary artery stenosis. Also, PCI is independently associated with higher risk of MACEs and re-revascularization.

Biomass pretreatment is considered a key step in the 2nd generation biofuel production from lignocellulosic biomass. Research on conventional biomass pretreatment solvents has mainly been focused on carbohydrate conversion efficiency, while their hazardousness and/or carbon intensity were not comprehensively considered. Recent sustainability issues request further consideration for eco-friendly and sustainable alternatives like biomass-derived solvents. Carbohydrate and lignin-derived solvents have been proposed and investigated as green alternatives in many biomass processes. In this review, the applications of different types of biomass pretreatment solvents, including organic, ionic liquid, and deep eutectic solvents, are thoroughly discussed. The role of water as a co-solvent in these pretreatment processes is also reviewed. Finally, current research challenges and prospects of utilizing biomass-derived pretreatment solvents for pretreatment are discussed. Given bioethanol's market potential and increasing public awareness about environmental concerns, it will be a priority adopting sustainable and green biomass pretreatment solvents in biorefinery.

Often serving as the backbone for public transport, any serious metro incident will have a severe impact on passengers. In the aftermath of a disruption, establishing alternative transport means to carry the affected metro passengers, such as via substitute bus (SB) service, is critical. After a particular routing and scheduling plan of SB service is determined, the question is how to assemble the SB fleet, which has different options. Few studies have addressed the issue of designing the contract with a bus company for the provision of SB, including SB availability and service start time guarantee and pricing schemes under uncertain metro system recovery time. This paper attempts to fill this gap. We investigated both the bus company’s profit in providing the SB service and the metro company’s gain in passenger loss reduction after a metro disruption for setting up the SB service contract. Two payment schemes were considered: fixed payment and linear payment. The objective is to design the SB service contract, which defines the payment scheme and guaranteed SB service start time, from both the perspective of the metro company and that of the bus company to explore feasible solutions. In addition, the scenarios of collaborative decision between the bus and metro companies, nonlinear passenger demand drop, fleet size, arrivals of new passengers, and passengers waiting time are investigated.

To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10‒8), and exhibited vertebral malformations involving the lower part of the spine (T8–S5, P = 4.4 × 10‒3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10‒7), while intraspinal anomalies were uncommon (P = 7.0 × 10‒7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10‒15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.

During percutaneous coronary intervention procedures, generally only 2D X-ray images are provided. The consequent lack of depth perception makes it difficult for interventionists to visually estimate the pose of medical tools inside the vasculature, especially for novices. Although some automatic methods have been developed to aid interventionists, it is still a challenging task to obtain stable and accurate pose estimation. In this paper, we describe a learning-based framework for estimating the pose of the catheter distal section (CDS). The main innovation of this framework is the proposal of a coarse-to-fine fusion network (CFF-Net) which can achieve the shape and orientation estimation for the CDS.By adopting a two-step fusion, CFF-Net progressively solves the shape and orientation ambiguities. The first step is the early fusion where the 2D projection image fuses with the shape prior before input, which makes the estimated result own a specific catheter distal shape. The second step is the late fusion where CFF-Net fuse feature maps and the orientation data from Electromagnetic (EM) sensors to confirm the overall orientation of the CDS. Finally, the estimated pose in the EM space will be obtained after we combine the estimated shape and orientation from CFF-Net with the position information from the EM sensor.The effectiveness of CFF-Net has been verified in a simulated environment where RMSE of CFF-Net is 0.706 ± 0.121 mm. This approach was further transferred from simulation to reality using the real-world data, where RMSE of CFF-Net is 1.121 ± 0.124 mm and RMSE of the whole proposed framework is 1.577 ± 0.144 mm.In simulated and real-world experiments, our proposed approach has been proven to achieve high accuracy while ensuring real-time processing for estimating the pose of the CDS.

In March 2020, when coronavirus disease 2019 (COVID-19) was just beginning to spread around the world, we presented the potential benefits and controversies of anti-inflammatory therapy in COVID-19 patients based on the limited experience and proposed some types of anti-inflammatory drugs with potential therapeutic value, while without evidence-based data. In the past one more year, many clinical trials or real-world studies have been performed, either confirm or deny the efficacy of certain anti-inflammatory drugs in the treatment of COVID-19. In this review we summarize the progress of anti-inflammatory and immune therapy in COVID-19, including glucocorticoids, IL-6 antagonist, IL-1 inhibitor, kinase inhibitors, non-steroidal anti-inflammatory drugs and chloroquine/hydroxychloroquine.

For myocardial infarction (MI) patients, delayed enhancement (DE) and T2-weighted cardiovascular magnetic resonance imaging (CMR) can play significant roles in diagnosis, prognosis and therapeutic strategy evaluation. However, the non-rigid registration between different CMR sequences is particularly challenging and prevents the use of multi-sequence image analysis. In this article, we propose an approach for segmenting T2 and DE CMR simultaneously with cross-constrained shape and shape discrepancy compensation. A framework for the unified segmentation of multi-sequence images is built based on the coupled level set method. Additionally, a sparse representation-based shape model is optimized under the constraints from both sequences for complementary information sharing. Considering the myocardium shape discrepancy between the two sequences due to non-perfect registration, an error term is added to explicitly model this difference. The intensity feature is extracted with a Gaussian mixture model from each sequence. To obtain a fully automatic approach, the conditional generative adversarial network is adopted for initialization. The results are evaluated with T2 and DE images from 32 MI patients. A promising Dice similarity coefficient of the myocardium is achieved (84.97±4.15% for T2 and 78.13±6.22% for DE CMR). This approach is a pilot work toward automatic, multi-sequence CMR image analysis.

Determining the initiation time of substitute bus (SB) services is critical for metro disruption management, especially under uncertain recovery time. This study develops a mathematical formulation to determine the optimal initiation time (OIT) of SB services by trading-off their initiation cost and passenger delay cost, thereby minimizing the total system cost. Given the probability distribution of metro disruption duration, we determine the OIT by formulating an optimization problem to minimize the expected total system cost. We then conduct sensitivity analyses of the initiation cost of SB services, passenger value of time, and SB services rate. The results show that SB services ought to be activated only if the metro incident lasts longer than a certain time interval, depending on the factors mentioned earlier, and the OIT should advance with the predicted incident duration. This paper derives analytical results for the case of linear passenger arrival, and determines the results numerically for the case of non-linear passenger arrival when analytical closed-form solutions are not available. The findings will facilitate transit operators to develop response plans in the aftermath of a metro disruption.

Headway variations between successive buses, which lead to bus bunching, is undesirable for both passengers and bus operators, instigating longer average passenger waiting times and capacity underutilization of buses bunched together. Limiting bus bunching, hence, is important for urban bus operations. In this study, we analyze a two-way-looking self-equalizing control method for both deterministic and stochastic running times, derive its convergence properties, study the knock-on effect, and optimize its control parameter as a function of the number of buses operating in the route. By comparing the headways from both upstream and downstream of the control point, the control scheme will hold buses, if needed, at the control point to gradually restore the common headway of the system. By utilizing properties of the headway transition matrices associated with the control scheme, we prove that the bus headways will self-equalize under deterministic travel time. In addition, under the context of stochastic travel time variations, we prove that the headway variance of all buses will be reduced to a certain value by the control scheme. Further, we analyze the headway control parameter to determine its optimal value and adopt the scheme for dynamic control. Finally, numerical simulations are conducted to illustrate the performance of this control scheme, with promising results.

NiO nanosheets were anchored at honeycomb amorphous porous carbon with ultrahigh surface area derived from activated wheat husk to obtain NiO@PC (porous carbon). The ultrahigh surface area of PC (634.4 m2 g−1) promoted the attachment of NiO nanosheets, and this hierarchical nanostructure (NiO@PC) was beneficial for facilitating electron and electrolyte ion transport and accelerating the reversible redox reaction, which successfully demonstrated its high energy storage properties as supercapacitor. The NiO@PC composite exhibited brilliant capacitance of 500 F g−1 at 10 A g−1 after 8000 cycles. Moreover, as symmetric supercapacitor, NiO@PC exhibited high specific capacitance of 76 mF cm−2 at 1 mA cm−2. The excellent electrochemistry performance of NiO@PC brings the possibility of using biomass waste as electrode materials for energy storage. This process is facile and environmental friendly.

A case-based design technique is used in this study to analyze the structural form efficiency, unit scale, and statistical relationships among umbrella-shaped structure morphological parameters. The differences, characteristics, and applicable scales are compared between different umbrella structure types in terms of their morphological characteristics. The changes in structural form efficiency under material innovations and optimized structural morphologies are explained. The orders of different structure types and morphological characteristics under different parameters are given. Steel umbrella and reinforced concrete umbrella structures have more prominent unit sizes, while light steel umbrella structure and membrane umbrella structure are more prominent in terms of form efficiency. In addition to the better performance of the tubular type in terms of height (H), the segmented ribbed columnar type features the most prominent coverage area (S1) and structure form efficiency (α, β, and η). The correlation between different variables related to structural morphology is also revealed. By combining the limit value and range of related variables, and by establishing a function model of the relationships between structural form efficiency and size, this work provides a workable reference for umbrella structure unit design. Among them, H-ηhigh, S1-ηhigh, and S2-ηhigh explain the change trend of ηhigh with increases in H, S1, and S2. In the two sets of linear relations S2-Hhigh and S2–S1high, the approximate growth relationship between variables are given. If S2 increases by 1m2, Hhigh can increase by 2.0m, if S2 increases by 1m2, S1high can increase by 83.6 m2. The Person correlation coefficients of the two sets of linear relations are 0.83 and 0.74, respectively, and the adjusted R2 values are 0.70 and 0.54, respectively. The practical application of the proposed technique for the conceptual design of umbrella structure building is also discussed.

The application and performance of ground source heat pump (GSHP) systems in Jiangsu, China are reported in this study. Fifty cases were selected from different areas including office, residence, and other building types. Half of the selected cases was measured in summer, and the other half was measured in winter. The water temperatures, energy efficiency, energy consumption and thermodynamic perfectibility were analyzed statistically. The ground provided an average water temperature of 25.4 °C in summer and 11.7 °C in winter. The temperature difference between the inlet and outlet on the ground side in both the seasons was 3.07 °C. The statistical average values of coefficient of performance (COP), energy efficiency ratio (EER), and thermodynamic perfectibility η were 4.62, 3.41, and 0.38 in summer and 4.34, 3.22, and 0.49 in winter, respectively. The energy used by heat pumps and water pumps was about 3:1 in both the seasons. Furthermore, a comprehensive evaluation was conducted based on the statistical baseline set by the collected data. This method included factors that influence the actual system performance and provided an approach to assess and compare the performance of the cases comprehensively.

Background: Coronavirus 2019 (COVID-19) first emerged in Wuhan, China in December 2019, but spread rapidly throughout the world and became a pandemic Critical

ObjectiveTo determine the profile of Chinese medical professionals with burnout symptoms at the national level and identify the association between capability well-being and burnout.Design and SettingA cross-sectional study in a nonrandom national sample of medical staff from 6 provinces across western, central and eastern China.ParticipantsPhysicians, medical laboratory scientists, nurses, and general practitioners aged 18 years or above who submitted a completed online questionnaire from June 2019 to January 2020 successfully (N = 25,120).Main Outcome MeasuresThe prevalence of burnout symptoms was assessed by the 22-item Maslach Burnout Inventory-Human Services Survey (MBI-HSS), which consists of three domains: emotional exhaustion (EE), depersonalization (DP), and personal achievement (PA). The overall high burnout was defined as EE score ≥27 or DP score ≥10. The capability well-being was measured by the Investigating Choice Experiments Capability Measure for Adults (ICECAP-A) and the overall ICECAP-A score was calculated using the UK value set, ranging from a score of 0–1. Multivariable logistic regression analysis was used to identify the association between well-being and the overall high burnout.ResultsAmong the 25,120 participants, 60.8% of the participants reported at least one symptom of burnout, whereas 11.2% reported all three symptoms of burnout. In the adjusted model, ICECAP-A score was independently associated with high burnout (AOR = 0.018, 95% CI = 0.015–0.022). Medical staff who were males, with shorter working years, working in tertiary hospitals, and those with the specialties of psychiatry, intensive care, emergency medicine, internal medicine, oncology, and pediatrics were at higher risk of reporting burnout symptoms.ConclusionThe burnout symptoms were relatively common among Chinese medical staff and they were found to be independently associated with capability well-being in health professionals. Interventions should be enhanced on vulnerable groups to reduce burnout and promote well-being in future studies.

The deployment of fuel cell vehicles in Shenzhen, China is far behind electric vehicles. In order to promote the application of fuel cell vehicles, significant efforts are required to construct hydrogen stations in the near future. The present study focused on the estimation of hydrogen demand and refueling station cost in Shenzhen between 2016 and 2025. Three scenarios of fuel cell vehicle penetration rate in the new car market were employed to predict the fuel cell vehicle number and daily hydrogen demand. Capital investment and operation and maintenance cost of on-site steam methane reforming hydrogen fueling stations were studied. The capital cost of a 1000 kg H2/day hydrogen refueling station was calculated as $ 7.84 million. Hydrogen fuel price of different size fueling stations at various years of return on investment were also compared. The lowest H2 price can be reached is $6.78/kg.

Immunoglobulin E (IgE), a key element of allergic reactions, was considered to be involved in the development of atherosclerosis and the pathogenesis of myocardial ischemia. This study was designed to test whether total serum IgE levels were associated with the atherosclerosis severity of coronary artery disease (CAD).Total serum IgE concentrations were measured in 708 consecutive patients who were presented to our center for coronary angiography. Atherosclerosis severity of CAD was assessed by the number of diseased vessels showing ≥50% diameter stenosis and quantified by Gensini score.Patients with CAD (N = 562) had higher serum IgE levels than those without CAD (N = 146) [55.90 (19.10-156.00) vs. 26.90 (11.80-62.10) KU/L, p = 0.003]. Furthermore, the serum IgE levels were significantly increased in patients with multivessel disease (MVD) compared to those with single-vessel disease [61.80 (23.20-159.00) vs. 32.45(14.15-94.38) KU/L, p = 0.003]. After adjustment for traditional cardiovascular risk factors, a high serum IgE level was an independent predictor for an increased risk of MVD (OR 1.003; 95% CI 1.001-1.004; p = 0.041). Receiver-operating characteristic curve analysis demonstrated that serum IgE levels improved the predictive capability of traditional risk factors for MVD (area under the curve with and without IgE: 0.734 and 0.713, respectively, p 0.001). Meanwhile, there was a significant linear relationship between Gensini score and the serum IgE level quartiles (p for linear trend0.001).Increased total serum IgE levels are associated with MVD and contribute to discriminating CAD severity independently of traditional cardiovascular risk factors.

Polymer grafted nanoparticles with different surface properties have been prepared and widely used in different fields recently. In this study, through the rheological study on the strength of interfacial adhesion relevant to the complex viscoelasticity and relaxation response of the well-defined polymer (polylactide, PLLA) grafted-nanoparticles (silica) mixed with free chains of the same polymer nanocomposites in melt state, we investigated the different interfacial entanglement and relaxation mechanisms of the polymer grafted nanocomposites (PGN), to bridge the relationship between the micro and macro-properties of PGN. The AFM observation illuminated that circles one by one were formed in “grafting from” prepared SiO2 (GF), while core–shell morphology found in “grafting to” prepared SiO2 (GT), because of the different surface properties of the modified SiO2. The interface relaxation was characterized around 300 s in the GT5 nanocomposites, due to the entanglement between the long grafted and matrix chains, which also contributed lots to the rheology properties enhancement, such as the improving viscosity. Combining the relaxation spectrum and stress relaxation testing, the relaxation units in different time scales, from short time to long time, were illuminated. Also the relaxation of the interfacial chains in different situations, through the introduction of the absorption and reptation models, was proposed to explain our observations. The comparative study reminded us that the strong interfacial interactions or the long interfacial relaxation time aroused by the entanglement, were essential for successfully preparing polymer nanocomposites.

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.

Coronary artery disease (CAD) is a major threat to human health. In clinical practice, X-ray coronary angiography remains the gold standard for CAD diagnosis, where the detection of stenosis is a crucial step. However, detection is challenging due to the low contrast between vessels and surrounding tissues as well as the complex overlap of background structures with inhomogeneous intensities. To achieve automatic and accurate stenosis detection, we propose a convolutional neural network-based method with a novel temporal constraint across X-ray angiographic sequences. Specifically, we develop a deconvolutional single-shot multibox detector for candidate detection on contrast-filled X-ray frames selected by U-Net. Based on these static frames, the detector demonstrates high sensitivity for stenoses yet unacceptable false positives still exist. To solve this problem, we propose a customized seq-fps module that exploits the temporal consistency of consecutive frames to reduce the number of false positives. Experiments are conducted with 148 X-ray angiographic sequences. The results show that the proposed method outperforms existing stenosis detection methods, achieving the highest sensitivity of 87.2% and positive predictive value of 79.5%. Furthermore, this study provides a promising tool to improve CAD diagnosis in clinical practice.

A novel nitrogen-doped three-dimensional hierarchically porous carbon (N-3DHPC) has been designed and prepared by the carbonization of polyaniline (PANI) covered on the three-dimensional macroporous carbon (3DMC), followed by KOH activation to generate micropores and mesopores on the wall of macropores. The pore structure, morphology and surface physicochemical properties of the carbon samples are characterized by nitrogen adsorption/desorption isotherm, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and elemental analysis. The N-3DHPC inherits the morphology of the pristine 3DMC and processes a hierarchically porous structure with a high specific area of 1084.0 m2 g−1 and some nitrogen-doped species on the surface. The electrochemical behaviors of the N-3DHPC are characterized by cyclic voltammetry (CV), galvanostatic charge-discharge (GCD) test, electrochemical impedance spectroscopy (EIS) and cycle life measurement. The results show that the N-3DHPC obtains high specific capacitance of 308.4 F g−1 at a current density of 1 A g−1. Moreover, the N-3DHPC supercapacitor exhibits excellent rate performance, low resistance, high energy density of 10.7 Wh kg−1 at the power density of 500 W kg−1 and excellent cyclic stability with the specific capacitance retention of 96 % even after 10000 cycles, thus the N-3DHPC will be a promising electrode material for supercapacitors.

Fuel adaptability of a lab-scale 2.5 kWth autothermal reforming system was experimentally investigated. Analyses of thermodynamics of autothermal reforming of different fuels at various temperatures were provided to determine the associated flow rates of fuel, air, and steam. The tested reformer has a specifically designed mixing chamber and NiO–Rh based bimetallic catalyst with promoters of Ce, K and La, which were originally designed for autothermal reforming of Jet-A fuel. The adaptability of the reformer to multiple fuels, including diesel, gasoline, ethanol, and methanol was experimentally studied at different operating conditions. Molar fractions of H2, CO, CO2, and CH4 in the dried reformate were measured and the results were compared with values reported in the literature. The autothermal reforming performance of the reformer for different fuels was evaluated with regard to hydrogen selectivity, COx selectivity, and energy conversion efficiency. It was concluded that the currently developed reformer and the associated catalyst have great fuel adaptability and high potential being used in a fuel-flexible autothermal reforming system.

This study assessed the combined utility of estimated glomerular filtration rate (eGFR) and serum high-sensitivity C-reactive protein (hsCRP) levels to predict long-term mortality and cardiovascular outcomes of patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Elevated CRP levels and renal dysfunction have both been shown to independently and jointly predict mortality and cardiovascular outcomes after PCI in the short term. However, long-term results in patients with acute STEMI undergoing PCI have not been reported.A total of 262 patients with acute STEMI undergoing primary PCI were classified at admission into quartiles according to eGFR (60, 60-70, 70-80 and ≥80 mL·min·1.73 m) and hsCRP (3 and ≥3 mg/L). Mortality, nonfatal myocardial infarction (MI) and major adverse cardiac events (MACEs) were compared among the groups.During a median follow-up of 48.3 months, the composite of all-cause mortality and nonfatal MI (mortality + MI) was significantly higher (35.09%) in the group with the lowest eGFR compared with that of the other 3 eGFR groups (14.29%, 3.77% and 9.43%, respectively, P0.0001) and the group with elevated hsCRP (34.29%) versus that with hsCRP3 mg/L (4.41%, P0.0001). A combined analysis showed an exaggerated hazard in patients with the lowest eGFR and highest hsCRP (hazard ratio: 44.658; 95% confidence interval: 5.955-111.890).Renal dysfunction and elevated hsCRP predict a high long-term incidence of MACE in patients with acute STEMI undergoing primary PCI, with the combination being of prognostic significance for long-term mortality and MI in these patients.

Background: Genetic variants such as inactivating mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene account for approximately 15-20% of the etiology of idiopathic pulmonary arterial hypertension (IPAH). Increasing evidence indicates the existence of other IPAH susceptibility genes. Methods: The whole-genome sequencing was performed in a discovery cohort including 42 IPAH patients who are lacking BMPR2 mutations. Putative IPAH genes were validated in an independent cohort that included 188 IPAH patients and 968 healthy controls. Functional assessments were conducted to analyze the effects of candidate genetic variants on transcript splicing, enzymatic activity and function. Results: An enrichment of rare variants in the gene encoding prostacyclin synthase (PTGIS) was initially identified by the whole-genome sequencing. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In total, fourteen patients (6.1%) were heterozygous for three PTGIS rare variants, including one splice-site variant (c.521 1G>A) and two missense variants (R252Q, A447T). These rare variants conferred a 7.8-fold greater risk of IPAH (95% confidence interval (CI), 3.2 to 18.8; P=5 x 10-6). Inhaled iloprost induced more significantly decrease of pulmonary vascular resistance (P=0.001) and increase of cardiac index (P A variant resulted in aberrant mRNA transcripts. The functional studies showed that the two missense variants caused a decrease in prostacyclin production and increased cell death in pulmonary microvascular endothelial cells. Conclusions: We have identified three loss-of-function rare variants in the PTGIS gene from two independent IPAH cohorts. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation and cause deleterious effects. These results provide a novel finding that PTGIS rare variants are involved in the pathogenesis of IPAH. Funding: The work was supported by the following grants: the Beijing Natural Science Foundation (7181009, 7172180), the National Natural Science Foundation of China (81320108005), the National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2016-I2M-4-003), the National Key Research and Development Program of China (2016YFC0901502), Sanming Project of Medicine in Shenzhen-Professor Zhi-Cheng Jing's Group for Precise Medicine Research in Thrombosis and Vascular Disease (SZSM201502001) , and the fund from State Key Laboratory of Cardiovascular Disease (2016-kf04, 2018ZR-02). Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study protocol was approved by the ethics committees of Shanghai Pulmonary Hospital and FuWai Hospital. The participants, who were all of Chinese Han ancestry, provided written informed consent.