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PDF file - 144K, Supplemental Figure 1 NY-ESO-1 antigen-specific CD4+ T cell lines were CD8 negative.

PDF file - 106K, Supplemental Table 1 Summary of NY-ESO-1 Immune responses.

CD4+ T cells provide help to enhance and sustain cytotoxic CD8+ T-cell responses. A direct lytic role for this cell population in mouse models further supports the use of tumor-reactive CD4+ T cells for cancer immunotherapy. CTLA-4 blockade has been shown to expand antigen-specific cytotoxic CD4+ T cells in mouse models. We took advantage of spontaneous immunity to the NY-ESO-1 cancer-testis antigen to investigate quantitative and qualitative changes in antigen-specific CD4+ T-cell responses after ipilimumab (anti-CTLA-4 monoclonal antibody) treatment in patients with advanced melanoma. Four patients with NY-ESO-1 seropositive melanoma were chosen upon the availability of suitable blood specimens for characterizing the functions of NY-ESO-1 antigen-specific CD4+ T-cell response by enzyme-linked immunospot (ELISPOT), intracellular cytokine staining (ICS), and cytotoxicity assays. Multiple NY-ESO-1 antigen-specific CD4+ T-cell responses with TH1 dominance were induced or enhanced after ipilimumab treatment in peripheral blood in all four patients. NY-ESO-1 antigen–specific CD4+ T-cell lines established from all four patients after ipilimumab treatment recognized naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed master transcription factor Eomesodermin (Eomes), and secreted perforin and Granzyme B. Finally, we showed that these NY-ESO-1 antigen-specific CD4+ T-cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in an MHC class II restricted manner. Our results show that antigen-specific cytotoxic CD4+ T-cell responses are induced after ipilimumab therapy in human cancer patients. Ipilimumab may induce the expression of lytic granules on antigen-specific cytotoxic CD4+ T cells via Eomes, revealing a novel consequence of immunologic checkpoint blockade. Cancer Immunol Res; 1(4); 235–44. ©2013 AACR.

In this paper we develop a family of arbitrarily high-order non-oscillatory hybrid Finite Volume/Discontinuous Galerkin schemes for turbulent flows on mixed-element unstructured meshes. The schemes are inherently compact in the sense that the central stencils employed are as compact as possible, and that the directional stencils are reduced in size, simplifying their implementation. Their key ingredient is the switch between a DG method and a FV method based on the CWENOZ scheme when a troubled cell is detected. Therefore, in smooth regions of the computational domain, the high order of accuracy offered by DG is preserved, while in regions with sharp gradients, the robustness of FV is utilized. This paper also presents the time evolution of troubled cells in unsteady test cases and the use of extended bounds for troubled cell detection. We assess the performance of these schemes in terms of accuracy, robustness and computational cost through a series of stringent 2D and 3D test problems. The results obtained demonstrate the accuracy and robustness that the schemes offer and highlight areas of future improvements that are considered.

To investigate the clinical and genetic characteristics of patients with idiopathic hypogonadotropic hypogonadism (IHH), the clinical data of 23 patients with IHH were retrospectively analyzed. Gene analyses were accomplished with whole-exome sequencing (WES) and Sanger sequencing. Functional prediction of mutation sites was conducted using two bioinformatics platforms, SIFT and Polyphen. Among the 23 patients with IHH, 9 patients carried prokinin 2 (PROKR2) gene mutations including 4 missense mutations (p.W178S, p.Y113H, p.A103V, p.R164Q), and 1 frameshift mutation (p.D42delinsDED), the remaining 14 cases were found negative in gene sequencing. Functional prediction showed that the above mutations may affect protein function suggestive of a pathogenic role of PROKR2 mutation in the patients. There were no significant differences in the levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol between the IHH patients with PROKR2 gene mutation and those without. PROKR2 gene mutation might associated with IHH, and the mutations reported in the present study could enrich the pathogenic spectrum of genes.为探讨特发性低促性腺激素性性腺功能减退症（IHH）患者的临床及遗传学特征，回顾性分析23例IHH患者的临床资料，应用全外显子测序（WES）结合Sanger方法进行基因分析，SIFT和Polyphen 2种生物信息学平台对突变位点进行功能预测。结果显示，在23例IHH患者中，9例患者存在前激动素2（PROKR2）基因突变，其中4种错义突变（p.W178S、p.Y113H、p.A103V、p.R164Q），1种移码突变（p.D42delinsDED），功能预测显示以上突变可能是该病的致病基因，余14例阴性。IHH患者无论PROKR2基因突变有无，其卵泡刺激素、黄体生成素、睾酮、雌二醇水平差异均无统计学意义。PROKR2基因突变与IHH疾病可能相关，其突变丰富基因致病谱。.

During the last several years, the HL-2A experiment has made significant progress in the following areas: (1) lower-hybrid wave (LHW) heating and current drive, (2) plasma confinement and turbulent transport, (3) magnetohydrodynamic (MHD) instabilities and energetic particle physics and (4) H-mode and edge localized mode (ELM) control. The results show that the LHW system working in the co-current mode can reach higher driving efficiency and full non-inductive lower-hybrid current drive (LHCD) has been achieved. The intrinsic poloidal torque characterized by the divergence of the residual stress is deduced from synthesis for the first time. The dynamics of spectral symmetry breaking in drift wave turbulence is in good agreement with the development of the poloidal torque to drive the edge poloidal flow. The influence of the cross-phase dynamics on turbulent stress was also investigated. The ion internal transport barrier has been observed in the NBI-heated plasma, and inside the barrier the ion thermal transport is reduced to the neoclassical level. Besides, micro-turbulence is modulated by the rotation frequency of the magnetic island, and this modulation effect is related to a critical island width. Strong E × B shear is found at the island boundary. Three kinds of axisymmetric modes, beta-induced Alfven eigenmode (BAE), toroidal Alfven eigenmode (TAE) and the ellipticity-induced Alfven eigenmode (EAE), are found to be driven unstable by nonlinear mode coupling between Alfven eigenmodes and tearing mode which is well explained by the nonlinear gyrokinetic theory. The fishbone and tearing modes were actively controlled by the electron cyclotron resonance heating (ECRH). The dynamics of the edge plasma flows and turbulence during the L–I–H transition have been dedicatedly investigated. The geodesic acoustic mode (GAM) and limit cycle oscillation (LCO) coexist for a short time and disappear in the H-mode plasma with the increasing of E × B shear flow before the I–H transition, which plays an important role in the turbulence suppression. Different techniques, such as LHW, ECRH, resonant magnetic perturbation (RMP), and impurity seeding by the laser blow-off (LBO) and supersonic molecular beam injection (SMBI), have been successfully applied to control the large ELMs. It has been found that pedestal turbulence enhancement might be responsible for the observed mitigation effect.

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences Background Inflammation plays a crucial role in coronary atherosclerosis progression, and growing evidence has demonstrated that the fibrinogen-to-albumin ratio index (FAR) is associated with the severity of coronary artery disease (CAD). However, the long-term risk of cardiovascular events remains indistinct in patients with different level of FAR and different glycemic metabolism status. This study was to access 5-year clinical outcomes of diabetic and non-diabetic patients who underwent percutaneous coronary intervention (PCI) with different level of FAR. Methods We consecutively enrolled 10,724 patients with CAD hospitalized for PCI and followed up for major adverse cardiac and cerebrovascular events (MACCE) covering all-cause mortality, non-fatal myocardial infarction, non-fatal ischemic stroke and unplanned coronary revascularization. FAR was computed using the following formula: Fibrinogen (mg/dL) / Albumin (g/L). According to the optimal cut-off value of FAR, which was determined by the surv_cutpoint function of the R package survminer via RStudio software (version 2021.09.0), patients were divided into higher level of FAR (FAR-H) and lower level of (FAR-L) subgroups, and were further categorized into for groups as FAR-H with DM and non-DM, and FAR-L with DM and non-DM. Results 5,298 patients (58.36 ± 10.36 years, 77.7% male) were ultimately enrolled in the present study. A total of 1,099 (20.7%) MACCEs were documented during the 5-year follow-up. The optimal cut-off value of FAR was 0.0783 by the surv_cutpoint function. Compared to ones with FAR-H and DM, patients with FAR-L and non-DM, FAR-H and non-DM, FAR-L and DM had decreased risk of MACCEs [adjusted hazard ratio (HR): 0.75, 95% confidence interval (CI) 0.64-0.89, p = 0.001; HR: 0.006, 95% CI 0.66-0.93, p = 0.006; HR: 0.81, 95% CI 0.68-0.97, p = 0.019]. Notably, non-diabetic patients with lower level of FAR also had lower all-cause mortality risk than those in the FAR-H/DM group (HR: 0.41, 95% CI 0.27-0.63, p < 0.001). Multivariate Cox proportional hazards regression analysis also indicated the highest risk of MACCEs in patients with FAR-H and DM than others (p for trend = 0.005). In addition, subgroup analysis revealed consistent effects on 5-year MACCE across various subgroups. Conclusion Diabetic patients with higher level of FAR had the worse 5-year outcomes compared with patients in other three groups. The level of FAR may help to identify high-risk individuals in this specific population.

Objective To estimate a stillbirth rate at 24 or more gestational weeks in 2015–2016 and to explore potentially preventable causes in China. Design A multi‐centre cross‐sectional study. Setting Ninety‐six hospitals distributed in 24 (of 34) provinces in China. Population A total of 75 132 births at 24 completed weeks of gestation or more. Methods COX Proportional Hazard Models were performed to examine risk factors for antepartum and intrapartum stillbirths. Population attributable risk percentage was calculated for major risk factors. Correspondence analysis was used to explore region‐specific risk factors for stillbirths. Main outcome measures Stillbirth rate and risk factors for stillbirth. Results A total of 75 132 births including 949 stillbirths were used for the final analysis, giving a weighted stillbirth rate of 13.2 per 1000 births (95% CI 7.9–18.5). Small for gestational age (SGA) and pre‐eclampsia/eclampsia increased antepartum stillbirths by 26.2% and 11.7%, respectively. Fetal anomalies increased antepartum and intrapartum stillbirths by 17.9% and 7.4%, respectively. Overall, 31.4% of all stillbirths were potentially preventable. Advanced maternal age, pre‐pregnant obesity, chronic hypertension and diabetes mellitus were important risk factors in East China; low education and SGA were major risk factors in Northwest, Southwest, Northeast and South China; and pre‐eclampsia/eclampsia and intrapartum complications were significant risk factors in Central China. Conclusions The prevalence of stillbirth was 13.2 per 1000 births in China in 2015–2016. Nearly one‐third of all stillbirths may be preventable. Strategies based on regional characteristics should be considered to reduce further the burden of stillbirths in China. Tweetable abstract The stillbirth rate was 13.2 per 1000 births in China in 2015–2016 and nearly one‐third of all stillbirths may be preventable., Tweetable abstract The stillbirth rate was 13.2 per 1000 births in China in 2015–2016 and nearly one‐third of all stillbirths may be preventable.

In the last several years, great progress of optical and spectroscopic diagnostics has been achieved on the HL-2A tokamak. The main physical goal of these diagnostics is to measure plasma parameters for research of turbulence and transport. These diagnostics include: (1) a Phase Contrast Imaging to calculate wavenumber spectra based on a 10.6-μm CO2 laser, (2) a multi-channel (48 channels now and 324 channels for future) Beam Emission Spectroscopy (BES) based on neutral beam injection to measure Doppler-shifted 659.1-nm Dα line for density fluctuation measurement, (3) a four-channel Lyman-Alpha-Based BES (LAB) to measure 121-nm vacuum ultraviolet line for edge density fluctuation measurement, (4) a Gas Puff Imaging (GPI) to measure the intensity of 587.6-nm He I line to investigate plasma evolution, (5) a Multi-Color GPI (MC-GPI) to specify electron temperature and plasma density based on the line-intensity-ratio technique, (6) a Doppler Coherent Imaging Spectroscopy (CIS) to measure two-dimensional plasma velocity, (7) a Near-Infrared PCI (NI-PCI) based on a 1.55-μm fiber laser, (8) a Main-Ion Charge eXchange Recombination Spectroscopy (MI-CXRS) for main ion temperature measurement, and (9) a Fast Ion Dα Imaging (FIDA-I) to image two-dimensional energetic ion profiles. The main characteristic of these diagnostics is the high spatiotemporal resolution which is at the orders of millimeters and microseconds to meet the requirement of turbulence investigation. First experimental results obtained by using some of these new diagnostics, such as poloidal asymmetry of flow velocity during edge localized modes (ELMs), localized pedestal mode in high-β ELM-free H-mode, two-dimensional evolution of density blobs and the quasi-coherent mode in H-mode configuration, are also presented.

OBJECTIVE: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods. METHODS: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. RESULTS: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95% confidence interval [CI] -11.7 to -11.3, p < 0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95% CI -13.8 to -12.7, p < 0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95% CI -13.7 to -10.3, p = 0.001). Recovery of stroke hospitalization volume (9.5%, 95% CI 9.2-9.8, p < 0.0001) was noted over the 2 later (May, June) vs the 2 earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was noted in 3.3% (1,722/52,026) of all stroke admissions. CONCLUSIONS: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID-19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months. © 2021 American Academy of Neurology.

To investigate the effect of corticosteroid on hospital mortality, hospital length of stay, and time of viral clearance in patients with severe and critical COVID-19.Patients with severe and critical COVID-19 who had been discharged or expired were enrolled in this study. Patients were divided into corticosteroid group and non-corticosteroid group according to the systemic corticosteroid use or not. Clinical data were collected, and hospital mortality, hospital length of stay, time of viral clearance, time of mechanical ventilation, and duration from illness onset to symptom resolution were compared between the two groups.A total of 72 inpatients who were diagnosed with severe and critical COVID-19 were enrolled, in which 47 patients were divided into corticosteroid group and 25 were involved as the non-corticosteroid group. Baseline characteristics were generally similar between the two groups. Four (5.6%) patients died during hospitalization, and 68 (94.4%) were discharged. Among survivors, the mean duration time from admission to discharge was 19.5d (SD 7.05 d). The mean time of viral clearance among survivors was 17.5d (SD 7.67 d), with a maximum of 37 d, and a minimum of 5 d. Hospital mortality (4.3% vs. 8.0%), length of hospital stay (18.7d vs. 21.0d), and time of viral clearance (16.1d vs. 19.4d) had no significant difference between two groups (p0.05). The duration of symptoms suffering was shorter in the corticosteroid group than non-corticosteroid group, with statistically significant difference (p0.05).Corticosteroid therapy in patients with severe COVID-19 cannot reduce the hospital mortality, and is not associated with delayed viral clearance, but it could relieve the inflammatory storm and improve clinical symptoms in brief. Patients with severe COVID-19 could benefit from low-dose corticosteroid treatment.

The aim of this study was to elucidate the neuronal protection effect of sodium butyrate (NaB) on neuronal apoptosis in rats with cerebral infarction (CI), and the involvement of the phosphatidilinositol 3-kinase/protein kinase B (PI3K/Akt) and extracellular-signal-regulated kinase 1/2 (ERK1/2) pathways. MI model in rats was performed by middle cerebral artery occlusion (MCAO). Three hours after reperfusion, gastric administration of 5 or 10 mg/kg NaB was performed. Neurological deficit score, infarct size and brain edema were evaluated in rats after 24 h of reperfusion. Enzyme-linked immunosorbent assay (ELISA) was conducted to determine contents of oxidative stress factors. Lactate dehydrogenase (LDH) activity, cell viability and apoptosis in extracted neurons were determined. Moreover, expression levels of Bcl-2, Bax, Akt and ERK1/2 were examined. NaB treatment markedly reduced infarct size and brain edema content in CI rats, and NaB treatment improved viability, decreased LDH activity and reversed contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in a dose-dependent manner. In addition, NaB treatment dose-dependently reduced apoptotic rate and Bax level, as well as enhanced Bcl-2 level. Protein levels of Akt and ERK1/2 were markedly upregulated in NaB-treated neurons. NaB treatment alleviates neuronal apoptosis via the PI3K/Akt and ERK1/2 pathways in CI rats, thus protecting the deterioration of CI.