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Drug-drug interactions are one of the main concerns in drug discovery. Accurate prediction of drug-drug interactions plays a key role in increasing the efficiency of drug research and safety when multiple drugs are c o-prescribed. With various data sources that describe the relationships and properties between drugs, the comprehensive approach that integrates multiple data sources would be considerably effective in making high-accuracy prediction. In this paper, we propose a Deep Attention Neural Network based Drug-Drug Interaction prediction framework, abbreviated as DANN-DDI, to predict unobserved drug-drug interactions. First, we construct multiple drug feature networks and learn drug representations from these networks using the graph embedding method; then, we concatenate the learned drug embeddings and design an attention neural network to learn representations of drug-drug pairs; finally, we adopt a deep neural network to accurately predict drug-drug interactions. The experimental results demonstrate that our model DANN-DDI has improved prediction performance compared with state-of-the-art methods. Moreover, the proposed model can predict novel drug-drug interactions and drug-drug interaction-associated events.

The assessment and diagnosis of agricultural drought vulnerability is the basis for the scientific control and prevention of agricultural drought risk. In order to quantitatively evaluate the regional agricultural drought vulnerability and effectively deal with the fuzziness and randomness between evaluation sample and evaluation grade, the entropy fuzzy pattern recognition model, which was coupled with maximum information entropy principle and fuzzy pattern recognition method, was applied to the evaluation of agricultural drought vulnerability. Furthermore, in order to find methods to reduce drought vulnerability, the subtraction set pair potential method was used to further identify the main influence factors of agricultural drought vulnerability. In addition, a case study was carried out in Bengbu City, China. The results showed that during the period from 2001 to 2010, the evaluation value of agricultural drought vulnerability in Bengbu dropped from grade IV to III, which meant that the tolerance of agricultural system to drought had been improved. Moreover, the main factors that affected the vulnerability in Bengbu were precipitation, water use efficiency and irrigation protection area rate. And the latter two were the main objects of regulation and control. Compared with the other three methods, the physical concept of drought vulnerability assessment model based on entropy fuzzy pattern recognition is more obvious, and the evaluation results are reasonable and credible. The drought vulnerability diagnosis method based on subtraction set pair potential can accurately identify key influence factor and provide measures to reduce drought vulnerability and improve drought risk management.

GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995).Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts.In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization.Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

We propose an ultrathin reconfigurable Mach–Zehnder interferometer (MZI) for realizing dynamic frequency and amplitude modulations of spoof surface plasmon (SSP) signal. Active varactor diodes are integrated in the SSP unit cells on one of the MZI arms to introduce asymmetry to the MZI structure, which can control the interference patterns by varying bias voltages applied on the varactor diodes. We show that the spectral positions of multiple sharp interference dips are very sensitive to the change of diode capacitance, thereby allowing for good frequency modulation. We also demonstrate continuous amplitude modulation by tuning the varactor diodes at multiple selected frequencies. To verify the reconfigurable feature of the proposed SSP MZI, the frequency shift keying (FSK) and amplitude modulations have been experimentally demonstrated on the same structure. The modulation depth of the amplitude modulation can be further improved by designing geometrical parameters of the SSP structure, reaching a significant amplitude change from 0.88 to 0.05 in experiments.

Large‐scale power systems exhibit more complex dynamics due to the increasing integration of inverter‐based resources (IBRs). Therefore, there is an urgent need to enhance the situational awareness capability for better monitoring and control of power grids dominated by IBRs. As a pioneering Wide‐Area Measurement System, FNET/GridEye has developed and implemented various advanced applications based on the collected synchrophasor measurements to enhance the situational awareness capability of large‐scale power grids. This study provides an overview of the latest progress of FNET/GridEye. The sensors, communication, and data servers are upgraded to handle ultra‐high density synchrophasor and point‐on‐wave data to monitor system dynamics with more details. More importantly, several artificial intelligence (AI)‐based advanced applications are introduced, including AI‐based inertia estimation, AI‐based disturbance size and location estimation, AI‐based system stability assessment, and AI‐based data authentication.

Traction transformers are one of the most important equipment in the traction power supply system. Thermal aging of transformer insulation system determines its reliable life. To achieve an estimation of the insulation life of traction power transformers operated under real load condition, the effects of traction loads on the thermal aging of oil-paper insulation in traction transformers were investigated. First, the design principles for the accelerated thermal aging experiment were studied and proposed by considering magnitude (i.e., load rate) and frequency (i.e. spare time and lasting time) of the traction load. Then, an experimental system was established in the laboratory to conduct extensive accelerated thermal aging experiments, in which the traction loads were mimicked by using positive temperature coefficient (PTC) heating plates and a programmable logic controller (PLC). Finally, the experimental results were analyzed and discussed to reveal the effects of traction load on the thermal aging of oil-paper insulation in traction transformers.

Perovskite nanocrystals are exceptional candidates for light-emitting diodes (LEDs). However, they are unstable in the solid film and tend to degrade back to the bulk phase, which undermines their potential for LEDs. Here we demonstrate that perovskite nanocrystals stabilized in metal–organic framework (MOF) thin films make bright and stable LEDs. The perovskite nanocrystals in MOF thin films can maintain the photoluminescence and electroluminescence against continuous ultraviolet irradiation, heat and electrical stress. As revealed by optical and X-ray spectroscopy, the strong emission originates from localized carrier recombination. Bright LEDs made from perovskite-MOF nanocrystals are demonstrated with a maximum external quantum efficiency of over 15% and a high brightness of over 105 cd m−2 after the device reaches stabilization. During LED operation, the nanocrystals can be well preserved, free of ion migration or crystal merging through protection by the MOF matrix, leading to a stable performance over 50 hours. The use of metal–organic frameworks helps protect perovskite nanocrystals, resulting in bright, stable light-emitting diodes.

Objective Esophageal white lesions (EWL) are commonly observed under upper endoscopy, while their clinical significance remains undetermined. The aim of this study was to identify the endoscopic characteristics of EWL and distinguish between different types of EWL. Methods Consecutive patients with upper gastrointestinal complaints and participants admitted for health check-up who underwent esophagogastroduodenoscopy from October 2018 to August 2019 in a tertiary hospital were prospectively screened. EWL were detected under endoscopy and biopsy was performed for histological analysis. Participants' characteristics, lifestyle, esophageal motility and reflux monitoring variables were analyzed. Results Of the 3641 consecutive participants screened, 303 of them aged 56.12 ± 10.95 years were found to have EWL (detection rate of 8.3%). More than one-third of them preferred hot drinks, eating pickled or spicy food, smoking and alcohol consumption and 5.3% had current or former upper gastrointestinal or head and neck cancers. The common endoscopic appearance of the EWL (2.9 mm ± 1.2 mm in diameter) included slightly elevated plaque, translucent white in color, with a clear border, round or oval in shape, and a scaly, rough or smooth surface. Histology showed low-grade intraepithelial dysplasia in 13 cases, leukoplakia in 10 and intestinal metaplasia in one. No significant differences were found between the histological findings and endoscopic manifestations of EWL. Conclusions EWL are not uncommon in daily endoscopic examination, with some of them being precancerous lesions. Conventional white-light endoscopy is insufficient to identify EWL, while histological assessment is important. Further studies using advanced endoscopic techniques with long-term follow-up are needed.

In the supply chain system, the working capital is the core factor of normal operation for each node enterprise, but the internal and external uncertainties seriously affect the stability of working capital. Therefore, how to effectively manage the dynamic working capital in the uncertain supply chain system is a challenge. This article aims to investigate a robust financing strategy of the uncertain supply chain system by introducing the fuzzy control theory. First, a basic dynamic working capital operation model of the supply chain system with the internal and external uncertainties is constructed. Then, in terms of the corresponding financing strategies for the different idle working capital levels, a multimodel supply chain system is designed based on the basic model. Second, the Takagi–Sugeno fuzzy system is used to transform the multimodel system into a fuzzy switching model. Third, a robust financing strategy is proposed to suppress the impact of uncertainties on the supply chain system. This robust financing strategy can not only guarantee the stability of the uncertain supply chain system, but also reduce the financing cost. Finally, the effectiveness of the proposed robust financing strategy is verified by the results of simulation experiments.

Background Intestinal lymphoma is a rare tumor. Contrast-enhanced ultrasound (CEUS) findings of intestinal lymphoma have not been reported previously, and the relationship between CEUS and clinicopathological features and prognostic factors is still unknown. Aim To describe the B-mode US and CEUS features of intestinal lymphoma and investigate the correlation of CEUS and histopathological features. Methods This was a single-center retrospective study. Eighteen patients with histologically confirmed intestinal lymphoma underwent B-mode US and CEUS examinations between October 2016 and November 2019. We summarized the features of B-mode US and CUES imaging of intestinal lymphoma and compared the frequency of tumor necrosis in intestinal lymphomas with reference to different pathological subtypes (aggressive or indolent) and clinical stage (early or advanced). The time-intensity curve parameters of CEUS were also compared between patients with normal and elevated serum lactate dehydrogenase. Results In B-mode imaging, four patterns were observed in intestinal lymphoma: Mass type (12/18, 66.7%), infiltration type (1/18, 5.6%), mesentery type (4/18, 22.2%) and mixed type (1/18, 5.6%). All cases were hypoechoic and no cystic areas were detected. On CEUS, most cases (17/18, 94.4%) showed arterial hyperechoic enhancement. All cases showed arterial enhancement followed by venous wash out. A relatively high rate of tumor necrosis (11/18, 61.1%) was observed in this study. Tumor necrosis on CEUS was more frequent in aggressive subtypes (10/13, 76.9%) than in indolent subtypes (1/5, 20.0%) (P = 0.047). There were no correlations between tumor necrosis and lesion size and Ann Arbor stage. There was no significant difference in time-intensity curve parameters between normal and elevated lactate dehydrogenase groups. Conclusion B-mode US and CEUS findings of intestinal lymphoma are characteristic. We observed a high rate of tumor necrosis, which appeared more frequently in aggressive pathological subtypes of intestinal lymphoma.

GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection to assess safety, tolerability, pharmacokinetics and pharmacodynamics. GSK3335065 displayed an apparent volume of distribution between 20.6 L and 44.6 L, a clearance between 0.462 L/h and 0.805 L/hr and a terminal half-life between 31.3 and 34.5 hr. In the single subject who received 1.3 mg GSK3335065, changes in tryptophan pathway metabolites were observed consistent with the changes seen in preclinical species suggesting that KMO enzyme activity was partially inhibited. However, a broad complex ventricular tachycardia was observed in this subject, which was judged to be a Serious Adverse Event (SAE) and resulted in early termination of the study. While development of GSK3335065 was subsequently discontinued, significant confounding factors hinder a clear interpretation that the tachycardia was directly related to administration of the compound.

The declining cost of solar Photovoltaics (PV) generation is driving its worldwide deployment. As conventional generation with large rotating masses is being replaced by renewable energy such as PV, the power system’s inertia will be affected. As a result, the system’s frequency may vary more dramatically in the case of a disturbance, and the frequency nadir may be low enough to trigger protection relays such as under-frequency load shedding. The existing frequency-watt function mandated in power inverters cannot provide grid frequency support in a loss-of-generation event, as PV plants usually do not have power reserves. In this article, a novel adaptive PV frequency control strategy is proposed to reserve the minimum power required for grid frequency support. A machine learning model is trained to predict system frequency response under varying system conditions, and an adaptive allocation of PV headroom reserves is made based on the machine learning model as well as real-time system conditions including inertia. Case studies show the proposed control method meets the frequency nadir requirements using minimal power reserves compared to a fixed headroom control approach.

Summary One in three people worldwide does not have access to safe drinking water. Notably, heavy-metal ions (HMIs) are major water pollutants threatening human health because of their severe toxicity, even at trace levels. Efficient HMI detection thus plays a major defense against metal poisoning by enabling early pollution warning and efficient regulatory enforcement. However, it remains a formidable challenge to accurately detect these pollutants on site at ultratrace levels in a cost- or time-effective manner. Here, we introduce an efficient, portable sensor to concurrently quantify five different HMIs down to the sub-nanomolar level by sulfiding them on a superhydrophobic surface. Sulfidation serves as a colorimetric reaction while the superhydrophobic surface concentrates analytes for sensitive visual detection. Our superhydrophobic concentrator (SPOT) sensor can be made portable by being integrated with a smartphone application to quantify HMIs in

Background Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. Results Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P P Conclusion This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426.

Intraspinal inflammatory and immune responses are considered to play central roles in the pathological development of spinal cord injury. This study aimed to decipher the dynamics of systemic immune responses, initiated by spinal cord injury. The spinal cord in mice was completely transected at T8. Changes in the in vivo inflammatory response, between the acute and subacute stages, were observed. A rapid decrease in C-reactive protein levels, circulating leukocytes and lymphocytes, spleen-derived CD4+ interferon-γ+ T-helper cells, and inflammatory cytokines, and a marked increase in neutrophils, monocytes, and CD4+ CD25+ FOXP3+ regulatory T-cells were observed during the acute phase. These systemic immune alterations were gradually restored to basal levels during the sub-acute phase. During the acute phase of spinal cord injury, systemic immune cells and factors showed significant inhibition; however, this inhibition was transient, and the indicators of these serious disorders gradually returned to baseline levels during the subacute phase. All experiments were performed in accordance with the institutional animal care guidelines, approved by the Institutional Animal Care and Use Committee of Experimental Animal Center of Drum Tower Hospital, China (approval No. 2019AE01040) on June 25, 2019.

Modern inverter-based air-conditioners (IACs) are generally equipped with power-electronic components to achieve higher efficiency and more advanced controllability. Thus, their operating behaviours can be very different from the conventional air-conditioners with direct motor connections, and their new characteristics have not been adequately studied in the current literature. Thus, hardware experiments are conducted to extract the novel dynamic frequency response features of modern inverter-based air-conditioners under a range of different frequency disturbances. Then, a new IAC model with physical meanings is developed by accommodating the discovered new features such as time delays, load frequency relief and the minimum operating power limit. Further, this letter also demonstrates that the developed air-conditioner model can accurately represent the dynamics of the IACs under various frequency events. The extracted dynamic frequency response behaviours and the developed air-conditioner model will provide a solid foundation for the modern appliance modelling in a large scale and will assist to improve the accuracy of the inertia response representations of distribution network’s loads.

Introduction: This study aimed to assess the efficacy of acupuncture in patients with herpes zoster (HZ) based on current randomized clinical trials (RCTs). Methods: Five databases were screened for RCTs published until August 2019. Studies that assessed the efficacy of acupuncture when used as an independent intervention for HZ were included. The outcomes of interest were pain intensity, as assessed using the visual analog scale (VAS), incrustation time, decrustation time, and incidence of post-herpetic neuralgia (PHN). Results: In total, 21 RCTs were included in this research. Compared with antiviral therapy, acupuncture was associated with a reduction in VAS score by 16.13, incrustation time by 1.86 days, decrustation time by 2.19 days, and incidence of PHN by 83%. According to a meta-regression analysis, the main sources of heterogeneity were sample size and duration of treatment. There was no publication bias except on decrustation time. A sensitivity analysis showed that the outcomes were relatively stable and reliable. Conclusion: Acupuncture may be effective for patients with HZ. Nevertheless, this finding should be validated by conducting high-quality trials with a larger sample size.

Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

The presence of organic contaminants in wastewater poses considerable risks to the health of both humans and ecosystems. Although advanced oxidation processes that rely on highly reactive radicals to destroy organic contaminants are appealing treatment options, substantial energy and chemical inputs limit their practical applications. Here we demonstrate that Cu single atoms incorporated in graphitic carbon nitride can catalytically activate H2O2 to generate hydroxyl radicals at pH 7.0 without energy input, and show robust stability within a filtration device. We further design an electrolysis reactor for the on-site generation of H2O2 from air, water and renewable energy. Coupling the single-atom catalytic filter and the H2O2 electrolytic generator in tandem delivers a wastewater treatment system. These findings provide a promising path toward reducing the energy and chemical demands of advanced oxidation processes, as well as enabling their implementation in remote areas and isolated communities.

Objective:The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE), underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate masks and respirators exposed to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus.Design:The 2 arms of the study included (1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment and (2) PPE treatment with MBL for 5 cycles of decontamination to determine maintenance of PPE performance.Methods:MBL treatment was used to inactivate coronaviruses on 3 N95 filtering facepiece respirator (FFR) and 2 medical mask models. We inoculated FFR and medical mask materials with 3 coronaviruses, including SARS-CoV-2, and we treated them with 10 µM MB and exposed them to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5 cycles of decontamination using multiple US and international test methods, and the process was compared with the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method.Results:Overall, MBL robustly and consistently inactivated all 3 coronaviruses with 99.8% to >99.9% virus inactivation across all FFRs and medical masks tested. FFR and medical mask integrity was maintained after 5 cycles of MBL treatment, whereas 1 FFR model failed after 5 cycles of VHP+O3.Conclusions:MBL treatment decontaminated respirators and masks by inactivating 3 tested coronaviruses without compromising integrity through 5 cycles of decontamination. MBL decontamination is effective, is low cost, and does not require specialized equipment, making it applicable in low- to high-resource settings.

Controllable nucleation sites play a key role in the selective growth of heterostructures. Here, we are the first to report a one-pot strategy to realize the confined and selective growth of large MoS2/WS2 lateral and vertical heterostructures. A hydroxide-assisted process is introduced to control the nucleation sites, thereby realizing the optional formation of lateral and vertical heterostructures. Time-of-flight secondary ion mass spectrometry verifies the critical role of hydroxide groups toward the controllable growth of these heterostructures. The size of the as-grown MoS2/WS2 lateral heterostructures can be as large as 1 mm, which is the largest lateral size reported thus far. The obtained MoS2/WS2 heterostructures have a high carrier mobility of ∼58 cm2 V-1 s-1, and the maximum on/off current ratio is >108. This approach provides not only a pathway for the selective growth of large MoS2/WS2 lateral and vertical heterostructures but also a fundamental understanding of surface chemistry for controlling the selective growth of transition-metal dichalcogenide heterostructures.

Vertically stacked hexagonal boron nitride (h-BN)/graphene heterostructures present potential applications in electronic, photonic, and mechanical devices, and their interface interaction is one of the critical factors that affect the performances. In this work, the vertical h-BN/graphene heterostructures with high coverage are synthesized by chemical vapor deposition (CVD) of h-BN on Ni substrates followed by segregation growth of graphene at the h-BN/Ni interfaces, which are monitored by in situ surface microscopy and surface spectroscopy. We find that h-BN overlayers can be decoupled from Ni substrates by the graphene interlayers. Furthermore, the h-BN domain boundaries exhibit a confinement effect on the graphene interlayer growth and the lower graphene domains are limited within the upper h-BN domains. This work provides new insights into the formation mechanism and interface interaction of the vertical heterostructures.

Background Cell-based therapy products are supposed to be the most complex medicine products in the history of human medical care. In this study, we established a safety evaluation system for therapeutic stromal cells based on the existing regulations and current testing techniques to provide general quality requirements for human umbilical cord mesenchymal stromal cell (HUCMSC) therapy product. Methods In this system, we comprehensively evaluate the environmental monitoring program, quality control of critical raw materials and reagents, donor screening criteria, cell safety, quality, and biological effects, not only in line with the basic criteria of biological products, but also following the general requirements of drugs. Results The qualified HUCMSCs were tested for various clinical researches in our hospital, and no severe adverse reaction was observed in 225 patients during a 1-year follow-up period. Conclusion In this study, we establish a systemic quality control and potent assays to guarantee the safety and effectiveness of HUCMSCs based on a minimum set of standards in MSC-based product.

Summary To realize improved human body thermal comfort and reduce energy consumption on building heating and cooling, personal thermal management emphasizing energy management of human body and its local environment is emerging as a promising solution. Advanced textiles are being invented and developed to effectively regulate heat exchange between human body and its surroundings. Here, recent progress on advanced textiles for personal thermal management and its significance in energy efficiency are reviewed. We will mainly discuss textiles with engineered properties targeting at passively controlling human body heat dissipation routes, the active warming and/or cooling textiles, and the responsive textiles that offer adaptive personal thermal management ability according to the external stimuli. An outlook discussing important challenges and opportunities in this field is also presented.

While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients do not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involve assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post challenge analysis identified a novel expression-based risk marker and histone modifier,PHF19, which featured prominently in several independent models. Lastly, we show that a simple four feature predictor composed of age, International Staging System stage (ISS), and expression ofPHF19andMMSETperforms similarly to more complex models with many more gene expression features included.Key pointsMost comprehensive and unbiased assessment of prognostic biomarkers in MM resulting in a robust and parsimonious model.Identification ofPHF19as the expression based biomarker most strongly associated with rapid progression in MM patients.

Double‐sided metal‐oxide‐semiconductor field‐effect‐transistor processing is demonstrated for the first time on an ultrathin crystalline silicon substrate of 6‐20 μm in a 100 mm diameter wafer format without a carrier wafer, the thinnest free‐standing silicon wafers ever fabricated. The compatibility of the flexible material with conventional semiconductor processing tools is enabled by supporting an interior ultrathin silicon with a surrounding thicker ring of silicon. Current‐voltage characteristics of transistors on ultrathin silicon show performance as expected from bulk silicon, with electron mobility ~1500 cm2 V−1 second−1. Mechanical measurements quantify the handleability.

The lateral incorporation of graphene and hexagonal boron nitride (h-BN) onto a substrate surface creates in-plane h-BN/graphene heterostructures, which have promising applications in novel two-dimensional electronic and photoelectronic devices. The quality of h-BN/graphene domain boundaries depends on their orientation, which is crucial for device performances. Here, the heteroepitaxial growth of graphene along the edges of h-BN domains on Ni(111) surfaces as well as the growth dynamics of h-BN using chemical vapor deposition (CVD) are in situ investigated by surface imaging measurements. The nucleating seed effect of h-BN has been revealed, which contributes to the single orientation of heterostructures with epitaxial stitching. Further, the growth of h-BN prior to that of graphene is essential to obtain high-quality in-plane h-BN/graphene heterostructures on Ni(111). The “compact to fractal” shape transition of h-BN domains appears with the increasing surface concentration of the growth blocks, suggesting that the dynamic growth mechanism follows diffusion-limited aggregation (DLA) but not reaction-limited aggregation (RLA). Our results provide insights into the synthesis of well-defined h-BN/graphene heterostructures and deep understanding of the growth dynamics of h-BN on metal surfaces.

Background: Angiogenesis and hypoxia-inducible factor 1α (HIF-1α) play major roles in solid tumors. This study aimed to establish a longitudinal and multimodal imaging model for in vivo evaluation of HIF1α and angiogenesis in breast cancer. Methods: By transfection of a 5 hypoxia-responsive element (HRE)/green fluorescent protein (GFP) plasmid, the cell line Ca761-hregfp was established, which emitted green fluorescence triggered by HIF-1α under hypoxia. The cells were subjected to CoCl2-simulated hypoxia to confirm the imaging strategy. We grew Ca761-hre-gfp cells in the left rear flanks of twelve 615 mice. Experiments were conducted on days 4, 9, 15, and 19. For in vivo analysis, Ca761-hre-gfp subcutaneous allografted tumors were imaged in vivo using contrast-enhanced ultrasound (CEUS) and fluorescence imaging (FLI) during tumor development. The tumor size, CEUS peak intensity, and FLI photons were measured to evaluate tumor growth, angiogenesis, and HIF-1α activity, respectively. After each experiment, three mice were randomly sacrificed and tumor specimens were collected to examine HIF-1α activity and the microvessel density (MVD). Results: In vitro, both green fluorescence and HIF-1α expression were detected in Ca761-hre-gfp cells treated with CoCl2, indicating the suitability of the cells to detect HIF-1α activity. In vivo, HIF-1α activity first increased and then decreased, which was significantly correlated with angiogenic changes (r = 0.803, P = 0.005). These changes were confirmed by immunohistochemical staining of HIF-1α and MVD. Conclusions: The findings validated the Ca761-hre-gfp murine allograft model for reliable evaluation of HIF-1α activity and angiogenesis longitudinally using both molecular and pre-clinical non-invasive imaging modalities. The cell line may be useful for studies of anti-HIF pathway therapies. Key words: Breast cancer; Hypoxia-inducible factor 1; Pathological neovascularization; Ultrasonography; Fluorescence imaging

Cross-border e-commerce (CBEC) has become an imperative mode for global trade. Research on cross-border e-commerce historically focuses mainly on the customer's behavior intention to purchase on a CBEC platform. However, B-buyers are more important compared with C-buyers for CBEC platforms. This is because B-buyers can contribute more gross merchandise volume (GMV) in a CBEC platform, and thus more margin for the firm. The authors apply trust transfer theory, perceived risk, and alternative website quality to study repurchase intention, focusing on B-buyers. The results show that perceived risk, trust in provider, and trust in the website affect repurchase intention significantly, where trust in website is found to be the most important factor. In addition, the authors found that the dimensions of perceived risk in CBEC context can be classified as the following: customer duties risk, confiscation risk, delivery risk, financial risk, and privacy risk. The contributions of the study are addressed lastly.

Background: Obstetric hemorrhage is a major cause of maternal death during cesarean delivery. The objective of this retrospective observational study was to evaluate the efficacy and safety of intra-operative cell salvage (IOCS) in cesarean section. Methods: We included a total of 361 patients diagnosed with central placenta previa who underwent cesarean section from May 2016 to December 2018. In this study, 196 patients received autologous transfusion using IOCS (IOCS group) and 165 patients accepted allogeneic blood transfusion (ABT group). Propensity score matched analysis was performed to balance differences in the baseline variables between the IOCS group and ABT group. Patients in the IOCS group were matched 1:1 to patients in the ABT group. Results: After propensity score matching, 137 pairs of cases between the two groups were successfully matched and no significant differences in baseline characteristics were found between the IOCS group and ABT group. Patients in the IOCS group were associated with significantly shorter length of hospital stay, compared with ABT group (8.9 ± 4.1 days vs. 10.3 ± 5.2 days, t= -2.506, P = 0.013). The postoperative length of hospital stay was 5.3 ± 1.4 days for patients in the IOCS group and 6.6 ± 3.6 days for those in the ABT group (t = -4.056, P < 0.001). The post-operative hemoglobin level in the IOCS group and ABT group was 101.3 ± 15.4 and 96.3 ± 16.6 g/L, respectively, which were significantly different (t= 2.615, P= 0.009). Allogeneic red blood cell transfusion was significantly lower at 0 unit (range: 0–11.5 units) in the IOCS group when compared with 2 units (range: 1–20 units) in the ABT group (P < 0.001). Conclusions: This retrospective observational study using propensity score matched analysis suggested that IOCS was associated with shorter length of postoperative hospital stay and higher post-operative hemoglobin levels during cesarean delivery. Key words: Allogeneic; Blood salvage; Cesarean section; Hemorrhage

Proton exchange membrane fuel cells (PEMFCs) have potential applications in electric vehicles, laptops, and power stations. The catalyst layers in a membrane electrode assembly (MEA) are the core locations in PEMFCs in which to convert the chemical energy of fuels to electrical energy. For a catalyst layer with high performance, it must possess three fast transfer ways to transfer mass (reactants and products), electrons (e−) and protons (H+) quickly and simultaneously. In this work, we greatly improved the performance and lifetime of a fuel cell by constructing these three fast transfer pathways based on a well-ordered and cone-shaped Nafion array with a very high density (5.7 × 108 cones per cm2) using an anodic aluminum oxide (AAO) template. To build a fast pathway for electron transfer, well-dispersed graphene nanosheets were further filled into the Nafion array. After a series of efforts based on the above, the performance of the fuel cell with a cone array as an anode reached 1240 mW cm−2, which is 2.5 times higher than that without an array. Since Pt loading was as low as 17.6 μg cm−2, the mass specific power of Pt was as high as 70.5 kW gPt−1. Consequently, the Pt loading successfully reached the U.S. DOE 2020 target at the anode side, i.e. 25 μg cm−2. In addition, the lifetime of the PEMFC with the cone array is at least 300 h, which is much longer than the 150 h for a PEMFC without an array. Therefore, this work fully exhibits the great potential advantages of using an ordered Nafion array, and is promising to promote the development of the next generation of MEA for use in PEMFCs.

Polyp recognition in colonoscopy images is crucial for early colorectal cancer detection and treatment. However, the current manual review requires undivided concentration of the gastroenterologist and is prone to diagnostic errors. In this article, we present an effective, two-stage approach called PLPNet, where the abbreviation “PLP” stands for the word “polyp,” for automated pixel-accurate polyp recognition in colonoscopy images using very deep convolutional neural networks (CNNs). Compared to hand-engineered approaches and previous neural network architectures, our PLPNet model improves recognition accuracy by adding a polyp proposal stage that predicts the location box with polyp presence. Several schemes are proposed to ensure the model’s performance. First of all, we construct a polyp proposal stage as an extension of the faster R-CNN, which performs as a region-level polyp detector to recognize the lesion area as a whole and constitutes stage I of PLPNet. Second, stage II of PLPNet is built in a fully convolutional fashion for pixelwise segmentation. We define a feature sharing strategy to transfer the learned semantics of polyp proposals to the segmentation task of stage II, which is proven to be highly capable of guiding the learning process and improve recognition accuracy. Additionally, we design skip schemes to enrich the feature scales and thus allow the model to generate detailed segmentation predictions. For accurate recognition, the advanced residual nets and feature pyramids are adopted to seek deeper and richer semantics at all network levels. Finally, we construct a two-stage framework for training and run our model convolutionally via a single-stream network at inference time to efficiently output the polyp mask. Experimental results on public data sets of GIANA Challenge demonstrate the accuracy gains of our approach, which surpasses previous state-of-the-art methods on the polyp segmentation task (74.7 Jaccard Index) and establishes new top results in the polyp localization challenge (81.7 recall). Note to Practitioners —Given the current manual review of colonoscopy is laborious and time-consuming, computational methods that can assist automatic polyp recognition will enhance the outcome both in terms of efficiency and diagnostic accuracy of colonoscopy. This article suggests a new approach using a very deep convolutional neural network (CNN) architecture for polyp recognition, which gains accuracy from deeper and richer representations. The method, called PLPNet, can effectively detect polyps in colonoscopy images and generate high-quality segmentation masks in a pixel-to-pixel manner. We evaluate the proposed framework on publicly available data sets, and we show by experiments that our method surpasses the state-of-the-art polyp recognition results. The finding of this article corroborates that CNNs with very deep architecture and richer semantics are highly efficient in medical image learning and inference. We believe that the proposed method will facilitate potential computer-aided applications in clinical practice, in that it can enhance medical decision-making in cancer detection and imaging.

This study was carried out to analyze the surgical effect of cervical spine sagittal alignment for patients with Hirayama disease (HD).Forty-four subjects were retrospectively analyzed for the parameters of cervical spine sagittal alignment. The case group consisted of 23 patients with HD, whereas the control group consisted of 21 healthy adolescent subjects. Pre- and postoperative cervical spine sagittal parameters of the patients with HD were collected; the cervical sagittal parameters of the healthy adolescent subjects were also collected. Sagittal alignment parameters were compared between the patients with HD and the healthy adolescent subjects, and between the pre- and postoperative parameters for the patients with HD.Forty-four subjects completed the follow-up, with the average follow-up period being 18.0 months. No significant differences were detected between the HD and control groups for clinical parameters (P0.05). The preoperative HD group had smaller values compared with the control group in the sagittal parameters of C2-7 cervical lordosis (CL) angle, T1 slope, thoracic inlet angle (TIA), and cervical tilt angle (P0.05). For the patients with HD, the preoperative values were smaller compared with the postoperative HD values for the parameters of C2-7 CL angle, T1 slope, and cervical tilt angle (P0.05). We found no significant differences between the postoperative patients with HD and the healthy subjects, including C2-7 CL angle, C2-7 sagittal vertical axis, T1 slope, TIA, neck tilt angle, cervical tilt angle, and cranial tilt angle (P0.05).Patients with HD have sagittal imbalance of the cervical spine compared with age-matched healthy adolescent subjects, and surgical treatment could correct the sagittal imbalance.

Background: Increased right ventricle afterload during acute respiratory distress syndrome (ARDS) may induce acute cor pulmonale(ACP), which is associated with a poor clinical outcome. Echocardiography is now considered as a rapid and non-invasive tool for diagnosis of ACP. The aims of this study were to investigate the morbidity and mortality rates of ACP in ARDS patients in intensive care units (ICUs) across the mainland of China and to determine the severity and prognosis of ACP in ARDS patients through an ultrasound protocol (TRIP). And the association between ACP related factors and the ICU mortality will be revealed. Methods: This study is a multicenter and cross-sectional study in China which will include ICU participants when diagnosed as ARDS. The ultrasound protocol, known as the TRIP, is proposed as severity assessment for ACP, which includes tricuspid regurgitation velocity (T), right ventricular size (R), inferior vena cava diameter fluctuation (I), and pulmonary regurgitation velocity(P). The 28-day mortality, ICU/hospital mortality, the length of stay in ICU, mechanical ventilation days, hemodynamic parameters and lab parameters of liver function and kidney function are all recorded. Discussion: This large-scale study would give a sufficient epidemic investigation of ACP in ARDS patients in China. In addition, with the TRIP protocol, we expect that we could stratify ACP with more echocardiography parameters. Trial registration: NCT03827863, https://clinicaltrials.gov/ct2/show/NCT03827863 Key words: Acute respiratory distress syndrome; Acute cor pulmonale; Echocardiography; Outcome

Background Physical activity and good nutrition are important behavioral factors in promoting health and preventing disease. It is important to understand the factors affecting physical activity and nutrition. The purpose of this study was to explore whether social capital has an effect on physical activity and nutrition, and whether health literacy plays a mediating role between social capital and physical activity as well as nutrition. Methods This cross-sectional study was performed in a certain district of Shanghai in March and April 2017. Data was collected using a self-reported questionnaire, which included questions on sociodemographic characteristics, social capital, health literacy and health-promoting lifestyle profile-II. Health-promoting lifestyle profile-II measures the behaviours or habits of physical activity and healthy nutrition. An explore factor analysis of the principal components with varimax rotation was carried out on the social capital scale. Descriptive statistics was used to summarize the sociodemographic of participants. Mediation analysis was performed using the bootstrapping tests to examine whether health literacy mediate the relationship between social capital and physical activity as well as nutrition. Results The explore factor analysis results showed that social capital has five dimensions, namely social participation, social support, social network, control over life and feelings about the community. There is a positive correlation between social capital, health literacy, physical activity and nutrition. The correlation coefficient varied from 0.135 to 0.594. Mediation analysis demonstrated health literacy played a partial mediating effect between social capital and physical activity as well as nutrition. In the relationship between physical activity and social capital, the indirect effect of health literacy accounted for 8.20 to 12.65% of the total effect. In the relationship between nutrition and social capital, the mediation effect of health literacy accounted for 4.93 to 12.71% of the total effect. Conclusion Social capital can promote physical activity and nutrition by disseminating health information. Enhancing the social capital of residents will help increase physical activity and develop healthy eating habits. Attention should also be paid to the improvement of residents’ health literacy.

Supplemental Digital Content is available in the text, Background: Post-operative pain is unpleasant for patients and may worsen surgical recovery. Peri-operative multimodal analgesia has been used for many years; however, its efficacy still needs improvement. In the present study, a thorough peri-operative pain counseling and stratified management program based on risk assessment was implemented, with the goal of improving post-operative analgesia and patient satisfaction. Methods: This prospective, controlled, pilot study included 361 patients who underwent elective surgery. Of these 361 patients, 187 received peri-operative pain risk assessment and stratified analgesia and counseling (stratified analgesia group), while 174 received conventional multimodal analgesia (conventional group). The two groups were compared regarding the post-operative pain intensity, rescue analgesia administration, post-operative quality of recovery as assessed via the quality of recovery 40 questionnaire, total dosage of peri-operative opioids, analgesic satisfaction, and analgesic costs. Results: Compared with the conventional group, the stratified analgesia group reported decreased pain intensity during motion at 24 h post-operatively and required lower dosages of rescue analgesia (P = 0.03). The total quality of recovery 40 questionnaire score and the scores for physical wellbeing and pain were significantly better in the stratified analgesia group than the conventional group (P = 0.04); the stratified analgesia group also reported better scores for analgesic satisfaction (P = 0.03) and received lower dosages of opioids (P = 0.03). Analgesic costs were lower in the stratified analgesia group than the conventional group; the cost-effective ratio was 109 in the conventional group and 62 in the stratified analgesia group. Conclusions: The analgesic efficacy was improved by the implementation of stratified analgesia based on surgical pain risk assessment and counseling. This stratified analgesia protocol increased the patients’ analgesic satisfaction and improved the quality of recovery without increasing healthcare costs. The present findings may help improve the efficacy of peri-operative multimodal analgesia in clinical practice. Clinical Trial Registry: NCT02728973; https://clinicaltrials.gov/ct2/show/NCT02728973?term=NCT02728973&draw=2&rank=1.

Reflection is a key activity in self-regulated learning (SRL) and a critical part of health professions education that supports the development of effective lifelong-learning health professionals. Despite widespread use and plentiful theoretical models, empirical understanding of and support for reflection in health professions education remains limited due to simple manual assessment and rare feedback to students. Recent moves to digital reflection practices offer opportunities to computationally study and support reflection as a part of SRL. The critical task in such an endeavor, and the goal of this paper, is to align high-level reflection qualities that are valued conceptually with low-level features in the data that are possible to extract computationally. This paper approaches this goal by (a) developing a unified framework for conceptualizing reflection analytics in health professions education and (b) empirically examining potential data features through which these elements can be assessed. Synthesizing the prior literature yields a conceptual framework for health professions reflection comprised of six elements: Description, Analysis, Feelings, Perspective, Evaluation, and Outcome. These elements then serve as the conceptual grounding for the computational analysis in which 27 dental students’ reflections (in six reflective statement types) over the course of 4 years were examined using selected LIWC (Linguistic Inquiry and Word Count) indices. Variation in elements of reflection across students, years, and reflection-types supports use of the multi-dimensional analysis framework to (a) increase precision of research claims; (b) evaluate whether reflection activities are engaged in as intended; and (c) diagnose aspects of reflection in which specific students need support. Implications for the development of health professions reflection analytics that can contribute to SRL and promising areas for future research are discussed.

Background: Reverse intertrochanteric fractures are usually initially treated with closed reduction. However, sometimes these fractures are not amenable to closed reduction and require open reduction. To date, few studies have been conducted on predictors of and reduction techniques for irreducible reverse intertrochanteric fractures. Therefore, this study aimed to summarize the displacement patterns of irreducible reverse intertrochanteric fractures and corresponding reduction techniques, and explore predictors of irreducibility. Methods: We reviewed 1174 cases of trochanteric fractures treated in our hospital from January 2006 to October 2018, 113 of which were reverse intertrochanteric fractures. An irreducible fracture was determined according to intra-operative fluoroscopy imaging after closed manipulation. Fractures were assessed for displacement patterns, radiographic features of irreducibility, and reduction techniques. Logistic regression analysis was performed on potential predictors for irreducibility, including gender, age, body mass index, AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification, and radiographic features. Results: Seventy-six irreducible fractures were identified, accounting for 67% of reverse intertrochanteric fractures. Six patterns of fracture displacement after closed manipulation were identified; the most common pattern was medial displacement and posterior sagging of the femoral shaft relative to the head-neck fragment. Multivariate logistic regression analysis identified three predictors of irreducibility: a medially displaced femoral shaft relative to the head-neck fragment on the anteroposterior (AP) view (odds ratio [OR], 8.00; 95% confidence interval [CI], 3.04-21.04; P < 0.001), a displaced lesser trochanter (OR, 3.61; 95% CI, 1.35-9.61; P = 0.010), and a displaced lateral femoral wall (OR, 2.92; 95% CI, 1.02-8.34; P = 0.046). Conclusions: A high proportion of reverse intertrochanteric fractures are not amenable to closed reduction. Six patterns of fracture displacement after closed manipulation were identified. Different reduction techniques are required for different displacement patterns. Predictors of irreducibility include a medially displaced femoral shaft relative to the head-neck fragment on the AP view, a displaced lesser trochanter, and a displaced lateral femoral wall. These patients warrant special consideration in terms of recognition and management. Key words: Intertrochanteric hip fractures; Irreducible; Predictors; Reduction techniques; Reverse oblique

Aim We aimed to develop a simple model combining protein induced by vitamin K antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) to detect early hepatocellular carcinoma (HCC) in liver cirrhosis (LC) patients. Method One hundred and sixty-nine newly diagnosed early HCC patients and 242 LC patients without HCC were enrolled in the current case-control study. All subjects were randomly divided into analysis group and validation group. Serum levels of PIVKA-II, AFP and other laboratory parameters were detected. Chi-squared test, t-test and logistic regression were employed in statistical analysis. Results PIVKA-II level in early HCC was significantly higher than that in LC (90.97 mAU/mL vs 18.00 mAU/mL, P < 0.01), as well as AFP level (15.00 ng/mL vs 2.00 ng/mL, P < 0.01) in analysis groups. Multivariate analysis showed that PIVAK-II, AFP, gender, and age were independent risk factors for early HCC detection among LC patients. A logistic regression model and a simple model combining PIVKA and AFP were conducted to detect early HCC. The ROC curve showed that among analysis groups, the area under the ROC curve (AUROC) of the logistic regression model and the simple model were 0.96 (95% CI 0.94-0.98) and 0.94 (95% CI 0.92-0.97), respectively. At a cut-off value of 56.03 the sensitivity and specificity of the simple model were 81.1% and 91.4%, respectively. In the validation group, the sensitivity and specificity of the simple model was 82.4% and 94.2%, respectively. The two models are comparable statistically for early HCC detection, but the logistic regression requires complex calculation. Conclusion The present study indicates that the simple model combining PIVKA-II and AFP has comparable diagnostic efficiency in contrast to the logistic model but is easy to use clinically. It might be helpful for early HCC detection among liver cirrhosis patients.

PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

Background: Impaired orthostatic blood pressure (BP) response is a frequent finding in the elderly. The goal of the study was to investigate the association of variability of supine-to-orthostatic ...

Supplemental Digital Content is available in the text, Background: The dose and time point for switching from clopidogrel to ticagrelor remain controversial, especially for Chinese acute coronary syndrome (ACS) patients with complicated coronary artery disease (CAD). Hence, the purpose of this study was to further explore the optimal dose and time point for the switching strategy to balance the increase in platelet inhibition and the decrease in adverse events in Chinese ACS patients with complicated CAD managed by percutaneous coronary intervention (PCI). Methods: From July 2017 to December 2017, the prospective, randomized, open-label study (the SwitcHIng from clopidogrel to ticagrelor study) assigned the eligible Chinese ACS patients with complicated CAD managed by PCI (n = 102) for 90 mg of ticagrelor at 12 h (T-90 mg-12 h), 90 mg of ticagrelor at 24 h (T-90 mg-24h) or 180 mg ticagrelor at 24 h (T-180 mg-24 h) after the last dose of clopidogrel. The primary endpoint was the comparison of maximal platelet aggregation (MPA) values at 2 h after switching strategies among the three groups. In addition, the MPA values at baseline, 8 h and before discharge and the rates of high on-treatment platelet reactivity were evaluated, the incidences of bleeding episodes and dyspnea during hospitalization and at 30-day follow-up in our study were also recorded. The MPA was measured by light transmittance aggregometry in our study. A repeated-measures analysis of variance (ANOVA) model and one-way ANOVA were used to compare data for the primary endpoint. Results: The MPA values were significantly decreased in the T-180 mg-24 h group compared with the T-90 mg-12 h group (P = 0.017) and decreased numerically compared with the T-90 mg-24 h group (P = 0.072) at 2 h. In particular, the MPA values were markedly reduced in the T-90 mg-24 h group compared with the T-90 mg-12 h group at 8 h after switching treatment (P = 0.002). There was no significant difference among the three groups in all bleedings and dyspnea events. Conclusions: The optimal treatment strategy recommended in this study for Chinese ACS patients with complicated CAD managed by PCI is 180 or 90 mg of ticagrelor at 24 h after the last dose of clopidogrel. In addition, a negative interaction was detected in this study between the overlap for clopidogrel and ticagrelor at 12 h after the last dose of clopidogrel. Trial Registration: ClinicalTrials.gov, NCT03577652; http://clinicaltrials.gov/ct2/show/NCT03577652.

Aim: The major symptom of many closed spinal dysraphism patients is that the laminas or arches of vertebra are not fused well. To date, the bone repair of spina bifida for young children is a significant challenge in clinical practice. Materials & methods: Bovine bone collagen particle (BBCP) scaffolds combined with human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were implanted in the defect area. X-ray analysis was performed after 3 months. Tissues were harvested for gross observation, and histological and immunohistochemical staining. Results: The BBCP supported hUC-MSCs adhesion and growth. Implanted BBCP combined with hUC-MSCs also promoted bone regeneration in the vertebral lamina and arch defect area. Conclusion: This method represents a new strategy for vertebral lamina and arch reconstruction in children.

Drought risk management can effectively reduce drought losses and improve drought resistance capability, of which drought risk assessment is the core issue. This study evaluated the agricultural drought risk in Huaibei Plain of Anhui Province in China by the approach of constructing drought loss risk curves and risk distribution maps. The results showed that: 1) The drought events that occurred in northern regions (Huaibei and Suzhou) were with the characteristics of high-frequency and low-intensity, while in southern regions (Huainan and Bengbu), the occurring characteristics were low-frequency, high-intensity, and long-duration. 2) Without irrigation, Fuyang was the high-risk region with more than 80% potential yield loss rate, while Huainan was the relatively low-risk area with a potential yield loss of 50%. 3) Irrigation had a significant effect on reducing drought risk loss, while the efficiency was influenced by the spatio-temporal distribution of precipitation. The irrigation scheme in study area still remains to be optimized based on the characteristics of precipitation and crop growth. This study established and practiced a quantitative framework for regional drought risk assessment by creating drought risk curves and risk maps, which have significant value in improving the regional agricultural drought risk management level.

Sangdu oral liquid (MFEC), a kind of traditional Chinese medicine, is used as a new immune enhancer for veterinary drugs or vaccines. In current study, we aimed to evaluate the effect and mechanism of MFEC on improving the immune response of B87 vaccine. Eighty SPF chickens were divided into blank control group (BC group), infectious bursal disease virus (IBDV) group (IBDV group), vaccine group (B87+IBDV group) and vaccine and Sangdu oral liquid combination group (MFEC+B87+IBDV group). In addition to the BC group, all other groups were infected with IBDV to establish immunosuppressive model. Chickens in both B87+IBDV and MFEC+B87+IBDV groups were immunized with B87 vaccine. Chickens in MFEC+B87+IBDV group were given MFEC for 7 days. Compared with B87+IBDV group, there were significantly lower morbidity and mortality, higher level of antibody, less tissue damage, lower expression of Bax and higher expression of Bcl-2 of MFEC+B87+IBDV group (P < 0.05). In MFEC+B87+IBDV group, the expression of IBDV-VP2, IL-6 and IFN-γ mRNA in bursal tissue was significantly lower than that in B87+IBDV group (P < 0.05). MFEC can effectively improve the immune response to B87 vaccine, and resist the invasion and replication of IBDV to avoid the tissue damage and apoptosis caused by IBDV infection.

Objectives To investigate the safety for clinic use and therapeutic effects of basic fibroblast growth factor (bFGF)-overexpressing human umbilical cord-derived mesenchymal stem cells (HUCMSCs) in mice with completely transected spinal cord injury (SCI). Methods Stable bFGF-overexpressing HUCMSCs clones were established by electrotransfection and then subjected to systematic safety evaluations. Then, bFGF-overexpressing and control HUCMSCs were used to treat mice with completely transected SCI by tail intravenous injection. Therapeutic outcomes were then investigated, including functional recovery of locomotion, histological structures, nerve regeneration, and recovery mechanisms. Results Stable bFGF-overexpressing HUCMSCs met the standards and safety of MSCs for clinic use. In the mouse SCI model, stable bFGF-overexpressing HUCMSCs markedly improved therapeutic outcomes such as reducing glial scar formation, improving nerve regeneration and proliferation of endogenous neural stem cells (NSCs), and increasing locomotion functional recovery of posterior limbs compared with the control HUCMSCs group. Furthermore, bFGF-overexpressing HUCMSCs promoted the proliferation and neuronal differentiation of NSCs in vitro through the PI3K-Akt-GSK-3β pathway. Conclusion bFGF-overexpressing HUCMSCs meet the requirements of clinical MSCs and improve evident therapeutic outcomes of mouse SCI treatment, which firmly supports the safety and efficacy of gene-modified MSCs for clinical application.

Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib

BackgroundCurrently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease.MethodsPatients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 minutes of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography – tandem Mass Spectrometry. ResultsDrug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants.ConclusionsIn this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route.Trial RegistrationA prospective clinical study approved by London Camden and Kings Cross Research Ethics Committee and registered on clinicaltrials.gov (NCT03136120)