In Situ Exfoliation Growth Strategy Realizing Controlled Synthesis of 3D to 2D MOF Materials as High-Performance Electrochemical Biosensors.

Two-dimensional (2D) metal-organic framework (MOF) nanosheets with large surface area, ultrathin thickness, and highly accessible active sites have attracted great research attention. Developing efficient approaches to realize the controllable synthesis of well-defined 2D MOFs with a specific composition and morphology is critical. However, it is still a significant challenge to construct thin and uniform 2D MOF nanosheets and resolve the reagglomeration as well as poor stability of target 2D MOF products. Here, an "in situ exfoliation growth" strategy is proposed, where a one-step synthetic process can realize the successful fabrication of PBA/MIL-53(NiFe)/NF nanosheets on the surface of nickel foam (NF) via in situ conversion and exfoliation growth strategies. The PBA/MIL-53(NiFe)/NF nanosheets combine the individual advantages of MOFs, Prussian blue analogues (PBAs), and 2D materials. As expected, the resulting PBA/MIL-53(NiFe)/NF as a glucose electrode exhibits an extremely high sensitivity of 25.74 mA mM-1 cm-2 in a very wide concentration range of 180 nM to 4.8 µM. The present exciting work provides a simple and effective strategy for the construction of high-performance nonenzymatic glucose electrochemical biosensors.

Plastic film mulching application improves potato yields, reduces ammonia emissions, but boosts the greenhouse gas emissions in China.

With global population growth and climate change, food security and global warming have emerged as two major challenges to agricultural development. Plastic film mulching (PM) has long been used to improve yields in rain-fed agricultural systems, but few studies have focused on soil gas emissions from mulched rainfed potatoes on a long-term and regional scale. This study integrated field data with the Denitrification-Decomposition (DNDC) model to evaluate the impacts of PM on potato yields, greenhouse gas (GHG) and ammonia (NH3) emissions in rainfed agricultural systems in China. We found that PM increased potato yield by 39.7 % (1505 kg ha-1), carbon dioxide (CO2) emissions by 15.4 % (123 kg CO2 eq ha-1), nitrous oxide (N2O) emissions by 47.8 % (1016 kg CO2 eq ha-1), and global warming potential (GWP) by 38.9 % (1030 kg CO2 eq ha-1), while NH3 volatilization decreased by 33.9 % (8.4 kg NH3 ha-1), and methane (CH4) emissions were little changed compared to CK. Specifically, the yield after PM significantly increased in South China (SC), North China (NC), and Northwest China (NWC), with increases of 66.1 % (2429 kg ha-1), 44.1 % (1173 kg ha-1), and 43.6 % (956 kg ha-1) compared to CK, respectively. The increase in GWP and greenhouse gas emission intensity (GHGI) under PM was more pronounced in the Northeast China (NEC) and NWC regions, with respective increases of 57.1 % and 60.2 % in GWP, 16.9 % and 10.3 % in GHGI. While in the Middle and Lower reaches of the Yangtze River (MLYR) and SC, PM decreased GHGI with 10.2 % and 31.1 %, respectively. PM significantly reduced NH3 emissions in all regions and these reductions were most significant in Southwest China (SWC), SCand MLYR, which were 41 %, 38.0 %, and 38.0 % lower than CK, respectively. In addition, climatic and edaphic variables were the main contributors to GHG and NH3 emissions. In conclusion, it is appropriate to promote the use of PM in the MLYR and SC regions, because of the ability to increase yields while reducing environmental impacts (lower GHGI and NH3 emissions). The findings provide a theoretical basis for sustainable agricultural production of PM potatoes.

Endoscopic submucosal dissection for early cancers or precancerous lesions of the upper GI tract in cirrhotic patients with esophagogastric varices: 10-year experience from a large tertiary center in China.

BACKGROUND AND AIMS: Treatment strategies for early cancers or precancerous lesions of the upper GI tract in patients with cirrhosis and esophagogastric varices (EGVs) are complicated and risky. The aim of this study was to assess the efficacy and safety of endoscopic submucosal dissection (ESD) in the treatment of such patients and explore optimal treatment strategies. METHODS: We retrospectively enrolled 15 patients with cirrhosis and EGV who underwent ESD for early cancers or precancerous lesions of the upper GI tract from January 2012 to December 2021 at our center. Clinical features, endoscopic findings, treatment methods, adverse events, and follow-up data were analyzed. RESULTS: Of the 15 patients, 1 had a platelet count <30 × 1000/mm3. Five were untreated for EGV, 1 was treated after ESD, 6 were treated before ESD, 1 was treated before and during ESD, and 2 were treated during ESD. The R0 resection rate was 100%. Of the 16 mucosal lesions, 15 were endoscopic resection bleeding (ERB)-0 or ERB-c1, and 1 was ERB-c2. No patient experienced deterioration in liver function. The only adverse events were fever in 2 patients and postoperative bleeding in 2 patients. During a median follow-up of 27 months, 1 patient's esophageal high-grade dysplasia recurred at 19 months. No death resulted from the ESD procedure, liver function injury, or GI tumor itself. CONCLUSIONS: ESD is an effective and safe treatment for early cancers or precancerous lesions of the upper GI tract in patients with cirrhosis and EGV. The incidence of severe adverse events is very low due to the development of individualized clinical treatment strategies.

UiO-66-Derived PBA Composite as Multifunctional Electrochemical Non-Enzymatic Sensor Realizing High-Performance Detection of Hydrogen Peroxide and Glucose.

In this work, a highly efficient multifunctional non-enzymatic electrochemical sensor is successfully fabricated based on a facile two-step synthetic strategy. It resolves two important challenges of poor stability and low reproducibility compared to conventional electrochemical enzyme-based sensors. Herein, a metal-organic framework (UiO-66) is selected as a sacrificial template to construct the corresponding Prussian blue analogue (PBA) target to improve its stability and conductivity, namely, PBA/UiO-66/NF. Target PBA/UiO-66/NF exhibits excellent electrochemical sensing performance as hydrogen peroxide (H2O2) and glucose sensors with ultrahigh sensitivity of up to 1903 µA mM-1 cm-2 for H2O2 and 22,800 µA mM-1 cm-2 for glucose, as well as a very low detection limit of 0.02 µM (S/N = 3) for H2O2 and 0.28 µM for glucose. Especially, extremely high stability can be observed, which will be beneficial for practical application.

Assessment of Rose Bengal Photodynamic Therapy on Viability and Proliferation of Human Keratolimbal Epithelial and Stromal Cells In Vitro.

PURPOSE: To investigate the effect of Rose Bengal photodynamic therapy (RB-PDT) on viability and proliferation of human limbal epithelial stem cells (T-LSCs), human corneal epithelial cells (HCE-T), human limbal fibroblasts (LFCs), and human normal and keratoconus fibroblasts (HCFs and KC-HCFs) in vitro. METHODS: T-LSCs and HCE-T cell lines were used in this research. LFCs were isolated from healthy donor corneal limbi (n = 5), HCFs from healthy human donor corneas (n = 5), and KC-HCFs from penetrating keratoplasties of keratoconus patients (n = 5). After cell culture, RB-PDT was performed using 0.001% RB concentration and 565 nm wavelength illumination with 0.14 to 0.7 J/cm2 fluence. The XTT and the BrdU assays were used to assess cell viability and proliferation 24 h after RB-PDT. RESULTS: RB or illumination alone did not change cell viability or proliferation in any of the cell types (p ≥ 0.1). However, following RB-PDT, viability decreased significantly from 0.17 J/cm2 fluence in HCFs (p < 0.001) and KC-HCFs (p < 0.0001), and from 0.35 J/cm2 fluence in T-LSCs (p < 0.001), HCE-T (p < 0.05), and LFCs ((p < 0.0001). Cell proliferation decreased significantly from 0.14 J/cm2 fluence in T-LSCs (p < 0.0001), HCE-T (p < 0.05), and KC-HCFs (p < 0.001) and from 0.17 J/cm2 fluence in HCFs (p < 0.05). Regarding LFCs proliferation, no values could be determined by the BrdU assay. CONCLUSIONS: Though RB-PDT seems to be a safe and effective treatment method in vivo, its dose-dependent phototoxicity on corneal epithelial and stromal cells has to be respected. The data and experimental parameters applied in this study may provide a reliable reference for future investigations.

Analysis of risk factors for post-endoscopic papillectomy bleeding.

BACKGROUND: Endoscopic papillectomy (EP) is an effective treatment for ampullary lesions but technically challenging because of anatomical specificities concerning the high rate of adverse events. Bleeding is one of the most feared complications and can be potentially life-threatening. AIM: To study the risk factors for bleeding after EP are presented with the goal of establishing preventive measures. METHODS: A total of 173 consecutive patients with ampullary lesions undergone EP from January 2006 to October 2020 were enrolled in this study. They were divided into a bleeding group and a non-bleeding group depending on whether postoperative bleeding occurred. Related factors were analyzed by univariate and multivariate logistics regression. RESULTS: Postoperative bleeding was experienced in 33 patients (19.07%). Multivariate analysis also identified intraoperative bleeding (OR: 4.38, 95% CI: 1.87-11.15, p = .001) and endoscopic closure (OR: 0.25, 95% CI: 0.10-0.58, p = .001) as independent factors significantly associated with bleeding after EP. Lesion size (≥3 cm) was shown as an independent factor significantly associated with intraoperative bleeding (OR: 4.25, 95% CI: 1.21-16.44, p = .028). CONCLUSIONS: This retrospective evaluation found that endoscopic closure was associated with reduced risk and intraoperative bleeding with increased risk of bleeding after EP. Lesion size may indirectly influence the risk of postoperative bleeding by increasing the risk of intraoperative bleeding.

Population management in an urban center using the dynamic integrated solution for an adequate atmospheric environmental quality.

Accelerated growth in urban populations has become a powerful force for human development, particularly in developed countries. Metropolitan cities are centers for technical and economic advancement, but air pollution, overflowing of water, and other climate effects still pose significant problems related to nature, climate, and the environment. Cities are vulnerable to increasingly dense, diverse, and interdependent urban systems. A single extreme occurrence can contribute to a systemic break-up of a city's infrastructure, often like dominoes. In this paper, a dynamic integration-assisted population management solution (DI-PMS) has been proposed. DI-PMS recognizes that the latest facilities' optimal usage of knowledge and technologies is needed to increase urbanization. They are one of the critical priorities of the weather community. Such integrated urban weather, environmental, and climate services will help cities address dangers including storms, floods, heatwaves, and air pollution, especially in climate change. The goal is to create urban facilities that satisfy communities' unique needs by high-resolution forecasting and pollution reduction climate services, which allow the construction of durable, robust, and thriving cities that support the Sustainable Development Goals. Several recent international surveys to explore these topics have been undertaken. DI-PMS gives a brief description of urban hydrometeorological, climate and air pollution activities, outlines the new urban integrated weather and environmental services concept, and emphasizes the need for science to be implemented.

Comparison between endoscopic submucosal tunnel dissection and endoscopic submucosal dissection for superficial neoplasia at esophagogastric junction: a case-matched controlled study of a single center from China.

BACKGROUND: So far, little evidence is available for the comprehensive comparison of endoscopic submucosal tunnel dissection (ESTD) with endoscopic submucosal dissection (ESD) for the treatment of superficial neoplasia at esophagogastric junction (EGJ). METHODS: EGJ superficial neoplasia patients with ESTD treatment between January, 2021 and August, 2020 were retrospectively reviewed and individually matched at 1:1 ratio with those with ESD treatment according to lesion size, specimen area and lesion location, forming ESTD and ESD group, respectively. A sample size of 17 patients was collected for each group. Treatment outcomes including resection time, specimen area, and resection speed as well as occurrence of complications were evaluated. RESULTS: Compared with ESD group, ESTD group got shorter resection time (111.00 ± 11.70 min for ESD group vs. 71.59 ± 6.18 min for ESTD group, p = 0.008) and faster section speed (0.23 ± 0.03 cm2/min for ESD group vs. 0.37 ± 0.06 cm2/min for ESTD group, p = 0.012). No complication was found to occur in ESTD group, while 1 patient with MP damage and 1 with delayed bleeding was found in ESD group. CONCLUSION: For the treatment of EGJ superficial neoplasia, ESTD is a safer and more effective and reliable endoscopic technique compared with ESD.

Ultraprecision machining and on-machine measurement of the radial Fresnel lens structure array of a large-scale roller mold.

Automation and on-machine manufacturing process measurement is essential in increasing product productivity. However, a significant challenge is the radial Fresnel lens structure-array machining and on-machine measurement research for a large-scale roller mold. We present a rotating A-axis machining method for manufacturing an array of a radial Fresnel lens structure, based on an ultraprecision four-axis drum roll lathe system developed by the team. Therefore, based on the principle of a virtual multiprobe, the traditional two-point method is improved and applied to the on-machine measurement of the radial Fresnel lens structure of the roll mold. Through the machining and on-machine measurement experiments of the radial Fresnel lens structure of the roller mold, the feasibility of the machining method and measurement method is verified.

A novel colorectal anastomotic method in natural orifice specimen extraction surgery for colorectal cancer.

PURPOSE: We introduced a novel colorectal anastomotic technique, double-angle anastomosis combined with the double stapling technique (DAA-DST), to simplify the anastomosis step during natural orifice specimen extraction surgery (NOSES) and compared its safety and effectiveness with purse string anastomosis combined with the double stapling technique (PSA-DST). METHODS: Between January 2018 and March 2021, 63 patients with colorectal cancer underwent NOSES with DAA-DST or PSA-DST. We compared the perioperative and oncological outcomes between the groups. RESULTS: There were no significant differences in the operation time, blood loss, time to first passage of flatus and excrement or hospital stay duration between PSA-DST and DAA-DST groups. The overall postoperative complication rates were similar (DAA-DST vs PSA-DST, 21.2% vs 26.7%, p = 0.78), including the rate of anastomotic leakage (6.1% vs 10%, p = 0.91). The rate of successful DAA-DST was higher than that of PSA-DST (100% vs 93.3%). The DAA-DST group had a lower rate of positive drain fluid culture than the PSA-DST group (18.2% vs 26.7% p = 0.61). Recurrence (3.01% vs 6.67%, p = 0.93) and metastasis rates (6.06% vs 6.67%, p = 0.98) were similar between the groups. CONCLUSION: DAA-DST is a safe and effective procedure and can simplify the procedure of NOSES.

Hybrid endoscopic submucosal dissection: An alternative resection modality for large laterally spreading tumors in the cecum?

BACKGROUND: Endoscopic resection for large, laterally spreading tumors (LSTs) in the cecum is challenging. Here we report on the clinical outcomes of hybrid endoscopic submucosal dissection (ESD) in large cecal LSTs. METHODS: We retrospectively reviewed data from patients with cecal LSTs ≥ 2 cm who underwent ESD or hybrid ESD procedures between January of 2008 and June of 2019. We compared the baseline characteristics and clinical outcomes, including procedure time, the en bloc and complete resection rates, and adverse events. RESULTS: A total of 62 patients were enrolled in the study. There were 27 patients in the ESD group and 35 patients in the hybrid ESD group, respectively. Hybrid ESD was more used for lesions with submucosal fibrosis. No other significant differences were found in patient characteristics between the two groups. The hybrid ESD group had a significantly shorter procedure time compared with the ESD group (27.60 ± 17.21 vs. 52.63 ± 44.202 min, P = 0.001). The en bloc resection rate (77.1% vs. 81.5%, P = 0.677) and complete resection rate (71.4% vs. 81.5%, P = 0.359) of hybrid ESD were relatively lower than that of the ESD group in despite of no significant difference was found. The perforation and post-procedure bleeding rate (2.9% vs. 3.7%, P = 0.684) were similar between the two groups. One patient perforated during the ESD procedure, which was surgically treated. One patient in the hybrid ESD group experienced post-procedure bleeding, which was successfully treated with endoscopic hemostasis. Post-procedural fever and abdominal pain occurred in six patients in the ESD group and five patients in the hybrid ESD group. One patient in the ESD group experienced recurrence, which was endoscopically resected. CONCLUSION: The results of this study indicate that hybrid ESD may be an alternative resection strategy for large cecal LSTs with submucosal fibrosis.

Endoscopic versus surgical resection in the management of gastric schwannomas.

BACKGROUND AND AIMS: Gastric schwannoma (GS) is not well clinically recognized and surgical resection (SR) remains the mainstay of treatment. Recently, endoscopic resection (ER) appears to be a safe and effective alternative. However, its comparative outcomes with SR is lacking. Our aim was to first compare clinical outcomes and costs between ER and SR in the management of GSs. METHODS: A total of 46 consecutive patients with GSs who underwent ER (n = 16) or SR (n = 30) in our large tertiary center between July 2007 and Oct 2018 were included. Clinicopathologic features, clinical outcomes, medical costs and follow-up were retrospectively reviewed and compared between two groups. RESULTS: Baseline characteristics are comparable except for a smaller tumor size in ER group (22.9 vs 41.0 mm, p = 0.002). Complete resection was achieved in 87.5% of patients with ER and 100% of patients with SR (p = 0.116). The ER group had a significant shorter operative time (91.6 vs 128.2 min), less blood loss (16.9 vs 62.7 mL) and lower operation cost (21,054.4 vs 30,843.4 RMB) than SR group (all p < 0.05). There was no significant difference in adverse events (12.5% vs 10%, p = 0.812) and length of postoperative hospital stay (8.3 vs 8.2 days, p = 0.945). During a long-term follow-up of mean 37.4 months (range 6-140 months), no residue, recurrence or metastasis was observed in both groups. CONCLUSIONS: Compared with SR, ER has the similar safety and efficacy in the management of GSs, but contributes to a shorter operation time and lower medical costs. ER may be considered as the first-line treatment, especially for patients with GSs smaller than 30 mm.

The outcomes of modified endoscopic mucosal resection and endoscopic submucosal dissection for the treatment of rectal neuroendocrine tumors and the value of endoscopic morphology classification in endoscopic resection.

BACKGROUND: To compare the outcomes of modified endoscopic mucosal resection (m-EMR) and endoscopic submucosal dissection (ESD) for rectal neuroendocrine tumors (NETs) and evaluate the value of endoscopic morphology classification in endoscopic resection (ER). METHODS: Patients with rectal NET diameters less than 2 cm who were treated between April 2007 and January 2019 were enrolled. The endoscopic morphology of rectal NETs was classified based on the endoscopic views. Patients who underwent ESD and m-EMR were compared. Baseline characteristics as well as en bloc resection, complete resection, the procedure time, adverse events and the risk factors associated with incomplete resection were analyzed. RESULTS: A total of 429 patients with 449 rectal NETs were enrolled for the classification of endoscopic morphology and were classified into four types (Ia, IIb, II, and III). There were 79 patients in the m-EMR group and 259 patients in the ESD group before matching. Propensity score matching created 77 pairs between the two groups that were well balanced. The mean procedure time was significantly shorter for m-EMR than for ESD (9.1 ± 4.4 min vs 16.0 ± 7.9 min, P = 0.000). The rates of en bloc resection (98.7% vs 100%; P = 1.000), complete resection (90.9% vs 93.5%, P = 0.548) and adverse events (2.6% vs 2.6%, P = 1.000) were similar between the two groups. Univariate and multivariate analyses showed that histopathological grade and endoscopic morphology were associated with incomplete resection. CONCLUSION: Both ESD and m-EMR are effective and safe for the treatment of rectal NETs. Endoscopic morphology should be considered along with histopathological grade for ER.

Endoscopic submucosal excavation and endoscopic full-thickness resection for gastric schwannoma: five-year experience from a large tertiary center in China.

BACKGROUND AND AIMS: Endoscopic resection (ER) is an effective and safe method for gastric submucosal tumors, mostly composed of gastrointestinal stromal tumors and leiomyomas. The role of ER in gastric schwannoma (GS) has rarely been described. Our aim was to evaluate the efficacy and safety of ER for GS. METHODS: This is a retrospective study in consecutive patients who underwent ER for GS from March 2013 to October 2018 at our center. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS: A total of 16 consecutive patients (9 females, 56.3%) were included, with a mean age of 50.4 years (range 25-75 years). The mean tumor size was 22.9 ± 15.1 mm (range 10-55 mm). Thirteen tumors (81.3%) were located in the middle third of the stomach and 12 tumors (75%) grew with intraluminal pattern. Endoscopic submucosal excavation (ESE) was performed in 7 patients while endoscopic full-thickness resection (EFTR) was done in 9 patients. R0 resection was achieved in 14 patients (87.5%). The mean operative time was 91.6 ± 52.8 min (range 36-203 min) and the mean postoperative length of hospital stays was 8.3 ± 2.7 days (range 6-13 days). No adverse events were encountered except for fevers in 2 patients. No patients required surgical resection or intervention. During long-term follow-up of mean 21.8 months (range 6-62 months), no residue, recurrence, or metastasis was observed. CONCLUSIONS: ER is effective and safe for patients with GS with favorable long-term outcomes.

Enhanced Computed Tomography-Based Radiomics Signature Combined With Clinical Features in Evaluating Nuclear Grading of Renal Clear Cell Carcinoma.

OBJECTIVE: The aim of the study was to explore the value of enhanced computed tomography (CT)-based radiomics signature combined with clinical features in evaluating nuclear grading of clear cell renal cell carcinoma (ccRCC). METHODS: One hundred one patients with ccRCC were classified into low- and high-grade group, and the data were divided into training set and verification set. Radiomics signatures were constructed in the training set in enhanced 3 stages and the combination of them. The predictive nomogram was constructed. The classification efficiency and the clinical practicability of the integrated radiomics model were evaluated. RESULTS: The classification efficiency of enhanced 3-stage integrated histology model was higher than that of each single-phase model. The predictive nomogram incorporated the best radiomics signature, and the independent clinical risk factors showed good performance. A decision curve analysis curve shows that the net benefit of the combined model. CONCLUSIONS: It is feasible to evaluate the nuclear grading of ccRCC based on enhanced CT radiomics signature combined with clinical features.

Single probe shear scanning method for on-machine measurement of an optical profile.

This study presents a new (to the best of our knowledge) error separation method with a single displacement probe, named as single probe shear scanning (SPSS) method, for the on-machine optical profile measurement to overcome the problems of the existing multiprobe method like the large deviation of probe spacing and the probes' performance difference. The confocal sensor with superior dynamic range, high lateral resolution, and large measurement angle to surface is applied in this study to fulfill the measurement of the optical aspheric surface. The single probe measurement system, in which the probe fixed on a flexure hinge is driven straight within a millimeter-level travel range, is established to realize the function of the multiprobe. For the established system, a new exact profile reconstruction algorithm is built to eliminate the influences of straightness errors of the scanning stage and the systemic errors of shear stage, and to reduce the effect of the sensor drift. The reconstruction algorithms by difference measurement with two shears are studied to build the bidirectional segment stitching reconstruction method, which reduces the error accumulation and improves the reconstruction accuracy under the condition of measuring errors. A profile reconstruction method with three shears measurement is proposed to make a further improvement on the reconstruction accuracy. The proposed reconstruction method with three shears measurement is successfully employed for the on-machine measurement of an aspheric surface profile, and the evaluation results agree well with those from the Taylor profiler.

Applying multiple approaches to deepen understanding of mixing and mass transfer in large-scale aerobic fermentations.

Different methods are used at Corteva® Agriscience to improve our understanding of mixing in large-scale mechanically agitated fermentors. These include (a) use of classical empirical correlations, (b) use of small-scale models, and (c) computational fluid dynamics (CFD). Each of these approaches has its own inherent strengths and limitations. Classic empirical or semi-empirical correlations can provide insights into mass transfer, blending, shear, and other important factors but are dependent on the geometry and condition used to develop the correlations. Laboratory-scale modelling can be very useful to study mixing and model the effect of heterogeneity on the culture, but success is highly dependent on the methodology applied. CFD provides an effective means to accelerate the exploration of alternative design strategies through physics-based computer simulations that may not be adequately described by existing knowledge or correlations. However, considerable time and effort is needed to build and validate these models. In this paper, we review the various approaches used at Corteva Agriscience to deepen our understanding of mixing in large-scale fermentation processes.

Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody.

Broadly neutralizing antibodies targeting the stalk region of influenza A virus (IAV) hemagglutinin (HA) are effective in blocking virus infection both in vitro and in vivo. The highly conserved epitopes recognized by these antibodies are critical for the membrane fusion function of HA and therefore less likely to be permissive for virus mutational escape. Here we report three resistant viruses of the A/Perth/16/2009 strain that were selected in the presence of a broadly neutralizing stalk-binding antibody. The three resistant viruses harbor three different mutations in the HA stalk: (1) Gln387Lys; (2) Asp391Tyr; (3) Asp391Gly. The Gln387Lys mutation completely abolishes binding of the antibody to the HA stalk epitope. The other two mutations, Asp391Tyr and Asp391Gly, do not affect antibody binding at neutral pH and only slightly reduce binding at low pH. Interestingly, they enhance the fusion ability of the HA, representing a novel mechanism that allows productive membrane fusion even in the presence of antibody and hence virus escape from antibody neutralization. Therefore, these mutations illustrate two different resistance mechanisms used by IAV to escape broadly neutralizing stalk-binding antibodies. Compared to the wild type virus, the resistant viruses release fewer progeny viral particles during replication and are more sensitive to Tamiflu, suggesting reduced viral fitness.

Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins.

The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC50) of <0.01 to 4.9 µg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 µg/ml; it contained HA2-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 µg/ml; they shared the substitution HA2-Asp19Asn/Ala. Conversely, H9 viruses harboring HA2-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA2-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA2-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses. IMPORTANCE: Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses.

Symptom-triggered alcohol vapor inhalation for postoperative alcohol withdrawal syndrome in patients with gastroesophageal carcinoma.

PURPOSE: The purpose of this study was to investigate the feasibility and efficacy of alcohol vapor inhalation during fasting time for cancer patients with alcohol withdrawal symptoms (AWS) after surgery. METHODS: The data of 51 patients after esophagectomy or gastrectomy for gastroesophageal carcinoma in two hospitals from January 2011 to December 2016 was retrospectively analyzed. These patients were diagnosed with AWS with Clinic Institute Alcohol Withdrawal Syndrome Scale (CIWA-Ar) score ≥ 9 in two hospitals during fasting time from January 2011 to December 2016, and they were accordingly divided into alcohol vapor group (n=25) and diazepam group (n=26). As oral intake of wine was forbidden in the first 7 postoperative days, these patients received either alcohol vapor inhalation or intravenous administration of diazepam every 12 hrs. The difference in scores of CIWA-Ar, Riker Sedation-Agitation Scale (SAS), side effects and complications were registered and analyzed. RESULTS: The patients in both groups gained satisfactory efficacy which was indicated by CIWA-Ar scores after therapy, without obvious difference in terms of surgery-related complications, chest and abdominal drainage, serum biomarkers of hepatic function or postoperative hospital stay. However, the patients treated with alcohol vapor inhalation displayed lower alcohol craving and sleepiness, more significant decreased CIWA-Ar scores, as well as encouragingly higher degree of satisfaction, comparing with the diazepam group. CONCLUSION: Alcohol vapor inhalation is feasible and effective to alleviate AWS timely, which is reliable for patients to get through the fasting time after surgery.