Vascular endothelial growth factor receptor 2 as a potential host target for the inhibition of enterovirus replication.

Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics. IMPORTANCE: As the first clinical case was identified in the United States, EV-A71, a significant neurotropic enterovirus, has been a common cause of hand, foot, and mouth disease (HFMD) in infants and young children. Developing an effective antiviral agent for EV-A71 and other human enteroviruses is crucial, as these viral pathogens consistently cause outbreaks in humans. In this study, we demonstrated that multiple inhibitors against VEGFRs effectively reduced EV-A71 replication, with Pazopanib emerging as the top candidate. Furthermore, Pazopanib also attenuated the replication of other enteroviruses, including CVA10, CVB1, EV-D70, and HRV-A, displaying broad-spectrum anti-enterovirus activity. Given that Pazopanib targets various VEGFRs, we narrowed the focus to VEGFR2 using knockdown and overexpression experiments. Transcriptomic analysis suggests that Pazopanib's potential downstream targets involve the TSAd-Src-PI3K-Akt pathway. Our work may contribute to identifying targets for antiviral inhibitors and advancing treatments for human enterovirus infections.

Intradermal Injection of a Thermoresponsive Polymeric Dexamethasone Prodrug (ProGel-Dex) Ameliorate Dermatitis in an Imiquimod (IMQ)-Induced Psoriasis-like Mouse Model.

Psoriasis is a chronic immune-mediated inflammatory skin disease, affecting ∼ 3% of the US population. Although multiple new systemic therapies have been introduced for the treatment of psoriatic skin disease, topical and intralesional glucocorticoids (GCs) continue to be used as effective psoriasis therapies. Their clinical utility, however, has been hampered by significant adverse effects, including skin atrophy and pigmentation as well as elevated blood glucose levels and hypertension. To mitigate these limitations, we have developed a N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug (ProGel-Dex) and assessed its therapeutic efficacy and safety in an imiquimod (IMQ)-induced psoriasis-like (PL) mouse model. ProGel-Dex was intradermally administered once at three dosing levels: 0.5, 1.0, and 2.0 mg/kg/day Dex equivalent at the beginning of the study. PL mice were also treated with daily topical saline or Dex, which were used as control groups. Treatment of PL mice with ProGel-Dex dosed at 0.5 mg/kg/day resulted in a significant reduction in scaling and erythema. Improvement in gross pathology scores, skin histological scores, and serum cytokine levels was also observed. Interestingly, for mice treated with ProGel-Dex at 1.0 and 2.0 mg/kg/day Dex equivalent, only improvement in skin erythema was observed. GC-associated side effects, such as elevation of serum alanine aminotransferase (ALT) and amylase levels and body weight loss, were not observed in mice treated with ProGel-Dex at 0.5 and 1.0 mg/kg/day Dex equivalent. Collectively, these results demonstrate the efficacy and improved safety of ProGel-Dex in treating psoriatic skin lesions when compared to topical Dex treatment, supporting its translational potential for clinical management of lesional skin psoriasis.

Thin-Film Composite Membranes Interlayered with Amphiphilic MoS2 Nanosheets via Controllable Interfacial Polymerization for Enhanced Desalination Performance.

Polyamide (PA)-based nanofiltration (NF) membranes have demonstrated extensive applications for a sustainable water-energy-environment nexus. A rational control of interfacial polymerization (IP) is highly efficacious to enhance NF separation performance yet remains a technical challenge. Herein, we proposed a regulation strategy of constructing amphiphilic molybdenum disulfide/cetyltrimethylammonium bromide interlayer atop the Kevlar hydrogel substrate. The amphiphilic nanosheet interlayered NF membrane exhibited a crumpled PA surface with an elevated cross-linking degree of 76.9%, leading to an excellent water permeance (16.8 L m-2 h-1 bar-1) and an impressive Na2SO4 rejection (99.1%). Meanwhile, the selectivity coefficient of Na2SO4/NaCl of the optimized TFC membrane reached 91, surpassing those of the recently reported NF membranes. Moreover, the optimized membrane exhibited a desirable rejection of over 90% against Mn2+ and Cu2+ in actual textile wastewater. Importantly, the underlying NF membrane formation mechanism was elucidated via both experiments and molecular simulations. The synchronous control of mass and heat transfer of IP process offers a new methodology for the state-of-the-art membrane fabrication, which opens more avenues in softening of brackish water and purification of industrial wastewater containing heavy metal ions.

Construction of a Decellularized Multicomponent Extracellular Matrix Interpenetrating Network Scaffold by Gelatin Microporous Hydrogel 3D Cell Culture System.

Interface tissue repair requires the construction of biomaterials with integrated structures of multiple protein types. Hydrogels that modulate internal porous structures provide a 3D microenvironment for encapsulated cells, making them promise for interface tissue repair. Currently, reduction of intrinsic immunogenicity and increase of bioactive extracellular matrix (ECM) secretion are issues to be considered in these materials. In this study, gelatin methacrylate (GelMA) hydrogel is used to encapsulate chondrocytes and construct a phase transition 3D cell culture system (PTCC) by utilizing the thermosensitivity of gelatin microspheres to create micropores within the hydrogel. The types of bioactive extracellular matrix protein formation by chondrocytes encapsulated in hydrogels are investigated in vitro. After 28 days of culture, GelMA PTCC forms an extracellular matrix predominantly composed of collagen type II, collagen type I, and fibronectin. After decellularization, the protein types and mechanical properties are well preserved, fabricating a decellularized tissue-engineered extracellular matrix and GelMA hydrogel interpenetrating network hydrogel (dECM-GelMA IPN) consisting of GelMA hydrogel as the first-level network and the ECM secreted by chondrocytes as the second-level network. This material has the potential to mediate the repair and regeneration of tendon-bone interface tissues with multiple protein types.

Identification of formulation parameters that affect the analgesic efficacy of ProGel-Dex - A thermoresponsive polymeric dexamethasone prodrug for chronic arthritis pain relief.

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis. The focus of the present study was to investigate the impact of ProGel-Dex formulation parameters on its physicochemical properties and in vivo efficacy. The results of this study provide essential knowledge for the future design of ProGel-Dex that can provide more effective, sustained and safe relief of joint pain and inflammation.

Digitally driven surgical guide planning.

To investigate the role of a fully digital process in the surgical treatment of mandibular fractures in children. We analyzed a complete dataset from 22 children with mandibular fractures treated with digital surgical assistance. The patient's treatment process included preoperative thin layer CT (Computed Tomography) scanning, computer-aided design (3D reconstruction, virtual reduction, and internal fixation device determination and shaping), and 3D printing (jaw model, bite plate). We used occlusal and shaping plates during surgery to assist in fracture reduction and fixation. During the follow-up, we observed the occurrence of fracture healing, occlusal relationships, opening degrees, and complications in pediatric patients after surgery. Next, we used the 3D overlay function of MIMICS software to compare the preoperative surgical design with postoperative jaw imaging data to evaluate the overall surgical effect. The postoperative imaging data showed good fracture healing, normal occlusion during follow-up, and significant improvement in opening degrees. The mean preoperative opening degree was 23.59 ± 2.89 mm, and the mean postoperative opening degree was 29.82 ± 1.79 mm; there was a significant difference between these two parameters (p < 0.05). There were no complications such as tooth germ injury, nerve injury or fracture block displacement. The postoperative mandibular imaging data was imported into MIMICS software for 3D overlay visualization, and the postoperative mandibular morphology recovery was well-matched with the preoperative design. We measured the average upper deviation (0.65 ± 0.09) mm and the average lower deviation (-0.57 ± 0.14) mm. The fully digital process has a precise, minimally invasive, and safe effect in the surgical treatment of mandibular fractures in children, and the clinical effect is satisfactory.

Engineered Anchor Peptide LCI with a Cobalt Cofactor Enhances Oxidation Efficiency of Polystyrene Microparticles.

A typical component of polymer waste is polystyrene (PS) used in numerous applications, but degraded only slowly in the environment due to its hydrophobic properties. To increase the reactivity of polystyrene, polar groups need to be introduced. Here, biohybrid catalysts based on the engineered anchor peptide LCI_F16C are presented, which are capable of attaching to polystyrene microparticles and hydroxylating benzylic C-H bonds in polystyrene microparticles using commercially available oxone as oxidant. LCI peptides achieve a dense surface coverage of PS through monolayer formation within minutes in aqueous solutions at ambient temperature. The catalytically active cobalt cofactor Co-L1 or Co-L2 with a modified NNNN macrocyclic TACD ligand (TACD=1,4,7,10-tetraazacyclododecane) is covalently bound to the anchor peptide LCI through a maleimide linker. Compared to the free cofactors, a 12- to 15-fold improvement in catalytic activity using biohybrid catalysts based on LCI_F16C was observed.

Pyridinium-Yne Click Polymerization: A Facile Strategy toward Functional Poly(Vinylpyridinium Salt)s with Multidrug-Resistant Bacteria Killing Ability.

Polymeric materials with antibacterial properties hold great promise for combating multidrug-resistant bacteria, which pose a significant threat to public health. However, the synthesis of most antibacterial polymers typically involves complicated and time-consuming procedures. In this study, we demonstrate a simple and efficient strategy for synthesizing functional poly(vinylpyridinium salt)s via pyridinium-yne click polymerization. This click polymerization could proceed with high atom economy under mild conditions without any external catalyst, yielding soluble and thermally stable poly(vinylpyridinium salt)s with satisfactory molecular weights and well-defined structures in excellent yields. Additionally, the incorporation of luminescent units such as fluorene, tetraphenylethylene, and triphenylamine into the polymer backbone confers excellent aggregation-enhanced emission properties upon the resulting polymers, rendering them suitable for bacterial staining. Moreover, the existence of pyridinium salt imparts intrinsic antibacterial activity against multidrug-resistant bacteria to the polymers, enabling them to effectively inhibit wound bacterial infection and significantly expedite the healing process. This work not only provides an efficient method to prepare antibacterial polymers, but also opens up the possibility of various applications of polymers in healthcare and other antibacterial fields.

Adding Flying Wings: Butterfly-Shaped NIR-II AIEgens with Multiple Molecular Rotors for Photothermal Combating of Bacterial Biofilms.

The ever-increasing threats of multidrug-resistant bacteria and their biofilm-associated infections have bred a desperate demand for alternative remedies to combat them. Near-infrared (NIR)-absorbing photothermal agent (PTAs)-mediated photothermal therapy (PTT) is particularly attractive for biofilm ablation thanks to its superiorities of noninvasive intervention, satisfactory antibacterial efficiency, and less likelihood to develop resistance. Herein, three butterfly-shaped aggregation-induced emission luminogens (AIEgens) with balanced nonradiative decay (for conducting PTT) and radiative decay (for supplying fluorescence in the NIR-II optical window) are rationally designed for imaging-assisted photothermal obliteration of bacterial biofilms. After being encapsulated into cationic liposomes, AIEgens-fabricated nanoparticles can eradicate a wide spectrum of biofilms formed by Gram-positive bacteria (methicillin-resistant Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) upon an 808 nm laser irradiation. In vivo experiments firmly demonstrate that the NIR-II AIE liposomes with excellent biocompatibility perform well in both the P. aeruginosa biofilm-induced keratitis mouse model and the MSRA biofilm-induced skin infection mouse model.

A lightweight strain glass alloy showing nearly temperature-independent low modulus and high strength.

Fast development of space technologies poses a strong challenge for elastic materials, which need to be not only lightweight, strong and compliant, but also able to maintain stable elasticity over a wide temperature range1-4. Here we report a lightweight magnesium-scandium strain glass alloy (Mg with 21.3 at.% Sc) that meets this challenge. This alloy is as light (density ~2 g cm-3) and compliant as organic-based materials5-7 like bones and glass fibre reinforced plastics, but in contrast with those materials, it possesses a nearly temperature-independent (or Elinvar-type), ultralow Young's modulus (~20-23 GPa) over a wide temperature range from room temperature down to 123 K; a higher yield strength of ~200-270 MPa; and a long fatigue life of over one million cycles. As a result, it exhibits a relatively high, temperature-independent elastic energy density of ~0.5 kJ kg-1 among known materials at a moderate stress level of 200 MPa. We show that its exceptional properties stem from a strain glass transition, and the Elinvar-type elasticity originates from its moderate elastic softening effect cancelling out the ever-present elastic hardening. Our findings provide insight into designing materials that possess unconventional and technologically important elastic properties.

Temperature-mediated diffusion of nanoparticles in semidilute polymer solutions.

The temperature is often a critical factor affecting the diffusion of nanoparticles in complex physiological media, but its specific effects are still to be fully understood. Here, we constructed a temperature-regulated model of semidilute polymer solution and experimentally investigated the temperature-mediated diffusion of nanoparticles using the particle tracking method. By examining the ensemble-averaged mean square displacements (MSDs), we found that the MSD grows gradually as the temperature increases while the transition time from sublinear to linear stage in MSD decreases. Meanwhile, the temperature-dependent measured diffusivity of the nanoparticles shows an exponential growth. We revealed that these temperature-mediated changes are determined by the composite effect of the macroscale property of polymer solution and the microscale dynamics of polymer chain as well as nanoparticles. Furthermore, the measured non-Gaussian displacement probability distributions were found to exhibit non-Gaussian fat tails, and the tailed distribution is enhanced as the temperature increases. The non-Gaussianity was calculated and found to vary in the same trend with the tailed distribution, suggesting the occurrence of hopping events. This temperature-mediated non-Gaussian feature validates the recent theory of thermally induced activated hopping. Our results highlight the temperature-mediated changes in diffusive transport of nanoparticles in polymer solutions and may provide the possible strategy to improve drug delivery in physiological media.

Quinoid Conjugated Polymer Nanoparticles with NIR-II Absorption Peak Toward Efficient Photothermal Therapy.

Recently, extensive efforts have been devoted to the development of the second near-infrared bio-window (NIR-II, 1000-1700 nm) theranostic agents owing to the excellent tissue-penetration capability of NIR-II light. The exploration of organic NIR-II photothermal therapy materials, especially those with absorption peak over 1000 nm, is an appealing yet significantly challenging task. Herein, we have designed conjugated polymer nanoparticles (PIS NPs) with NIR-II absorption peak at 1026 nm through a combined strategy of introducing quinoid donor-acceptor (D-A) structures, constructing intramolecular "conformational locks" and extending the conjugation area to narrow the band gap. Irradiated at 1064 nm, PIS NPs showed remarkable photothermal conversion performance for efficient photothermal ablation of tumor cells in vitro and in vivo. This study provides useful insights into the rational design of organic NIR-II photothermal agents based on multiple strategies.

The Development of Thermoresponsive Polymeric Simvastatin Prodrug for the Treatment of Experimental Periodontitis in Rats.

Periodontitis (PD) is a severe inflammatory gum pathology that damages the periodontal soft tissue and bone. It is highly prevalent in the US, affecting more than 47% of adults. Besides routine scaling and root planing, there are few effective treatments for PD. Developed as an effective treatment for hyperlipidemia, simvastatin (SIM) is also known for its well-established anti-inflammatory and osteogenic properties, suggesting its potential utility in treating PD. Its clinical translation, however, has been impeded by its poor water-solubility, lack of osteotropicity, and side effects (e.g., hepatoxicity) associated with systemic exposure. To address these challenges, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive polymeric prodrug of SIM (ProGel-SIM) was developed as a local therapy for PD. Its aqueous solution is free-flowing at 4 °C and transitions into a hydrogel at ∼30 °C, allowing for easy local application and retention. After a thorough characterization of its physicochemical properties, ProGel-SIM was administered weekly into the periodontal pocket of an experimental rat model of PD. At 3 weeks post initiation of the treatment, the animals were euthanized with palate isolated for µ-CT and histological analyses. When compared to dose equivalent simvastatin acid (SMA, active form of SIM) treatment, the rats in the ProGel-SIM treated group showed significantly higher periodontal bone volume (0.34 mm3 vs 0.20 mm3, P = 0.0161) and less neutrophil (PMN) infiltration (P < 0.0001) and IL-1ß secretion (P = 0.0036). No measurable side effect was observed. Collectively, these results suggest that ProGel-SIM may be developed as a promising drug candidate for the effective clinical treatment of PD.

Stiff Shape Memory Polymers for High-Resolution Reconfigurable Nanophotonics.

Reconfigurable metamaterials require constituent nanostructures to demonstrate switching of shapes with external stimuli. Yet, a longstanding challenge is in overcoming stiction caused by van der Waals forces in the deformed configuration, which impedes shape recovery. Here, we introduce stiff shape memory polymers. This designer material has a storage modulus of ∼5.2 GPa at room temperature and ∼90 MPa in the rubbery state at 150 °C, 1 order of magnitude higher than those in previous reports. Nanopillars with diameters of ∼400 nm and an aspect ratio as high as ∼10 were printed by two-photon lithography. Experimentally, we observe shape recovery as collapsed and touching structures overcome stiction to stand back up. We develop a theoretical model to explain the recoverability of these sub-micrometer structures. Reconfigurable structural color prints with a resolution of 21150 dots per inch and holograms are demonstrated, indicating potential applications of the stiff shape memory polymers in high-resolution reconfigurable nanophotonics.

Mutations of PTCH1 gene in two pedigrees with bifid rib-basal cell nevus-jaw cyst syndrome. / 肋骨分叉-基底细胞痣-é¢Œéª¨å›Šè‚¿ç»¼åˆå¾ä¸¤å®¶ç³»åŸºå› åºåˆ—å˜å¼‚åˆ†æž.

Two male patients with bifid rib-basal cell nevus-jaw cyst syndrome (BCNS) were admitted to Department of Stomatology, the First Affiliated Hospital of Bengbu Medical College due to radiological findings of multiple low density shadows in the jaw. Clinical and imaging findings showed thoracic malformation, calcification of the tentorium cerebellum and falx cerebrum as well as widening of the orbital distance. Whole exon high-throughput sequencing was performed in two patients and their family members. The heterozygous mutations of c.C2541C>A(p.Y847X) and c.C1501C>T(p.Q501X) in PTCH1 gene were detected in both patients. Diagnosis of BCNS was confirmed. The heterozygous mutations of PTCH1 gene locus were also found in the mothers of the two probands. Proband 1 showed clinical manifestations of low intelligence, and heterozygous mutations of c.C2141T(p.P714L) and c.G3343A(p.V1115I) were detected in FANCD2 gene. Proband 2 had normal intelligence and no FANCD2 mutation. The fenestration decompression and curettage of jaw cyst were performed in both patients. Regular follow-up showed good bone growth at the original lesion, and no recurrence has been observed so far.

Biodegradable Dual-Network Cellulosic Composite Bioplastic Metafilm for Plastic Substitute.

With the escalating environmental and health concerns over petroleum-based plastics, sustainable and biodegradable cellulosic materials are a promising alternative to plastics, yet remain unsatisfied properties such as fragility, inflammability and water sensitivity for practical usage. Herein, we present a novel dual-network design strategy to address these limitations and fabricate a high-performance cellulosic composite bioplastic metafilm with the exceptional mechanical toughness (23.5 MJ m-3 ), flame retardance, and solvent resistance by in situ growth of cyclotriphosphazene-bridged organosilica network within bacterial cellulose matrix. The phosphorus, nitrogen-containing organosilica network, verified by the experimental and theoretical results, plays a triple action on significantly enhancing tensile strength, toughness, flame retardance and water resistance of composite bioplastic metafilm. Furthermore, cellulosic bioplastic composite metafilm demonstrates a higher maximum usage temperature (245 °C), lower thermal expansion coefficient (15.19 ppm °C-1 ), and better solvent resistance than traditional plastics, good biocompatibility and natural biodegradation. Moreover, the composite bioplastic metafilm have a good transparency of average 74 % and a high haze over 80 %, which can serve as an outstanding substrate substitute for commercial polyethylene terephthalate film to address the demand of flexible ITO films. This work paves a creative way to design and manufacture the competitive bioplastic composite to replace daily-used plastics.

Cascade C-H-Activated Polyannulations toward Ring-Fused Heteroaromatic Polymers for Intracellular pH Mapping and Cancer Cell Killing.

The development of straightforward and efficient synthetic methods toward ring-fused heteroaromatic polymers with attractive functionalities has great significance in both chemistry and materials science. Herein, we develop a facile cascade C-H-activated polyannulation route that can in situ generate multiple ring-fused aza-heteroaromatic polymers from readily available monomers in an atom-economical manner. A series of complex polybenzimidazole derivatives with high absolute molecular weights of up to 24 000 are efficiently produced in high yields within 2 h. Benefiting from their unique imidazole-containing ring-fused structures with multiple aryl pendants, the obtained polymers show excellent thermal and morphological stability, good solution processability, high refractive index, small chromic dispersion, as well as remarkable acid-base-responsive fluorescence. Taking advantage of the ratiometric fluorescence response of the triphenylamine-substituted heteroaromatic polymer to pH variations, we successfully apply it as a sensitive fluorescence probe for the mapping and quantitative analysis of intracellular pH in live cells. Furthermore, through the simple N-methylation reaction of the ring-fused polybenzimidazoles, diverse azonia-containing polyelectrolytes are readily produced, which can efficiently kill cancer cells via the synergistic effects of dark toxicity and phototoxicity.

Non-equilibrium Nanoassemblies Constructed by Confined Coordination on a Polymer Chain.

Biological systems employ non-equilibrium self-assembly to create ordered nanoarchitectures with sophisticated functions. However, it is challenging to construct artificial non-equilibrium nanoassemblies due to lack of control over assembly dynamics and kinetics. Herein, we design a series of linear polymers with different side groups for further coordination-driven self-assembly based on shape-complementarity. Such a design introduces a main-chain confinement which effectively slows down the assembly process of side groups, thus allowing us to monitor the real-time evolution of lychee-like nanostructures. The function related to the non-equilibrium nature is further explored by performing photothermal conversion study. The ability to observe and capture non-equilibrium states in this supramolecular system will enhance our understanding of the thermodynamic and kinetic features as well as functions of living systems.

Unraveling Amphiphilic Poly(N-vinylcaprolactam)/Water Interface by Nuclear Magnetic Resonance Relaxometry: Control of Clathrate Hydrate Formation Kinetics.

Water-soluble amphiphilic polymers are vital chemicals in the oil and gas industry to retard crystal growth of hydrocarbon hydrate via surface adsorption and suppress nucleation of a pristine hydrate nucleus, thereby preventing formation of hydrate blockages in flow lines during oil and natural gas production. Apart from a few theoretical modeling studies, an experimental method to study the polymer/water interface in the crystal growth is critically needed. Here, water motions in the hydration shells of an exemplary kinetic inhibitor, poly(N-vinylcaprolactam), during hydrate formation from the tetrahydrofuran/water system are revealed via nuclear magnetic resonance relaxometry. Unequivocal experiments show that the pivotal interfacial water in the tightly bound state gradually freezes at rates depending on the polymer molecular weight (MW). This is supported by nonfreezable water analysis, which is correlated to the inhibition time. The polymers tune the kinetics of the hydration process via interaction with and perturbation of the water molecules. The free water component in the polymer solution crystallizes at a very slow rate when in partially restricted mobility, whereas the bound water component increases in the reaction, with the polymer/water interface serving as the reaction sites. The appropriate MW (including average MW and polydispersity values) of the inhibitive polymers can give rise to maximal retardation of the hydrate crystal growth. This work will help control other multiphase crystallization kinetic processes through the design of inhibitors or promoters functioning in the interface.

Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial.

BACKGROUND: Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days. METHODS: This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis. RESULTS: A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups. CONCLUSIONS: In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications.