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Liquid crystalline elastomers (LCEs) are increasingly considered as advanced materials that prospectively may enable distinctive functional utility in medical devices, consumer goods, and aerospace. This report details the contribution of the polymerization conditions within the thermotropic phase behavior of material compositions and systematically illustrates the substantive contributions of nematic genesis to the resulting thermomechanical response. Compositionally identical LCEs were polymerized in the monodomain orientation over a range of temperatures in the nematic phase of the formulations. Upon polymerization, the thermomechanical response of the compositionally identical LCEs prepared over a range of temperatures had a 15% increase in the nematic to isotropic transition temperature (TNI), 50% decrease in the magnitude of the thermomechanical response, and 25% decrease in total actuation stroke. X-ray scattering was utilized to elucidate the correlation of polymerization temperature (e.g., nematic genesis) to the orientational order of LCEs. These measurements show, in addition to differences in mechanical properties between the LCEs, the nematic genesis of the polymerization reaction affects the overall degree of liquid crystallinity, the coherence length of the cybotactic nematic domains, and the orientation parameter of the LCE.

•The combination of ibrutinib and venetoclax induced deep and durable responses in treatment-naïve patients with Waldenström macroglobulinemia.•Planned study therapy was stopped early due to a higher-than-expected occurrence of ventricular arrhythmia in 4 of the 45 participants.

ABSTRACT:The island of Ireland is divided, not only politically into two states, Ireland and Northern Ireland, but also in the world of soccer. Thus, it represents a suitable subject for research from an international relations (IR) perspective. This article explores the roles of the Football Association of Ireland (FAI) and the Irish Football Association (IFA), domestic political actors, and the game's international governance institutions that may have impacted the international relations of Ireland's two states. The evidence shows that football actors in Northern Ireland attempted to impact the IR of football of Ireland. Also, the preservation of the status quo as regards a football merger is related to the interests of individuals in key international football governance positions on both sides of the border and on attempts by the two states to secure an All-Ireland international representation as proposed by the constructivist theory of international relations.

Liquid crystal elastomers (LCEs) are a class of active materials that can generate rapid, reversible mechanical actuation in response to external stimuli. Fabrication methods for LCEs have remained a topic of intense research interest in recent years. One promising approach, termed 4D printing, combines the advantages of 3D printing with responsive materials, such as LCEs, to generate smart structures that not only possess user-defined static shapes but also can change their shape over time. To date, 4D-printed LCE structures have been limited to flat objects, restricting shape complexity and associated actuation for smart structure applications. In this work, we report the development of embedded 4D printing to extrude hydrophobic LCE ink into an aqueous, thixotropic gel matrix to produce free-standing, free-form 3D architectures without sacrificing the mechanical actuation properties. The ability to 4D print complex, free-standing 3D LCE architectures opens new avenues for the design and development of functional and responsive systems, such as reconfigurable metamaterials, soft robotics, or biomedical devices.

Disappearing intracranial aneurysms are rare and have not been extensively reported in the literature. They are often small or partially thrombosed and carry a significant risk of recurrence. We discuss a unique case of a 65-year-old woman who presented in 2006 with a subarachnoid hemorrhage and was found to have a ruptured posterior communicating artery and an unruptured P1 aneurysm. Follow-up angiography and imaging showed no changes in the size of a left P1 aneurysm for 11 years (2006–2017). However, in 2021, 15 years after initial presentation, no aneurysm was seen on magnetic resonance angiography, and subsequent digital subtraction angiography in 2022 showed almost complete disappearance of the unruptured P1 aneurysm. Literature review reveals only six reported cases during which a small, unruptured anterior circulation aneurysm disappeared, or regressed on follow-up imaging and no reported cases in the posterior circulation.

Liquid crystalline elastomers (LCEs) are shape-changing materials that exhibit large deformations in response to applied stimuli. Local control of the orientation of LCEs spatially directs the deformation of these materials to realize a spontaneous shape change in response to stimuli. Prior approaches to shape programming in LCEs utilize patterning techniques that involve the detailed inscription of spatially varying nematic fields to produce sheets. These patterned sheets deform into elaborate geometries with complex Gaussian curvatures. Here, we present an alternative approach to realize shape-morphing in LCEs where spatial patterning of the crosslink density locally regulates the material deformation magnitude on either side of a prescribed interface curve. We also present a simple mathematical model describing the behavior of these materials. Further experiments coupled with the mathematical model demonstrate the control of the sign of Gaussian curvature, which is used in combination with heat transfer effects to design LCEs that self-clean as a result of temperature-dependent actuation properties.

Liquid crystalline elastomers (LCEs) are stimulus-responsive materials that, when macroscopically aligned, undergo large, directional deformation amplified by the disruption of order within a polymer network. Recently, surface-enforced alignment has been used to prepare LCEs with spatial variation in the director orientation that enables the realization of complex 3-D shape transformation. Surface-enforced alignment is advantageous because it allows for high-resolution, nonlinear patterning of the nematic director within an LCE. When using surface alignment to enforce orientation within LCEs, multiple two-step reaction schemes have been commonly used, primarily aza-Michael oligomerization or thiol-Michael oligomerization with each addition reaction followed by photopolymerization of the residual acrylate-terminated oligomers. Here, LCEs were prepared by each polymerization technique with varied amine or thiol concentrations. The mechanical properties, thermomechanical response, reaction kinetics, and alignment were characterized and assessed for LCEs. This examination emphasizes the importance of the molecular weight between crosslinks over the reaction used to form the oligomer in determining the magnitude of the stimulus response of LCEs.

The large, directional stimuli-response of aligned liquid crystalline elastomers (LCEs) could enable functional utility in robotics, medicine, consumer goods, and photonics. The alignment of LCEs has historically been realized via mechanical alignment of a two-stage reaction. Recent reports widely utilize chain extension reactions of liquid crystal monomers (LCM) to form LCEs that are subject to either surface-enforced or mechanical alignment. Here, we prepare LCEs that contain intra-mesogenic supramolecular bonds synthesized via direct free-radical chain transfer photopolymerization processible by a distinctive mechanical alignment mechanism. The LCEs were prepared by the polymerization of a benzoic acid monomer (11OBA), which dimerized to form a liquid crystal monomer, with a diacrylate LCM (C6M). The incorporation of the intra-mesogenic hydrogen bonds increases the achievable nematic order from mechanical programming. Accordingly, LCEs prepared with larger 11OBA concentration exhibit higher magnitude thermomechanical strain values when compared to a LCE containing only covalent bonds. These LCEs can be reprogrammed with heat to return the aligned film to the polydomain state. The LCE can then be subsequently programmed to orient in a different direction. The facile preparation of (re)programmable LCEs with supramolecular bonds opens new avenues for the implementation of these materials as shape deployable elements.

Aneurysmal subarachnoid hemorrhage (SAH) continues to be a difficult cerebrovascular disease with limited pharmacologic treatment options. Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are leading causes of morbidity and mortality after SAH. Despite the advances in the understanding of its pathophysiology and tremendous efforts to date, nimodipine is currently the sole Food and Drug Administration–approved treatment for patients with SAH, with benefits that are marginal at best. The neuromodulation therapies are promising, especially those that target CV and DCI to improve functional outcomes. The aim of this review is therefore to summarize the available evidence for each type of neuromodulation for CV and DCI, with a special focus on its pathophysiological mechanisms, in addition to their clinical utility and drawbacks, which we hope will lead to future translational therapy options after SAH.

Introduction Quantitative magnetic resonance angiography and non-invasive optimal vessel analysis serve as powerful tools to collect and analyze hemodynamic data from pipeline embolization patients. At our institution, patients receive post-embolization quantitative magnetic resonance angiography within 24 h of treatment and within 6 months for follow-up to evaluate pipeline patency. Here, we aim to elucidate the long-term hemodynamic changes following pipeline embolization device placement and report two cases in which in-stent stenosis was detected.Methods Medical records of patients who underwent pipeline embolization device placement for an internal carotid artery aneurysm between 2017 and 2019 were reviewed. Patients who received post-procedure NOVA and follow-up NOVA were included in the study (n= 32). Location and size of aneurysm, number of pipeline embolization device deployed, and complications were collected along with the non-invasive optimal vessel analysis report (flow volume rate (ml/min), mean, systolic, and diastolic flow velocities (cm/s), and vessel diameter (mm)). Internal carotid artery vessel flow rate was measured proximal to the pipeline embolization device. Derivations of hemodynamic parameters (pulsatility index, Lindegaard ratio, and wall shear stress) were calculated.Results The middle cerebral artery mean and diastolic flow velocities were significantly lower on the follow-up NOVA compared to the post-procedure NOVA. Moreover, follow-up NOVA demonstrated lower middle cerebral artery wall shear stress on the side with flow diversion compared to the post-procedure NOVA. In-stent stenosis, requiring intervention, was detected in two patients on follow-up NOVA. One patient had a successful balloon angioplasty of the stented internal carotid artery that resolved her stenosis. However, the second patient developed progressive stenosis and expired despite intervention.Conclusion Long-term hemodynamic adaptations post-pipeline embolization device demonstrate decreased wall shear stress and decreased mean and diastolic flow velocities in the distal middle cerebral artery, which suggest decreasing velocity of blood flow with endothelialization of the device. Furthermore, follow-up NOVA is a useful tool for detecting potential flow-related complications such as in-stent stenosis.

Liquid crystal elastomers (LCEs) are stimuli-responsive materials that undergo large shape transformations after undergoing an order–disorder transition. While shape reconfigurations in LCEs are predominantly triggered by heat, there is a considerable interest in developing highly specific triggers that work at room temperature. Herein, we report the fabrication of biocatalytic LCEs that respond to the presence of urea by covalently immobilizing urease within chemically responsive LCE networks. The hydrogen-bonded LCEs developed in this work exhibited contractile strains of up to 36% upon exposure to a base. Notably, the generation of ammonia by immobilized urease triggered a disruption in the supramolecular network and a large reduction of liquid crystalline order in the films when the LCEs were exposed to urea. This reduction in order was macroscopically translated into a strain response that could be modulated by changing the concentration of urea or exposure time to the substrate. Local control of the mechanical response of the LCE was realized by spatially patterning the enzyme on the surface of the films. Subsequent exposure of enzymatically patterned LCE to urea-triggered 3D shape transformations into a curl, arch, or accordion-like structure, depending on the motif patterned on the film surface. Furthermore, we showed that the presence of salt was critical to prevent bridging of the network by the presence of ammonium ions, thereby enabling such macroscopic 3D shape changes. The large actuation potential of LCEs and the ability to translate the biocatalytic activity of enzymes to macroscopic 3D shape transformations could enable use in applications ranging from cell culture, medicine, or antifouling.

Abstract

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Covalent adaptable crosslinks, such as the alkyl‐hydrazone, endow hydrogels with unique viscoelastic properties applicable to cell delivery and bioink systems. However, the alkyl‐hydrazone crosslink lacks stability in biologically relevant environments. Furthermore, when formed with biopolymers such as hyaluronic acid (HA), low molecular weight polymers (<60 kDa), or low polymer content (<2 wt%) hydrogels are typically employed as entanglements reduce injectability. Here, a high molecular weight (>60 kDa) HA alkyl‐hydrazone crosslinked hydrogel is modified with benzaldehyde‐poly(ethylene glycol)3‐azide to incorporate azide functional groups. By reacting azide‐modified HA with a multi‐arm poly(ethylene glycol) (PEG) functionalized with bicyclononyne, stabilizing triazole bonds are formed through strain‐promoted azide‐alkyne cycloaddition (SPAAC). Increasing the fraction of triazole bonds within the hydrogel network from 0% to 12% SPAAC substantially increases stability. The slow gelation kinetics of the SPAAC reaction in the 12% SPAAC hydrogel enables transient self‐healing properties and a similar extrusion force as the 0% SPAAC hydrogel. Methyl‐PEG4‐hydrazide is then introduced to further slowdown network evolution, which temporarily lowers the extrusion force, improves printability, and increases post‐extrusion mesenchymal stem cell viability and function in the 12% SPAAC hydrogel. This work demonstrates improved stability and temporal injectability of high molecular weight HA‐PEG hydrogels for extrusion‐based printing and cell delivery. High molecular weight hyaluronic acid in hydrogels with alkyl‐hydrazone crosslinks lack stability and are difficult to inject. Adding slow forming triazole bonds increases the stability, and injectability becomes time dependent. Adding a small monofunctional molecule slows down network evolution and improves injectability. Using both improves viability and function of encapsulated mesenchymal stem cells post‐extrusion.

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Introduction Delayed intraparenchymal hemorrhage is a known complication of the Pipeline Embolization device (PED); however, its etiology is unclear and some have suggested it is a flow related phenomenon. Quantitative magnetic resonance angiography (QMRA) serves as a powerful tool to collect and analyze hemodynamic data. We report a detailed characterization of short-term hemodynamics after PED placement.Methods Patients who underwent PED placement for a distal internal carotid artery (ICA) aneurysm between 2017 to 2019 with post embolization QMRA were reviewed. Aneurysm characteristics, flow volume rate (ml/min), mean, systolic, and diastolic flow velocities (cm/s), vessel diameter (mm), pulsatility index, Lindegaard ratio, and wall shear stress (WSS) were collected.Results A total of 67 patients were included. Post-procedure patients were found to have a significantly lower ICA flow on the side with flow diversion when compared to the side without flow diversion (218 vs. 236.3; P< 0.05). Average ICA flow after flow diversion for aneurysms >2 cm was significantly lower when compared to the untreated side (187.7 vs. 240.4; P< 0.05). There was no difference in MCA or ACA flow or velocity. WSS was significantly lower in the treated ICA (8.2 vs. 9.0; P< 0.05). Lindegaard ratio was not different in the treated vs. contralateral untreated sides.Conclusion PED placement for distal ICA aneurysms results in lower flow, mean velocity, and WSS when compared to the contralateral untreated ICA. This is not demonstrated distal to the Pipeline device in the ACA or MCA territories. Ultimately these findings suggest hemodynamic changes are not a cause of PED complications.

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4mutations (14% vs. 44%; p= 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4at 1.7 months (p= 0.07) and 7.3 months (p= 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4mutations (59% vs. 92%; p= 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

BackgroundRapid time to reperfusion is essential to minimize morbidity and mortality in acute ischemic stroke due to large vessel occlusion (LVO). We aimed to evaluate the workflow times when utilizing a direct-to-angiography suite (DTAS) pathway for patients with suspected stroke presenting at a comprehensive stroke center compared with a conventional CT pathway.MethodsWe developed a discrete-event simulation (DES) model to evaluate DTAS workflow timelines compared with a conventional CT pathway, varying the admission NIHSS score treatment eligibility criteria. Model parameters were estimated based on 2 year observational data from our institution. Sensitivity analyses of simulation parameters were performed to assess the impact of patient volume and baseline utilization of angiography suites on workflow times utilizing DTAS.ResultsSimulation modeling of stroke patients (SimStroke) demonstrated door-to-reperfusion time savings of 0.2–3.5 min (p=0.05) for a range of DTAS eligibility criteria (ie, last known well to arrival <6 hours and National Institutes of Health Stroke Scale ≥6–11), when compared with the conventional stroke care pathway. Sensitivity analyses revealed that DTAS time savings is highly dependent on baseline utilization of angiography suites.ConclusionsThe results of the SimStroke model showed comparable time intervals for door-to-reperfusion for DTAS compared with a conventional stroke care pathway. However, the DTAS pathway was very sensitive to baseline angiography suite utilization, with even a 10% increase eliminating the advantages of DTAS compared with the conventional pathway. Given the minimal time savings modeled here, further investigation of implementing the DTAS pathway in clinical care is warranted.

Liquid crystalline elastomers (LCEs) are functional materials whose stimuli response is strongly influenced by the composition and structure of the polymer network. LCEs are commonly fabricated by copolymerizing acrylate monomers with thiols. This work explores the formation of LCE polymer networks via photopolymerization reactions of diacrylate liquid crystalline monomers with dithiols. Detailed analysis of model systems based on monoacrylate–dithiol reactions indicates that the polymer network architecture of LCEs prepared by this reaction contains extensive unreacted thiol content as dangling ends. Further, kinetic analysis indicates that polymerization in a liquid crystalline phase strongly hinders the mobility of reactive species during the formation of the LCE polymer network, which is evident in the substantial difference in viscosity between liquid crystalline monomers (0.0195 Pa s) and non-liquid crystalline monomers (0.0025 Pa s). In copolymerization with the diacrylate liquid crystal monomers, the dithiol comonomer significantly decreases the elastic modulus and Tg. The residual thiol in the LCE polymer network can be postfunctionalized with reactive additives.

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mutin WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P< .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4MutWM. This trial was registered at www.clinicaltrials.govas #NCT03225716.

Liquid crystal polymer networks (LCNs) are stimuli-responsive materials that can be programmed to realize spatial variation in mechanical response and undergo shape transformation. Herein, we report a process to introduce chemical specificity to the stimuli response of LCNs by integrating enzymes as molecular triggers. Specifically, the enzyme urease was immobilized in LCN films via acyl fluoride conjugation chemistry. Activity assays and confocal fluorescence imaging confirmed retention of urease activity after immobilization as well as widespread distribution of enzyme on the film. The addition of urea triggered a response in the LCN whereby newly generated ammonia reacted with free acyl fluorides to form benzamide moieties. These moieties were capable of dimerizing through the formation of supramolecular hydrogen bonds, which was reflected in a 4-fold increase in Young’s modulus. Through dynamic mechanical analysis and calorimetry, we further confirmed that the degree of hydrogen bonding in the LCNs could be judiciously designed to fine-tune the mechanical properties and glass transition temperature. These findings demonstrate the untapped potential of biochemical mechanisms as molecular triggers in LCNs and open the door to the use of nucleophilic chemistries in modulating the mechanical properties of LCNs.