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Mismatch in the potency from quantitative 1H NMR (∼96%) and the calculated potency (∼94%) of an aldehyde intermediate led to the investigation of an unknown impurity peak observed in the chromatography. The HR-MS/MS analysis of the unknown impurity suggested it to be the cyanohydrin derivative of the corresponding aldehyde intermediate with the addition of ∼27 amu. Further investigation was performed using analogous 3-methyl iso-nicotinaldehyde as a model compound. A postcolumn hydrogen to deuterium exchange (H/D exchange) experiment further supported the proposed impurity structure as cyanohydrin. The source of HCN for the possible generation of this impurity was traced to certain brands of acetonitrile used duirng the analysis, where the presence of HCN as a contaminant was confirmed and quantified using ion chromatography. The aforementioned model compound was used to investigate the effect of other parameters like diluent composition, sample temperature and storage time, pH of the diluent, and duration of sonication, which impact the formation of such artifact impurity. Based on the results of all the experiments, mitigation strategies were proposed to avoid/control the formation of these impurities during the analytical processing such as use of methanol or HCN-free acetonitrile as a sample diluent, reduced composition of acetonitrile in the diluent, and use of freshly prepared solutions for injections to avoid longer storage time specially when certain sensitive substrates like aldehydes and ketones are analyzed. To evaluate if the formation of this impurity is limited to the compound of interest or if it is a common artifact peak for other similar compounds, various substrates involving aldehyde and ketone functional groups were analyzed under similar analytical conditions. The results indicated that aldehydes were more reactive than ketones, specifically the aldehydes containing a heterocyclic ring such as pyridine were prone to generate the cyanohydrin impurity.

•An international panel of 38 experts and clinical trialists in MF participated in the preparation of the current document.•New definitions of transfusion status, gender-specific hemoglobin thresholds, and criteria for major and minor responses are submitted.

La mastocytose systémique indolente (MSI), maladie clonale des mastocytes principalement induite par la mutation D816V du gène KIT, s’accompagne de symptômes invalidants à long terme, dont une anaphylaxie pouvant mettre la vie en danger, mais aussi une mauvaise qualité de vie (QdV) et une morbidité significative. La plupart des patients reçoivent des traitements axés sur les symptômes qui s’avèrent souvent inefficaces. L’avapritinib, un inhibiteur oral, puissant et sélectif de la mutation D816V de KIT, est le premier et le seul traitement approuvé pour les patients adultes atteints de MSI dans l’UE et aux États-Unis.

ABSTRACTIntroductionCytopenic myelofibrosis is increasingly recognized as a phenotype of myelofibrosis presenting with low blood counts, lower driver mutation allele burden, increased likelihood of arising de novo, i.e. primary myelofibrosis, greater genomic complexity, worse survival, and higher rates of leukemic transformation compared to the more traditional ‘myeloproliferative’ phenotype. Both anemia and thrombocytopenia are very common, often coexist, and can be worsened by treatment. Several JAK inhibitors with different kinome profiles are now available for routine clinical use. Additionally, ancillary therapies can also provide some, albeit non-durable, benefit.Areas coveredIn this review, we discuss the prevalence and clinical significance of cytopenias in myelofibrosis. We then discuss the various Janus kinase (JAK) inhibitors and ancillary therapies available with a special focus on their use in cytopenic populations, ability to improve cytopenias, and notable adverse events. Articles included were selected through literature searches using the PubMed database.Expert OpinionPacritinib and momelotinib are new treatment options for patients with cytopenic myelofibrosis. These JAK inhibitors are less myelosuppressive and allow for cytopenia stabilization or improvement while providing additional benefits. It is likely that their use will expand and these newer JAK inhibitors will become backbones for future combinations with novel, ‘disease modifying’ agents.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

BackgroundThe Woven EndoBridge (WEB) device is a novel intrasaccular flow disruptor tailored for bifurcation aneurysms. We aim to describe the degree of aneurysm occlusion at the latest follow-up, and the rate of complications of aneurysms treated with the WEB device stratified according to rupture status.MethodsOur data were taken from the WorldWideWeb Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups: ruptured and unruptured. We compared clinical and radiologic outcomes of both groups. Propensity score matching (PSM) was done to match according to age, gender, bifurcation, location, prior treatment, neck, height, dome width, daughter sac, incorporated branch, pretreatment antiplatelets, and last imaging follow-up.ResultsThe study included 676 patients with 691 intracranial aneurysms (529 unruptured and 162 ruptured) treated with the WEB device. The PSM analysis had 55 pairs. In both the unmatched (85.8% vs 84.3%, p=0.692) and matched (94.4% vs 83.3%, p=0.066) cohorts there was no significant difference in the adequate occlusion rate at the last follow-up. Likewise, there were no significant differences in both ischemic and hemorrhagic complications between the two groups. There was no documented aneurysm rebleeding after WEB device implantation.ConclusionThere was no significant difference in both the radiologic outcomes and complications between unruptured and ruptured aneurysms. Our findings support the feasibility of treatment of ruptured aneurysms with the WEB device.

The paper presents modelling, control architecture, analysis and design of digital compensators for single feedback-loop voltage mode control as well as two feedback-loop average current mode control and peak current mode control of current controlled DC-DC Buck converter operating in continuous conduction mode with output current as control variable. The compensators are derived using digital redesign approach, simulated on MATLAB, implemented as control algorithms on Texas Instruments' 32-bit TMS320F28069M microcontroller platform, and experimentally validated by testing with a laboratory prototype of current controlled Buck converter. Simulation and experimental results are discussed, compared and evaluated for converter output current performance in tracking reference current signal as well as in regulation against input voltage and load disturbances. Salient features of each control technique are identified and described to determine its suitability in applications of DC-DC converters requiring controlled output current.

BackgroundThe Woven EndoBridge (WEB) device has Food and Drug Administration approval for treatment of wide-necked intracranial bifurcation aneurysms. The WEB device has been shown to result in adequate occlusion in bifurcation aneurysms overall, but its usefulness in the individual bifurcation locations has been evaluated separately only in few case series, which were limited by small sample sizes.ObjectiveTo compare angiographic and clinical outcomes after treatment of bifurcation aneurysms at various locations, including anterior communicating artery (AComA), anterior cerebral artery (ACA) bifurcation distal to AComA, basilar tip, internal carotid artery (ICA) bifurcation, and middle cerebral artery (MCA) bifurcation aneurysms using the WEB device.MethodsA retrospective cohort analysis was conducted at 22 academic institutions worldwide to compare treatment outcomes of patients with intracranial bifurcation aneurysms using the WEB device. Data include patient and aneurysm characteristics, procedural details, angiographic and functional outcomes, and complications.ResultsA total of 572 aneurysms were included. MCA (36%), AComA (35.7%), and basilar tip (18.9%) aneurysms were most common. The rate of adequate aneurysm occlusion was significantly higher for basilar tip (91.6%) and ICA bifurcation (96.7%) aneurysms and lower for ACA bifurcation (71.4%) and AComA (80.6%) aneurysms (p=0.04).ConclusionTo our knowledge, this is the most extensive study to date that compares the treatment of different intracranial bifurcation aneurysms using the WEB device. Basilar tip and ICA bifurcation aneurysms showed significantly higher rates of aneurysm occlusion than other locations.

Patrolling strategies primarily deal with minimising the time taken to visit specific locations and cover an area. The use of intelligent agents in patrolling has become beneficial in automation and analysing patterns in patrolling. However, practical scenarios demand these strategies to be adaptive in various conditions and robust against adversaries. Traditional Q-learning based patrolling keeps track of all possible states and actions in a Q-table, making them susceptible to the curse of dimensionality. For multi-agent patrolling to be adaptive in various scenarios represented using graphs, we propose a formulation of the Markov Decision Process (MDP) with state-representations that can be utilised for Deep Reinforcement Learning (DRL) approaches such as Deep Q-Networks (DQN). The implemented DQN can estimate the MDP using a finite length state vector trained with a novel reward function. Proposed state-space representation is independent of the number of nodes in the graph, thereby addressing scalability to graph dimensions. We also propose a reward function to penalise the agents for lack of global coordination while providing immediate local feedback on their actions. As independent policy learners subject to the MDP and reward function, the DRL agents formed a collaborative patrolling strategy. The policies learned by the agents generalise and adapt to multiple behaviours without explicit training or design to do so. We provide empirical analysis that shows the strategy’s adaptive capabilities with changes in agents’ position, non-uniform node visit frequency requirements, changes in a graph structure representing the environment, and induced randomness in the trajectories. DRL patrolling proves to be a promising patrolling strategy for intelligent agents by potentially being scalable, adaptive, and robust against adversaries.

The robot localization problem is typically solved using state estimation techniques, where process and sensing inaccuracies are invariably present. Moreover, disturbances in the sensing and actuating mechanisms add to the uncertainties. Any system may degrade over time, and its parameter values may be ambivalently known. Cumulatively, all these sources of errors and uncertainties are considered as unknown inputs. This work aims to address the unknown inputs using a robust state (pose in the robot localization problem) estimator. The proposed robust state estimator deals with the unknown inputs such that the solution of the estimator is constrained in a way that warrants unbiased state estimates in the presence of the unknown inputs. This article explores the formulation of these constraints and the development of a constrained state estimator for a system, where the unknown inputs appear in both the state transition map (i.e., system model) and the state-output map (i.e., measurement model). The theoretical development of such a strategy stems from the localization problem of a wheeled mobile robot. The residuals of the constrained state estimator developed contain information about the unknown inputs. We conceive a recursive least squares strategy to estimate the unknown inputs simultaneously with the states using this information. Using simulations and experimental studies, we demonstrate the adequacy of our strategy for a differential drive robot.

No significant difference in the angiographic and clinical outcomes was observed for the treatment of sidewall versus bifurcation intracranial aneurysms with use of Woven EndoBridge.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3Aor TET2(DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

A spherical robot has many practical advantages as the entire electronics are protected within a hull and can be carried easily by any Unmanned Aerial Vehicle (UAV). However, its use is limited due to finding mounts for sensors. Pendulum actuated spherical robot provides space for mounting sensors at the yoke. We study the non-linear dynamics of a pendulum-actuated spherical robot to analyze the dynamics of internal assembly (yoke) for mounting sensors. For such robots, we provide a coupled dynamic model that takes care of the relationship between forward and sideways motion. We further demonstrate the effects of wobbling and precession captured by our model when the bot is controlled to execute a turning maneuver while moving with a moderate forward velocity - a practical situation encountered by spherical robots moving in an indoor setting. A simulation setup based on the developed model provides visualization of the spherical robot motion.

Deploying mobile instrumentation for railway track inspection is a routing and scheduling problem, that can be benefited from plans which don’t disrupt regular train schedules. In this work, we avoid disrupting train schedules by modeling unavailability of railway tracks, thereby improving reliability without sacrificing on costs. The approach involves a novel mathematical formulation for Capacitated Arc Routing Problem with Temporal restrictions due to arc Unavailabilities (CARP-TU). In addition, we discuss the challenges in CARP-TU w.r.t sibling problems, and propose a suitable column generation algorithm for improving upper and lower bounds. The proposed algorithm is validated over few benchmark datasets, and then two variants of the proposed algorithm are compared to analyse the bound improvements w.r.t problem size.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.govas #NCT01929408.

BackgroundThe Woven EndoBridge (WEB) device is approved in the USA for treatment of unruptured wide-neck bifurcation aneurysms. However, the safety and effectiveness of the WEB device in the treatment of ruptured intracranial aneurysms is not clear. We aim to evaluate the perioperative safety and effectiveness of the WEB device in patients with ruptured intracranial aneurysms.MethodsThis retrospective study, conducted at eight centers in the USA, included patients with ruptured intracranial aneurysms treated with the WEB device in the setting of subarachnoid hemorrhage (SAH). Safety outcomes included intraoperative complications such as vessel perforation, thromboembolic events, and postoperative hemorrhagic or thromboembolic complications based on radiologic imaging. The primary effectiveness outcome was adequate (complete and neck remnant) aneurysm occlusion, according to the Raymond–Roy classification.ResultsA total of 91 patients with 94 ruptured intracranial aneurysms were included (mean age 57.7±15.2 years; 68.1% women; 82.9% wide-necked). Aneurysms were located in the anterior communicating artery (42/94, 44.6%), middle cerebral artery (16/94, 17%), and basilar artery (15/94, 16%). Adequate occlusion was achieved in 48.8% (41/84) and 80.0% (40/50) at discharge and last follow-up (mean of 3.4 months), respectively. At discharge, procedural-related morbidity was 3.3% (3/91) and there was no procedure-related mortality. No re-rupture or delayed aneurysm rupture was observed.ConclusionsThis study demonstrates the perioperative safety and effectiveness of the WEB device for the treatment of patients with ruptured intracranial aneurysms in the setting of SAH, with low periprocedural morbidity and mortality. Long-term follow-up is warranted.

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This paper proposes trajectory planning strategies for reconfiguration of a multi-agent formation on a Lissajous curve. In our earlier work (Borkar et al., 2016), a multi-agent formation with constant parametric speed was proposed in order to address multiple objectives such as repeated collision-free surveillance and guaranteed sensor coverage of the area with ability for rogue target detection and trapping. Here we address formation reconfiguration within this framework. Smooth parametric trajectories are designed for this purpose using calculus of variations. These are employed in conjunction with a local cooperation scheme to achieve collision-free reconfiguration between different Lissajous curves. A detailed theoretical analysis is provided. The claims are validated through simulations in MATLABⓇfor agents performing parametric motion along the curves, by Software-In-The-Loop simulation for quadrotors, and also experimentally with a team of quadrotors flying in a motion capture environment.

Patients with high-risk acute promyelocytic leukemia (APL) have inferior outcomes compared with patients with low-risk APL, predominantly due to higher risk of early mortality related to hemorrhage. The majority of regimens contain prolonged maintenance, but the impact of this phase is not clear in the era of all trans retinoic acid (ATRA) and arsenic trioxide (ATO). We present a retrospective analysis of 10 patients that were treated for high risk APL based on the consolidation treatment phase of APL 0406 study without subsequent maintenance. With a median follow up of 38 months, all patients remain in remission.

Practice-based studies of organization have drawn attention to the importance of the body as a site of knowledge and knowing. However, relational encounters between bodies and objects, and the affects they generate, are less well understood in organization studies. This article uses new materialist theory to explore the role of affect in embodied practices of craft making. It suggests that craft work relies on affective organizational relations and intensities that flow between bodies, objects and places of making. This perspective enables a more affective, materially inclusive understanding of organizational practice, as encounters between human and nonhuman entities and forces. We draw on empirical data from a qualitative study of four UK organizations that make bicycles, shoes and hand-decorated pottery. We track the embodied techniques that enable vital encounters with matter and the affective traces and spatial, aesthetic atmospheres that emerge from these encounters. We suggest that a concern with the vitality of objects is central to the meaning that is attributed to craft work practices and the ethical sensibilities that arise from these encounters. We conclude by proposing an affective ethics of mattering that constructs agency in ways that are not confined to humans and acknowledges the importance of orientations towards matter in generating possibilities for ethical generosity towards others.

Zirconium dioxide (ZrO2) nanoparticles were synthesized using co-precipitation technique and their structural, particle size, UV-Visible (UV–vis), and gas sensing properties were studied. In this paper, the particle size-dependent properties of ZrO2have been investigated. XRD analysis indicated that the crystal structure of ZrO2nanoparticles varies with sintering temperature, while crystallite size decreases with an increase in sintering temperature. A small variation in the optical energy band gap is observed in UV–vis spectroscopy. Resistance versus time data was carried out for the gas sensing application, and it was observed that the particle size and nature of the gas play a key role in the sensing of the gases. In the present case, ZrO2nanoparticles possess more sensitivity to acetone than methanol.

Background Endovascular treatment with the woven endobridge (WEB) device has been widely utilized for managing intracranial aneurysms. However, predicting the probability of achieving adequate occlusion (Raymond–Roy classification 1 or 2) remains challenging.Objective Our study sought to develop and validate a predictive calculator for adequate occlusion using the WEB device via data from a large multi-institutional retrospective cohort.Methods We used data from the WorldWide WEB Consortium, encompassing 356 patients from 30 centers across North America, South America, and Europe. Bivariate and multivariate regression analyses were performed on a variety of demographic and clinical factors, from which predictive factors were selected. Calibration and validation were conducted, with variance inflation factor (VIF) parameters checked for collinearity.Results A total of 356 patients were included: 124 (34.8%) were male, 108 (30.3%) were elderly (≥65 years), and 118 (33.1%) were current smokers. Mean maximum aneurysm diameter was 7.09 mm (SD 2.71), with 112 (31.5%) having a daughter sac. In the multivariate regression, increasing aneurysm neck size (OR 0.706 [95% CI: 0.535–0.929], p= 0.13) and partial aneurysm thrombosis (OR 0.135 [95% CI: 0.024–0.681], p= 0.016) were found to be the only statistically significant variables associated with poorer likelihood of achieving occlusion. The predictive calculator shows a c-statistic of 0.744. Hosmer–Lemeshow goodness-of-fit test indicated a satisfactory model fit with a p-value of 0.431. The calculator is available at: https://neurodx.shinyapps.io/WEBDEVICE/.Conclusion The predictive calculator offers a substantial contribution to the clinical toolkit for estimating the likelihood of adequate intracranial aneurysm occlusion by WEB device embolization.

Inspired by the catechol and amine-rich adhesive proteins of mussels, polydopamine (pDA) has become one of the most widely employed methods for functionalizing material surfaces, powered in part by the versatility and simplicity of pDA film deposition that takes place spontaneously on objects immersed in an alkaline aqueous solution of dopamine monomer. Despite the widespread adoption of pDA as a multifunctional coating for surface modification, it exhibits poor mechanical performance. Attempts to modify the physical properties of pDA by incorporation of oxidizing agents, cross-linkers, or carbonization of the films at ultrahigh temperatures have been reported; however, improving mechanical properties with mild post-treatments without sacrificing the functionality and versatility of pDA remains a challenge. Here, we demonstrate thermal annealing at a moderate temperature (130 °C) as a facile route to enhance mechanical robustness of pDA coatings. Chemical spectroscopy, X-ray scattering, molecular force spectroscopy, and bulk mechanical analyses indicate that monomeric and oligomeric species undergo further polymerization during thermal annealing, leading to fundamental changes in molecular and bulk mechanical behavior of pDA. Considerable improvements in scratch resistance were noted in terms of both penetration depth (32% decrease) and residual depth (74% decrease) for the annealed pDA coating, indicating the enhanced ability of the annealed coating to resist mechanical deformations. Thermal annealing resulted in significant enhancement in the intermolecular and cohesive interactions between the chains in the pDA structure, attributed to cross-linking and increased entanglements, preventing desorption and detachment of the chains from the coating. Importantly, improvements in pDA mechanical performance through thermal annealing did not compromise the ability of pDA to support secondary coating reactions as evidenced by electroless deposition of a metal film adlayer on annealed pDA.

CADI-05, a TLR-2 agonist, induces Th1 immune response following intradermal administration and has been found useful in management of lung cancer and melanoma. To evaluate CADI-05 in patients with BCG recurrent and unresponsive Non-muscle invasive bladder cancer (NMIBC) for 15-months recurrence free survival (RFS) rate. In BCG unresponsive (BU) or recurrent (BR) NMIBC, CADI-05 was administered intradermally every two weeks for 3 months followed by every month for 3 months and subsequently every 2 months for 6 months following transurethral resection (TUR) in a single arm study (ClinicalTrials.gov: NCT00694798). Cystoscopy, cytology, and sonography were performed for the presence/recurrence of NMIBC at 3, 6, 9, 12, 15 months and beyond and confirmed by biopsy. Evaluation of preoperative biopsy for Desmocollin-3 (DSC3) expression and tumor infiltrating lymphocytes (TIL) was optional. Twenty patients with NMIBC received intradermal CADI-05. RFS at 15 and 30 months was 35% (7/20) patients. The median RFS was also better for BU compared to BR group (HR, 0.329; 95% CI, 0.071 to 1.532). DSC3 expression was present in 68.8% (11/16) patients. TIL and RFS beyond 30 months were seen 2.3 times and 2.8 times more often in DSC3 expressing NMIBC respectively. No grade IV or V adverse events occurred. Local site reactions were the most common adverse event. Intradermal CADI-05 following TUR is associated with 35% RFS at 30 months.

Background:Treatment-free remission (TFR) is increasingly becoming a treatment goal for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although strict criteria guide tyrosine kinase inhibitor (TKI) discontinuation, there exists a knowledge gap in understanding patient and provider experience regarding TFR in real-world clinical practice. Here, we report our TFR experience in patients with CML-CP, treated at an academic center in the Deep South.