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Background: Human pluripotent stem cell (hPSC)–derived cardiomyocytes (hPSC-CMs) have tremendous promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. We hypothesized that large-scale manufacturing of mature hPSC-CMs could be achieved through culture on polydimethylsiloxane (PDMS)-lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes than with conventional immature hPSC-CM populations. Methods: We comprehensively phenotyped hPSC-CMs after in vitro maturation for 20 and 40 days on either PDMS or standard tissue culture plastic substrates. All hPSC-CMs were generated from a transgenic hPSC line that stably expressed a voltage-sensitive fluorescent reporter to facilitate in vitro and in vivo electrophysiological studies, and cardiomyocyte populations were also analyzed in vitro by immunocytochemistry, ultrastructure and fluorescent calcium imaging, and bulk and single-cell transcriptomics. We next compared outcomes after the transplantation of these populations into a guinea pig model of myocardial infarction using end points including histology, optical mapping of graft- and host-derived action potentials, echocardiography, and telemetric electrocardiographic monitoring. Results: We demonstrated the economic generation of >1×10 8 mature hPSC-CMs per PDMS-lined roller bottle. Compared with their counterparts generated on tissue culture plastic substrates, PDMS-matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More important, intracardiac grafts formed with PDMS-matured myocytes showed greatly enhanced structure and alignment, better host-graft electromechanical integration, less proarrhythmic behavior, and greater beneficial effects on contractile function. Conclusions: We describe practical methods for the scaled generation of mature hPSC-CMs and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo.

The metaverse is an emerging convergence of technologies (e.g. virtual reality and blockchains) that enables users to experience mixed/extended realities for a range of legitimate purposes (e.g. gaming, entertainment and education). Unfortunately, the crime and security implications of emerging technologies are often overlooked. To anticipate crimes that the metaverse might facilitate, in this paper we report the findings of a nominal group technique (NGT) study which was informed by a state-of-the-art scoping review of the existing literature. We elicited views from two expert groups: 1) a mixed European sample (with participants from law enforcement, industry, academia and the voluntary sector), and; 2) an international sample of law enforcement stakeholders. A total of 22 crime threats were identified in the existing literature and an additional eight were identified by experts. These included sexual offenses, crimes against the person, crime against property, and financial crimes. Participants were asked to rate these according to their likely harm, frequency, achievability and defeat-ability. Ratings were largely consistent across the two samples, with crimes of a sexual nature (e.g. child sexual abuse material and sexual assault), and against the person (e.g. harassment and hate crime) being rated as presenting the highest future risks (ie being high harm and high frequency). The findings are discussed with the aim of informing approaches to preventing crime in the metaverse.

Glioblastoma cells adapt to changes in glucose availability through metabolic plasticity allowing for cell survival and continued progression in low-glucose concentrations. However, the regulatory cytokine networks that govern the ability to survive in glucose-starved conditions are not fully defined. In the present study, we define a critical role for the IL-11/IL-11Rα signalling axis in glioblastoma survival, proliferation and invasion when cells are starved of glucose. We identified enhanced IL-11/IL-11Rα expression correlated with reduced overall survival in glioblastoma patients. Glioblastoma cell lines over-expressing IL-11Rα displayed greater survival, proliferation, migration and invasion in glucose-free conditions compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα reversed these pro-tumorigenic characteristics. In addition, these IL-11Rα-over-expressing cells displayed enhanced glutamine oxidation and glutamate production compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα or the pharmacological inhibition of several members of the glutaminolysis pathway resulted in reduced survival (enhanced apoptosis) and reduced migration and invasion. Furthermore, IL-11Rα expression in glioblastoma patient samples correlated with enhanced gene expression of the glutaminolysis pathway genes GLUD1, GSS and c-Myc. Overall, our study identified that the IL-11/IL-11Rα pathway promotes glioblastoma cell survival and enhances cell migration and invasion in environments of glucose starvation via glutaminolysis.

The increasing age of the patient population around the globe and in the United States has resulted in a growing number of patients with dementia. In this manuscript, we examined the role of the ethics consultation service in patients who have dementia and associated cognitive and neuropsychiatric sequelae. We addressed a particularly challenging case presenting with behavioral and psychological symptoms of dementia. We discussed the ethical questions and challenges considered by the ethics consultation service and compared these with current suggestions and expectations from the research literature regarding the role of ethics consultation service in dementia management. We demonstrated two potentially useful approaches of clinical ethical analysis, the principalist theorem and Jonsen's four quadrants approach. While the number of consults in patients with behavioral and psychological symptoms of dementia is likely to increase in clinical ethics, the role of the ethics consultation service in this cohort of patients still remains to be determined. There are significant gaps in understanding of the ethics consultation service role in dementia management, and much work remains to be undertaken on the part of regulatory and healthcare systems in clarifying their roles, expectations, and competencies.

There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II

Coccidioides meningoencephalitis is a central nervous system (CNS) fungal infection withCoccidioides species which can lead to various CNS complications, such as hydrocephalus,vasculitis, and stroke. Most cases reported with Coccidioides meningoencephalitis were inimmunocompromised patients, and the radiologic characteristics on this condition are not wellestablished. Here we report a case of Coccidioides meningoencephalitis in an immunocompetentpatient with one-year follow-up brain magnetic resonance image (MRI) studies after successfultreatment with antifungal drugs. The MRI demonstrated subcortical parenchymal lesions,selectively involving the white matter, and persistent meningeal enhancement.

The cardiomyocyte (CM) subtypes in the mammalian heart derive from distinct lineages known as the first heart field (FHF), the anterior second heart field (aSHF), and the posterior second heart field (pSHF) lineages that are specified during gastrulation. We modeled human heart field development from human pluripotent stem cells (hPSCs) by using single-cell RNA-sequencing to delineate lineage specification and progression. Analyses of hPSC-derived and mouse mesoderm transcriptomes enabled the identification of distinct human FHF, aSHF, and pSHF mesoderm subpopulations. Through staged manipulation of signaling pathways identified from transcriptomics, we generated myocyte populations that display molecular characteristics of key CM subtypes. The developmental trajectory of the human cardiac lineages recapitulated that of the mouse, demonstrating conserved cardiovascular programs. These findings establish a comprehensive landscape of human embryonic cardiogenesis that provides access to a broad spectrum of cardiomyocytes for modeling congenital heart diseases and chamber-specific cardiomyopathies as well as for developing new therapies to treat them.

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.

Dental caries can be effectively managed and prevented from developing into cavitated lesions while preserving tooth structure at all levels. However, the strong correlation between caries and socioeconomic factors may compromise the efficacy of preventive strategies. The high prevalence of persistent inequalities in dental caries in Latin American and Caribbean countries (LACC) is a matter of concern. The estimates of the burden of disease in some countries in this region are outdated or absent. This paper aims to summarize and present the final recommendations of a regional Consensus for Dental Caries Prevalence, Prospects, and Challenges for LACC. This consensus is based on four articles that were written by a team of Latin American experts, reviewed by dental associations, and presented and discussed in two consensus events. The following domains were explored: epidemiology, risk factors, prevention strategies, and management of dental caries with a focus on restorative procedures. Dental caries can manifest throughout the lifespan of an individual, making it a matter of concern for infants, children, adults, and older people alike. The prevalence rates of untreated caries in deciduous and permanent teeth are high in many parts of the world, including LACCs. Previous evidence suggests that the prevalence of dental caries in 12-year-olds is moderate to high in most Latin American countries. Moreover, the prevalence of treatment needs and dental caries in the adult and elderly population can also be regarded as high in this region. The risk/protective factors (e.g., sugar consumption, exposure to fluoride, and oral hygiene) probably operate similarly in all LACCs, although variations in the interplay of these factors in some countries and within the same country cannot be ruled out. Although salt and water fluoridation programs are implemented in many countries, there is a need for implementation of a surveillance policy. There is also room for improvement with regard to the introduction of minimal intervention techniques in practice and public health programs. Dental caries is a marker of social disadvantage, and oral health promotion programs and interventions aimed at reducing the burden of dental caries in LACCs must consider the complexity of the socioeconomic dynamics in this region. There is an urgent need to promote engagement of stakeholders, policymakers, medical personnel, universities, dental associations, community members, and industries to develop regional plans that enhance the oral health agenda for LACCs. A list of recommendations has been presented to underpin strategies aimed at reducing the prevalence and severity of dental caries and improving the quality of life of the impacted LACC population in the near future.

Simple Summary A key molecule, EGFRvIII has been shown to provide several growth advantages for brain tumors. However, we have found a new mechanism in which the EGFRvIII provides increased survival to brain cancer cells when under sub-optimal conditions. Specifically, we have found that the EGFRvIII drives the expression of a molecule called Reticulocalbin 1 (RCN1) and that RCN1 blocks cell stress and cell death, thereby allowing cells to survive and proliferate. Importantly, these findings will allow for the generation of drugs that block the function of EGFRvIII and RCN1 with the hope that these drugs will induce brain cancer cell death. Abstract Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

Introduction: Migraine is common and often disabling. Recent research has focused on a new class of treatments targeting the pain-signaling molecule calcitonin-gene-related peptide (CGRP). CGRP inhibitors are the first preventive therapies designed specifically for migraine. However, CGRP also induces vasodilation, and plays a role in cerebral blood flow autoregulation. The clinical cerebrovascular effects of long-term blockade of CGRP are not yet known. Methods: We analyzed a retrospective cohort of migraine patients from a large administrative dataset in the United States (OPTUM) that covers patients with commercial insurance and Medicare Advantage, during 2018 and 2019, using ICD-10 codes for all types of migraines. Migraine patients were divided into two groups based on their use of CGRP inhibitors (erenumab, fremanezumab, galcanezumab). We determined the incidence of stroke during 2018 and 2019 among both groups. For the group of migraine patients who used CGRP inhibitors, we focused on the incidence of stroke after these medications were initiated. Results: We identified 646,404 migraine patients; 18, 692 (2.9%) of them had used a CGRP inhibitor. Among the users of CGRP inhibitors, 86% were females, and 58% of patients were in the 41 to 65-year-old range. The average time of follow-up was 197 days after initiation of the medication. A total of 1.3 % of patients who used CGRP inhibitors had an ischemic stroke during the follow-up period versus 2.4% of patients who did not use CGRP inhibitors. The lower rate of stroke in the CGRP antibody group was found in both sexes and all age groups. Conclusions: These preliminary results suggest that CGRP inhibitors are not associated with a higher frequency of stroke in the initial months of use. This could be related to the avoidance of these medications in patients with known cardiovascular risk factors. Further analyses will be completed on vascular risk factor incidence in these populations as well as multiple regression. Prospective, long term studies are needed to confirm these results.

Introduction: Overall poor COVID-19 outcomes have been reported among males. We evaluated sex differences in mortality among patients with stroke related to COVID-19. Methods: Utilizing pooled deidentified data from 30 healthcare organizations, we identified COVID-19 patients via ICD-10 diagnosis or documented laboratory confirmation of SARS-CoV-2 RNA or antibodies. Patients with ICD-10 diagnoses of ischemic stroke or intracerebral hemorrhage within 30 days before or after the COVID-19 event were flagged. Male and female patients were propensity score (PS) matched on other demographic and comorbidity variables. Risk Ratio (RR) and 95% Confidence Interval (CI) for association between sex and 90-day mortality is reported. Kaplan-Meier analyses with log rank test (LRT) were conducted for time-to-death. As a sensitivity analysis, we only included a smaller sub-set with first instance of IS or ICH ± 30-days of COVID-19 diagnosis. Results: Among 149,410 COVID-19 patients, 1,618 (1.1%) had a stroke diagnosis ± 30-days of confirmed COVID-19. Of whom, 1,609 patients (847 males and 762 females) were included in primary analyses. Females were older (67.7 vs. 65.7 years) and were more likely to be of black race (34.1% vs. 27.6%). Females had a significantly higher proportion of chronic pulmonary disease (38.8% vs. 28.8%) and obesity (34.2% vs. 24.8%); whereas males had higher proportion of alcohol abuse (8.5% vs. 3.8%). A 1:1 PS algorithm yielded an optimally matched sample of 634 males and females each, balanced on all covariates. In the matched sample, 11.7% of females and 15.8% of males experienced 90-day mortality; RR (CI): 1.35 (1.02 - 1.78), LRT p value 0.04. Higher risk of 90-day mortality among males with COVID-19 and stroke was maintained in the sensitivity analyses, RR (CI): 1.47 (1.06 - 2.00), LRT p value = 0.03 (graphic). Conclusion: Future studies examining the socio-demographic and biological mechanisms for poor stroke outcomes among males with COVID-19 are needed.

Study Design: Prospective cohort study. Objective: Reconstruction with microvascular free flaps is quite predictable but excessive fluids intraoperatively and excessive use of vasopressors have been implicated in postoperative complications. However, vasopressors assist in limiting fluid administration and counteract vasodilatory effects of general anesthetics, while maintaining proper intravascular volume. This is of paramount importance during surgery to ensure adequate tissue and organ perfusion. The purpose of this study is to quantify perfusion changes in free flaps at specific time points during peri- and postoperative periods, incorporating SPY technology. Methods: A prospective study of patients who underwent free flap reconstruction was conducted (n = 9), using SPY laser angiography with indocyanine green to assess effects of general anesthetics and vasopressors on flap perfusion. Free flaps were evaluated prior to pedicle division, after inset and anastomosis, and in the immediate postoperative setting. Mean perfusion, mean arterial pressure, total operative time, fluid shifts, and vasopressor use were recorded. Data were analyzed with univariate and multivariable analyses. Results: Those with major complications in this cohort, on average received less vasopressors, had shorter operation times and less blood loss, however, they received more fluids intraoperatively. Conclusion: Changes in mean perfusion to the free flap during the intraoperative and immediate postoperative period are nominal.

Background The goal of this study was to evaluate hard tissue response following guided bone regeneration using commercially available bovine bone grafts and collagen membranes; bilayer collagen membrane and porcine pericardium-based membrane, by means of a non-destructive three-dimensional (3D) computerized volumetric analysis following microtomography reconstruction. Material and Methods Bone regenerative properties of various bovine bone graft materials were evaluated in the Göttingen minipig model. Two standardized intraosseous defects (15mm x 8mm x 8mm) were created bilaterally of the mandible of eighteen animals (n=72 defects). Groups were nested within the same subject and randomly distributed among the sites: (i) negative control (no graft and membrane), (ii) bovine bone graft/bilayer collagen membrane (BOB) (iii) Bio-Oss® bone graft/porcine pericardium-based membrane (BOJ) and (iv) cerabone® bone graft/porcine pericardium-based membrane (CJ). Samples were harvested at 4, 8, and 12-week time points (n=6 animal/time point). Segments were scanned using computerized microtomography (μCT) and three dimensionally reconstructed utilizing volumetric reconstruction software. Statistical analyses were performed using IBM SPSS with a significance level of 5%. Results From a temporal perspective, tridimensional evaluation revealed gradual bone ingrowth with the presence of particulate bone grafts bridging the defect walls, and mandibular architecture preservation over time. Volumetric analysis demonstrated no significant difference between all groups at 4 weeks (p>0.127). At 8 and 12 weeks there was a higher percentage of new bone formation for control and CJ groups when compared to BOB and BOJ groups (p

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

Despite aggressive treatment with temozolomide and radiotherapy and extensive research into alternative therapies there has been little improvement in Glioblastoma patient survival. Median survival time remains between 12 and 15 months mainly due to treatment resistance and tumor recurrence. In this study, we aimed to explore the underlying mechanisms behind treatment resistance and the lack of success with anti-EGFR therapy in the clinic. After generating a number of treatment resistant Glioblastoma cell lines we observed that resistant cell lines lacked EGFR activation and expression. Furthermore, cell viability assays showed resistant cells were significantly less sensitive to the anti-EGFR agents when compared to parental cell lines. To further characterise the resistance mechanism in our cells microRNA prediction software identified miR-221 as a negative regulator of EGFR expression. miR-221 was up-regulated in our resistant cell lines, and this up-regulation led to a significant reduction in EGFR expression in both our cultured cell lines and a large cohort of glioblastoma patient tumor tissue.

With the incidence of failed and ailing dental implants increasing, the authors conducted research to evaluate and characterize all known criteria used in the assessment of implant health in the clinical setting. A review of articles found in electronic databases was performed. Once all parameters for implant assessment as supported by current literature were selected, implant assessment documents were created: a data acquisition form and a quantitative comprehensive evaluation. These documents provide the clinician an algorithm that yields a prognosis of survival for each implant. Diagnostic criteria were organized to offer a comprehensive assessment of risk factors related to implant health. Data acquisition prior to establishing the prognosis is necessary in accordance with the staging system developed. Parameters for diagnosis and staging include a thorough medical/social history of the patient, implant history, and clinical evaluation. The authors concluded that the establishment of parameters for comprehensive implant evaluation in the clinical setting is feasible. This assessment process enables an effective clinical approach to evaluate and treat ailing implants while facilitating a clinical diagnostic algorithm.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

The effect of surface PEGylation on nanoparticle transport through an extracellular matrix (ECM) is an important determinant for tumor targeting success. Fluorescent stealth liposomes (base lipid DOPC) were prepared incorporating different proportions of PEG-grafted lipids (2.5, 5 and 10% of the total lipid content) for a series of PEG molecular weights (1000, 2000 and 5000 Da). The ECM was modelled using a collagen matrix. The kinetics of PEGylated liposome adhesion to and transport in collagen matrices were tracked using fluorescence correlation spectroscopy (FCS) and confocal microscopy, respectively. Generalized least square regressions were used to determine the temporal correlations between PEG molecular weight, surface density and conformation, and the liposome transport in a collagen hydrogel over 15 hours. PEG conformation determined the interaction of liposomes with the collagen hydrogel and their transport behaviour. Interestingly, liposomes with mushroom PEG conformation accumulated on the interface of the collagen hydrogel, creating a dense liposomal front with short diffusion distances into the hydrogels. On the other hand, liposomes with dense brush PEG conformation interacted to a lesser extent with the collagen hydrogel and diffused to longer distances. In conclusion, a better understanding of PEG surface coating as a modifier of transport in a model ECM matrix has resulted. This knowledge will improve design of future liposomal drug carrier systems.

Despite years of excellent individual studies, the impact of nanoparticle (NP) cytotoxicity studies remains limited by inconsistent data collection and analysis. It is often unclear how exposure conditions can be used to determine cytotoxicity quantitatively. Discrepancies due to using different measurement conditions, readouts and controls to characterize NP interactions with cells lead to further challenges. To examine which parameters are critical in NP cytotoxicity studies, we have chosen to examine two NP types (liposomes and quantum dots) at different concentrations incubated with two primary vascular endothelial cells, HUVEC and HMVEC-C for a standard time of 24 h. We paid close attention to the effects of positive controls and cell association on interpretation of cytotoxicity data. Various cellular responses (ATP content, oxidative stress, mitochondrial toxicity, and phospholipidosis) were measured in parallel. Interestingly, cell association data varied significantly with the different image analyses. However, cytotoxicity responses could all be correlated with exposure concentration. Cell type did have an effect on cytotoxicity reports. Most significantly, NP cytotoxicity results varied with the inclusion or exclusion of positive controls. In the absence of positive controls, one tends to emphasize small changes in cell responses to NPs.

Nanoparticle (NP) interactions with biological tissues are affected by the size, shape and surface chemistry of the NPs. Here we use in vivo (zebrafish) and in vitro (HUVEC) models to investigate association of quantum dots (QDs) with endothelial cells and the effect of fluid flow. After injection into the developing zebrafish, circulating QDs associate with endothelium and penetrate surrounding tissue parenchyma over time. Amino-functionalized QDs cluster, interact with cells, and clear more rapidly than carboxy-functionalized QDs in vivo, highlighting charge influences. QDs show stronger accumulation in slow-flowing, small caliber venous vessels than in fast-flowing high caliber arterial vessels. Parallel-plate flow experiments with HUVEC support these findings, showing reduced QD-EC association with increasing flow. In vivo, flow arrest after nanoparticle injection still results in venous accumulation at 18 h. Overall our results suggest that both QD charge and blood flow modulate particle-endothelial cell interactions.

Here we introduce methodological guidelines for designing policies against organized crime. We employ the evolutionary ontology proposed by Kurt Dopfer for conceiving organized crime as the outcome of social, intelligent agents whose strategies evolve through time. To illustrate the use of this ontology we explore the case of corruption in public procurement processes in Colombia in which criminal organizations—groups of corrupt agents—converge spontaneously. The ontology leads to conceive corruption as a knowledge process that adapts according to the evolution of problem-solving rules that are created, used and discarded by agents that seek to attain personal gains by means of public resources. We also use an engineering perspective that favors model-aided design. We built a simulation model that illustrates how the dynamics of such evolving-rules systems can be conceptualized for exploring potential policies. The application of the evolutionary ontology shows why corruption exhibits self-organization: system-level patterns develop from spontaneous interactions that use only local information. Rule dynamics form a changing structure of rule-populations that adapt to novel environmental conditions and generate meta-stable adaptions that explain why corruption persists despite continuous challenges from the environment. This engineering approach forms the ground for proposing policies that instead of addressing the operant level of a social system (according to observed operations and data), should meet the dynamics of rules that govern those operations. Hence, the role of regulators shifts from “controllers” to inventors of selectionist environments that facilitate suitable change through the introduction or promotion of counter-crime rules, the design of selective pressures that favor the evolution of desirable rules and the attention to coordination gaps at the macro-structure. The recognition of organized crime as the outcome of an evolving-rules system changes the questions that orient policy-making and focuses on the redesign of evolving knowledge. Accordingly, our methodological guidelines address such evolutionary dynamics and can be applied to several forms of organized crime.

Objectives To identify whether intracranial atherosclerotic disease large vessel occlusion strokes differ compared to embolic large vessel occlusion strokes in angiographic response to mechanical thrombectomy and clinical course. Methods Retrospective analysis of acute ischemic stroke patients with large vessel occlusion, due to intracranial atherosclerotic disease or embolic etiology, who underwent mechanical thrombectomy in a primary stroke center from 11/2015 to 4/2018. We categorized patients into intracranial atherosclerotic disease or embolic large vessel occlusion based on the procedural findings. We compared pretreatment, procedural variables, and post-procedural outcomes. Results Ninety-five patients were included, 13 with intracranial atherosclerotic disease large vessel occlusion strokes and 82 with embolic large vessel occlusion strokes. Between the two groups, there was no statistically significant difference in angiographic success (100% for intracranial atherosclerotic disease and 89% for embolic large vessel occlusion strokes); first pass success (38% for intracranial atherosclerotic disease and 34% for embolic large vessel occlusion strokes); puncture-to-first-pass time; puncture-to-recanalization time (68 minutes for intracranial atherosclerotic disease and 62 minutes for embolic large vessel occlusion strokes); number of passes; or clinical outcomes. Intracranial angioplasty was performed in 6 (46%) of intracranial atherosclerotic disease large vessel occlusion patients, and in 5 (6%) of embolic large vessel occlusion patients (p Conclusions Similar angiographic success and procedural time metrics are achievable with intracranial atherosclerotic disease large vessel occlusion and embolic large vessel occlusion therapy. This occurred with more frequent intracranial angioplasty for intracranial atherosclerotic disease large vessel occlusion strokes.

Nanoparticles in the bloodstream are subjected to complex fluid forces as they move through the curves and branches of healthy or tumor vasculature. While nanoparticles are known to preferentially accumulate in angiogenic vessels, little is known about the flow conditions in these vessels and how these conditions may influence localization. Here, we report a methodology which combines confocal imaging of nanoparticle-injected transgenic zebrafish embryos, 3D modeling of the vasculature, particle mapping, and computational fluid dynamics, to quantitatively assess the effects of fluid forces on nanoparticle distribution in vivo. Six-fold lower accumulation was found in zebrafish arteries compared to the lower velocity veins. Nanoparticle localization varied inversely with shear stress. Highest accumulation was present in regions of disturbed flow found at branch points and curvatures in the vasculature. To further investigate cell-particle association under flow, human endothelial cells were exposed to nanoparticles under hemodynamic conditions typically found in human vessels. Physiological adaptations of endothelial cells to 20 hours of flow enhanced nanoparticle accumulation in regions of disturbed flow. Overall our results suggest that fluid shear stress magnitude, flow disturbances, and flow-induced changes in endothelial physiology modulate nanoparticle localization in angiogenic vessels.