Length-Dependent Cellular Internalization of Nanobody-Functionalized Poly(2-oxazoline) Nanorods.

The ability to target specific tissues and to be internalized by cells is critical for successful nanoparticle-based targeted drug delivery. Here, we combined "stealthy" rod-shaped poly(2-oxazoline) (POx) nanoparticles of different lengths with a cancer marker targeting nanobody and a fluorescent cell internalization sensor via a heat-induced living crystallization-driven self-assembly (CDSA) strategy. A significant increase in association and uptake driven by nanobody-receptor interactions was observed alongside nanorod-length-dependent kinetics. Importantly, the incorporation of the internalization sensor allowed for quantitative differentiation between cell surface association and internalization of the targeted nanorods, revealing unprecedented length-dependent cellular interactions of CDSA nanorods. This study highlights the modularity and versatility of the heat-induced CDSA process and further demonstrates the potential of POx nanorods as a modular nanomedicine platform.

Intrinsic Green Fluorescent Cross-Linked Poly(ester amide)s by Spontaneous Zwitterionic Copolymerization.

The spontaneous zwitterionic copolymerization (SZWIP) of 2-oxazolines and acrylic acid affords biocompatible but low molecular weight linear N-acylated poly(amino ester)s (NPAEs). Here, we present a facile one-step approach to prepare functional higher molar mass cross-linked NPAEs using 2,2'-bis(2-oxazoline)s (BOx). In the absence of solvent, insoluble free-standing gels were formed from BOx with different length n-alkyl bridging units, which when butylene-bridged BOx was used possessed an inherent green fluorescence, a behavior not previously observed for 2-oxazoline-based polymeric materials. We propose that this surprising polymerization-induced emission can be classified as nontraditional intrinsic luminescence. Solution phase and oil-in-oil emulsion approaches were investigated as means to prepare solution processable fluorescent NPAEs, with both resulting in water dispersible network polymers. The emulsion-derived system was investigated further, revealing pH-responsive intensity of emission and excellent photostability. Residual vinyl groups were shown to be available for modifications without affecting the intrinsic fluorescence. Finally, these systems were shown to be cytocompatible and to function as fluorescent bioimaging agents for in vitro imaging.

Low-dose aspirin for primary prevention of cardiovascular disease: Trends in use patterns among African American adults in Minnesota, 2015-2019.

Cardiovascular disease (CVD) disproportionately affects African Americans. Aspirin has long been recommended to reduce cardiovascular events. However, national guideline changes in 2016 limited the aspirin recommended population and several clinical trials questioning the utility of primary prevention aspirin were published in 2018. In light of the recent guidelines and study findings, we investigated primary prevention aspirin use among urban African American adults. Using three cross-sectional surveys, we collected data from self-identified African Americans with no CVD in 2015, 2017 and 2019, querying information on CVD risk factors, health behaviors and beliefs, and aspirin use. Poisson regression modeling was used to estimate age- and risk-factor adjusted aspirin prevalence, trends and associations. A total of 1491 African Americans adults, ages 45-79, were included in this analysis; 61% were women. There was no change in age- and risk factor-adjusted aspirin use over the 3 surveys for women (37%, 34% and 35% respectively) or men (27%, 25%, 30% respectively). However, fewer participants believed aspirin was helpful in 2019 compared to 2015-75% versus 84% (p < 0.001). Aspirin discussions with a health care practitioner were highly associated with aspirin use (adjusted RR 2.97, 95% CI 2.49-3.54) and aspirin use was 2.56 times higher (adjusted RR 95% CI 2.17-3.03) in respondents who agreed that people close to them thought they should take aspirin compared with those who disagreed or did not know. Despite major changes in national guidelines, overall primary prevention aspirin use did not significantly change in these African American samples from 2015 to 2019.

Extending the Scope of "Living" Crystallization-Driven Self-Assembly: Well-Defined 1D Micelles and Block Comicelles from Crystallizable Polycarbonate Block Copolymers.

Fiber-like block copolymer (BCP) micelles offer considerable potential for a variety of applications; however, uniform samples of controlled length and with spatially tailored chemistry have not been accessible. Recently, a seeded growth method, termed "living" crystallization-driven self-assembly (CDSA), has been developed to allow the formation of 1D micelles and block comicelles of precisely controlled dimensions from BCPs with a crystallizable segment. An expansion of the range of core-forming blocks that participate in living CDSA is necessary for this technique to be compatible with a broad range of applications. Few examples currently exist of well-defined, water-dispersible BCP micelles prepared using this approach, especially from biocompatible and biodegradable polymers. Herein, we demonstrate that BCPs containing a crystallizable polycarbonate, poly(spiro[fluorene-9,5'-[1,3]-dioxan]-2'-one) (PFTMC), can readily undergo living CDSA processes. PFTMC- b-poly(ethylene glycol) (PEG) BCPs with PFTMC:PEG block ratios of 1:11 and 1:25 were shown to undergo living CDSA to form near monodisperse fiber-like micelles of precisely controlled lengths of up to ∼1.6 µm. Detailed structural characterization of these micelles by TEM, AFM, SAXS, and WAXS revealed that they comprise a crystalline, chain-folded PFTMC core with a rectangular cross-section that is surrounded by a solvent swollen PEG corona. PFTMC- b-PEG fiber-like micelles were shown to be dispersible in water to give colloidally stable solutions. This allowed an assessment of the toxicity of these structures toward WI-38 and HeLa cells. From these experiments, we observed no discernible cytotoxicity from a sample of 119 nm fiber-like micelles to either healthy (WI-38) or cancerous (HeLa) cell types. The living CDSA process was extended to PFTMC- b-poly(2-vinylpyridine) (P2VP), and addition of this BCP to PFTMC- b-PEG seed micelles led to the formation of well-defined segmented fibers with spatially localized coronal chemistries.

Enabling Heterogeneous Gold Catalysis with Patchy Micelles.

Patch works! Patchy block copolymer micelles with a corona consisting of two chemically different patches have been designed for the selective binding of catalytically active nanoparticles. The fabrication of nonwoven supports by electrospinning was combined with crystallization-driven self-assembly for precise control over micelle formation to prepare a new recyclable catalyst platform.

In Situ Visualization of Block Copolymer Self-Assembly in Organic Media by Super-Resolution Fluorescence Microscopy.

Analytical methods that enable visualization of nanomaterials derived from solution self-assembly processes in organic solvents are highly desirable. Herein, we demonstrate the use of stimulated emission depletion microscopy (STED) and single molecule localization microscopy (SMLM) to map living crystallization-driven block copolymer (BCP) self-assembly in organic media at the sub-diffraction scale. Four different dyes were successfully used for single-colour super-resolution imaging of the BCP nanostructures allowing micelle length distributions to be determined in situ. Dual-colour SMLM imaging was used to measure and compare the rate of addition of red fluorescent BCP to the termini of green fluorescent seed micelles to generate block comicelles. Although well-established for aqueous systems, the results highlight the potential of super-resolution microscopy techniques for the interrogation of self-assembly processes in organic media.

Anticipating change, sparking innovation: framing the future.

As the 100th anniversary of the 1915 Welch-Rose report approaches, the Association of Schools and Programs of Public Health (ASPPH) has been pursuing two initiatives to spark innovation in academic partnerships for enhancing population health: (1) Framing the Future: The Second 100 Years of Education for Public Health and (2) Reconnecting Public Health and Care Delivery to Improve the Health of Populations. We describe how ASPPH-member schools and programs accredited by the Council on Education for Public Health, along with their extraordinarily diverse array of partners, are working to improve education that better prepares health professionals to meet 21st-century population health needs.

Gradient crystallization-driven self-assembly: cylindrical micelles with "patchy" segmented coronas via the coassembly of linear and brush block copolymers.

Block copolymers (BCPs) with a short crystallizable poly(ferrocenyldimethylsilane) (PFS) core-forming block self-assemble in selective solvents to afford cylindrical micelles, the ends of which are active to further growth via a process termed living crystallization-driven self-assembly (CDSA). We now report studies of the CDSA of a series of crystalline-brush BCPs with C6 (BCP(6)), C12 (BCP(12)), and C18 (BCP(18)) n-alkyl branches that were prepared by the thiol-ene functionalization of PFS-b-PMVS (PMVS = poly(methylvinylsiloxane)). Although the increased n-alkyl brush length of BCP(12) and BCP(18) hindered micelle growth, the increased intercoronal chain repulsion could be alleviated by their coassembly with linear PFS-b-PMVS. When the coassembly was initiated by short cylindrical seed micelles, monodisperse block comicelles of controllable length with "patchy" coronal nanodomains were accessible. TEM and AFM analysis of micelles prepared from BCP(18) and PFS-b-PMVS were found to provide complementary characterization in that the OsO4-stained PMVS coronal domains were observed by TEM, whereas the brush block domains of BCP(18) (which displayed greater height) were detected by tapping mode AFM. The results showed that the coassembly afforded a gradient structure, with an initial bias for the growth of the linear BCP over that of the more sterically demanding brush BCP, which was gradually reversed as the linear material was consumed. This represents the first example of living gradient CDSA, a process reminiscent of a living covalent gradient copolymerization of two different monomers. Although other possible explanations exist, simulations based on a statistical model indicated that the coronal nanodomains detected likely result from a segmented, gradient comicelle architecture that arises as a consequence of: (i) different rates of addition of BCP unimer to the micelle termini, and (ii) a cumulative effect resulting from steric hindrance associated with the brush block.

Socioeconomic differences in the risk profiles of susceptibility and ever use of tobacco among Indian urban youth: a latent class approach.

PURPOSE: To empirically determine the socioeconomic differences in risk profiles of susceptibility and ever use of tobacco among adolescents in India and to investigate the association between the risk profiles and the psychosocial factors for tobacco use. METHODS: Students in 16 private (higher socioeconomic status [SES]; n = 4,489) and 16 government (lower SES; n = 7,153) schools in two large cities in India were surveyed about their tobacco use and related psychosocial factors in 2004. Latent class analysis was used to identify homogenous, mutually exclusive typologies existing within the data. RESULTS: Overall, 3 and 4 latent classes of susceptibility and ever use of tobacco best described students in higher- and lower- SES schools, respectively. Profiles with various combinations of susceptibility and ever use of tobacco were differentially related to psychosocial factors, with lower- SES students being more vulnerable to increased levels of tobacco use than higher- SES students. CONCLUSIONS: Acknowledging the multiple dimensions of tobacco use behaviors and identifying constellations of risk behaviors will enable more accurate understanding of etiological processes and will provide information for refining and targeting preventive interventions. Additionally, identifying the socioeconomic differences in susceptibility and ever use risk profiles and their psychosocial correlates will enable policy makers to address these inequities through improved allocation of resources.

A 16-month community-based intervention to increase aspirin use for primary prevention of cardiovascular disease.

INTRODUCTION: Cardiovascular diseases are the leading causes of disability and death in the United States. Primary prevention of these events may be achieved through aspirin use. The ability of a community-based intervention to increase aspirin use has not been evaluated. The objective of this study was to evaluate an educational intervention implemented to increase aspirin use for primary prevention of cardiovascular disease in a small city in Minnesota. METHODS: A community-based intervention was implemented during 16 months in a medium-sized community in Minnesota. Messages for aspirin use were disseminated to individuals, health care professionals, and the general population. Independent cross-sectional samples of residents (men aged 45-79, women aged 55-79) were surveyed by telephone to identify candidates for primary prevention aspirin use, examine their characteristics, and determine regular aspirin use at baseline and after the campaign at 4 months and 16 months. RESULTS: In primary prevention candidates, regular aspirin use rates increased from 36% at baseline to 54% at 4 months (odds ratio = 2.05; 95% confidence interval, 1.09-3.88); the increase was sustained at 52% at 16 months (odds ratio = 1.89; 95% confidence interval, 1.02-3.49). The difference in aspirin use rates at 4 months and 16 months was not significant (P = .77). CONCLUSION: Aspirin use rates for primary prevention remain low. A combined public health and primary care approach can increase and sustain primary prevention aspirin use in a community setting.

Individual and neighborhood socioeconomic status effects on adolescent smoking: a multilevel cohort-sequential latent growth analysis.

OBJECTIVES: We examined the prospective effects of parental education (as a proxy for individual socioeconomic status [SES]) and neighborhood SES on adolescent smoking trajectories and whether the prospective effects of individual SES varied across neighborhood SES. METHODS: The study included 3635 randomly recruited adolescents from 5 age cohorts (12-16 years) assessed semiannually for 3 years in the Minnesota Adolescent Community Cohort study. We employed a cohort-sequential latent growth model to examine smoking from age 12 to 18 years with predictors. RESULTS: Lower individual SES predicted increased levels of smoking over time. Whereas neighborhood SES had no direct effect, the interaction between individual and neighborhood SES was significant. Among higher and lower neighborhood SES, lower individual SES predicted increased levels of smoking; however, the magnitude of association between lower individual SES and higher smoking levels was significantly greater for higher neighborhood SES. CONCLUSIONS: We found evidence for differential effects of individual SES on adolescent smoking for higher and lower neighborhood SES. The group differences underscore social conditions as fundamental causes of disease and development of interventions and policies to address inequality in the resources.

Public health as a distinct profession: has it arrived?

This article reviews the elements consistent with the definition of a "profession" in the contemporary United States and argues that public health should be considered a distinct profession, recognizing that it has a unique knowledge base and career paths independent of any other occupation or profession. The Welch-Rose Report of 1915 prescribed education for public health professionals and assumed that, although at first the majority of students would be drawn from other professions, such as medicine, nursing, and sanitary engineering, public health was on its way to becoming "a new profession." Nearly a century later, the field of public health has evolved dramatically in the direction predicted. It clearly meets the criteria for being a "profession" in that it has (1) a distinct body of knowledge, (2) an educational credential offered by schools and programs accredited by a specialized accrediting body, (3) career paths that include autonomous practice, and (4) a separate credential, Certified in Public Health (CPH), indicative of self-regulation based on the newly launched examination of the National Board of Public Health Examiners. Barriers remain that challenge independent professional status, including the breadth of the field, more than one accrediting body, wide variation in graduate school curricula, and the newness of the CPH. Nonetheless, the benefits of recognizing public health as a distinct profession are considerable, particularly to the practice and policy communities. These include independence in practice, the ability to recruit the next generation, increased influence on health policy, and infrastructure based on a workforce of strong capacity and leadership capabilities.

Visible Light-Accelerated Photoiniferter Polymerization in Ionic Liquid.

The effect of ionic liquids on the reversible addition-fragmentation chain transfer (RAFT) polymerization mediated by a visible-light-induced photoiniferter mechanism was investigated. N,N-Dimethyl acrylamide was polymerized by photoiniferter polymerization in 1-ethyl-3-methylimidazolium ethylsulfate [EMIM][EtSO4] ionic liquid. We observed a considerable increase in the polymerization rate constants in ionic liquids (ILs), as well as in the mixed solvent of water and the IL, compared to those observed with water alone as the solvent. To demonstrate the robustness of the process, block copolymers with varying block ratios were synthesized with precise control over their molecular weight and mass dispersity (D). The very high chain-end fidelity provided by the photoiniferter polymerization in IL was described by using MALDI-ToF MS analysis.

Association of a Community Population and Clinic Education Intervention Program With Guideline-Based Aspirin Use for Primary Prevention of Cardiovascular Disease: A Nonrandomized Controlled Trial.

Importance: Low-dose aspirin is used for primary prevention of cardiovascular disease in approximately one-third of the US adult population. Overuse and underuse are common and not concordant with guidelines. Objective: To test a community and clinic education intervention to improve guideline-based aspirin use for the primary prevention of cardiovascular disease. Design, Setting, and Participants: The Ask About Aspirin project was a nonrandomized controlled trial conducted from, July 1, 2015, to March 31, 2020, using professional education, traditional media, and digital media to improve guideline-based aspirin use. The adult population (aged 45-79 years for men and 55-79 years for women) and primary care clinics in Minnesota were the education targets. The 4 adjacent states were controls. Interventions: The statewide campaign distributed billboards, newspaper articles and other print material, and radio announcements. An Ask About Aspirin website was heavily promoted. Primary care clinics identified appropriate aspirin candidates, and clinicians received continuing education about aspirin. Main Outcomes and Measures: Guideline-based aspirin use by the target population. Results: Cross-sectional random telephone surveys of 8342 men aged 45 to 79 years and women aged 55 to 79 years were conducted at baseline, 2 years, and 4 years after the intervention. Participation was similar between men and women (baseline: 973 [49%] vs 1001 [51%]; year 4: 912 [50%] vs 930 [50%]). Age during the study also was similar (baseline: 64.7 [IQR, 64.4-65.1] years; year 4: 66.2 [IQR, 65.8-66.5] years). A validated questionnaire evaluated aspirin use. The Ask About Aspirin website had more than 1 million visits; 124 primary care clinics with more than 1000 participating clinicians were part of the education program. Small, nonsignificant increases in discussions with clinicians regarding aspirin resulted (baseline: 341 of 1001 [34%]; year 4: 339 of 930 [36%]; P = .27). Overall aspirin use decreased after the release of new US Preventive Services Task Force guidelines in 2016 and 3 aspirin randomized clinical trials in 2018 suggested reduced aspirin use (baseline: 816 of 1974 [41%]; year 4: 629 of 1842 [34%]; P < .001). Decreases were also noted from year 2 to year 4 in appropriate use (year 2: 597 of 1208 [49%]; year 4: 478 of 1191 [40%]; P < .001) and overuse (year 2: 170 of 602 [28%]; year 4: 151 of 651 [23%]; P = .04). There were no significant differences between Minnesota and the control states. Conclusions and Relevance: In this nonrandomized controlled trial, a multiyear statewide campaign was not associated with increased appropriate aspirin use for cardiovascular disease prevention. Contextual factors during the project, including guideline changes and media controversy following the new trials, undermined study goals. These findings suggest that although education programs using social media for cardiovascular disease prevention can result in millions of hits, the use of this strategy to encourage behavior change is problematic, even with supportive clinical sites. Trial Registration: ClinicalTrials.gov Identifier: NCT02607917.

Stealth nanorods via the aqueous living crystallisation-driven self-assembly of poly(2-oxazoline)s.

The morphology of nanomaterials critically influences their biological interactions. However, there is currently a lack of robust methods for preparing non-spherical particles from biocompatible materials. Here, we combine 'living' crystallisation-driven self-assembly (CDSA), a seeded growth method that enables the preparation of rod-like polymer nanoparticles, with poly(2-oxazoline)s (POx), a polymer class that exhibits 'stealth' behaviour and excellent biocompatibility. For the first time, the 'living' CDSA process was carried out in pure water, resulting in POx nanorods with lengths ranging from ∼60 to 635 nm. In vitro and in vivo study revealed low immune cell association and encouraging blood circulation times, but little difference in the behaviour of POx nanorods of different length. The stealth behaviour observed highlights the promising potential of POx nanorods as a next generation stealth drug delivery platform.

A community-based group randomized trial to increase aspirin use for primary prevention of cardiovascular disease: Study protocol and baseline results for the "Ask About Aspirin" initiative.

BACKGROUND: USPSTF evidence-based recommendations for the use of low-dose aspirin for primary prevention of cardiovascular disease were published in 2009. We describe a statewide campaign using innovative methods to educate the public and health communities about appropriate aspirin use. METHODS/DESIGN: The "Ask About Aspirin" initiative is designed to lower the number of first heart attacks and strokes in the State of Minnesota by promoting the appropriate use of low dose aspirin. A health system intervention combined with an aspirin awareness media campaign will be evaluated in a pragmatic group randomized controlled trial including 267 primary care clinics within 84 health systems over a four year period. Matched pairs of geographic territories will be randomized to intervention (12 territories) or control (12 territories). The primary outcome of appropriate aspirin use will be measured at the individual level, by community-based telephone surveys of 100 participants in each of the 24 geographically determined clusters. DISCUSSION: We briefly describe the rationale for the interventions being studied, as well as the major design choices. Rigorous research designs such as the one described here are necessary to determine whether evidence-based recommendations can be effectively disseminated in multiple health systems. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02607917.

Aspirin Use and Misuse for the Primary Prevention of Cardiovascular Diseases.

INTRODUCTION: Daily aspirin use for primary cardiovascular disease prevention is common among adults. Numerous clinical trials observe reduced cardiovascular disease with regular low-dose aspirin. The U.S. Preventive Services Task Force in 2016 published guidelines for aspirin use, but controversy exists about the side effects, and overuse or underuse may be common despite the guidelines. Using the Task Force recommendations, this paper describes the prevalence of appropriate aspirin use and physician advice in a population sample. METHODS: A random sample of men and women (aged 50-69 years) living in the Upper Midwest in 2017-2018 were surveyed, collecting demographic data, health history, and aspirin use. Appropriate primary prevention with aspirin was defined as having ≥10% cardiovascular disease risk (hypertension, hyperlipidemia, diabetes, smoking) with daily or every other day aspirin use. Those with prevalent cardiovascular disease were labeled as secondary prevention. RESULTS: A total of 1,352 adults were surveyed (697 women, 655 men). The criteria for secondary prevention were fulfilled in 188 participants, and these were eliminated from the analysis. In the remaining group, aspirin was indicated in 32.9% (383 of 1,164). Among those, 46.0% (176 of 383) were appropriate users, and 54.0% (207 of 383) were nonusers despite indications. Overuse, where aspirin is not indicated, was common at 26.9% (210 of 781). Discussion with a physician, although reported in 29% of subjects, was associated with some improvement in the appropriate use but also with overuse and underuse. CONCLUSIONS: Aspirin use for primary cardiovascular disease prevention is common. However, many adults are medicating without indication (overuse) or are not using aspirin despite guidelines (underuse).

Long-range exciton transport in conjugated polymer nanofibers prepared by seeded growth.

Easily processed materials with the ability to transport excitons over length scales of more than 100 nanometers are highly desirable for a range of light-harvesting and optoelectronic devices. We describe the preparation of organic semiconducting nanofibers comprising a crystalline poly(di-n-hexylfluorene) core and a solvated, segmented corona consisting of polyethylene glycol in the center and polythiophene at the ends. These nanofibers exhibit exciton transfer from the core to the lower-energy polythiophene coronas in the end blocks, which occurs in the direction of the interchain π-π stacking with very long diffusion lengths (>200 nanometers) and a large diffusion coefficient (0.5 square centimeters per second). This is made possible by the uniform exciton energetic landscape created by the well-ordered, crystalline nanofiber core.