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Herein, two water‐soluble PROXYL‐based magnetic resonance imaging (MRI) macromolecular organic contrast agents (mORCAs) are designed and synthesized: linear and cross‐linked PCE‐mPEG‐Ppa‐PROXYL. They are prepared by conjugating linear and cross‐linked poly(carboxylate ester) (PCE) with poly(ethylene glycol) (mPEG2000)‐modified nitroxides (PROXYL), respectively. Both mORCAs form self‐assembled aggregates in an aqueous phase and PROXYL is protected inside a hydrophobic core to achieve great resistance to reduction in the physiological environment, and they have low toxicity. Since cross‐linked PCE‐mPEG‐Ppa‐PROXYL possess a branched architecture, its self‐assembled aggregate is more stable and compact with a greater particle size. Cross‐linked PCE‐mPEG‐Ppa‐PROXYL outperform the linear one in the following aspects: 1) its longitudinal relaxivity (r1 = 0.79 mm−1 s−1) is higher than that of the linear one (r1 = 0.64 mm−1 s−1) and both excel the best mORCA reported so far (r1 = 0.42 mm−1 s−1); 2) its blood retention time (≈48 h) is longer than that of its linear counterpart (≈10 h); 3) cross‐linked PCE‐mPEG‐Ppa‐PROXYL provided better MR imaging contrast resolution in normal organs (liver and kidney) and tumor of mice than the linear one. Overall, cross‐linked PCE‐mPEG‐Ppa‐PROXYL may have great potential to be a novel metal‐free macromolecular contrast agent for MR imaging. Two biodegradable PEGylated and nitroxides functionalized poly(carboxylate ester) are prepared. The cross‐linked polymer is superior to the linear one in terms of longitudinal relaxivity (0.79 vs 0.64 mm−1 s−1) and MR imaging in liver and tumor of mice, so it shows great potential to be a novel metal‐free macromolecular contrast agent for MR imaging.

Curt Flood in the Media examines the public discourse surrounding Curt Flood (1938-1997), the star center fielder for the St. Louis Cardinals throughout the sixties. In 1969, Flood was traded to the Philadelphia Phillies. At the time, all Major League Baseball players were subject to the reserve clause, which essentially bound a player to work in perpetuity for his original team, unless traded for another player or sold for cash, in which case he worked under the same reserve conditions for the next team.Flood refused the trade on a matter of principle, arguing that Major League Baseball had violated both U.S. antitrust laws and the 13th Amendment's prohibition of involuntary servitude. In a defiant letter to Commissioner Bowie Kuhn asking for his contractual release, Flood infamously wrote, \"after twelve years in the major leagues, I do not feel that I am a piece of property to be bought and sold irrespective of my wishes.\" Most significantly, Flood appeared on national television with Howard Cosell and described himself as a \"well-paid slave.\" Explosive controversy ensued.Khan examines the ways in which the media constructed the case and Flood's persona. By examining the mainstream press, the black press, and primary sources including Flood's autobiography, Khan exposes the complexities of what it means to be a prominent black American athlete-in 1969 and today.

In a randomized trial involving more than 900 patients undergoing resection of advanced melanoma, adjuvant nivolumab was associated with a higher rate of 12-month recurrence-free survival than ipilimumab (70.5% vs. 60.8%) and with fewer adverse events.

The last five years have witnessed a steady growth in the use of agency workers to fill core professional roles in public sector organizations. Whereas in the past the use of agency workers was driven mainly by employer demands for improved flexibility, this current expansion is predominantly supply led occurring against a backdrop of increasingly tight labour markets. In this article our objective is to explore some of the factors that lie behind this change. Specifically, we raise questions about how far current trends can be explained using the ‘free agent perspective’ and the notion of portfolio careers. Focusing on one group of professionals in the UK public sector — local authority social workers — we find only limited evidence to support this interpretation. Instead, it is argued that current moves into agency work are in large part a reaction to increasing rigidities in the employment system and to deteriorating conditions of work.

•The vascular water exchange MRI (VEXI) is a contrast-agent-free method proposed to assess BBB permeability•Apparent water exchange rate across BBB (AXRBBB) becomes higher specifically in the hippocampus, medial orbital frontal cortex, and thalamus in AD•AXRBBB is significantly correlated with cognitive dysfunction Blood-brain barrier (BBB) impairment is an important pathophysiological process in Alzheimer's disease (AD) and a potential biomarker for early diagnosis of AD. However, most current neuroimaging methods assessing BBB function need the injection of exogenous contrast agents (or tracers), which limits the application of these methods in a large population. In this study, we aim to explore the feasibility of vascular water exchange MRI (VEXI), a diffusion-MRI-based method proposed to assess the BBB permeability to water molecules without using a contrast agent, in the detection of the BBB breakdown in AD. We tested VEXI on a 3T MRI scanner on three groups: AD patients (AD group), mild cognitive impairment (MCI) patients due to AD (MCI group), and the age-matched normal cognition subjects (NC group). Interestingly, we find that the apparent water exchange across the BBB (AXRBBB) measured by VEXI shows higher values in MCI compared with NC, and this higher AXRBBB happens specifically in the hippocampus. This increase in AXRBBB value gets larger and extends to more brain regions (medial orbital frontal cortex and thalamus) from MCI group to the AD group. Furthermore, we find that the AXRBBB values of these three regions is correlated significantly with the impairment of respective cognitive domains independent of age, sex and education. These results suggest VEXI is a promising method to assess the BBB breakdown in AD.

Each year, major league baseball (MLB) teams face complex decisions about which players to retain and which players to recruit. In addition to operational, team and budget constraints, these decisions are further complicated by the fact that an athlete’s future performance and its impact on the team are both uncertain. In this paper, we combine prediction modeling with decision optimization to study the MLB free agent market. We develop optimization models for the allocation of a team’s recruitment budget using six different metrics that evaluate a player’s contributions to a team’s success. We consider both an ideal case, where each team can choose among all free agents, and a sequential case, where we assume that teams with stronger appeal (big market) are more successful in attracting talent, while teams with less pull must optimize their rosters over a much smaller pool of remaining players. Using the best-performing metric, which takes into account both players’ positions and their positional flexibility, we develop a series of quantitative tools that help teams, especially those with small budgets, identify (1) the players who deliver a key competitive advantage to their teams, appearing in both their ideal and sequential rosters and (2) the players who are in many ideal rosters and thus are likely to be hired by teams with big budgets, perhaps at a substantial salary premium. In order to gain and maintain an edge in the fiercely competitive free agent market, teams need to continuously adapt their strategies, and our models represent a first step towards prescriptive (not just predictive) analytics designed to help them do so. Further, our analysis indicates that a few players are in high demand from many teams (for instance, in every year of the period considered, the ten most in-demand players appear in the ideal rosters of at least seven teams), while most players appear in one ideal roster or none at all. Our models go beyond players’ individual performance metrics to help teams understand which players will be in high demand due to teams’ position needs in a given year. The results further emphasize the increasing importance of contract extensions as a strategy to bypass the free agent market.

Can free agency be compatible with determinism? Compatibilists argue that the answer is yes, and it has been suggested that the computer science principle of “computational irreducibility” sheds light on this compatibility. It implies that there cannot, in general, be shortcuts to predict the behavior of agents, explaining why deterministic agents often appear to act freely. In this paper, we introduce a variant of computational irreducibility that intends to capture more accurately aspects of actual (as opposed to apparent) free agency, including computational sourcehood, i.e., the phenomenon that the successful prediction of a process’ behavior must typically involve an almost-exact representation of the relevant features of that process, regardless of the time it takes to arrive at the prediction. We argue that this can be understood as saying that the process itself is the source of its actions, and we conjecture that many computational processes have this property. The main contribution of this paper is technical, in that we analyze whether and how a sensible formal definition of computational sourcehood is possible. While we do not answer the question completely, we show how it is related to finding a particular simulation preorder on Turing machines, we uncover concrete stumbling blocks towards constructing such a definition, and demonstrate that structure-preserving (as opposed to merely simple or efficient) functions between levels of simulation play a crucial role.

With its iconic stars and gleaming ballparks, baseball has been one of the most captivating forms of modern popular culture. In Expanding the Strike Zone, Daniel A. Gilbert examines the history and meaning of the sport’s tumultuous changes since the midtwentieth century, amid Major League Baseball’s growing global influence. From the rise of ballplayer unionism to the emergence of new forms of scouting, broadcasting, and stadium development, Gilbert shows that the baseball world has been home to struggles over work and territory that resonate far beyond the playing field. Readers encounter both legendary and unheralded figures in this sweeping history, which situates Major League Baseball as part of a larger culture industry. The book examines a labor history defined at once by the growing power of big league stars—from Juan Marichal and Curt Flood to Fernando Valenzuela and Ichiro Suzuki—and the collective struggles of players working to make a living throughout the baseball world. It also explores the territorial politics that have defined baseball’s development as a form of transnational popular culture, from the impact of Dominican baseball academies to the organized campaign against stadium development by members of Seattle’s Asian American community. Based on a rich body of research along with new readings of popular journalism, fiction, and film, Expanding the Strike Zone highlights the ways in which baseball’s players, owners, writers, and fans have shaped and reshaped the sport as a central element of popular culture from the postwar boom to the Great Recession.

Cryopreservation is widely used to maintain backups of cells as it enables the semipermanent storage of cells. During the freezing process, ice crystals that are generated inside and outside the cells can lethally damage the cells. All conventional cryopreservation methods use at least one cryoprotective agent (CPA) to render water inside and outside the cells vitreous or nanocrystallized (near-vitrification) without forming damaging ice crystals. However, CPAs should ideally be avoided due to their cytotoxicity and potential side effects on the cellular state. Herein, we demonstrate the CPA-free cryopreservation of mammalian cells by ultrarapid cooling using inkjet cell printing, which we named superflash freezing (SFF). The SFF cooling rate, which was estimated by a heat-transfer stimulation, is sufficient to nearly vitrify the cells. The experimental results of Raman spectroscopy measurements, and observations with an ultrahigh-speed video camera support the near-vitrification of the droplets under these conditions. Initially, the practical utility of SFF was demonstrated on mouse fibroblast 3T3 cells, and the results were comparable to conventional CPA-assisted methods. Then, the general viability of this method was confirmed on mouse myoblast C2C12 cells and rat primary mesenchymal stem cells. In their entirety, the thus-obtained results unequivocally demonstrate that CPA-free cell cryopreservation is possible by SFF. Such a CPA-free cryopreservation method should be ideally suited for most cells and circumvent the problems typically associated with the addition of CPAs.

Objectives To overcome the limitations of power Doppler in imaging angiogenesis, we sought to develop and investigate new quantitative biomarkers of a contrast-free ultrasound microvasculature imaging technique for differentiation of benign from malignant pathologies of breast lesion . Methods In this prospective study, a new high-definition microvasculature imaging (HDMI) was tested on 521 patients with 527 ultrasound-identified suspicious breast masses indicated for biopsy. Four new morphological features of tumor microvessels, microvessel fractal dimension (mvFD), Murray’s deviation (MD), bifurcation angle (BA), and spatial vascularity pattern (SVP) as well as initial biomarkers were extracted and analyzed, and the results correlated with pathology. Multivariable logistic regression analysis was used to study the performance of different prediction models, initial biomarkers, new biomarkers, and combined new and initial biomarkers in differentiating benign from malignant lesions. Results The new HDMI biomarkers, mvFD, BA, MD, and SVP, were statistically significantly different in malignant and benign lesions, regardless of tumor size. Sensitivity and specificity of the new biomarkers in lesions > 20 mm were 95.6% and 100%, respectively. Combining the new and initial biomarkers together showed an AUC, sensitivity, and specificity of 97% (95% CI: 95–98%), 93.8%, and 89.2%, respectively, for all lesions regardless of mass size. The classification was further improved by adding the Breast Imaging Reporting and Data System (BI-RADS) score to the prediction model, showing an AUC, sensitivity, and specificity of 97% (95% CI: 95–98%), 93.8%, and 89.2%, respectively. Conclusion The addition of new quantitative HDMI biomarkers significantly improved the accuracy in breast lesion characterization when used as a complementary imaging tool to the conventional ultrasound. Key Points • Novel quantitative biomarkers extracted from tumor microvessel images increase the sensitivity and specificity in discriminating malignant from benign breast masses. • New HDMI biomarkers Murray’s deviation, bifurcation angles, microvessel fractal dimension, and spatial vascularity pattern outperformed the initial biomarkers. • The addition of BI-RADS scores based on US descriptors to the multivariable analysis using all biomarkers remarkably increased the sensitivity, specificity, and AUC in all size groups.