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Additional co-authors: Ivan Ropovik, Balazs Aczel, Lena F. Aeschbach, Luca Andrighetto, Jack D. Arnal, Holly Arrow, Peter Babincak, Bence E. Bakos, Gabriel Banik, Ernest Baskin, Radomir Belopavlovic, Michael H. Bernstein, Michal Bialek, Nicholas G. Bloxsom, Bojana Bodroža, Diane B. V. Bonfiglio, Leanne Boucher, Florian Bruhlmann, Claudia C. Brumbaugh, Erica Casini, Yiling Chen, Carlo Chiorri, William J. Chopik, Oliver Christ, Antonia M. Ciunci, Heather M. Claypool, Sean Coary, Marija V. Cˇolic, W. Matthew Collins, Paul G. Curran, Chris R. Day, Anna Dreber, John E. Edlund, Filipe Falcao, Anna Fedor, Lily Feinberg, Ian R. Ferguson, Maire Ford, Michael C. Frank, Emily Fryberger, Alexander Garinther, Katarzyna Gawryluk, Kayla Ashbaugh, Mauro Giacomantonio, Steffen R. Giessner, Jon E. Grahe, Rosanna E. Guadagno, Ewa Halasa, Rias A. Hilliard, Joachim Huffmeier, Sean Hughes, Katarzyna Idzikowska, Michael Inzlicht, Alan Jern, William Jimenez-Leal, Magnus Johannesson, Jennifer A. Joy-Gaba, Mathias Kauff, Danielle J. Kellier, Grecia Kessinger, Mallory C. Kidwell, Amanda M. Kimbrough, Josiah P. J. King, Vanessa S. Kolb, Sabina Kolodziej, Marton Kovacs, Karolina Krasuska, Sue Kraus, Lacy E. Krueger, Katarzyna Kuchno, Caio Ambrosio Lage, Eleanor V. Langford, Carmel A. Levitan, Tiago Jesse Souza de Lima, Hause Lin, Samuel Lins, Jia E. Loy, Dylan Manfredi, Łukasz Markiewicz, Madhavi Menon, Brett Mercier, Mitchell Metzger, Venus Meyet, Jeremy K. Miller, Andres Montealegre, Don A. Moore, Rafal Muda, Gideon Nave, Austin Lee Nichols, Sarah A. Novak, Christian Nunnally, Ana Orlic, Anna Palinkas, Angelo Panno, Kimberly P. Parks, Ivana Pedovic, Emilian Pekala, Matthew R. Penner, Sebastiaan Pessers, Boban Petrovic, Thomas Pfeiffer, Damian Pienkosz, Emanuele Preti, Danka Puric, Tiago Ramos, Jonathan Ravid, Timothy S. Razza, Katrin Rentzsch, Juliette Richetin, Sean C. Rife, Anna Dalla Rosa, Kaylis Hase Rudy, Janos Salamon, Blair Saunders, Przemyslaw Sawicki, Kathleen Schmidt, Kurt Schuepfer, Thomas Schultze, Stefan Schulz-Hardt, Astrid Schutz, Ani N. Shabazian, Rachel L. Shubella, Adam Siegel, Ruben Silva, Barbara Sioma, Lauren Skorb, Luana Elayne Cunha de Souza, Sara Steegen, L. A. R. Stein, R. Weylin Sternglanz, Darko Stojilovic, Daniel Storage, Gavin Brent Sullivan, Barnabas Szaszi, Peter Szecsi, Orsolya Szoke, Attila Szuts, Manuela Thomae, Natasha D. Tidwell, Carly Tocco, Ann-Kathrin Torka, Francis Tuerlinckx, Wolf Vanpaemel, Leigh Ann Vaughn, Michelangelo Vianello, Domenico Viganola, Maria Vlachou, Ryan J. Walker, Sophia C. Weissgerber, Aaron L. Wichman, Bradford J. Wiggins, Daniel Wolf, Michael J. Wood, David Zealley, Iris Žeželj, Mark Zrubka, and Brian A. Nosek

Background Recent literature suggests that living in a rural setting may be associated with adverse cancer outcomes. This study examines the burden of travel from home to cancer center for clinical trial (CT) enrollees. Materials and Methods Patients from the University of California San Francisco Clinical Trial Management System database who enrolled in a cancer CT for a breast, genitourinary, or gastrointestinal malignancy between 1993 and 2014 were included. Cancer type, household zip code, race/ethnicity, phase of study, study sponsor, and year of signed consent were exported. Distance traveled from home to center was calculated using a GoogleMaps application programming interface. The relationships of distance with phase of CT, household income, and race/ethnicity were examined. Results A total of 1,600 patients were enrolled in breast (55.8%), genitourinary (29.4%), or gastrointestinal (14.9%) cancer CTs. The overall median unidirectional distance traveled from home to study site was 25.8 miles (interquartile range [IQR] 11.5–75.3). Of the trial sponsors examined, principal investigator (56.4%), industry (22.2%), cooperative group (11.6%), and National Institutes of Health (NIH; 9.8%), the longest distance traveled was for NIH-sponsored trials, with a median of 39.4 miles (p Conclusion This study found that the burden of travel is highest among patients enrolled in NIH-sponsored trials, phase I studies, or living in low-income areas. These data suggest that travel burden for cancer CT participants may be significant. Implications for Practice This study is one of the first to measure travel distance for patients in cancer clinical trials using a real-world GoogleMaps calculator. Out-of-pocket expenses such as travel are not typically covered by health care payers; therefore, patients may face considerable cost to attend each study visit. Using a single-center clinical trials enrollment database, this study found that the burden of travel is highest for patients enrolled in National Institutes of Health-sponsored trials and phase I studies, as well as for patients living in low-income areas. Results suggest that a significant proportion of patients enrolled in clinical trials face a substantial travel burden.

An estimated 1.5 billion microbial infections occur globally each year and result in ∼4.6 million deaths. A technology gap associated with commercially available diagnostic tests in remote and underdeveloped regions prevents timely pathogen identification for effective antibiotic chemotherapies for infected patients. The result is a trial-and-error approach that is limited in effectiveness, increases risk for patients while contributing to antimicrobial drug resistance, and reduces the lifetime of antibiotics. This paper addresses this important diagnostic technology gap by describing a low-cost, portable, rapid, and easy-to-use microfluidic cartridge-based system for detecting the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) bacterial pathogens that are most commonly associated with antibiotic resistance. The point-of-care molecular diagnostic system consists of a vacuum-degassed microfluidic cartridge preloaded with lyophilized recombinase polymerase amplification (RPA) assays and a small portable battery-powered electronic incubator/reader. The isothermal RPA assays detect the targeted ESKAPE pathogens with high sensitivity (e.g., a limit of detection of ∼10 nucleic acid molecules) that is comparable to that of current PCR-based assays, and they offer advantages in power consumption, engineering, and robustness, which are three critical elements required for the point-of-care setting. IMPORTANCE This paper describes a portable system for rapidly identifying bacteria in resource-limited environments; we highlight the capabilities of the technology by detecting different pathogens within the ESKAPE collection, which cause nosocomial infections. The system is designed around isothermal DNA-based assays housed within an autonomous plastic cartridge that are designed with the end user in mind, who may have limited technological training. Displaying excellent sensitivity and specificity, the assay systems that we demonstrate may enable future diagnoses of bacterial infection to guide the development of effective chemotherapies and may have a role in areas beyond health where rapid detection is valuable, including in industrial processing and manufacturing, food security, agriculture, and water quality testing.

This paper describes the performance of junctions based on self-assembled monolayers (SAMs) as the functional element of a half-wave rectifier (a simple circuit that converts, or rectifies, an alternating current (AC) signal to a direct current (DC) signal). Junctions with SAMs of 11-(ferrocenyl)-1-undecanethiol or 11-(biferrocenyl)-1-undecanethiol on ultraflat, template-stripped Ag (Ag(TS)) bottom electrodes, and contacted by top electrodes of eutectic indium-gallium (EGaIn), rectified AC signals, while similar junctions based on SAMs of 1-undecanethiol-SAMs lacking the ferrocenyl terminal group-did not. SAMs in these AC circuits (operating at 50 Hz) remain stable over a larger window of applied bias than in DC circuits. AC measurements, therefore, can investigate charge transport in SAM-based junctions at magnitudes of bias inaccessible to DC measurements. For junctions with SAMs of alkanethiols, combining the results from AC and DC measurements identifies two regimes of bias with different mechanisms of charge transport: (i) low bias (|V|1.3 V), at which direct tunneling dominates, and (ii) high bias (|V|1.3 V), at which Fowler-Nordheim (FN) tunneling dominates. For junctions with SAMs terminated by Fc moieties, the transition to FN tunneling occurs at |V| ≈ 2.0 V. Furthermore, at sufficient forward bias (V0.5 V), hopping makes a significant contribution to charge transport and occurs in series with direct tunneling (V ≲ 2.0 V) until FN tunneling activates (V ≳ 2.0 V). Thus, for Fc-terminated SAMs at forward bias, three regimes are apparent: (i) direct tunneling (V = 0-0.5 V), (ii) hopping plus direct tunneling (V ≈ 0.5-2.0 V), and (iii) FN tunneling (V ≳ 2.0 V). Since hopping does not occur at reverse bias, only two regimes are present over the measured range of reverse bias. This difference in the mechanisms of charge transport at forward and reverse bias for junctions with Fc moieties resulted in large rectification ratios (R100) and enabled half-wave rectification.

Lessons LearnedIn abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication. Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population. This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space.BackgroundSelinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO-1), leading to nuclear accumulation of tumor suppressor proteins.MethodsThis phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide.ResultsFourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had ≥50% prostate-specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3–4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability.ConclusionSelinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents.

This Account describes a strategy for fabricating multicomponent microsystems in which the structures of essentially all of the components are formed in a single step of micromolding. This strategy, which we call "cofabrication", is an alternative to multilayer microfabrication, in which multiple layers of components are sequentially aligned ("registered") and deposited on a substrate by photolithography. Cofabrication has several characteristics that make it an especially useful approach for building multicomponent microsystems. It rapidly and inexpensively generates correctly aligned components (for example, wires, heaters, magnetic field generators, optical waveguides, and microfluidic channels) over very large surface areas. By avoiding registration, the technique does not impose on substrates the size limitations of common registrations tools, such as steppers and contact aligners. We have demonstrated multicomponent microsystems with surface areas exceeding 100 cm(2), but in principle, device size is only limited by the requirements of generating the original master. In addition, cofabrication can serve as a low-cost strategy for building microsystems. The technique is amenable to a variety of laboratory settings and uses fabrication tools that are less expensive than those used for multistep microfabrication. Moreover, the process requires only small amounts of solvent and photoresist, a costly chemical required for photolithography; in cofabrication, photoresist is applied and developed only once to produce a master, which is then used to produce multiple copies of molds containing the microfluidic channels. From a broad perspective, cofabrication represents a new processing paradigm in which the exterior (or shell) of the desired structures are produced before the interior (or core). This approach, generating the insulation or packaging structure first and injecting materials that provide function in channels in liquid phase, makes it possible to design and build microsystems with component materials that cannot be easily manipulated conventionally (such as solid materials with low melting points, liquid metals, liquid crystals, fused salts, foams, emulsions, gases, polymers, biomaterials, and fragile organics). Moreover, materials can be altered, removed, or replaced after the manufacturing stage. For example, cofabrication allows one to build devices in which a liquid flows through the device during use, or is replaced after use. Metal wires can be melted and reset by heating (in principle, repairing a break). This method leads to certain kinds of structures, such as integrated metallic wires with large cross-sectional areas or optical waveguides aligned in the same plane as microfluidic channels, that would be difficult or impossible to make with techniques such as sputter deposition or evaporation. This Account outlines the strategy of cofabrication and describes several applications. Specifically, we highlight cofabricated systems that combine microfluidics with (i) electrical wires for microheaters, electromagnets, and organic electrodes, (ii) fluidic optical components, such as optical waveguides, lenses, and light sources, (iii) gels for biological cell cultures, and (iv) droplets for compartmentalized chemical reactions, such as protein crystallization.

This paper describes several low-cost methods for fabricating flexible electronic circuits on paper. The circuits comprise i) metallic wires (e.g., tin or zinc) that are deposited on the substrate by evaporation, sputtering, or airbrushing, and ii) discrete surface-mountable electronic components that are fastened with conductive adhesive directly to the wires. These electronic circuits—like conventional printed circuit boards—can be produced with electronic components that connect on both sides of the substrate. Unlike printed circuit boards made from fiberglass, ceramics, or polyimides, however, paper can be folded and creased (repeatedly), shaped to form three-dimensional structures, trimmed using scissors, used to wick fluids (e.g., for microfluidic applications) and disposed of by incineration. Paper-based electronic circuits are thin and lightweight; they should be useful for applications in consumer electronics and packaging, for disposable systems for uses in the military and homeland security, for applications in medical sensing or low-cost portable diagnostics, for paper-based microelectromechanical systems, and for applications involving textiles.

Ovarioles are the functional unit of the female insect reproductive organs and the number of ovarioles per ovary strongly influences egg-laying rate and fecundity. Social evolution in the honeybee (Apis mellifera) has resulted in queens with 200–360 total ovarioles and workers with usually 20 or less. In addition, variation in ovariole number among workers relates to worker sensory tuning, foraging behavior, and the ability to lay unfertilized male-destined eggs. To study the genetic architecture of worker ovariole number, we performed a series of crosses between Africanized and European bees that differ in worker ovariole number. Unexpectedly, these crosses produced transgressive worker phenotypes with extreme ovariole numbers that were sensitive to the social environment. We used a new selective pooled DNA interval mapping approach with two Africanized backcrosses to identify quantitative trait loci (QTL) underlying the transgressive ovary phenotype. We identified one QTL on chromosome 11 and found some evidence for another QTL on chromosome 2. Both QTL regions contain plausible functional candidate genes. The ovariole number of foragers was correlated with the sugar concentration of collected nectar, supporting previous studies showing a link between worker physiology and foraging behavior. We discuss how the phenotype of extreme worker ovariole numbers and the underlying genetic factors we identified could be linked to the development of queen traits.

This Communication describes a method of fabricating complex metallic microstructures in 3D by injecting liquid solder into microfluidic channels, and allowing the solder to cool and solidify; after fabrication, the metallic structures can be flexed, bent, or twisted. This method of fabrication—which we call microsolidics—takes advantage of the techniques that were developed for fabricating microfluidic channels in poly(dimethylsiloxane) (PDMS) in 2D and 3D, uses surface chemistry to control the interfacial free energy of the metal– PDMS interface, and uses techniques based on microfluidics, but ultimately generates solid metal structures. This approach makes it possible to build flexible electronic circuits or connections between circuits, complex embedded or freestanding 3D metal microstructures, 3D electronic components, and hybrid electronic–microfluidic devices. There are several techniques for making metal microstructures in 3D. Electroplating and electroless deposition are routinely used to construct microstructures with metallic layers several nanometers to several microns thick in 2D or 3D. [1–11] To generate solid replicas of 3D objects, several groups have developed a technique, referred to as “microcasting”, to form metals in order to fabricate microparts (e.g., posts and gears) with features as small as 10 lm and aspect ratios as high as 10 from steel, zirconia, and alumina. [12,13] Techniques based on LIGA (Lithographie, Galvanoformung, und Abformung) produce even more complicated metallic objects by depositing a metal onto a molded polymer template that is subsequently removed to yield an open structure (such as a honeycomb arrangement of cells). [14,15] In principle, these approaches can be used to pattern metals of any thickness to produce features with an aspect ratio that is larger than that produced using electroplating.

Heat-shielding is a method used by honey bee workers to insulate temperature sensitive brood from localized heat stress during development. Due largely to data collection techniques, heat-shielding has been defined as stationary bees congregating with their ventral side facing the heat stress. We conducted tests to determine if shielding behavior was limited to bees fitting this description. Specifically, we examined the behavior in response to heat and cold stress, and recorded both stationary and moving workers on the hive wall (ventral side visible) and on the brood comb (dorsal side visible). Our observations strongly suggest that stationary bees on the brood comb shield the developing brood from both localized heat and cold stress: after temperature-stress, the number of bees under the stressor significantly increased. A uniform response from stationary bees on the hive wall, however, was not observed: stationary bee number increased significantly after heat stress but tended to decrease after cold stress. Movement of bees on both the hive wall and brood comb decreased in response to cold stress. Movement of bees on brood comb decreased after heat stress, whereas the movement of bees on the hive wall increased in response to heat stress. This latter result raises the possibility that these bees are creating currents used to dissipate the heat and/ or are absorbing heat near the source and moving it to nonsensitive areas. Our data indicate that ‘heat-shielding’, as previously defined, is a category within a broader response of honey bees to localized temperature stress: Apis mellifera appear to respond adaptively to all localized temperature stressors.

Heat shielding is a recently identified mechanism used by worker honey bees (Apis mellifera) to help maintain constant hive temperatures. Only workers perform this behavior; in our experiment, drones actively avoided heated hive regions. Observations of marked day-old cohorts within broodcomb regions indicate that heat shielding is performed by young bees to preferentially protect advanced stage larvae and pupae. As expected, the number of heat-shielders significantly increased with both the temperature of the heat source and the size of the colony. Of the young bees observed to perform the behavior, those aged 12--14 days were significantly more likely to heat-shield than expected. Combined, these data suggest that classifications of age-based tasks in honey bees should include heat shielding, and that the behavior is an adaptation designed to protect temperature-sensitive brood. Copyright 2005.

(2003). Missile defense at the waterfront: Implications of the SCUD missile attack and Al Jubayl Port, 15–16 February 1991. Defense & Security Analysis: Vol. 19, No. 1, pp. 15-33.

This paper describes a model of the motion of superparamagnetic beads in a microfluidic channel under the influence of a weak magnetic field produced by an electric current passing through a coplanar metal wire. The model based on the conventional expression for the magnetic force experienced by a superparamagnetic bead (suspended in a biologically relevant medium) and the parameters provided by the manufacturer failed to match the experimental data. To fit the data to the model, it was necessary to modify the conventional expression for the force to account for the non-zero initial magnetization of the beads, and to use the initial magnetization and the magnetic susceptibility of the beads as adjustable parameters. The best-fit value of susceptibility deviated significantly from the value provided by the manufacturer, but was in good agreement with the value computed using the magnetization curves measured independently for the beads from the same vial as those used in the experiment. The results of this study will be useful to researchers who need an accurate prediction of the behavior of superparamagnetic beads in aqueous suspensions under the influence of weak magnetic fields. The derivation of the force on a magnetic bead due to a magnetic field also identifies the correct treatment to use for this interaction, and resolves discrepancies present throughout the literature.

This article describes an electronic display that is fabricated by patterning electrically conductive wires (heaters) with micron-scale dimensions on one side of a sheet of paper, and thermochromic ink on the opposite side. Passing electrical current through the wires heats the paper and changes the thermochromic ink from colored (black, green, or other colors) to transparent; this change in property reveals the paper underneath the ink-exposing any messages printed on the paper-and serves as the basis for a two-state "shutter" display. This type of display is thin (100 microm), flat, lightweight (the display weighs20 mg/cm(2)), can be folded, rolled, twisted, and creased while maintaining function, and ultimately can (if required) be disposed of by incineration. The display is appropriate for applications where information must be presented clearly (usually only once) for little cost (each display costs$0.10/m(2) in materials) and where limited electrical power is available.